2013 Annual Meeting, Sunday, October 13, 2013 Poster Session Rehabilitation and Regeneration S101. DTI Versus fMRI: Accuracy and Reliability in Predicting Response to TMS in Stroke David A. Cunningham, Andre Machado, Venkateswaran Rajagopalan, Mark J. Lowe, Stephen Jones, Erik Beall, Ken Sakaie and Ela B. Plow. Cleveland, OH and West Orange, NJ In stroke, functional MRI (fMRI) is a poor guide to direct Transcranial Magnetic Stimulation (TMS) due to poor spatial resolution. Further, response to TMS depends upon integrity of corticospinal tracts (CST). We examined whether sites with best integrity of CST terminations are more reliable than highest fMRI activation and align more closely to optimal sites of TMS. Four patients with stroke and four aged-matched healthy controls underwent fMRI during hand movement and Diffusion Tensor Imaging (DTI) of CST. Stereotactic TMS was delivered to motor cortices while responses in contralateral hand muscle were noted. Overall, responses were reliable when TMS was applied to sites with best CST terminations; however, when TMS was applied to fMRI activation, response was absent in 50% of patients and 25% of controls. The site with best CST terminations was closer to the optimal TMS site than site of fMRI activation in patients (4.2 mm 6 5.0 mm vs. 14.7 mm 6 3.8 mm)(t(3) 5 24.58, p < .05). Preliminary results of this ongoing study suggest that imaging corticospinal tracts may be reliable and accurate in guiding TMS in stroke and healthy. Future studies can explore whether DTIguidance maximizes outcomes of therapeutic TMS in stroke rehabilitation. Study supported by: 1K01HD069504 NIH Career Development award S102. Function Reorganization of Motor Cortex in Acute Stroke Patient: A Longtidual fMRI Study Yin-Kai Li, Yan Liu and Li-Xin Han. Guangzhou, Guangdong Province, China We have already known that the motor cortex experienced a process of functional remodeling after cerebral stroke when motor pathways affected. We used functional MRI (fMRI) to consecutively observe the human cortex motor area migration following both dominant hemisphere and nondominant hemisphere stroke. There were 16 acute cortical and subcortical stroke patients (9R and 7L) and 10 normal volunteers, the fMRI as well as finger tip test and grip strength test were checked after stroke. We found that the motor cortical activation induced by moving paretic hand was changing with stages after stroke. The improvements of index finger tap test from acute stage to early chronic stage as well as from early chronicle stage to chronic stage have positive correlation to the contralateral S1M1 activation enhancement, but a negative correlation to the ipsilateral
S1M1’s. The contralateral and ipsilateral motor cortex activation of dominant hemisphere stoke were more extensive than those in non-dominant hemisphere stroke both in acute stage and early chronic stage. We concluded that there is difference of motor functional recovery and motor cortex compensation between dominant hemisphere and nondominant hemisphere after stroke. Study supported by: Guangzhou Science and Technology Key Project (No. 122732961131543). Health Services Research S201. Cumulative Incidence of Stroke Following Emergency Department Presentation of Dizziness: A Population-Based Study Kevin A. Kerber, Darin B. Zahuranec, Devin L. Brown, William J. Meurer, James F. Burke, Melinda A. Smith, Lynda D. Lisabeth, A. Mark Fendrick and Lewis B. Morgenstern. Ann Arbor, MI Objective: Cerebral ischemia is a serious cause of Emergency Department (ED) dizziness presentations, but can be missed at the initial visit. We aimed to determine stroke risk following ED dizziness presentations. Methods: From 5/8/2011 to 5/7/2012, patients 45 years of age presenting to EDs in Nueces County, Texas, with dizziness, vertigo, or imbalance were identified, excluding those with stroke as the initial diagnosis. Subsequent stroke was determined with rigorous surveillance and neurologist validation. Cumulative stroke risk was determined using Kaplan-Meier estimates. Results: 1,246 patients with dizziness were followed for a median of 355 days (interquartile range [IQR], 239–438 days). Median age was 61.9 years. After the ED visit, sixteen patients (1.3%) had a stroke. Stroke risk was 0.48% at 2 days; 0.48% at 7 days; 0.56% at 30 days; 0.56% at 90 days; and 1.49% at 12 months. Conclusions: Stroke risk after presumed non-stroke ED dizziness presentation is very low. A relatively small subgroup of patients may be at high-risk for stroke soon after a dizziness presentation since most of the 90-days stroke risk occurred within 2-days. Efficient methods to identify these patients are needed. Study supported by: NIH K23NS058359. S202. Mortality in the Acute Care Setting in Amyotrophic Lateral Sclerosis Dustin G. Nowacek, Brian C. Callaghan and James F. Burke. Ann Arbor, MI Objective: Characterize place of death for amyotrophic lateral sclerosis (ALS) patients and predict which patients are more likely to die in an acute care facility (ACF). Methods: We used the Centers for Disease Control and Prevention Mortality files from 2005–2009 to identify individuals with an underlying cause of death (UCOD) of ALS in the United States. Patient characteristics and place of death were abstracted from death certificates. Results: From 2005 to 2009, 33,683 patients had ALS as their UCOD. The mean number of patients who died C 2013 American Neurological Association S1 V
annually in an acute care facility (ACF) was 1,704 (25.3%) and the mean number of patients who died at home or in a hospice facility annually was 3,296 (48.9%). 24% of NonHispanic Whites died in an ACF compared to 44% of African-Americans and 36% of Hispanic Whites (p < 0.001). Conclusions: A high proportion of ALS deaths occur in an ACF. African-Americans and Hispanic Whites are more likely to die in an ACF than Non-Hispanic Whites. These data suggest that there is an opportunity to improve the quality of end-of-life care in patients with ALS, particularly underrepresented minorities. Study supported by: Robert Wood Johnson. S203. Impact of Atrial Fibrillation on Stroke-Related Healthcare Costs Matthew Sussman, Iris Lin, Winghan J. Kwong, Lauren Lee, Michael Munsell, Mark Friedman, Magdy Selim and Joseph Menzin. Waltham, MA; Parsippany, NJ and Boston, MA Objective: To compare healthcare costs associated with ischemic stroke (IS), hemorrhagic stroke (HS), or transient ischemic attack (TIA) in patients with and without atrial fibrillation (AF). Methods: MarketScan claims data (2005–2011) for adult patients 18 years with 1 inpatient claim for stroke/TIA, or emergency department claim for TIA who had 12 months continuous enrollment prior to and after initial stroke were analyzed. Presence of AF was identified by medical claims with AF diagnosis. Adjusted mean stroke-related costs (index plus 1 year post-index) were compared among patients with and without AF, controlling for demographics, comorbidities, anticoagulant use and baseline resource use. Results: 23,807 stroke patients with AF and 136,649 without AF met inclusion criteria. Post-index readmission rates were higher in AF than non-AF patients across stroke types (P < 0.001). After controlling for potential confounders, adjusted mean costs for the AF patients were higher than those for non-AF patients over a 1-year follow-up period by $4,726, $7,824, and $2,007 for IS, HS, and TIA respectively (P 0.002). Conclusion: Ischemic and hemorrhagic stroke and TIA is costly, especially among individuals with AF. Reducing stroke risk in AF patients is important from both clinical and economic standpoints. Study supported by: This study was sponsored by Daiichi Sankyo. Winghan Jacqueline Kwong is an employees of the study sponsor. Lauren Lee was an employee of the study sponsor at the time of research. Winghan Jacqueline Kwong is an employees of the study sponsor. S204. Disease-Targeted Versus Generic Measurement of Health-Related Quality of Life (HRQOL) in Epilepsy Christine B. Baca, Barbara G. Vickrey, Rochelle Caplan, Stefanie Vassar and Anne T. Berg. Los Angeles, CA and Chicago, IL Rationale: Generic HRQOL measures allow comparisons between groups with and without a condition, but may not be sensitive to important disease-related factors affecting HRQOL.
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Methods: Young adults with epilepsy (N 5 108, age 21.6y SD 5 3.8), followed since diagnosis in a prospective community-based study, completed the Quality of Life in Epilepsy-89 (QOLIE-89), an epilepsy-targeted HRQOL instrument that includes within it a generic core measure (the SF-36). Sibling controls (N 5 82, age 5 20.7y, SD 5 2.1) completed the SF-36. Results: QOLIE-89 scores were significantly different on 8 of 17 scales, the overall health item, and the epilepsytargeted, cognitive, and overall summary measures (all p’s < 0.03) depending on seizure recency: seizure-free 5years (higher HRQOL), n 5 57; seizure-free 1–5 years, n 5 22; or seizure-free < 1 year, n 5 29 (lower HRQOL). On the SF-36, there were few differences across these seizure-recency groups, or for cases compared to sibling controls, across its 8 scales, physical and mental health summary scores, and the change in health item. Conclusions: The epilepsy-targeted HRQOL measure containing a generic core is preferable in studies of epilepsy in which both sensitivity to seizure-related factors and the ability to compare to non-epilepsy groups is desired. Study supported by: NINDS R37-NS31146.
S205. Structured Handoffs Improve Clinical Measures in Patients Discharged from the Neurointensive Care Unit Elizabeth A. Coon, Neha P. Morparia, Rachel R. Fabris, David B. Burkholder, James P. Klaas, Jonathan Graff-Radford, Samuel A. Moore, Jeffrey W. Britton and Lyell K. Jones. Rochester, MN Objective: To measure the effect of standardized neurosciences intensive care unit (ICU) transfer documentation on clinical measures and provider satisfaction. Background: Improving transfers of patient care is a priority. Standardization of patient handoffs can reduce medical errors often due to inaccurate transfer documentation or physician miscommunication. Methods: All neurosciences ICU transfers were prospectively studied before and after implementation of a standardized transfer template. Length of stay, times of order placement, medication reconciliation of IV antihypertensives or pressors, urinary catheter use, ICU readmission and adverse events were analyzed. Physician satisfaction survey data was obtained throughout the study period. Results: Transfer template use was 93%. Introduction of the template was associated with increased medication reconciliation of IV antihypertensives or pressors by 72% (p 5 0.0001) and increased rate of urinary catheter removal prior to transfer (p 5 0.004) in non-comfort care patients. The length of urinary catheterization was thereby decreased by 22% (p 5 0.03). Participating physicians generally viewed the transfer template favorably. Interpretation: Implementation of a standardized transfer template increased medication reconciliation of IV antihypertensives or pressors and reduced unnecessary urinary catheter use in patients transferred from a neurosciences ICU. Study supported by: None.
S206. Comparison of Various Online Patient Education Materials (PEMs) for Neurological Diseases Mohammad H. El-Ghanem, Anjali Dagar, Nitin Agarwal, Vineet Punia and Machteld E. Hillen. Newark, NJ Objective: Internet has become a major contributor to health literacy promotion. The average American reads at the 7th28thgrade level and it is recommended to write PEMs at or below the 6thgrade reading level. We assessed the readability of PEMs commonly available on the Internet on neurological diseases and compared them to ones provided by a professional Neurologist’s association. Methods: PEMs available on the website of the American Academy of Neurology(AAN) were downloaded. Any online PEM source, which had a link on the first Google search webpage for 85% or more of the AAN’s PEM was included. All PEMs were converted to Microsoft word and analyzed on ten readability scales using Readability Studio Professional Edition Version 2012.1. Results: 14 disease specific PEMs were available on AAN website.3 other online sources (MedlinePlusV, MayoClinic, Wikipedia) qualified for analyses. All PEMs resources were found to be above the recommended reading level with Wikipedia being significantly more difficult to read (p < 0.01) compared to others. Conclusions: PEMs on neurological diseases from a professional association and other online resources are being written above the average American and recommended reading levels. This may be undermining the utility of these PEMs. Study supported by: Neurology Department. R
S207. Patient Perceptions of Clinical Trials: Feasibility Data for a Public Education Campaign David Charles and On Behalf of the ANA Public Policy Committee. Nashville, TN Clinical trials are a key step in creating new therapies. Lack of awareness of societal benefit likely limits recruitment. The ANA Public Policy Committee conducted a feasibility study that included a telephone survey to evaluate the potential impact of a public education campaign designed to increase participation in clinical trials. 600 adults answered 27 questions about awareness, likelihood of participation, and reasons for declining. Most participants had little (36%) or no knowledge (30%) of clinical trials; only 8% reported knowing “a lot”. Of those recently exposed to information about clinical trials (n 5 199), most (69%) reported a more favorable perception as a result. Only 45% were very likely to participate; 48% were very likely to recommend participation to a family member. Those unlikely to participate (n 5 312) cited concerns about treatment effectiveness or side effects (44%), mistrust of research organizations (20%), desire to wait for treatment approval (18%), and cost (15%). These data demonstrate poor public awareness and negative opinions of clinical trials, but that providing information can improve perceptions. A public awareness campaign would likely increase participation rates, thus reducing a major barrier to the development of new therapies.
Study supported by: This study was supported by grants and donations from Allergan, Medtronic, Pfizer, Pharmaceutical Research and Manufacturers Association (PhRMA), and Upsher-Smith. Vanderbilt University receives income from grants or contracts with Allergan and Medtronic for research led by Dr. Charles. Dr. Charles receives income from Allergan and Medtronic for consulting services. S208WIP. Disparities in Deep Brain Stimulation Surgery among Insured Elders with Parkinson Disease Allison W. Willis, Mario Schootman, Nathan Kung, Xiao-Yu Wang, Joel S. Perlmutter and Brad A. Racette. St. Louis, MO Objective: To identify sociodemographic, clinical and physician/practice factors associated with Deep Brain Stimulation (DBS). Design/Methods: Retrospective cohort study of >657,000 Medicare beneficiaries with PD. Multivariable logistic regression models examined the association between demographic, clinical, socioeconomic (SES), physician/ practice factors and DBS therapy. Results: There were significant disparities in use of DBS. Blacks (AOR 0.20, 0.16-0.25), Asians (AOR 0.55, 0.440.70) and women (AOR 0.79, 0.75-0.83) were considerably less likely to receive DBS. Eighteen percent of surgeries were performed on PD patients with cognitive impairment/ dementia, a reported contraindication to DBS. Beneficiaries treated in minority serving PD practices were less likely to receive DBS, regardless of individual race (AOR 0.76, 0.660.87). Even after adjustment for demographic and clinical covariates, high neighborhood SES was associated with 1.4fold higher odds of DBS (AOR 1.42, 1.33-1.53). Conclusions: Race, gender and neighborhood SES are strong independent predictors of DBS receipt in a universally insured elderly population. Racial disparities are amplified when adjusting for physician/clinic characteristics. Future investigations will examine sociodemographic differences in clinical need/usefulness of DBS, ease of DBS attainment, and actual/opportunity DBS costs, to inform policies to reduce DBS disparities and improve PD quality of care. Study supported by: This work was supported primarily by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (K23NS081087), Washington University Institute of Clinical and Translational Sciences grants UL1 TR000448 and KL2 TR000450 from the National Center for Advancing Translational Sciences, the National Institute for Environmental Health Sciences at the National Institutes of Health (K24ES017765), the St. Louis Chapter of the American Parkinson Disease Association, The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, APDA. Other support: Walter and Connie Donius; and the Robert Renschen Fund. Education S301. Neurohospitalists: Defining Need and Training Elements in Academic Neurology John C. Probasco, Benjamin P. George, E. Ray Dorsey and Arun Venkatesan. Baltimore and Rochester
Abstracts, American Neurological Association
Purpose: To determine the current practices and plans of neurohospitalists at academic medical centers and to identify the core features of a neurohospitalist training program. Methods: We surveyed department chairs or residency program directors at 123 ACGME accredited U.S. adult neurology training programs. Results: Sixty-three responded (51% response rate, 76% program directors). Twenty-four (38%) academic neurology departments reported employing neurohospitalists, and ten have plans to hire neurohospitalists in the next year. Four departments have created a neurohospitalist training program, and ten have plans to create a training program within the next two years. Most respondents agree there should be an ACGME accredited neurohospitalist fellowship (n 5 39; 65%). The highest priority neurohospitalist training elements reported include stroke, epilepsy, and consult neurology as well as patient safety and cost-effective inpatient care. The most important procedural skills for a neurohospitalist include performance of brain death evaluations, lumbar punctures, and EEG interpretation. Conclusions: Neurohospitalists are in demand among academic departments, with many departments developing their existing presence or establishing a new presence in the field. A neurohospitalist training program may encompass training in stroke, epilepsy, and consult neurology with additional focus on patient safety and cost-effective care. Study supported by: Not applicable. Dr. Probasco reports no disclosures. Mr. George conducts research funded by the Parkinson’s Disease Foundation (Summer Student Fellowship No. PDF-SFW-1204) and has previously received research funding from the National Institute on Aging, American Academy of Neurology, and New York Academy of Medicine. Dr. Dorsey is consultant to Lundbeck Pharmaceuticals and Medtronic, and has received research funds from the Robert Wood Johnson Foundation, Prana Biotechnology, Google, and Lundbeck Pharmaceuticals. Dr. Venkatesan has received research funds from the National Institutes of Health, the Howard Hughes Medical Institute, the Maryland Stem Cell Research Foundation, and the Accelerated Cure Project for Multiple Sclerosis. S302. Emergency Medicine Residents’ Experience with IV tPA in Acute Stroke Angel Pulido and Jennifer R. Simpson. Aurora, CO Introduction: Emergency room physicians are crucial to the identification and treatment of patients who present with acute ischemic stroke. In this study, we identify the experiences and attitudes of emergency medicine residents (EMRs) regarding IV tPA. Methods: Emergency medicine residency program directors and coordinators of 157 programs in the U.S. were emailed and asked to forward a secure, online questionnaire to current EMRs. The survey asked about their experience, confidence, and attitudes associated with tPA administration in acute stroke patients. Results: After an initial email to participate, 302 responses were collected. Of the respondents, 75.6%
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reported experience with patients who received tPA for ischemic stroke, 92.1% doing so only with supervision. 29.8% felt confident independently administering tPA. In the 3 hour tPA window, 90.7% of respondents agreed with giving IV tPA, while 53% agreed within the 4.5 hour window. NIH Stroke Scale certification was completed in 19% of respondents. Results of follow up survey requests are pending, but will be completed prior to presentation. Conclusion: The treatment rate of ischemic stroke in the future is dependent upon EMRs experiences and attitudes, and neurologists should be aware of current training practices. Study supported by: Not applicable. S303. Neurotoxicity of 1-Bromopropane, an Alternative to Ozone-Depleting or Global-Warming Solvents Makoto Samukawa, Gaku Ichihara, Masami Ueda, Yoshiyuki Mitsui, Nobuyuki Oka and Susumu Kusunoki. OsakaSayama, Osaka, Japan; Nagoya, Aichi, Japan and Joyo, Kyoto, Japan 1-Bromopropane (1-BP) is a substitute for traditional ozone-depleting solvents in the industrial and commercial setting. While the demand for 1-BP is increasing around the world, its biological activity is generally not well understood. Previous articles reported 1-BP-induced neurotoxicity in animal experiments and 12 human cases. We summarized clinical features of 12 previous patients and our new patient, who underwent nerve biopsy for the first time for this disease. A 43-year-old male industrial worker developed muscle weakness, sensory deficits and gait disturbance. Neurologic examination indicated sensory ataxic neuropathy with impairment of upper motor neurons. He had used 1-BP as a cleaning agent for metal parts at his workplace without appropriate protection. The serum bromide level was high at two months from the onset. Sural nerve biopsy showed axonal damage. Keeping him away from exposure to the solvent gradually recovered motor function and sensory deficits. Our summarized data suggests that main clinical features of this disease are pyramidal tract involvement and sensory ataxic neuropathy. We suggest that 1-BP should be used carefully in the workplace and 1-BP neurotoxicity should be considered in patients with unexplained neurological signs and history of exposure. Study supported by: N/A. S304. A Structured Intervention To Improve Pain Management in Hospitalized Neurologic Patients: Interim Results Maisha T. Robinson, James F. Meschia, Sothear M. Luke and Kevin M. Barrett. Jacksonville, FL The burden of pain in hospitalized patients is significant and studies suggest that pain management is suboptimal. The purpose of this study is to compare effectiveness of pain control before and after a structured pain management educational intervention. The pre-intervention cohort is prospectively enrolling 30 patients with pain as a presenting symptom. A standardized pain questionnaire (0, no pain – 10, severe pain) is administered. Demographic information, vital signs, analgesic medication use is recorded. Pain is
reassessed within 24 hours of discharge and at 30 days after discharge using a telephone survey. Following standardized pain assessment and management education of Neurology residents, 30 additional patients will be prospectively enrolled into the post-intervention cohort. The primary outcome is pain control at the time of discharge and at 30 days. Within five weeks (as of 3/28/13), 21/30 of the preintervention cohort have been enrolled. The mean age is 52.9 years, 67% women. Pain locations include head (57%) and back (33%). Neurological diagnoses include radiculopathy (19%), intracerebral hemorrhage (19%), primary headache (14%). Median pain score at initial evaluation is 8 (IQR, 7.5–9.5) Final results will be presented at the meeting. Study supported by: None. S305. NeurologicDx - Internet Based Differential Diagnostic Checklist in Clinical Neurology Pasquale F. Finelli and Andrew L. McCabe. Hartford, CT and Storrs Mansfield, CT Diagnosis of a difficult neurologic case can be aided by a differential diagnostic checklist created by intelligent relational queries in neurologic literature. A system with diagnostic capability has important implications for patient care. To meet this need, NeurologicDx, an information system in clinical neurology that utilizes an innovative “smart” algorithm to generate a differential diagnostic checklist was developed. Most of what physicians see in everyday practice is repetitive and thus pattern recognition is a frequent method of diagnosis. However, a condition may be rare or uncommon, or common with an uncommon presentation and thus illusive and a system with “diagnostic” capability may be preferable. The strategy used by most physicians is to find information on an already suspected disease entity rather than use the computer as a “diagnostic” tool. This result is in large measure because the current information retrieval systems return journal citations or clinical summary titles and are not designed to generate differential diagnostic lists. NeurologicDx can be used to generate a differential diagnostic checklist in clinical neurology from signs, symptoms, and key terms at point of care. In addition to being specialty specific, continuous updates distinguish NeurologicDx. Study supported by: N/A. Cerebrovascular Disease S401. Differences in the MRI Classifications of Penumbral Tissue between Trials Richard Leigh. Baltimore, MD Two large trials looking at MRI based selection of patients for endovascular therapy, MR Rescue and DEFUSE 2, were recently reported and seem to contradict each other. Both used the concept of DWI and PWI mismatch on MRI as a marker of at-risk, or penumbral, tissue. However they used different definitions for classifying tissue. The goal of this study is to investigate how the difference in definitions
could introduce variability which may account for the difference in results. A model was used to generate hypothetical voxels whose ADC value varied from 0 to 1000 and whose Tmax value varied from 2 to 10 seconds in increments of 0.1. This resulted in 81081 voxels. These voxels were classified based on the MR Rescue and the DEFUSE 2 criteria. DEFUSE 2 criteria resulted in 16400 (20%) voxels being classified as penumbra where as MR Rescue criteria resulted in 50629 (62%) voxels being classified as penumbra. The two criteria resulted in the same classification in 46852 (58%) voxels. Thus there was a substantial discrepancy between the trials. This may have contributed to the conflicting results. Study supported by: R01DC05375. S402. Association between Admission Hematocrit and Mortality among Ischemic Stroke Patients Jason J. Sico, Laura J. Myers, John Concato, Linda S. Williams and Dawn M. Bravata. West Haven, CT; New Haven, CT and Indianapolis, IN Background: –Little is known regarding the relationship between anemia and mortality among patients with acute ischemic stroke. Methods and Results –Medical records were abstracted for a sample of 3965 veterans from 131 Veterans Health Administration (VHA) facilities who were admitted with acute ischemic stroke (fiscal year 2007). Hematocrit values within 24-hours of admission were categorized into 6-tiers (27%, 28–32%, 33–37%, 38–42%, 43–47%, 48%). We used multivariate logistic regression to examine the relationship between anemia and in-hospital, 30-day, 6-month and 1-year mortality, after adjusting for age, National Institute of Health Stroke Scale, medical comorbidities, and modified Acute Physiology and Chronic Health Evaluation scores. Patients with the lowest hematocrit values (27%) were 2.5 to 3.5 times more likely to have died across all of the outcome time points compared to patients with normal hematocrit levels (38–42%). The odds of in-hospital mortality were higher for patients with the highest hematocrit levels (48%; OR 5 2.9; CI95: 1.4–6.0) compared to patients with normal admission hematocrits. Conclusions –Anemia is independently associated with an increased risk of death throughout the first year poststroke. Very low and very high hematocrits are associated with early post-stroke mortality. Study supported by: The Department of Veterans Affairs, Veterans Health Administration (VHA), Office of Quality and Performance and Health Services Research and Development Service Quality Enhancement Research Initiative (RRP 09–184) supported this project. S403. Depressive Symptoms after Intracerebral Haemorrhages: Characteristics and Predictive Factors Nelly Dequatre-Ponchelle, Costanza Rossi, Hilde Henon, Didier Leys and Charlotte Cordonnier. Lille, France Background Data on poststroke depressive symptoms (DS) mainly comes from ischemic stroke cohorts. We evaluated prevalence, characteristics and predictive factors of DS in patients with intracerebral hemorrhages (ICH).
Abstracts, American Neurological Association
Methods The PITCH cohort is a hospital-based, prospective (11/04-03/09), observational registry that included 562 consecutive patients with a spontaneous ICH. DS were evaluated (6 months, 1 year,2 years) with the MongomeryAsberg Depression Rating Scale. Patients with a score 7 were considered as having DS. Characteristics of patients with DS and influence of DS on vital outcome at 2 years (survival models) were evaluated. Results 262 patients were alive at 6 months. Prevalence of DS was 33% at 6 months and remained stable at 1 and 2 years. At 6 months, DS were influenced by: level of dependency (OR1.951; 95%CI 1.001–3.812), and past history of depression (OR3.294; 95%CI 1.586-6.844). Cognitive decline influenced mood at 1 year (OR1.088; 95%CI 1.001-1.176) and 2years (OR1.128; 95%CI 1.034-1.230). Characteristics of the bleeding did not predict occurrence of DS. DS did not influence vital outcome after 2 years of follow-up. Conclusion. ICH patients should screened for DS during follow-up. Predictive models could be used to identify and treat patients at high risk. Study supported by: x.
S404. A New Class of Antioxidant Nanoparticles Thomas A. Kent, Errol L.G. Samuel, Daniela C. Marcano, Vladimir Berka, James M. Tour and Ah-Lim Tsai. Houston, TX Introduction: Antioxidant therapy has been largely ineffective in clinical trials of acute neurological injury. Our primary defense against pathological oxidative radicals consists of a series of enzymes and proteins. However, this series can generate toxic intermediates and the protective agents are further consumed after injury. We hypothesized antioxidant failures were due to limitations including low capacity, requirement for regeneration, limited range or further generation of toxic intermediates. We developed a new class of antioxidant based on highly modified 3X40nm nanoparticles termed PEGylated hydrophilic carbon clusters (PEGHCCs). We previously reported rapid cellular uptake and complete restoration of neurovascular unit dysfunction in a rat model of traumatic brain injury and hypotension/resuscitation. Here we explored their mechanism and in-vitro effectiveness. Methods/Results: Electron paramagentic resonance (EPR) demonstrated high capacity for catalytic transformation of superoxide to oxygen while also quenching hydroxyl radical. In-vitro, they protected 80–90% of baseline cell count when administered AFTER the mitochondrial toxin, Antimycin A, or direct application of hydrogen peroxide in brain endothelial or primary neuronal culture. Implications: The uniquely favorable mechanisms of these materials suggest their potential to overcome limitations of current antioxidants particularly in ischemia/reperfusion. Additional in-vivo experiments in stroke models are underway. Study supported by: DoD W81XWH-08-2-0141 (TAK), W81XWH-08-2-0143 (JMT), NIH HL095820 (A-LT).
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S405. Mesenchymal Stem Cells Induce Neuron Recovery and Improve Limb Function Following Hemorrhagic Stroke Peng Huang, Nichole Gebhart, William D. Freeman, James F. Meschia, Thomas G. Brott and Abba C. Zubair. Jacksonville, FL Following stroke, neurons near the penumbra are vulnerable to delayed but progressive damage as a result of ischemia. We hypothesized that mesenchymal stem cells (MSC) can rescue damaged neurons following exposure to OxygenGlucose Deprivation (OGD) stress. Human bone marrow derived MSC were cultured and expanded to passage 5 (P5). MSC expressed CD73, CD90 and CD105, lacked expression of CD34, CD45 and can differentiate into bone, cartilage and fat tissues. M17 cell line, which was derived from neuroblastoma, was used in the OGD stress model. We showed that M17 proliferation was significantly decreased after 48 hours of OGD. In addition, we demonstrated increased rate of apoptosis after 48 hours of OGD. These effects were alleviated via co-culture with MSC. Neuron recovery was observed within 24 hours after exposure to MSC. Following exposure to injured neuron MSC increased expression and secretion of IL-6 and VEGF and this may likely be the mechanism of their neuro-protective effect. Rat model of hemorrhagic stroke showed MSC therapy improved limb function. Taken together our data will form the basis for using MSC to treat patients with recent hemorrhagic stroke. Study supported by: Mayo Clinic Center For Regenerative Medicine.
S406. Human iPSC-Derived Neural Progenitor Grafts Survive and Integrate after Focal Ischemia in Adult Rats Danielle K. Lewis, Aaron C. Ajlen, Yu Liu, Helen Zhang and Jack M. Parent. Ann Arbor, MI Neural progenitor cell (NPC) grafting is a promising regenerative stroke therapy. Clinical translation requires an understanding of the optimal graft source and differentiation, and the potential for NPC grafts to restore neural circuitry. We examined human induced pluripotent stem cell (iPSC)derived NPC grafts in experimental stroke. iPSC-NPCs were retrovirally labeled with a synaptic reporter (synapsin-1 promoter driving synaptophysin-YFP). After 2-wk differentiation, cells (100,000) were grafted into the adult rat striatum 4 d after transient MCA occlusion. After 2–56 d survival, brains were examined for graft proliferation, migration and phenotypes. Human nuclear protein (HNP)labeled cells were seen at all timepoints. They were confined to the striatum at 48 h and migrated extensively at later timepoints. At 28 d, many (63%) HNP1 cells co-expressed the neuroblast marker doublecortin; few co-expressed the proliferation marker Ki67 (11%) or GFAP (0.08%). Grafted neurons exhibited long-distance, YFP1 projections to the globus pallidus, a striatal projection area. YFP1 puncta co-expressed synaptic markers, including the vesicular GABA transporter, suggesting inhibitory synapses onto host cells. These findings suggest that iPSC-NPC
transplants survive, migrate and form neurons that integrate into the host circuitry after stroke. Study supported by: NIH NS065450. S407. Abnormalities in Reaching Trajectories after Stroke Are Stereotypical Exaggerations of Those Seen in Healthy Non-Dominant Arms Tomoko Kitago, Jeff Goldsmith, Adrian Haith, Ciprian M. Crainiceanu, Pietro Mazzoni and John W. Krakauer. New York, NY and Baltimore, MD The non-dominant arm, the “unaffected” arm, and the affected arm after stroke all have impaired motor control compared to the healthy dominant arm. We asked whether the motor impairment is qualitatively distinct in each of these cases, or whether stroke results in a parametrically worse version of the non-dominant arm. We used functional principal components analysis (FPCA) to characterize planar reaching trajectories in both arms of stroke patients (n 5 37) and control subjects (n 5 24). Each trajectory was expressed as the linear combination of shared basis functions and movement-specific scores. We computed Mahalanobis distances (MD) for each score and classified trajectories as “normal-appearing” or “outlying” using the control dominant arm as reference. We further decomposed MD into group-specific biases (differences in mean trajectories) and variances. The proportion of outlying movements increased in an order consistent with handedness and clinical severity. We also found stereotyped deficits in trajectory biases and variances, manifested in increasing degrees, in the healthy nondominant, unaffected, and affected arms. The deficits in motor control post-stroke may thus be an exaggerated version of relative difficulty faced by the non-dominant hand in healthy individuals. Study supported by: Orentreich Foundation, NIH K02 NS 048099-01, NIH R21 NS054718-01. S408. The Metabolic Syndrome Is Not Associated with MRI White Matter Progression: The Atherosclerosis Risk in Communities (ARIC) Study Jennifer L. Dearborn, Thomas H. Mosley, David S. Knopman, A. Richey Sharrett, Andrea L.C. Schneider, Clifford R. Jack, Laura H. Coker, Alvaro Alonso, Elizabeth Selvin and Rebecca F. Gottesman. Baltimore, MD; Jackson, MI; Rochester, MN; Winston-Salem, NC and Minneapolis, MN Introduction: It is unclear whether the metabolic syndrome (MetS) is associated with cerebral small vessel disease and white matter (WM) progression. Methods: The MetS was defined using AHA criteria from 1987-89 in 990 subjects in the ARIC study that had MRI’s at two time points (1993-95 and 2004-06). Scans were rated for qualitative appearance of WM hyperintensities using a 0 to 9 scale; imputed volumes at the first MRI visit were subtracted from standardized volumes from the second visit. WM progression was defined as the difference in volumes between visits and the top quintile of progression was compared with the bottom quintile in adjusted logistic regression models.
Results: The MetS was not associated with increased risk of WM progression (OR top quintile of progression 1.15, 95% CI 0.81-1.64). Hypertension was the only MetS component significantly associated with WM progression (OR top quintile 1.71 95% CI 1.18-2.48). Conclusion: Risk of WM progression did not differ in individuals with or without MetS. Among the MetS components, only elevated blood pressure was independently associated with increased risk of WM progression. Study supported by: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN2682011 00006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN 268201100011C, and HHSN268201100012C). The authors thank the staff and participants of the ARIC study for their important contributions. S409. Tissue-Type Plasminogen Activator Induces the Neuronal Uptake of Glucose in the Ischemic Brain Via a Plasminogen-Independent Mechanism Manuel Yepes, Fang Wu, Andrew Nicholson and John Votaw. Atlanta, GA Treatment with recombinant tPA (rtPA) induces neurological recovery in ischemic stroke patients. Here we investigated the effect of tPA on neuronal survival. We found that mice with genetic overexpression of neuronal tPA have better neurological outcome following transient middle cerebral artery occlusion (tMCAO) than wild-type (Wt) mice, and that treatment with 0.9 mg/Kg/IV rtPA improves neurological outcome in plasminogen deficient (Plg-/-) mice, indicating a plasminogen-independent neuroprotective effect. We showed that tPA promotes neuronal survival in neurons previously exposed to hypoxia. This effect was also observed with proteolytically inactive rtPA (with an alanine for serine substitution at Ser481). Mass spectrometry indicated that rtPA activates the mammalian target of rapamycin (mTOR) pathway, induces HIF-1a accumulation and the membrane recruitment of the glucose transporter GLUT 3. In vivo micro-18FDG-PET scanning showed that rtPA induces the uptake of glucose in the ischemic brain, independently of tPA’s ability to cleave plasminogen into plasmin. These data indicate that tPA has a neuroprotective effect independent of its proteolytic properties and instead mediated by its ability to induce the neuronal uptake of glucose. Study supported by: NIH R01 grant 1R01NS079331 to Manuel Yepes. S410. Glyburide Attenuates Markers of Brain Edema in Stroke Patients W. Taylor Kimberly, Thomas W. Battey, Ly Pham, Ona Wu, Albert Yoo, Karen L. Furie, Aneesh B. Singhal, Jordan J. Elm, Barney J. Stern and Kevin N. Sheth. Boston, MA; Providence, RI; Charleston, NC; Baltimore, MD and New Haven, CT Background: Ischemic brain edema is a serious complication that can lead to secondary neurological deterioration. Glyburide prevents swelling in preclinical models. To assess
Abstracts, American Neurological Association
whether glyburide prevents swelling in patients, we evaluated neuroimaging and blood biomarkers of edema. Methods: We analyzed brain MRIs of patients in the GAMES-Pilot trial and a control cohort of similar large infarctions. Vasogenic edema was assessed through FLAIR ratio and plasma MMP-9. Cytotoxic edema was evaluated by ADC ratio at 24 hours and ionic edema by the change in ADC at 60 hours. These metrics were correlated with total swelling within the stroke. Results: Compared to controls, stroke patients treated with glyburide (RP-1127) have a lower FLAIR signal intensity ratio (1.51 6 0.15 vs. 1.81 6 0.23; p 5 0.006) and lower MMP-9 (54 6 23 ng/mL versus 136 6 84 ng/mL; p 5 0.005). Glyburide did not alter the ADC24hr ratio (0.595 6 0.095 vs. 0.615 6 0.115;p 5 0.70). However, there was a difference in the change ADC (“pseudonormalization”; 0.003 6 0.034 vs. 0.093 6 0.062; p 5 0.006). ADC measures, but not FLAIR ratio or MMP9, correlated with total brain swelling (ADC24hr:r 5 20.66, p 5 0.01; ADCpseudo: r 5 0.75, p 5 0.003). Conclusions: IV glyburide attenuates both vasogenic and ionic edema in patients. FLAIR signal intensity ratio, ADC ratio, and MMP-9 levels are potential biomarkers of edema formation after stroke and should be prospectively studied. Study supported by: Remedy Pharmaceuticals, Inc. NIH/ NINDS K23NS076597. S411. Perfusion Computed Tomography Compared to 15O-Water-PET in Ischemic Stroke Olivier Zaro Weber, Jan Sobesky and Wolf-Dieter Heiss. Cologne, Germany and Berlin, Germany The accuracy of perfusion computed tomography (pCT) based relative maps of cerebral blood flow (rCBF-CT), cerebral blood volume (rCBV-CT), mean transit time (rMTTCT) and time to peak (rTTP-CT) in acute stroke remains a matter of debate. We validated these maps on quantitative CBF measurement by 15O-water-positron emission-tomography (CBF-PET) with respect to penumbral flow ( < 20 ml/100g/min). pCT was performed on a Philips 64-row CT scanner. CBF-PET was performed on an ECAT EXACT HR scanner (Siemens/CTI). In a region of interest based approach, the performance of pCT was assessed using quantitative CBFPET maps with respect to penumbral and the best PW threshold to detect penumbral flow was calculated. A good congruence was found for pCT derived maps. In a pooled analysis of 6 acute stroke patients (median time MRI to PET: 55 minutes; patients imaged within 6 hours) the best relative penumbral flow threshold was 0,53 on rCBF-CTP; 0,49 on rCBV-CTP; 1,10 on rMTT-CTP and 4.45 seconds on rTTP-CTP maps. pCT and CBF-PET yielded good agreement. Critical hypoperfusion was well depicted by relative pCT in acute ischemic stroke. Our results support pCT derived perfusion measurement in clinical stroke imaging. Study supported by: WDH Foundation of the Max Planck Society.
Annals of Neurology Vol 74 (suppl 17) 2013
S412. Normal HDL but Not the HDL from Patients with Coronary Heart Disease Prevent LDL Induced Toxicity in Cultured iCell Neurons Samra Vazirian, Alan M. Fogelman, Mohammad Navab and Greg Hough. Los Angeles Low density lipoprotein is known to undergo enzymatic oxidation by cultured cells presenting cytotoxicity. Normal HDL is capable of preventing LDL lipid oxidation. HDL from patients with systemic inflammation including those with coronary artery disease is not only non protective, it can even add to the proinflammatory effect of oxidized lipids in LDL.We cultured iCell neurons, added either no LDL, human LDL, LDL plus normal HDL or patient HDL followed by incubation overnight. The cell layers were washed, living cell number was determined using dye exclusion. On separate wells, morphology was captured and analyzed microscopically. There was a significant reduction in living cell number for wells that received LDL and patient HDL as compared to wells that were treated with no LDL or with LDL plus normal HDL. There was no significant difference between no LDL and LDL1normal HDL treatment. Morphologically, there was widespread abnormality and damage to neurons that were incubated with LDL and patient HDL. LDL lipid oxidation by cells and cytotoxicity is not inhibited by HDL from CAD patients while it is by normal HDL. Study supported by: US Public Health Service Grants HL-30568,HL-34343, and the Laubisch, Castera, M.K. Grey Funds at UCLA and the Leducq Foundation. S413. Memory Impairment in African-Americans after Small Vessel-Type Stroke Associated with VCAM-1 Cheryl Bushnell, Deborah Attix, Natalia Rost, Lisa Cloonan, Candice Brown, Gregory Samsa and Larry B. Goldstein. Winston Salem; Durham and Boston African-Americans (AA) are 3-times more likely to have small-vessel-type ischemic strokes (SVS) than whites. SVS is associated with cognitive impairment, a relationship incompletely explained by white matter hyperintensity burden. We determined whether inflammatory/endothelial biomarkers were associated with cognition after SVS in AAs. Biomarkers were obtained in 24 subjects (median age 56.5-yrs, 54% women, median 12-yrs education). Cognition was assessed > 6 weeks poststroke; the memory composite score (MCS) was generated using recall from the Hopkins Verbal Learning Test-II and Brief Visuospatial Memory TestRevised. A semi-automated, volumetric protocol using MRIcro software (Nottingham, UK) was applied to quantify WMH volume (WMHv) on clinical MRI scans. Of the logtransformed biomarker levels (VCAM-1, IL-1ra, IL-6, IL-8, IL-10, IFN, and TAT), VCAM-1 correlated with MCS (r 5 20.659; p 5 0.0006). VCAM-1 (r 5 0.554; p 5 0.005) and age (r 5 0.479; p 5 0.018) correlated with WMHv; VCAM-1 remained associated with MCS in multivariable analysis adjusted for WMHv, age, and education (p 5 0.023). These data show VCAM-1, a marker of inflammatory/endothelial dysfunction, was associated with poorer memory independent of extent of white matter
injury in a unique population (AAs with SVS), suggesting inflammation may be related to impaired poststroke cognition. Study supported by: American Stroke Association/Bugher Foundation. S414. IV-Tissue Plasminogen Activator (IV-TPA) for Acute Ischemic Stroke (AIS) in HIV1 Adults Farrah J. Mateen, Elizabeth M. Sweeney, Kiran T. Thakur, Jennifer L. Lyons, Bryan R. Smith, Anna M. CervantesArslanian, Russell T. Shinohara, Lee H. Schwamm, Mitchell S.V. Elkind and Josh Z. Willey. Baltimore, MD; Boston, MA; Philadelphia, PA and New York City, NY Background: Limited data exist on the use of IV-TPA in HIV1 AIS patients. Methods: The U.S. National Inpatient Sample (NIS) (2006–2010) and records of Johns Hopkins Hospital (2001–2013), Columbia University (2011–2013), and Boston University (2011–2013) were searched for HIV1 individuals treated with IV-TPA for AIS. In the NIS, a 4:1 agematched, case-control study of HIV1 versus HIV- patients treated with IV-TPA for AIS was performed. Results: In the NIS, there were 68/4,053 cases of HIV1 AIS treated with TPA (mean age 50 years, range 16–78, 35% female, 26% Caucasian) vs. 20,152/1,366,545 HIV(mean age 69 years, range 17–102 years, 51% female, 74% Caucasian). In the case-control study, no survival difference between IV-TPA-treated HIV1 and HIV- groups was found (mortality 10% vs. 5%, p 5 0.15), and mean length of hospital stay was comparable (14.4 vs. 8.8 days, p 5 0.12). Among the 11 hospital-based cases (mean age 51 years, 7 with CD4 < 400/mL, mean CD4 347/mL, mean NIHSS 11 (range 2–23), 3 stroke mimics), one HIV1 AIS patient (CD4 >600/mL, NIHSS 17) experienced hemorrhagic conversion. Conclusion: HIV1 individuals rarely receive IV-TPA for AIS but may have comparable outcomes to HIV- groups, even when immunosuppressed. Study supported by: Dr. Mateen is supported by an HIV/AIDS priority grant from the Canadian Institute of Health Research, the Canadian Federation of University Women, and the Johns Hopkins University Bloomberg School of Public Health Sommer Scholars Program. S415. HINTS Outperforms ABCD2 To Screen for Stroke in Acute Vestibular Syndrome David E. Newman-Toker, Kevin A. Kerber, Yu-Hsiang Hsieh, John H. Pula, Rodney Omron, Ali S. Saber Tehrani, Georgios Mantokoudis, Daniel F. Hanley, David S. Zee and Jorge C. Kattah. Baltimore, MD; Ann Arbor, MI and Peoria, IL Objectives: We compared two approaches to stroke screening in acute dizziness (HINTS decision rule versus ABCD2 vascular risk-stratification). Methods: Cross-sectional study at one center (1999– 2012). Acute vestibular syndrome (AVS) patients (acute, continuous vertigo/dizziness with nystagmus plus nausea/ vomiting, head-motion-intolerance, gait unsteadiness) with 1 vascular risk factor underwent neuro-otologic examination and neuroimaging (97.4% MRI). ABCD24 (suggest-
ing stroke) was compared to any central abnormality on a three-component vestibular eye movement battery (HINTS– Head Impulse, Nystagmus, Test-of-Skew) 1/- new hearing loss (HINTS ‘plus’). We measured sensitivity, specificity, likelihood ratios (LR1, LR-) for stroke and all central causes. Results: Among 190 patients (median age 60.5; 60.5% men) we found vestibular neuritis (34.7%), posterior fossa stroke (59.5% [105 infarctions, 8 hemorrhages]), or other central causes (5.8%). Sensitivity/specificity for stroke was 61.1%/62.3% (LR1 1.62/LR- 0.62) (ABCD24) versus 96.5%/84.4% (LR1 6.19, LR- 0.04) (HINTS). Sensitivity/ specificity for any central lesion was 96.8%/98.5% (LR1 63.9/LR- 0.03) (HINTS) and 99.2%/97.0% (HINTS ‘plus’) (LR1 32.7/LR- 0.01). Initial MRIs were falsely negative for stroke in 14.3% of infarctions (n 5 15/105, all < 48 hrs after symptom onset), as confirmed by delayed MRI. Conclusion: HINTS outperforms ABCD2 and early MRI for stroke diagnosis in patients with AVS. Study supported by: This study was not funded nor received financial support from any institution.
S416. Risk Factors for Subcortical Lacunes Versus Intracerebral Hemorrhage in Hypertensive Patients Elisabeth B. Marsh, Rafael H. Llinas, Argye E. Hillis, Joyce Maygers, Erin Lawrence and Rebecca F. Gottesman. Baltimore, MD Background: It is unclear why some individuals with hypertension develop subcortical lacunes and others develop intracerebral hemorrhage (ICH). The predisposing risk factors may differ for each population. Methods: Demographic and laboratory data were collected for hypertensive patients presenting with ischemic stroke or ICH over 2.5 years. Neuroimaging was retrospectively reviewed for subcortical lacunes ( < 2.0 cm), subcortical ICH, periventricular white matter disease (PVWMD), and cerebral microbleeds. We hypothesized that race (nonAfrican-American), extensive PVWMD, and absence of microbleeds would predict lacunes, creating a composite variable: ‘stroke risk’. We also evaluated the impact of age, gender, and serum creatinine on ICH risk using multivariate logistic regression. Results: 197 patients had subcortical pathology. Patients with a high ‘stroke risk’ were 6.25 times more likely to present with a lacune than ICH (p 5 0.002). Older age (OR per 10 year increase 1.19, CI 0.88-1.59); elevated serum creatinine (OR 1.15, CI 0.51-2.58); and male gender (OR 1.30, CI 0.63-2.70) trended toward predicting ICH. Conclusions: Non-African American hypertensive patients with PVWMD and no cerebral microbleeds are more likely to present with subcortical lacunes than ICH. Other factors may also differentiate between these types of vascular events and require further study. Study supported by: Dr. Marsh is supported by a Clinicain Scientist Award through the Johns Hopkins School of Medicine.
Abstracts, American Neurological Association
S417. Tumor Necrosis Factor-alpha Increases Caspase-3 Activation in Focal Cerebral Ischemia Luther C. Pettigrew. Lexington, KY Background: Tumor necrosis factor-alpha (TNFa) is an inflammatory cytokine that becomes elevated in ischemic brain. Interaction between TNFa and its receptors may activate pro-apoptotic cysteine aspartyl-specific protease (caspase; “executioner” casp-3). The hypothesis that elevated TNFa protein level will alter regional casp-3 activity was tested by focal cerebral ischemia applied to a transgenic (Tg) rat overexpressing the murine TNFa gene in brain. Methods: TNFa-Tg rats and non-Tg littermates (4–8 per group) underwent middle cerebral artery occlusion (MCAO) for 1 hr. Ischemic core (IC) and penumbra (PN) sampled after 3–48 hr of reperfusion were assayed for casp3 activity (CA units). Results: Casp-3 activity was insignificantly elevated in na€ıve TNFa-Tg brain compared to non-Tg (5.53 6 0.68 [SD] v. 3.78 6 0.58 CA units; p 5 NS). At 3 and 24 hrs, there was no significant difference in casp-3 activity in TNFa-Tg compared to non-Tg IC/PN (p 5 NS). At 48 hrs, casp-3 activity was increased in TNFa-Tg compared to non-Tg IC (3.78 6 4.85 v. 1.30 6 0.96 CA units; ANOVA/Fisher; p 0.02). Conclusion: In chronically ischemic brain, elevated TNFa protein is associated with increasing casp-3 activation that will contribute to delayed neuronal death. Study supported by: McGeorge Neurological and Spinal Cord Grant. S418. Visual Migraines Presenting after Catheter Ablation for Atrial Fibrillation Regina Kayse, Federico Rodriguez-Porcelli, Jeffrey Winterfield and Michael J. Schneck. Maywood, IL A few series described visual migraines in patients who underwent atrial fibrillation (AF) ablation. This phenomenon is not well-known, however. We explored our retrospective experience with this under-recognized phenomenon and reviewed 800 AF ablation cases to determine frequency of visual disturbances distinct from TIAs following AF ablation. Descriptive data was collected. Of 800 patients who had AF ablations, 7 patients had documented visual symptoms evaluated by a neurologist post-ablation. All events occurred within 2 weeks of ablation and typically were described as bright flashing lights. All patients had MRIs with no acute/sub-acute ischemic changes identified. All patients had CHADS2 score of zero. Four were on aspirin; one on warfarin. Five had paroxysmal AF. Five required only pulmonary vein isolation during ablation. Associated headache was uncommon. Several patients had symptoms immediately post-ablation but did not report symptoms until the first post-procedural visit when symptoms were initially thought to represent TIA or stroke.These auras following AF ablation are rare but the true frequency is unknown and the syndrome is not well-recognized, A prospective observational study is therefore under development. Study supported by: not-funded and no reolevant finacncial disclosures/conflicts.
Annals of Neurology Vol 74 (suppl 17) 2013
S419. A Pooled Outcome Model Identifies the Potential To Improve upon Intravenous rt-PA Shreyansh Shah, Pitchaiah Mandava, Anand K. Sarma and Thomas A. Kent. Houston, TX Introduction: Intravenous thrombolysis (IVT) remains the most effective therapy for ischemic stroke. While nonrandomized series suggested better outcomes for endovascular approaches, larger randomized clinical trials (RCTs) were usually negative. Because baseline imbalances affect all but the largest trials, we developed analytical techniques to accommodate imbalances and applied them to assess trials intended to improve upon IVT. Methods: We generated pooled outcome (mRS 0-1/0-2) models from the IVT arms of all RCTs, with the novel feature of multi-dimensional statistical intervals to assess each study’s outcomes at its own baseline median NIHSS and age against the model. We analyzed early and late phase IVT add-on and extended window endovascular/thrombectomy trials. Results: Functions generated from 14 IVT RCT arms representing 1785 subjects resulted in excellent fits (r2 .67). Of the 19 studies analyzed, only TUCSON (3 hour IVT/ultrasound with microspheres), CLOTBUST (3 hour IVT/ultrasound) and SYNTHESIS (3 hour IA rt-PA) approached significance. No thrombectomy or extended window trial showed benefit. Interpretation: Three hour treatment with adjunctive ultrasound or IA rt-PA appear to be the most promising approaches and there remains little evidence that the window can be extended other than by IV rt-PA alone. Study supported by: Institute of Clinical and Translational Research at the Baylor College of Medicine.
S420. Anti Inflammatory Peptide F Markedly Reduces Oxidized Fatty Acids in the Brain of LDL Receptor Deficient Mouse on a High Fat Diet Samra Vazirian, Anahita Dona Navab, Jonathon Swartz and Mohammad Navab. Los Angeles and Santa Barbara Upon feeding the LDL receptor deficient mice a high fat diet the circulating apoB lipoproteins rise, lipid oxidation increase and inflammatory state is induced. Oxidation products of cell membrane including HETEs and HODES that are produced, induce inflammatory molecules in organs. We studied effect of high fat diet on concentration of oxidized fatty acids and potential protective effect of the antiinflammatory peptide 4F. Groups of female LDL R-/- mice were provided high cholesterol diet for 6 weeks and were given drinking water or water containing anti inflammatory peptide 4F daily. LC-ESI-MS brains were analyzed for oxidized fatty acids. Concentration of HETEs, HODEs, PGs, TXB2 were significantly higher in the group that did not receive the peptide compared to mice that received the peptide 4F (p from 0.039 to 0.002). The oxidative cascade from hyperlipidemia and inflammatory pressure was inhibited by the anti inflammatory peptide 4F reducing the level of pro-inflammatory oxidized fatty acids and reducing their concentration in brain. If the peptide would have a similar
effect in humans, it might have major implications in reducing neuronal inflammation. Study supported by: US Public Health Service Grants HL-30568,HL-34343, and the Laubisch, Castera, M.K. Grey Funds at UCLA and the Leducq Foundation. S421. Hospital Arrival Mode Does Not Influence ShortTerm Outcome in Ischemic Stroke Dominique J. Monlezun, Karen C. Albright, Melissa P. Herman, Tyler Scullen, James E. Siegler, Nehal Munshi, Alex J. George, Amelia K. Boehme, T. Mark Beasley and Sheryl Martin-Schild. New Orleans, LA and Birmingham, AL Background: Worse stroke outcomes are associated with delayed hospital arrival. We sought to analyze outcome differences between patients arriving at our center via New Orleans Emergency Medical Services (NOEMS) versus private vehicle (PV). Methods: Patients with acute ischemic stroke (AIS) who presented to our center between 01/2010-11/2011 were selected from our prospective stroke registry. After adjusting for key covariates, we analyzed whether the transport method was a significant independent predictor for discharge modified Rankin Scale (mRS) or length of stay (LOS). Results: Among 584 patients with AIS, 256 met our criteria (135 NOEMS and 91 PV). Patients arriving via NOEMS had more severe strokes compared to PV arrival (median NIHSS 8 vs. 3, p < 0.001). After adjusting for age, stroke severity, admission glucose, and tPA administration, the method of transport was not a significant independent predictor for mRS 3–6 at discharge (OR 1.40, CI 0.692.82, p 5 0.350). After adjusting for baseline stroke severity, method of arrival was not a significant independent predictor of LOS (p 5 0.973). Conclusion: After adjustment for baseline predictors of poor outcome, patients arriving via NOEMS were not at greater odds of any poor outcome or prolonged LOS. Study supported by: The project described was supported by Award Numbers 5 T32 HS013852-10 from The Agency for Healthcare Research and Quality (AHRQ), 3 P60 MD000502-08S1 from The National Institute on Minority Health and Health Disparities (NIMHD), National Institutes of Health (NIH) and 13PRE13830003 from the American Heart Association (AHA). The content is solely the responsibility of the authors and does not necessarily represent the official views of the AHRQ, AHA or the NIH. S422. New Thrombotic Events in Ischemic Stroke Patients with Elevated Factor VIII Brittany M. Gouse, Amelia K. Boehme, James E. Siegler, Katie Bragg, Alex J. George, Dominique J. Monlezun, Karen C. Albright, T. Mark Beasley and Sheryl Martin-Schild. New Orleans, LA and Birmingham, AL Background: Elevated plasma level of FVIII increases risk of thrombotic events (TE) and is common in acute ischemic stroke (AIS). Methods: AIS patients with FVIII measured on admission who presented to our center (07/2008-12/2012) were
identified from our prospective stroke registry. Baseline data and rates of new TE were compared in patients according to FVIII levels. Results: Among 206 patients, 132 (64.1%) had elevated FVIII. Elevated FVIII was associated with higher rates of new TEs (9.1% vs. 2.7%, p 5 0.0805) compared to normal FVIII. This association remained after adjustment for stroke severity, but was not statistically significant (OR 3.18, 95%CI 0.67-15.13. p 5 0.1455). Patients with new TEs had higher FVIII levels (207.8% vs. 167.0%, p 5 0.1016) and significantly higher rates of death (14.3% vs. 1.6%, p 5 0.0369) and major disability (35.7% vs. 3.7%, p < 0.0001) than patients without a new TE. Conclusion: We found an increase in recurrent TEs in AIS patients with elevated FVIII, and subsequently higher rates of death and major disability. Further study with larger populations is needed to determine if elevated FVIII levels on admission represent a threat for recurrent TEs. Study supported by: The project described was supported by Award Numbers 5 T32 HS013852-10 from The Agency for Healthcare Research and Quality (AHRQ), 3 P60 MD000502-08S1 from The National Institute on Minority Health and Health Disparities (NIMHD), National Institutes of Health (NIH) and 13PRE13830003 from the American Heart Association (AHA). The content is solely the responsibility of the authors and does not necessarily represent the official views of the AHRQ, AHA or the NIH. S423. Impact of Telemedicine on Access to Acute Stroke Care in Texas Tzu-Ching Wu, Michael J. Lyerly, Karen C. Albright, Eric Ward, Amanda Hessler, Jessica Messier, Catherine Wolff, Charles Brannas, James C. Grotta, Sean I. Savitz and Brendan G. Carr. Houston, TX Objectives: To examine the impact of telemedicine on access to acute stroke expertise in Texas and determine duplication of resources for acute stroke (AIS) care. Methods: Texas hospitals were surveyed using a prescripted phone questionnaire and designated into 4 categories: Primary Stroke center (PSC), PSC with Telemedicine (TM), TM for AIS care, or other. Population data were obtained from the US Census Bureau. Access within 60 minutes to a designated facility was calculated at the block group level. Results: Our analysis found that 75.4% of Texans had access to PSCs within 60 minutes. PSCs that utilize TM increases access by 6.5%. An additional 2% of Texans had access to hospitals that utilize TM and are not designated PSCs. Approximately 16% of Texans do not have access to AIS care within 60 minutes’ drive time. Approximately 15 million Texans are double covered by two facilities that can provide AIS care. Conclusion: Use of TM increased access to over 2 million Texans. Our data supports use of TM for AIS to expand coverage to underserved regions and may be useful in AIS care optimization that can improve access while conserving resources. Study supported by: No relevant support for this abstract.
Abstracts, American Neurological Association
S424. Thyroid Hormone Contributes to Rat Hippocampal Neural Progenitor Cell Proliferation Li Ting, Brian Chisulo and Wang Qu. Guangzhou, GZ, China and Kitwe, Zambia Background Thyroid hormone (TH) plays a critical role in the developing nervous system, regulating proliferation, survival and differentiation of neural progenitor cells. This study investigated the effects of TH on proliferation of stem cells in the hippocampal subgranular zone (SGZ). Materials and Methods We achieved cognitive impairment in animal model by permanent bilateral occlusion of common carotid arteries, set interventions of thyroid hormone treatment, and observe the effect on proliferation of adult dentate granule cell progenitors after chronic cerebral ischemia by immunofluorescence staining method. Rats were administered with T3 (10 mg /30g.d) for 7d or a single T3 (10 mg /30g) after ischemia, and same dose of saline in control animals. Neurogenesis was studied by Bromodeoxyuridine (BrdU) immunohisto-chemistry in the SGZ. Results T3 treatment for 7d after ischemia increased the number of BrdU cells in the SGZ compared to saline (p 5 0.005, p < 0.001, respectively). A single T3 injection 10h before death also enhanced proliferation in SGZ 7d after chronic cerebral ischemia compared to saline (p 5 0.015, p < 0.001, respectively). Conclusion T3 enhance ischemia-induced proliferation of hippocampal in adult rats, and a short T3 influence on mitotic activity suggested T3 may act directly on progenitor cell populations. Study supported by: Nanfang Hospital; China Scholarship Council; Bursaries Committee of Zambia. S425. Mice Develop B Cell Dependent Delayed Cognitive Deficits Weeks after Stroke Kristian P. Doyle, Montse Sole, Robert C. Axtell, Thuy-Vi Nguyen, Gilberto J. Soler-Llavinia, Lisa N. Quach, Jullet Han, Arpeet T. Shah, Lawrence Steinman, Frank M. Longo, Robert C. Malenka and Marion S. Buckwalter. Stanford, CA and Barcelona, Spain Worldwide, 10 million people survive stroke each year and more than 1 in 3 subsequently develop dementia. It is unknown how long inflammation lasts after stroke, and the hypothesis that chronic inflammation in the brain can cause later onset of dementia has not been tested. We investigated whether chronic inflammation occurs after stroke and whether it can cause delayed cognitive impairment in a model of stroke that does not cause immediate cognitive impairment. We found that in mice the inflammatory response to stroke continues for at least 3 months, and is characterized by the presence of macrophages, and B and T lymphocytes in the stroke lesion, and IgG in the surrounding cortex, and hippocampus. Between weeks 1 and 7 after stroke mice develop delayed loss of staining for cholinergic neurons in areas of IgG accumulation, deficits in hippocampal long-term potentiation, and measurable short-term memory deficits. Notably, cognitive impairment and cholinergic neuronal loss are mitigated in mice that lack mature B
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lymphocytes. Our results demonstrate that not only does the inflammatory response to stroke persist for months, at least one component, B lymphocyte infiltration, contributes to delayed cognitive dysfunction. Study supported by: NINDS. S426. EMS and Hospital Stroke Care Coordination Not Associated with Racial Disparities in Pre-Hospital Stroke Activation and Transportation Melissa P. Herman, Karen C. Albright, Dominique J. Monlezun, Tyler Scullen, James E. Siegler, Nehal Munshi, Alex J. George, Amelia K. Boehme, T. Mark Beasley and Sheryl Martin-Schild. New Orleans, LA and Birmingham, AL Background: Racial disparities in stroke pose significant problems to equitable healthcare delivery, including thrombolytic treatment. We previously identified that Blacks experienced prolonged arrival times to our center. We compared pre-hospital time intervals from last seen normal (LSN) to emergency department (ED) between Blacks and Whites in a biracial population. Methods: Consecutive patients with ischemic stroke admitted to our center from 01/2010 to 11/2011 were selected from our prospective stroke registry. Only patients who arrived via New Orleans EMS were included. Time intervals, obtained from patient care reports, were compared in Black and White patients. Results: Of the 120 included patients, 90 (75%) were Black. No significant differences in time intervals comparing Blacks with Whites: notification, activation, pre-alarm, response, patient access, on-scene, transport, and delivery were detected. Conclusion: Our results indicate that the difference in time from symptom recognition to ED arrival was not related to race for those who arrived via EMS. Delays in ED arrival among Blacks may be related to greater likelihood of arrival by private vehicle or other EMS agencies. Study supported by: The project described was supported by Award Numbers 5 T32 HS013852-10 from The Agency for Healthcare Research and Quality (AHRQ), 3 P60 MD000502-08S1 from The National Institute on Minority Health and Health Disparities (NIMHD), National Institutes of Health (NIH) and 13PRE13830003 from the American Heart Association. The content is solely the responsibility of the authors and does not necessarily represent the official views of the AHRQ, AHA or the NIH. S427. For Stroke, EMS Trumps Private Vehicle for Pre-Hospital Transport Melissa P. Herman, Karen C. Albright, Dominique J. Monlezun, Tyler Scullen, James E. Siegler, Nehal Munshi, Alex J. George, Amelia K. Boehme, T. Mark Beasley and Sheryl Martin-Schild. New Orleans, LA and Birmingham, AL Background: Worse stroke outcomes are associated with delayed recognition and hospital arrival. We compared the timeline and treatment rates of patients arriving via New Orleans Emergency Medical Services (NOEMS) versus private vehicle (PV).
Methods: Consecutive patients with acute ischemic stroke (AIS) who presented to our center between 01/2010-11/ 2011 were selected from our prospective stroke registry. Tissue plasminogen activator (tPA) treatment rates were compared between patients arriving via NOEMS versus PV. Results: Among 584 patients, 256 met criteria. Patients arriving via NOEMS were at greater odds of arriving in 3 hours compared to PV (OR 2.72, 95% CI 1.51-4.90, p 5 0.001) with shorter median last seen normal (LSN)arrival (56 vs. 110min, p 5 0.004), and lower odds of having an unknown LSN (OR 0.18, 95% CI 0.08-0.41, p < 0.001). NOEMS patients were at greater odds of receiving tPA compared to PV (OR 3.58, CI 2.02–6.37, p < 0.001). No difference in median door-to-needle time (59 vs. 65min, p 5 0.502) was found. Conclusion: Patients with AIS who utilized NOEMS arrived at the hospital faster than PV arrivals and were more likely to be treated with tPA administration. Community education on importance of early access via EMS may increase treatment rates. Study supported by: The project described was supported by Award Numbers 5 T32 HS013852-10 from The Agency for Healthcare Research and Quality (AHRQ), 3 P60 MD000502-08S1 from The National Institute on Minority Health and Health Disparities (NIMHD), National Institutes of Health (NIH) and 13PRE13830003 from the American Heart Association. The content is solely the responsibility of the authors and does not necessarily represent the official views of the AHRQ, AHA or the NIH.
S428. Posterior Fossa Vascular Catastrophes in Patients with Exserohilum Meningitis Following Epidural Injections of Contaminated Steroid Preparations James W. Schmidley, Joseph M. Ferrara and Della C. Williams. Roanoke, VA Patients with Exserohilum meningitis from epidural injection of contaminated steroid preparations may suffer catastrophic vascular complications. We describe 2 such patients, a 60year-old man (Pt 1) and 49-year-old woman. Both presented with symptoms typical of an indolent meningitis. Patient 1: Initial neurological examination and head CT were normal. After 6 days of antifungal treatment, with symptomatic improvement, coma rapidly occurred. Investigations showed subarachnoid and intraventricular hemorrhage, and hydrocephalus; then, just before death, basilar hyperdensity and hypodensity throughout the vertebrobasilar circulation (VBC). Patient 2: Despite a difficult early course with hydrocephalus, she gradually improved over 3 months on vorconizole and amphotericin. She was discharged with improved CSF, but returned 4 days later with stupor, 3 limb paresis and impaired eye movements. Imaging showed pontine infarction and tenuous basilar flow, confirmed on angiography. Mechanical thrombectomy/stenting opened the occlusion, but she died of retroperitoneal bleeding the next day, without recovering. Exserohilum is angioinvasive, may prefer the VBC, and is capable of inducing both occlusion and rupture of vessels. Vascular complications occur while
on antifungal agents, even as symptoms of meningitis and CSF parameters are improving. Study supported by: n/a. S429. Optimizing Model Parameters for Mortality and Functional Outcome after Ischemic Stroke Brett Kissela, Heidi Sucharew, Kathleen Alwell, Charles Moomaw, Jane Khoury, Christopher Lindsell, Daniel Woo, Matthew L. Flaherty, Pooja Khatri, Opeulu Adeoye, Simona Ferioli and Dawn Kleindorfer. Cincinnati, OH Introduction: We previously validated models predicting 3 month mortality and functional outcomes after ischemic stroke, and found variability in results from three cohorts examined. We sought to test the models on a combined data set. Methods: Ischemic stroke patient cohorts from 1999, 2005, and 2010 were pooled for this analysis. From prior work, mortality model (logistic regression) variables included age and post-stroke modified Rankin Scale (mRS); mortality model (linear regression) variables included age, diabetes, severe periventricular white matter disease (versus < severe), pre-stroke mRS, post-stroke mRS, and the retrospective NIHSS (per Williams et al.). We allowed parameter estimates to vary but maintained the same variable structure. Random effects models were used to examine parameter estimate variability across cohorts. Results: The mortality model C-statistic was 0.83 (SE 0.023), and subsequent comorbidities significantly contributed to the predictive value of the model (life-threatening, psychiatric categories). For the functional outcomes model (predicting mRS at 3 months), the R2 was 0.52 and subsequent comorbidities significantly contributed (life threatening, medical, psychiatric, infectious, neurovascular categories). The parameter estimates did not significantly change across study periods. Conclusions: Our prediction models are robust and optimal parameters were obtained. Study supported by: Research funding: NIH NINDS R01-NS30678. S430. Stroke Mechanism of Acute Ischemic Stroke in the Corpus Callosum Rohini Bhole, Cheryl L. Brown and Elias A. Giraldo. Philadelphia, PA Objective: To demonstrate the stroke mechanism in patients with acute ischemic stroke (AIS) in the corpus callosum (CC). Background: Ischemic strokes in the CC are rare. There is scant information in the literature about clinical characteristics, stroke risk factors, stroke mechanisms and functional outcomes in patients with AIS in the CC. Methods: Retrospective chart review. The study was approved by our IRB. Results: We identified 11 patients (3.2%) with AIS in the CC amongst 339 consecutive stroke patients admitted between October 2010 and July 2012. Of them, 6 were female and 8 were African American. Mean age was 63 years (range 45–92 years). Hypertension (n 5 9), diabetes
Abstracts, American Neurological Association
mellitus (n 5 7) and dyslipidemia (n 5 7) were the most common stroke risk factors.On admission mean NIHSS score was 3.6 (range 1–7). Stroke syndromes were variable depending on the location of the infarct. Eight patients had infarcts in the splenium and three in the genu confirmed with brain MRI. Using the TOAST classification, we found that most patients had large-artery atherosclerosis (n 5 10) and only one had a cardioembolic stroke after complete stroke workup. Mean mRS score was 2 (range 1–3) at hospital discharge. Conclusions: Our study suggests that most patients with AIS in the CC have large-artery atherosclerosis. Further research is warranted. Study supported by: None. S431. Stroke Is Indistinguishable from Stroke Mimic According to Baseline Demographics in the Setting of a Stroke Activation Melissa P. Herman, Karen C. Albright, Dominique J. Monlezun, James E. Siegler, Alex J. George, Amelia K. Boehme, T. Mark Beasley and Sheryl Martin-Schild. New Orleans, LA and Birmingham, AL Background: Pre-hospital information regarding patients with possible stroke may help distinguish stroke mimics from true strokes prior to hospital arrival. Methods: At our center, patients with suspected stroke in the field are codified as “stroke activations” in order to expedite pre-hospital readiness. Stroke activations arriving via New Orleans Emergency Medical Services (NOEMS) evaluated at our center (01/2010-11/2011) were selected from our prospective stroke database. Baseline demographics were compared between patients with stroke or stroke mimic. Results: Of the 304 patients evaluated at our center as NOEMS stroke activations, 111 (36.5%) were stroke mimics. There were no significant differences in age, gender, race, or if the event was witnessed between patients with stroke or stroke mimic. Conclusion: Over one-third of stroke activations presented by NOEMS had a final diagnosis of stroke mimic. There were no baseline differences between stroke patients and mimics. Although stroke mimics are common, patients codified as stroke activations by EMS should be considered as having a stroke until proven otherwise. Study supported by: The project described was supported by Award Numbers 5 T32 HS013852-10 from The Agency for Healthcare Research and Quality (AHRQ), 3 P60 MD000502-08S1 from The National Institute on Minority Health and Health Disparities (NIMHD), National Institutes of Health (NIH) and 13PRE13830003 from the American Heart Association. S432. The Effects of Telemedicine on Racial and Ethnic Disparities in Acute Stroke Care Michael J. Lyerly, Tzu-Ching Wu, Michael T. Mullen, Karen C. Albright, Catherine Wolff, Amelia K. Boehme, Charles C. Branas, James C. Grotta, Sean I. Savitz and Brendan G. Carr. Birmingham, AL; Houston, TX and Philadelphia, PA
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Background: Racial and ethnic disparities have been previously reported in acute stroke care. We sought to determine the effects of telemedicine on access to care for racial and ethnic minorities in the state of Texas. Methods: Data was collected from the US Census Bureau, The Joint Commission and the American Hospital Association. Access for racial and ethnic minorities was determined by summing the population that could reach a Primary Stroke Center (PSC) or telemedicine spoke within specified time intervals using validated models. Results: In Texas, a higher proportion of Blacks had 60minute PSC access pre-telemedicine (83% vs. 73%) and post-telemedicine (88% vs. 80%) when compared to Whites. While Hispanics began with similar 60-minute PSC access when compared to non-Hispanics (75% vs. 76%), telemedicine led to greater increases in access for Hispanics (85% vs. 81%). Conclusions: We found that telemedicine increased access to acute stroke care for 1.5 million Texans. While racial and ethnic disparities exist in other components of stroke care, we did not find evidence of disparities in access to stroke expertise pre- or post-telemedicine. Study supported by: N/A. S433. The Role of Elevated Factor VIII in Renal Dysfunction in Ischemic Stroke Patients Dominique J. Monlezun, Amelia K. Boehme, Brittany M. Gouse, James E. Siegler, Katherine Brag, Alex J. George, Karen C. Albright, T. Mark Beasley and Sheryl Martin-Schild. New Orleans, LA and Birmingham, AL Background: Elevated Factor VIII (FVIII) is associated with acute ischemic stroke (AIS) and progression of kidney disease, but it is unknown if elevated FVIII levels exacerbate kidney injury in the acute phase of ischemic stroke. Methods: Consecutive patients with AIS admitted 07/ 2008-12/2012 with measured FVIII levels were identified from our prospective stroke registry. Patients with a history of hemodialysis were excluded. Demographic data as well as renal function throughout admission were analyzed in patients with and without elevated FVIII (>150%) levels. Results: Patients with high FVIII levels were more often black, had higher baseline glucose, lower hematocrit, higher inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), and lower baseline glomerular filtration rates (GFR) compared to patients with normal FVIII. Nadir GFR was significantly lower and peak serum creatinine was higher in patients with elevated FVIII than normal FVIII. FVIII positively correlated with the admission-to-peak creatinine (r 5 0.22, p 5 0.0022). Conclusion: Our results lend support for increased risk of AKI among patients with AIS and elevated FVIII. Further study is indicated to confirm the association and determine if elevated FVIII is a target for nephroprotection after stroke. Study supported by: The project described was supported by Award Numbers 5 T32 HS013852-10 from The Agency for Healthcare Research and Quality (AHRQ), 3 P60 MD000502-08S1 from The National Institute on Minority
Health and Health Disparities (NIMHD), National Institutes of Health (NIH) and 13PRE13830003 from the American Heart Association. The content is solely the responsibility of the authors and does not necessarily represent the official views of the AHRQ, AHA or the NIH. S434. Factors Associated with EMS Mode of Arrival Versus Private Vehicle among Patients with Acute Ischemic Stroke Melissa P. Herman, Karen C. Albright, Dominique J. Monlezun, Tyler Scullen, James E. Siegler, Nehal Munshi, Alex J. George, Amelia K. Boehme, T. Mark Beasley and Sheryl Martin-Schild. New Orleans, LA and Birmingham, AL Background: Worse stroke outcomes are associated with delayed recognition and treatment, particularly among Blacks. We analyzed factors associated with utilization of Emergency Medical Services (EMS) versus private vehicle (PV) in acute ischemic stroke (AIS) patients. Methods: AIS patients who presented to our center (01/ 2010-11/2011) were selected from our prospective registry. Baseline characteristics among patients who presented via New Orleans EMS (NOEMS) versus PV were compared. Results: Among 584 patients with AIS, 259 met our criteria (135 arrived via NOEMS and 91 via PV). NOEMS patients were older (66 vs. 64, p 5 0.009), had higher baseline glucose (119 vs. 105mg/dL, p 5 0.018) and National Institutes of Health Stroke Scale scores (8 vs. 3, p < 0.001). No racial difference NOEMS utilization was found. Medicare beneficiaries were at greater odds of utilizing NOEMS over PV (OR 1.94, 95%CI 1.17-3.20, p 5 0.010). Conclusion: Similar to prior studies, patients who use EMS are more likely to be older with more severe strokes. We found no evidence of a racial bias in utilization of EMS in our population of AIS patients. Study supported by: The project described was supported by Award Numbers 5 T32 HS013852-10 from The Agency for Healthcare Research and Quality (AHRQ), 3 P60 MD000502-08S1 from The National Institute on Minority Health and Health Disparities (NIMHD), National Institutes of Health (NIH) and 13PRE13830003 from the American Heart Association. The content is solely the responsibility of the authors and does not necessarily represent the official views of the AHRQ, AHA or the NIH. S435. Circle of Willis, Cerebral Blood Flow, and White Matter Hyperintensities in Migraine Brett L. Cucchiara, Ronald L. Wolf, Lidia M. Nagae, Quan Zhang, Scott E. Kasner and John A. Detre. Philadelphia, PA; Philadelpia, PA and Tianjin, China Background: Anatomical variations in the circle of Willis (CoW) may be associated with migraine pathogenesis by altering cerebral blood flow (CBF) regulation. Methods: Migraine patients with aura (MWA), migraine without aura (MwoA), and control subjects were enrolled in a 1:1:1 ratio for multimodal 3T MRI (including MRA, FLAIR/T2, and ASL) to assess CoW integrity, parenchyma, and cerebral blood flow (CBF). Results: 170 subjects were studied. Incomplete CoW was more common in MWA compared to controls (p 5 0.02),
with a similar trend for MwoA (p 5 0.08). MWA had more CoW variants than controls (p 5 0.02). PCA distribution CBF was lower in subjects with incomplete posterior CoW (p 5 0.02) and subjects with incomplete CoW also had greater hemispheric CBF asymmetries than subjects with complete CoW (p 5 0.05). High white matter hyperintensity (WMH) load was non-significantly more common in migraine than controls (p 5 0.33) and in subjects with 2 CoW variants (p 5 0.08). While increased WMH was not generally associated with lower CBF, CBF was reduced in MWA subjects with high WMH load (p 5 0.049). Conclusions: There appears to be a complex interaction between circle of Willis variants, CBF, and white matter hyperintensities in migraine. Study supported by: NIH grant NS061572. S436. Systematic Review of Telestroke Mark N. Rubin, Kay E. Wellik, Dwight D. Channer and Bart M. Demaerschalk. Rochester, MN and Phoenix, AZ Background: The use of two-way audio-visual (AV) technology for delivery of acute stroke, termed “telestroke,” is supported by a well established literature base. A systematic review that provides a comprehensive overview is lacking. Data Sources: Databases Ovid MEDLINE, EMBASE, PsychINFO, CINAHL, PubMed and Cochrane were searched with numerous keywords relevant to telestroke from 1996 through July 2012. Study Selection: Studies were included if the title or abstract expressed use of two-way audio/visual communication for acute stroke evaluation and management. Data Extraction: Each article was classified using a scoring rubric to assess the level of functionality, application, technology, and evaluative stage (F.A.T.E.). Data Analysis: The search yielded 1,405 potentially eligible hits, which were independently reviewed by two investigators. There were 344 unique studies that met eligibility criteria and underwent full-text review. Ultimately there were 145 unique manuscripts that were scrutinized by the F.A.T.E. template. Conclusions: Telestroke is in the mainstream of stroke practice in North America and internationally. There is a dearth of randomized controlled trials and cost analyses, but the field appears to be advancing in sophistication due to post-implementation studies. Study supported by: N/A. S437. Alterations of Brain Capillaries in Alzheimer’s Disease Stavros J. Baloyannis, Ioannis Mavroudis, Ioannis S. Baloyannis and Demetrios Psaroulis. Thessaloniki, Greece Alzheimer’s disease is an heterogeneous neurodegenerative disorder of aging, characterized mostly by decline of cognition, impairment of behaviour, speech eloquence and various neurological manifestations. The morphological, vascular, neurochemical, molecular alterations that result in Alzheimer’s disease are based on interacted pathogenetic mechanisms.We attempted to describe the brain capillaries in the cortex of the brain hemispheres, the hypothalamus, the globus pallidus and the cerebellum in early cases of
Abstracts, American Neurological Association
Alzheimer’s disease. The morphological analysis is based on ten brains processed for Golgi and electron microscopy.The morphological and morphometric analysis revealed substantial neuronal loss adn Alzheimer’s pathology in the hippocampus, the cortex of the cerebral hemispheres, the globus pallidus and no neuritic plaques in the hypothalamus. Synaptic alterations, loss of dendritic spines, mitochondrialalterations and fragmentation of Golgi apparatus were also seen. Brain capillaries in Golgi staining demonstrated dilatations, varicosities and microaneurysms. The capillaries were better perservered in the hypothalamus. Electron microscope revealed disruption of the tight junctions, proliferation of pericytes and perivascular astrocytosis.The alterations of the capillaries in early cases of Alzheimer’s disease plead in favour of the contribution of the vascular factor in the pathogenesis of Alzheimer’s disease. Study supported by: None. S438. Next Generation qPCR and Validation of StrokeRelated Whole Blood Gene Expression Mateusz G. Adamski, Yan Li, Erin Wagner, Chloe SealesBailey, Hua Yu, Steven Soper, Michael Murphy and Alison E. Baird. Brooklyn, NY; Cracow, Poland; Chapel Hill and Baton Rouge In three prior microarray studies alterations in gene expression were found in the circulating leukocytes of patients with acute ischemic stroke. As there was incomplete overlap in the reported transcript panels and the results were semiquantitative, it is not clear if the findings will be robust in independent samples or how they can be clinically applied. mRNA from the whole blood samples of 18 ischemic stroke patients and 15 referent subjects was analyzed using a new high throughput next generation qPCR method to quantitate the expression of 41 previously reported genes. Absolute quantitation was achieved by adjusting for the input cell count and the use of a commercial cDNA standard. Relative quantification was based on the average of 3 reference genes. It was found that 24 of the published 41 genes were significantly altered in the stroke patients (p < 0.05, Wilcoxon rank sum test). Four genes were altered at the p < 0.01 level (CD93, S100A9, CYBB and S100A12). The two analytic methods gave concordant results. We conclude that a proportion of the previously reported genes seem to be replicable. Evaluation of their sensitivity and specificity is deserving of further study. Study supported by: NIIH grant R01 EB010087. S439. Prognosis of Ischemic Stroke in Pakistan Umar A. Shuaib, Hiba Khan, Ismail A. Khatri, Sabeena I. Malik, Nadia Mahboob, Jamal F. Khattak, Ristya M. Kakar and Rashid Nazir. Islamabad, Pakistan Introduction: There are very few studies from the developing world on acute ischemic stroke. Methods: This is an institutional review board approved study of consecutive stroke patients admitted to the Shifa International Hospital Islamabad. Data on risk factors, presentation, investigations, management and 90 day followups was collected. Results: 289 patients mean age of 64 (26–95, 138 M and 151 F) were studied. Risk factors included hypertension in 227
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(79%), diabetes in 151 (52%), dyslipidemia in 126 (44%), IHD in 64 (22%), atrial fibrillation in 34 (12%), TIA/stroke in 81 (28%), and smoking both current (44, 15%), and ex (19, 7%). Uncontrolled and/or unrecognized disease was present in 82 (36%) hypertensives, 52 (34%) diabetics, 100 (79%) and dyslipidemics, 23 (36%). Clinical presentation included weakness (139 right, 123 left) and aphasia (66). The 90-d mean mRS score was 3.57. Diabetes and dyslipidemia were associated with poorer mRS scores on follow up. Conclusions: Risk factors for stroke in Pakistan are similar to patients in North America but the majority of patients are either unaware or poorly managed. Efforts at risk factor management are important to reduce the burden of stroke in this population. Study supported by: none. S440. A Tale of Two Thrombi: A Case of Hyperhomocystenemia and MTHFR Gene Mutation Sonia Nayyar, Michael Mendoza and Julius G. Latorre. Syracuse, NY Introduction: Strokes among young adults occurs in 3–5% of the population, presenting a diagnostic challenge for stroke etiology. Genetic mutations may promote hypercoaguable states, which may first present as ischemic events such as stroke. We report a case of acute stroke and cardiac thrombus in a 40 year old with hyperhomocysteinemia secondary to a methylenetetrahydrofolate reductase (MTHFR) gene mutation. Case: A 40 year old male with hypertension, tobacco abuse, and previous transient ischemic attack, presented with headache, dysarthria, and left upper extremity weakness for two days. The stroke workup included a MRI Brain which showed an acute right MCA infarct. Transesophageal echocardiogram demonstrated a left atrial thrombus. Patient had elevated homocysteine levels and was homozygous for T allele of the MTHFR 677 C-to-T mutation. Discussion: MTHFR is involved in homocysteine metabolism. A homozygous mutation of C-to-T at nucleotide 677 of the MTHFR gene is associated with a 50% reduction of the MTHFR enzyme. A systematic and thorough stroke workup for young adults is essential to offer optimal secondary stroke prevention and ultimately a good quality of life. Study supported by: No. S441. Young Caucasian Lady with Takayasu Arteritis (TA) in Remission- Hypoperfusion Stroke Shruthikaa Ramanathan, Sathis Mogan and Gunaratnam Gunathilagan. London, United Kingdom and Margate, Kent, United Kingdom The rarity of the Takayasu arteritis results in low clinical awareness in the Western world. 20 yrs old Caucasian lady was admitted with transient episode of parasthesia on both arms and legs, slurred speech lasting for 4 hours. She stopped taking fludrocortisone last 5 days before admission for severe hypotension. On examination, BP (Hypotensive)80/50mm Hg. absent Radial pulse bilaterally. MRI head showed multiple left sided frontal-parietal watershed infarcts. MRA showed occlusion of both common
carotid arteries, narrowing of the origin of the left vertebral artery,occlusion of Right and left subclavian artery. Causes of ischemic stroke in Takayasu’s disease include
1. Embolism from stenotic or occlusive lesions in the aortic arch and its main branches, cardiac disease, hypertension and dilative pathology in branches of the aortic arch. 2. Klos et al. Takayasu’s disease who had ischemic stroke due to intracranial involvement, the cause of infarction was proposed to be vasculitis  3. High rates of atherosclerotic plaques and increased intima media thickness are present in chronic inflammatory diseases such as Takayasu’s arteritis . References 1. Klos K, Takayasu’s arteritis with arteriographic evidence of intracranial involvement. Neurology 60:1550–1551 2. Seyahi E, Atherosclerosis in Takayasu arteritis. Ann Rheum Dis 65:1202–1207. Study supported by: None. S442. Hemorrhagic Transformation of Ischemic Stroke in Patient Treated with Rivaroxaban Robert Fekete, Dhruve S. Jeevan, Stephen J. Marks and Virany H. Hillard. Valhalla, NY Rivaroxaban (BAY 59-7939) is an oral factor Xa inhibitor used for stroke prevention in atrial fibrillation. There are currently no evidence based guidelines for treatment of hemorrhagic side effects of factor Xa inhibitors. We report a case of hemorrhagic conversion 16 days after ischemic infarct in a 60-year-old male treated with rivaroxaban for stroke prevention in a setting of paroxysmal atrial fibrillation. Hemorrhagic transformation in this case remained clinically stable following conservative therapy, likely due to pharmacological clearance of rivaroxaban. Prothrombin complex concentrates may be considered for emergent reversal of rivaroxaban. Study supported by: None. RF served as consultant for Lundbeck, LLC., and Teva Neuroscience, Inc. and received honoraria from Medlink, Inc. DSJ has not disclosures. SJM served as consultant for Boehringer Ingelheim, Inc. VHH has no disclosures. S443. Adherence with Post-Stroke Follow-Up Clinic Visits and Factors Influencing Compliance in a Large Urban Hospital Mohammad H. El-Ghanem, Vineet Punia and Machteld E. Hillen. Newark, NJ Background: A post-stroke clinic visit helps to ensure that stroke risk factor mitigation, started during hospitalization, is reinforced. This is required by the “Get With the Guidelines–Stroke” program. We attempted to find adherence with post-stroke follow-up visits and tried to identify factors influencing compliance with such visits in a large urban hospital Methods: A retrospective review of acute stroke patients discharged during a one year period was performed. Only patients who were provided a follow up appointment before
discharge were analyzed. Patients were divided into”visited”and “missed” groups. Descriptive statistical tools were used to analyze data. Results: 100 (36.5%) of 274 eligible patients returned to clinic, with an average duration of 51 days post-discharge. There was no statistical significant difference between the 2 groups in terms of age, sex, BMI, stroke type, modified Rankin scale (mRS) and insurance status. Significantly more patients in “missed” group were discharged to an inpatient rehab/nursing home (p 5 0.03), African American (p < 0.01) and non-ambulatory (p 5 0.01). Conclusions: We found poor compliance with poststroke follow-up clinic visits, which may be influenced by race, discharge placement and ambulatory status. Study supported by: Neurology and Neuroscience Department. S444. Experimental Stroke during Aging: Docosahexaenoic Acid Complexed to Albumin Provides Robust Neuroprotection Nicolas G. Bazan, Tiffany N. Eady, Larissa Khoutorova, Andre Obenaus and Ludmila Belayev. New Orleans and Loma Linda Background: Recently we have shown that docosahexaenoic acid complexed to albumin (DHA-Alb) is neuroprotective after experimental stroke in young rats. The purpose of this study was to determine whether treatment with DHA-Alb would be protective in aged rats after focal cerebral ischemia. Methods: SD aged rats (18-months old) received 2 h middle cerebral artery occlusion (MCAo). The behavior was conducted on days 1, 2, 3 and 7 after MCAo. DHA (5mg/ kg), Alb (0.63g/kg), DHA-Alb (5mg/kg10.63g/kg) or saline was administered i.v. 3 h after onset of stroke (n 5 8–10 per group). Ex vivo T2-weighted imaging (T2WI), immunohistochemistry were conducted on day 7. Results: DHA-Alb treatment improved neurological scores on day 1 (33%), day 2 (39%), day 3 (41%) and day 7 (45%). Total and cortical lesion volumes computed from T2WI were significantly reduced by DHA-Alb treatment (62 and 69%, respectively). DHA-Alb treatment reduced cortical and total brain infarction, decreased ED-1 positive microglia/microphages and increased SMI-71 positive vessels in the ischemic penumbra. Conclusion: DHA-Alb therapy is highly neuroprotective in aged rats following focal cerebral ischemia and has potential for the effective treatment of ischemic stroke in aged individuals. Study supported by: National Institutes of Health, National Institute of Neurological Disorders and Stroke (R01 NS065786 and R01 NS046741). S446WIP. Argatroban Improves Outcomes Following MCAo at Clinically Relevant Delay Times Lifu Zhao, Benedict Periera, Jessica Lamb, Padmesh Rajput and Patrick Lyden. Los Angeles, CA Thrombin inhibitors, e.g. argatroban, powerfully protect the neurovascular unit when given immediately after MCAo. We sought to extend the therapeutic window per RIGOR and STAIR guidelines. Male Sprague-Dawley rats underwent MCAo then began argatroban to run over 24 hours.
Abstracts, American Neurological Association
Blood flow was restored at pre-defined intervals. Animals were rated using the Bederson scale. After 48 hours lesion volume quantified with TTC (planimetry; Image Pro Plus). Treatment was assigned randomly and studies were triple blinded during surgery, behavioral assessment, and histology. We used a quantal bioassay (Exp Neurol 1997;147:346–352) to compute the ED50 for each group. Argatroban treatments (10 or 18mg/kg over 24 hours) were superior to saline. For example, lesional area after argatroban (n 5 136) was 42.55 6 5.04 mm2, compared to saline (n 5 48) lesional area 71.20 6 11.74mm2 (p 5 0.028, t-test). Argatroban significantly ameliorated behavior deficits: after 1 hour delay, the ED50 6 SD for placebo (n 5 19) was 24.0 6 5.6min, 10mg/kg argatroban (n 5 19) 46.3 6 3.4min, 18mg/kg argatroban (n 5 19) 40.6 6 5.7min (p < 0.05, t-test, Bonferroni). After 3 hours, placebo (n 5 25) was 15.5 6 3.3min, 10mg/kg argatroban (n 5 20) 30.1 6 5.6min, and 18mg/kg argatroban (n 5 20) 30.1 6 3.74min (P < 0.05). Following RIGOR and STAIR guidelines for pre-clinical modeling, we extended the therapeutic window to a clinically relevant 3 hours. Study supported by: NINDS. Autoimmune Neurology S501. Neonatal Fc Receptor: A Therapeutic Target for Treating Autoantibodies-Mediated Nerve Injury. Gang Zhang, Julia J. Song, Weiqiang Liu and Kazim A. Sheikh. Houston, TX Guillain-Barre syndrome (GBS) is a monophasic autoimmune neurological disorder. Autoantibodies against gangliosides/glycan are commonly present in patients with GBS. Several studies indicated that these autoantibodies can injure intact nerves and adversely affect the repair of injured axons. Therefore lowering pathogenic autoantibodies levels could be key to treat GBS patients with anti-glycan Abs. Neonatal Fc receptor (FcRn) plays a vital role in regulating IgG hemostasis. The blockade of FcRn had been demonstrated to be effective in an arthritis mouse model. We previously reported that anti-glycan Abs inhibited axon regeneration in a murine model. We then examined whether modulation of FcRn expression can alter Ab-mediated pathological effects in this model. We found that the half-life of anti-glycan Abs is significantly shortened in mice lacking FcRn. Morphological and electrophysiologic studies showed that the adverse effects of anti-glycan Abs on nerve repair are prevented in FcRn-null mice. Our results support the notion that interruption of FcRn function can increase the clearance of autoantibodies to prevent Ab-mediated neural injury. This approach has translational potential as reagents which can modulate FcRn function in humans to increase the clearance of autoantibodies are beginning to emerge. Study supported by: Supported by GBS/CIDP Foundation and NIH/NINDS (NS42888 and NS54962). S502. Pilot Study of Immunotherapy as a Diagnostic Test in Evaluating Patients with Presumed Autoimmune Epilepsy Michel Toledano, Jeffrey W. Britton, Andrew Mckeon, Cheolsu N. Shin, Lennon A. Vanda, Quek M.L. Amy, So Elson,
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Worrell A. Gregory, Wirrell C. Elaine, Nickels C. Katherine, Klein J. Cristopher, Cascino D. Gregory, Lagerlund D. Terrence and Pittock J. Sean. Rochester Objective: To evaluate a trial of immunotherapy as an aid to diagnosis when autoimmune epilepsy is suspected. Method: Twenty-nine patients with suspected autoimmune epilepsy (serological, personal history, or physical stigmata of autoimmunity), and frequent seizures or medically intractable epilepsy were started on a 6–12 week diagnostic and therapeutic trial of either intravenous methylprednisolone or immune-globulin, or both. Patients were defined as “responders” if there was a 50% reduction in seizure frequency. Results: Eighteen patients (62%) responded, 10 (34%) became seizure-free (7 responders also had a change in anticonvulsant treatment): 52% improved with the first agent; 43% of those receiving a second agent improved after not responding to the first. Six subjects (21%) reported side effects; only 1 prompting cessation of the trial. Early institution of immunotherapy was predictive of response (median 9.5 vs 22 months; p < 0.048). Of 13 responders who initiated long-term oral immunosuppression with >6 months follow up, 11 (85%) had sustained response. Conclusions: The findings provide retrospective evidence for consideration of a diagnostic trial of immunotherapy in patients with medically intractable epilepsy in which there is evidence of an autoimmune cause. A prospective trial is warranted. Study supported by: None. S503. Antibodies to Myelin Oligodendrocyte Glycoprotein (MOG) in Children and Adults with Demyelinating Disorders (NMO) Patrick Waters, Mark Woodhall, Yael Hacohen, Kevin O’Connor, Michael Absoud, Jacqueline Palace, Markus Reindl, Ming Lim, M. Isabel Leite and Angela Vincent. Oxford, United Kingdom; New Haven, CT; London, United Kingdom and Innsbruck, Austria Up to 30% of patients who fulfil the clinical criteria for Neuromyelitis optica (NMO) do not have aquaporin-4 antibodies. MOG-Abs have been described predominantly in children with demyelinating diseases, and also in a few adults with NMOSD, but the demographics and disease specificity of this antibody are not yet clear. We used cellbased assays to test 1100 consecutive serum samples, sent to our NMO Service for AQP4-Abs and for MOG-Abs (using short (SL, KO’C) and full-length (FL, MR) constructs), and compared the demographics between the AQP4-Ab and MOG-Ab patients. AQP4-Abs were found in 52 patients, and MOG antibodies in 87 (with FL, including 17 SL), including two adult females with AQP4-Abs. MOG-Ab patients (median age 35.5; 2–79 years; 56% females) were younger (p < 0.001) and with less female bias (p < 0.001) than AQP4 patients (median age 48, range 7–84 years; 85% female). Moreover, 23% of the MOG-Ab patients were children, compared with only 3.8% of the AQP4-Ab patients (p 5 0.0032). MOG-Abs are found at all ages; their detection may help define antibody-mediated demyelinating
diseases, particularly in children. The clinical phenotypes will be presented. Study supported by: NIHR Biomedical Research Centre Oxford. NHS National Service for Neuromyelitis optica. S504. The Role of Vitamin D Status in Clinically Isolated Syndrome Ellen M. Mowry, Emmanuelle Waubant, Daniel Pelletier and Scott S. Zamvil. Baltimore, MD; San Francisco, CA and New Haven, CT Objective: To determine the association of vitamin D status with disease activity in clinically isolated syndrome (CIS). Methods: In the phase II trial of atorvastatin versus placebo in CIS (NCT00094172), 25-hydroxyvitamin D levels were evaluated for their age-adjusted association with meeting the primary endpoint ( 3 new lesions or 1 relapse) within twelve months; generalized estimating equations) or with relapse risk during the entire follow-up period (up to 18 months; Cox proportional hazards models). Vitamin D status and atorvastatin interactions were assessed. Results: Mean baseline vitamin D levels in 61 (of 81 enrolled) patients for whom baseline serum was available were 26 6 12 ng/mL. There was a strong tendency for an inverse association of vitamin D levels and meeting the primary endpoint within the first year (OR per 10 ng/mL higher vitamin D level 5 0.74, 95% CI [0.51, 1.07], p 5 0.11) and with overall relapse risk (HR per 10 ng/mL higher vitamin D 5 0.64, 95% CI [0.39, 1.06], p 5 0.082). There was no strong evidence for interaction with atorvastatin. Conclusions: Vitamin D status may be an important factor in disease activity after CIS. Assessments of other potential interactions or covariates are underway. Study supported by: This research was performed as an Immune Tolerance Network (ITN020AI, ITN contract number N01-AI-15416) project. Atorvastatin, placebo, and grant support were provided by Pfizer. IFN 21a IM and grant support were supported by Biogen Idec. The Irene Perstein Award (E.M.M.) supported measurement of vitamin D levels. Dr. Mowry received support from the NIH (NINDS K23 NS067055), the National MS Society, and the Irene Perstein Award. She has received free medication from Teva Neuroscience to use in the conduct of a randomized controlled trial of vitamin D in multiple sclerosis. Dr. Waubant serves on a data safety monitoring board for the NIH and on a scientific advisory board for Actelion Pharmaceuticals Ltd; has received speaker honoraria from Teva Pharmaceutical Industries Ltd.; served as a consultant for Actelion Pharmaceuticals Ltd, Roche, and sanofi-aventis; and receives research support from sanofi-aventis, Biogen Idec, the NIH, the National MS Society, and the Nancy Davis Foundation. Dr. Pelletier serves/has served as a consultant for Synarc Inc., Biogen Idec, Bayer Schering Pharma, Genentech, Inc., Teva Pharmaceutical Industries Ltd., and CNS Imaging Consultant, LLC; serves on the speakers’ bureau for Biogen Idec; and receives research support from Biogen Idec, the NIH, and the National Multiple Sclerosis Society. Dr. Zamvil serves as Consulting Editor of the Jour-
nal of Clinical Investigation, on the editorial board of Neurotherapeutics, and as an Associate Editor for the Journal the Neurological Sciences; has served as a consultant for and received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Genentech, Inc., and EMD Serono, Inc.; has served on speakers’ bureaus for Advanced Health Media and Health Logix; and receives research support from the NIH, the National Multiple Sclerosis Society, the Guthy Jackson Charitable Foundation, the Maisin Foundation, and Teva Pharmaceutical Industries Ltd. Drs. Pelletier and Zamvil have consulted for and served on a speakers’ bureau for Biogen Idec. S505. Cigarette Smoke Induction of Systemic Proinflammatory Responses and Brain Inflammation in a Rat Model Walter Royal III, Joseph Bryant, Ming Guo, Harry Davis, Janine Davenport and Sandra Navas-Reyes. Baltimore, MD Objectives: To examine early effects of cigarette smoke (CS) on the induction of inflammatory and potentially neurotoxic responses in a rat model. Methods: Brains from Fisher F334 rats exposed for 10 days to CS from regular cigarettes and control rat brains were analyzed by PCR for proinflammatory cytokine, prooxidant and antioxidant gene expression. Also, brain frozen sections were immunostained for GFAP and Iba1. Peripheral blood mononuclear cells (PBMC) were activated with CD3/ CD28 beads or lipopolysaccharide (LPS) and examined for proliferative responses in MTT assays and for secretion of IFN-c and TNF-a by ELISA. Results: Astrocytosis and increased numbers of Iba11 cells were present in CS1 rat brains, and, of the genes examined, expression was increased for TNF-a (p 5 0.0042) and DUOX1 (p 5 0.007) but slightly decreased for iNOS (p 5 0.03). PBMC proliferative responses were similar for the two rat groups. However, compared to PBMC from CS- rats, CD3/CD28-activated CS1 rat PBCM secreted higher levels of both TNF-a (p < 0.0001) and IFN-c (p < 0.0001), and LPS-activated cells secreted higher levels of TNF-a (p < 0.0001). Conclusions: CS can induce significant systemic and brain proinflammatory response and may do so by activating innate immune mechanisms. Study supported by: NIMH, NINDS (NIH). S506. KIR4.1-Specific IgG Not Detected in Multiple Sclerosis Patients’ Sera Adipong Brickshawana, Shannon R. Hinson, James P. Fryer, Andrew McKeon, Sean J. Pittock, Claudia F. Lucchinetti and Vanda A. Lennon. Rochester, MN An IgG autoantibody specific for an inwardly rectifying potassium channel, KIR4.1, was recently reported detectable in 46.9% of multiple sclerosis (MS) patients’ sera (Srivastava et al, NEJM 367:115–123, 2012). Using recombinant and native sources of KIR4.1 antigen, we tested 50 MS patients’ sera (median age 40 years [range 17 to 69], 36 females; 37 treatment-na€ıve at time of blood draw). Diagnoses were: clinically isolated syndrome (22%); relapsing-remitting MS (48%); primary progressive MS (20%); secondary
Abstracts, American Neurological Association
progressive MS (10%). Control sera were from 4 healthy subjects and 4 NMO patients. Sera were tested immunocytochemically on two fixed-permeabilized cell substrates: HEK293 cells transiently transfected with eGFP-tagged human KIR4.1, and primary neonatal mouse astrocytes. Monoclonal KIR4.1-specific-IgG was the positive control probe. Visualized by confocal microscopy, IgG in several MS patients’ sera yielded non-specific nuclear or cytoplasmic staining of all cells; a minority yielded plasma membrane staining of glial cells. In all cases, binding of MS-IgG, but not the KIR4.1-specific-IgG probe, was abrogated by preabsorption with liver powder or wild-type HEK293 cell lysates. KIR4.1-specific-IgG binding was abrogated only by KIR4.1-HEK293 cell lysates. Our results do not support the presence of KIR4.1-specific IgG in MS patients’ sera. Study supported by: Funding provided by the Mayo Clinic Foundation and the National Institutes of Health (R01 NS065829). The American Neurological Association is aware of the potential for conflict of interest in its scientific and educational endeavors. It is ANA’s policy that public disclosure of possible conflict of interest is mandatory. By submitting this abstract, the presenting author acknowledges that ALL authors have read and agreed with the content of this abstract submitted to the 2013 Annual Meeting. Acknowledged below is all support for studies relating to the abstract. If, within the past one year, you or any immediate family member has had a relevant financial relationship relating to the support of the abstract, this relationship must be described briefly below. Such relationships include: salaries, royalties, intellectual property rights, consulting fees, honoraria, ownership interest (e.g., stocks, stock options or other ownership interest, excluding diversified mutual funds), or other financial benefit. Financial benefits are usually associated with roles such as: employment, management position, independent contractor (including contracted research), consulting, speaking, and teaching, membership on advisory committees or review panels, board membership, and other activities from which remuneration is received, or expected. S507. Human NaV1.5-Positive Macrophages Promote Clinical Recovery in Experimental Autoimmune Encephalomyelitis Michael D. Carrithers, Erik Wright and Kusha Rahgozar. Madison, WI Existing treatments for multiple sclerosis (MS) demonstrate little efficacy on prevention or recovery from disability. This laboratory focuses on the development of immune-mediated approaches for repair. Our prior work demonstrated that a variant of the NaV1.5 sodium channel is expressed intracellularly in human macrophages and regulates basic cellular mechanisms. Because this channel is not expressed in mouse macrophages, we developed a novel transgenic mouse model (C57BL6c-fms-hSCN5A) where the human macrophage NaV1.5 splice variant is expressed in mouse macrophages. These mice are protected from experimental autoimmune encephalomyelitis, the mouse model of MS. Bone marrowderived macrophages (BMDM) from these trangenic mice express high levels of arginase and interleukin 10, two
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markers of alternative activation, as compared to littermate control cells. NaV1.51 macrophages that were adoptively transferred cells into wild type recipients with established disease homed to CNS lesions, formed phagocytic nodules containing arginase-positive cells, and promoted clinical recovery that was not observed in vehicle or wild type BMDM-treated controls. These results suggest that NaV1.51 macrophages enhance recovery from CNS inflammatory disease and could potentially be developed as a cellbased therapy for the treatment of MS-associated disability. Study supported by: VA Merit Award to MDC. S508. Imaging Markers of Disability Worsening in Early Multiple Sclerosis Amir-Hadi Maghzi, Nisha Revirajan, Laura Julian, Rebecca Spain, Shuang Liu, Chengshi Jin, Ari Green, Charles McCulloch, Daniel Pelletier and Emmanuelle Waubant. San Francisco, CA; Portland, OR and New Haven, CT Objective: To find imaging markers that may be associated with clinical progression in early MS. Methods: Relapsing-remitting MS patients seen within 12 months of onset and naive to disease-modifying therapies were enrolled in a trial of neuroprotection with riluzole vs. placebo in combination with intramuscular interferon-beta 1a. Baseline and month 12 clinical [symbol digit modality test; and different domains of MS functional composite: timed 25-foot walk (T25FW), 9-hole peg test (9HPT), 3” paced auditory serial addition test (PASAT)], time domain optical coherence tomography [peripapillary retinal nerve fiber layer (RNFL), and radial macular volume (MV)], and MRI brain volume data were obtained. Spearman’s rank correlation was used to assess the association between the measures. Results: Data were available for 41 patients (73% females; mean age 35.8 6 9.1; median baseline EDSS 2.0; mean disease duration of 7.3 6 5.3 months). RNFL change was correlated with T25FW change (n 5 26, r 5 20.46, 95% CI: 20.72 to 20.08, p 5 0.019) and MV change was correlated with PASAT change (n 5 24, r 5 0.41, 95%CI: 0.01 to 0.7, p 5 0.046). Conclusion: That RNFL correlates with T25FW while MV correlates with PASAT suggests that these measures may represent promising markers of distinct clinical dimension of MS. Study supported by: Amir Hadi Maghzi is funded by the Multiple Sclerosis International Federation (www.msif.org) through a McDonald’s Fellowship. This research was performed as a research grant funded by the National MS Society. Sanofi Aventis and Biogen Idec provided riluzole and placebo, and interferon beta-1a. Dr. Waubant has received honorarium from Biogen Idec for three educational lectures, and is an adhoc consultant for Actelion, Sanofi-Aventis, and Roche. S509. Class I Haplotype Determines the Development of Brain Atrophy in the TMEV Model of MS Jeffrey D. Gamez, Pascal A. Atanga, Stephanie J. LaFrance, Aaron J. Johnson and Istvan Pirko. Rochester, MN Brain atrophy is an important component of MS, detectable from the earliest disease stages, becoming prominent in secondary progressive disease. In TMEV infected SJL/J mice we previously demonstrated the development of brain and
spinal cord atrophy. The exact mechanism and determinants leading to atrophy remain poorly understood. Our aim was to determine if class I haplotype plays a role in atrophy development in this model. FVB/NJ mice displaying H2D(q) class I haplotype are susceptible to chronic demyelination following TMEV infection. We compared FVB/NJ mice with transgenic FVB mice displaying H2D(b) haplotype. Brain atrophy was assessed using 125 micron isometric resolution 7 Tesla MRI. Mice with H2D(q) haplotype did not develop significant brain atrophy over 3 months (p 5 0.48) whereas very significant brain atrophy was demonstrated within a month in H2D(b) mice (p 5 0.02) and persisted during the observation period. H2D(b) mice are known to clear the virus more efficiently by utilizing CD8 T-cell mediated cytotoxicity directed at neurons and axons. In this model, brain atrophy is likely mediated by that mechanism, with potential contribution from altered neuronal development in the context of different class I haplotypes. Study supported by: NIH NINDS R01 award and Mayo Clinic Intramural Funds. S510. A Search for the Antigenic Region Responsible for Caspr2-Associated Encephalitis and Peripheral Nerve Hyperexcitability Abby L. Olsen, Josep O. Dalmau, Steven S. Scherer and Eric Lancaster. Philadelphia, PA and Barcelona, Spain Background: Autoantibodies to the voltage-gated potassium channel (VGKC) complex do not target channel subunits, but rather associated proteins. In some patients with encephalitis and/or peripheral nerve hyperexcitability, these antibodies target contactin-associated protein 2 (Caspr2), a protein responsible for localization of VGKCs. To gain insight into how Caspr2 antibodies are pathogenic, we sought to identify the target epitope of Caspr2 autoantibodies. Methods: Extracellular sub-domains of Caspr2 were individually deleted. Transfected cells were assayed by immunofluorescence staining with a commercial Caspr2 antibody and sera from patients. Chimeric proteins of Caspr2 and its closest homolog, Caspr, were similarly tested. Results: All tested deletion constructs were expressed at the plasma membrane. No single domain deletion completely abolished staining by patient sera, though reactivity was quantitatively reduced with several constructs. Caspr/ Caspr2 chimeras with larger regions of Caspr2 absent were not recognized. Significance: Epitope mapping of autoantigens can provide insight into the mechanism of disease, and these constructs represent novel tools for the study of Caspr2 biology. Caspr2 autoantibodies recognize the extracellular domain of Caspr2 but not its Caspr. Reactivity is unlikely to be confined to a single subdomain of Caspr2. Study supported by: K08-NS-075142-01A1 to EL. S511. Diagnoses Alternative to Suspected Gluten-Related Neurological Disorders Andrew McKeon, Joseph A. Murray, Thomas J. Kryzer, Sean J. Pittock and Vanda A. Lennon. Rochester, MN
Celiac disease (CD) serologies are controversial biomarkers of gluten-initiated neurological disorders. First generation antibodies (FGA; gliadin IgA/IgG) do not reliably predict CD, but second generation antibodies (SGA; transglutaminase-2 or deamidated-gliadin IgA) and MHCII haplotype HLA-DQ2/DQ8 do. We reviewed 69 patients identified as CD antibody-seropositive in evaluating cerebellar ataxia (31) or other neurological disorders (38), 2002– 2012. Patients fell into 3 groups: Group 1, only FGA detected; Group 2, FGA plus HLA-DQ2/DQ8 detected; Group 3, SGA plus HLA-DQ2/DQ8 detected. Of 40 patients with clinical CD (58%; all group 3), four (10%, and no others) improved neurologically with gluten-free diet. Alternative neurological diagnoses were established for 43/69 patients. Group 1: 13/15, including autoimmune cerebellar ataxia, 3 (GAD65-IgG1  or VGKC-complexIgG1 ); Group 2: 4/9, including paraneoplastic myelopathy, 1; Group 3: 26/44, including malabsorption of vitamin E or copper, 6, and autoimmune neurological disorders, 6 (ataxia or stiff-man syndrome, 3 [GAD65-IgG1], peripheral neuropathy, 2 [VGKC-complex-IgG1], NMO, 1 [aquaporin-4-IgG1]). We concluded that for most neurological patients with positive CD serologies, an alternative diagnosis should be sought rather than attributing the neurological disorder to gluten sensitivity. Of those with coexisting CD, a minority may benefit neurologically from gluten-free diet. Study supported by: None. S512. Typical and Atypical Initial Presentation of Neuromyelitis Optica: A Retrospective Study Juebin Huang, Burhan Z. Chaudhry, Kim R. McDonald, Vettaikorumakan V. Vedanarayanan, Collete C. Parker, James J. Corbett and Robert M. Herndon. Jackson, MS Background: Despite the remarkable progress in understanding Neuromyelitis optica (NMO) since the introduction of the NMO antibody test, opportunities for early diagnosis and treatment are often missed largely due to failure to recognize atypical presentation. Methods: We retrospectively reviewed clinical records of patients diagnosed as NMO or NMO spectrum disorder at University of Mississippi Medical Center from 2005 to 2013. The initial presentation was classified as transverse myelitis (TM), optic neuritis (ON) and other atypical presentation including those with Ponto-medullary syndrome. Results: Medical records of 38 patients diagnosed as NMO or NMO spectrum disorder were reviewed consecutively. 29 (76%) of them were female and 37 (97%) were African-American. Mean onset age was 28 (9–60) years old and 60.5% were NMO antibody positive. Initial presentation: TM, 60.5 %; ON, 18.4 %; Ponto-medullary syndrome, 21.1 %, including intractable vomiting, Hiccups, facial paresthesias and bulbar palsy. In pediatric group (onset age < 16, N 5 12), 41.7% initially presented as pontomedullary syndrome. Conclusions: NMO with atypical presentation including Ponto-medullary syndrome is not uncommon, especially in pediatric population. It is important to be aware of these
Abstracts, American Neurological Association
atypical presentation to ensure treatment. Study supported by: None.
S513. Treatment of Neuromyelitis Optica/Neuromyelitis Optica Spectrum Disorders with Methotrexate Ramanth Santosh Ramanathan, Konark Malhotra and Thomas Scott. Pittsburgh, PA Objective: To review our experience using methotrexate (MTX) as an initial immunosuppressant (IS) therapy in neuromyelitis optica/neuromyelitis optica spectrum disorders (NMO/NMOSD). Design: Retrospective case series. Methods: Retrospective review of patient records of all patients with a diagnosis of NMO/NMOSD, supported by a positive acquaporin-4 antibodies (AQP4-ab)/NMO-IgG testing, who were treated with MTX. Result: We followed 9 patients meeting criteria for the study for a median of 62 months. Five patients (55.55%) were started on MTX as an initial long-term immunosuppressant strategy. Three patients were (33.33%) were initially treated with pulse cyclophosphamide (CTX) followed by MTX as a preplanned step-down strategy. One patient was started on azathioprine (AZA) prior to MTX. No patient had side effects requiring change in MTX therapy. Five patients (55.55%) had stabilization of EDSS on MTX. Three patients (33.33%) had MTX treatment failure evidenced by worsening EDSS and ongoing relapses while on MTX, mandating a change in MTX therapy. One patient had a small increase in EDSS due to concomitant illness. Conclussion: In our experience, MTX is safe and possibly efficacious as an initial long-term IS therapy that can reasonably be offered to patients with NMO/NMOSD. Study supported by: No financial disclosures to be reported, No Conflict of interest. No targeted funds to disclose. S514. Effectiveness of Repeated Intravenous Immunoglobulin Therapy for Refractory Acute Disseminated Encephalomyelitis Associated with AntiGalactocerebroside Antibody Makoto Samukawa, Makito Hirano, Jun Tsugawa, Hikaru Sakamoto, Emi Tabata, Kazuo Takada, Motoi Kuwahara, Seiko Suzuki, Mari Katou, Tatsuo Yamada, Hideo Hara, Yoshio Tsuboi, Yusaku Nakamura and Susumu Kusunoki. Sakai, Osaka, Japan; Osaka-Sayama, Osaka, Japan; Fukuoka, Japan and Saga, Japan Acute disseminated encephalomyelitis causes multifocal demyelination (ADEM) in the central nervous system. Although this disease generally responds to steroid therapy, it is occasionally steroid-resistant. Steroid resistance has been clinically associated with the coexistence of neuropathy, but no serological prognostic marker is available. We measured anti-glycolipid antibodies in 25 patients with ADEM, and found that four patients were positive for antibodies to galactocerebroside (Gal-C), a glycolipid located within central and peripheral myelin. All four patients had a poor response to steroids. We summarized clinical information on these four patients and three similar patients reported previously. Only one of six patients treated with steroids recovered
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well. Repeated intravenous immunoglobulin (IVIg) resolved severe disability in one of our patients, whereas three courses of steroid pulse therapy together with one course of IVIg were not effective in this patient or in other patients. Similarly, two of three previously reported patients who received only steroids or antibacterial agents had poor outcomes. This is the first report to describe that anti-Gal-C antibody may be a serological prognostic marker for refractoriness of ADEM, and to suggest the effectiveness of repeated IVIg. Study supported by: Health and Labour Science Research Grants from the Ministry of Health, Labor, and Welfare of Japan. S515. Soluble Amyloid A (SSA) in Cerebrospinal Fluid (CSF) as a Biomarker for Neurosarcoidosis Maria I. Reyes-Mantilla, Jorjetta Ilieva, Edward Chen, David Moller and Carlos A. Pardo. Baltimore, MD Sarcoidosis is a systemic inflammatory granulomatous disease that occasionally presents with neurological involvement. Accurate identification of neurosarcoidosis may represent a challenge due its mimicry with other neurological disorders. Brain biopsy is the diagnostic gold standard in neurosarcoidosis. Therefore, the development of less invasive diagnostic biomarkers is needed. Serum amyloid A (SAA), an acute phase reactant protein, is involved in granulomatous inflammation in sarcoidosis (Chen, et al. 2010). We hypothesize that elevation of SAA in CSF would serve as a diagnostic biomarker in neurosarcoidosis patients. We measured the concentrations of SSA by ELISA in CSF in three groups of patients: Neurosarcoidosis (n 5 10), relapsing multiple sclerosis (MS) (n 5 12) and controls (n 5 13). SAA levels ranged from 1.4 to 424.1 ng/mL (mean 110.9 ng/ mL) in neurosarcoidosis patients; from 0.9 to 55.8 ng/mL (mean 9.8 ng/mL) in MS patients and from 0.6 to 10.8 ng/ mL (mean 3.15 ng/mL) in controls. CSF SAA was significantly higher in neurosarcoidosis as compared with MS patients (P 5 0.006) and controls (P 5 0.001). SAA in CSF might represent a novel diagnostic biomarker for neurosarcoidosis, especially when diagnostic challenges with other neuroinflammatory conditions are encountered. Study supported by: Bart McLean Fund for Neuroimmunology Research- Project Restore. S516. Genetic Associations of Clinical Progression in Multiple Sclerosis Sabeen T. Lulu, Ellen M. Mowry, Robert F. Carey, Maria R. Blasco, Jean Pelletier, Pierre Duquette, Pablo Villoslada, Irina Malikova, Elaine Roger, Revere P. Kinkel, Jaime McDonald, Pierre Antoine Gourraud and Emmanuelle Waubant. San Francisco, CA; Baltimore, MD; Majadahonda (Madrid), Spain; Marseille, France; Montreal, Canada; Barcelona, Spain and Boston, MA Background: Although many multiple sclerosis (MS) susceptibility genes have been identified, it has not been determined whether these genes are associated with clinical progression. Methods: This is retrospective study of white subjects evaluated within a year of MS onset. The seventeen known MS susceptibility genes as of 2010 were genotyped by SNP
analysis. Multivariate logistic regression models were used to evaluate each polymorphism adjusting for disease duration and time on disease-modifying therapy. Our main outcome was an expanded disability status scale (EDSS) of more than 3.5 from baseline. Results: Our cohort included 503 subjects (71% female, mean age at onset of 32.7 years (SD 7.7), median disease duration at the time of last EDSS of 4.4 years). Preliminary analysis showed IL-12A (rs4680534) c risk allele was associated with higher odds (OR 5 2.3, p 5 0.005, 95% CI 5 1.3–4) of an EDSS of more than 3.5 at the time of last evaluation. CD58 (rs2300747) was found not to be in Hardy-Weinberg equilibrium (p 5 0.0112). Conclusions: Some MS susceptibility polymorphisms may be associated with disease progression. Further characterization of these genes may lead to a better understanding of MS pathogenesis and an individualized treatment approach. Study supported by: Dr. Lulu is supported by a Sylvia Lawry fellowship grant from the National Multiple Sclerosis Society and an educational grant from Biogen-Idec. S517. “Oligoclonal Bands” in Mutliple Sclerosis: Evidence for Antigen-Driven Immune Stimulation on Both Sides of the Blood Brain Barrier Jaishree Bankoti, Ewa H. Witkowska, Simon Allen, Leonard Apeltsin, Stephen L. Hauser and H.-Christian von Budingen. San Francisco Cerebrospinal fluid (CSF) “oligoclonal bands” (OCB; clonal IgG) are a diagnostic hallmark feature of multiple sclerosis (MS); they are indicative of a pathologically relevant antigen-driven immune response. It remains unknown whether OCB producing B cells are also present in the periphery and whether OCB reflect static immune responses or are associated with active intrathecal immune responses. We approached these questions by combining massspectrometric proteomic analysis of isoelectrically focused (IEF) CSF IgG with deep-immune repertoire sequencing of peripheral blood (PB) and CSF IgG heavy chain variable regions (IgG-VH) with from 5 MS patients. We find strong evidence that ongoing antigenic stimulation and maturation to antibody expressing B cells mainly occurs inside the CNS compartment. Furthermore, during active MS B cells closely related to OCB producing cells may migrate across the blood-brain barrier (BBB) and be subjected to further antigen-stimulation in the periphery. Overall, our data strongly support the presence of stimuli driving B cell affinity-maturation and plasma cell differentiation on both sides of the BBB. Study supported by: Pfizer/QB3, Brass Family Foundation, Small Ventures USA, Nancy Davis Foundation, NIH/ NINDS. S518. Adrenocorticotropic Hormone and a-Melanocyte Stimulating Hormone Induce Indoleamine 2,3-Dioxygenase Activity in Monocytic Cells Mark A. Jensen, Rachel Yanowitch, Eugene Lee and Barry G.W. Arnason. Chicago, IL
Objective: Subcutaneous injection of adrenocorticotropic hormone (ACTH/H.P. Acthar Gel, repository corticotrophin injection; Questcor Pharmaceuticals, Inc.) is one treatment modality for relapses in Remitting Relapsing Multiple Sclerosis patients (RRMS). ACTH, cleaved from proopiomelanocortin, shares sequence homology with a-melanocyte stimulating hormone (a-MSH). Five melanocortin receptors (MCRs) mediate the biologic effects of ACTH; four bind a-MSH. MCRs are g protein-coupled receptors which when ligand bound, modulate immune responses. We studied indoleamine 2,3-dioxygenase (IDO) induction in the monocytic cell line, THP1, by ACTH and the a-MSH analogue, NDP-MSH. IDO cleaves tryptophan into L-kynurenine (KYN). High KYN levels suppress TH1 and Th17 cells and induce regulatory T cells. Methods: PMA-matured THP1 cells were incubated with log fold dilutions of ACTH/H.P. ACTHAR gel and NDP-MSH for 48 hours. KYN levels in 72 hour supernatants (SNs) were determined by colorimetric assay. Results: ACTH and NDP-MSH had a dose dependent inverted U-shape effect on KYN SN levels. High and low melanocortin concentrations increased (p < .05) KYN levels in THP SNs. Conclusion: IDO induction in monocytic cells provides one plausible mechanism whereby ACTH suppresses relapse in RRMS. Study supported by: This study supported by an Investigator Initiated Research Grant from Questcor Pharmaceuticals, Inc. Barry Arnason, MD has received consulting fees from Questcor Pharmaceuticals, Inc. over the past 12 months. S519. Low Prevalence of Malignant Gliomas in a Large Multiple Sclerosis (MS) Population William A. Sheremata, Silvia R. Delgado, Alireza Minagar and Joycelyn Bruce. Miami, FL and Shreveport, LA We present evidence that, contrary to prevailing opinion; cerebral gliomas are not more common in MS. Based on an expected 11.1/100,000 incidence of intracranial neoplasms, with a projected 30% malignant gliomas, we found a paucity of cases in 15,000 patients at our center. We reviewed 30 years experience with intracranial neoplasms in our MS center population, the period from MRI availability to the present. Two biopsy proven malignant gliomas (1 glioblastoma in a 34 yr. old woman, 1 oligodendroglioma in a 41 yr. old man) were found. This contrasts with 5 cases diagnosed as glioma; where review of the biopsies established a pathological diagnosis of MS, not glioma. The number of gliomas in our MS population markedly falls short of the expected 24 cases of gliomas (from an expected total of 78 intracranial neoplasms). There is an also a similar marked reduction in numbers of other intracranial neoplasms with no cases of primary CNS lymphoma. Our findings point to lower than expected incidence of malignant glioma in MS, not an increase. This may, in part, reflect activation of the innate immune system within the CNS. Study supported by: No Support has been received.
Abstracts, American Neurological Association
S520. IG Treatment Outcomes Assessment and Clinical Guidelines Study (the “INSIGHTS Study”) – Preliminary Findings from the INSIGHTS Database Todd Levine, Jonathan Katz, Richard Barohn, Tahseen Mozaffar, Gil Wolfe, David Saperstein, Lara Katzin, Elissa Ritt, Leslie Vaughan and Michelle Greer. Phoenix, AZ; San Francisco, CA; Kansas City, KS; Orange, CA; Buffalo, NY; Tampa, FL and Temecula, CA Introduction: IVIg is considered standard of care for several neuromuscular disorders but is only FDA-approved for two of these conditions. Off-label use is common; treatment is frequently provided without the benefit of guidance from clinical trials. Prescribing regimens are variable. INSIGHTS is a physician-led, quality-improvement study that examines the correlation between IVIg prescribing habits and clinical outcomes. Objectives: To collect clinical data and IVIg prescribing regimens, and to examine the correlation of clinical features with treatment outcomes. This abstract aims to report interim data on diagnosis, dosing, and branded vs. unbranded IVIg prescriptions. Methods: Data collected is that which is supplied through routine clinical care for patients prescribed IVIg. Interim data from 129 patients was pulled from the INSIGHTS database. Results: The most common diagnosis was CIDP (38.0%), followed by myasthenia gravis without acute exacerbation (14.0%). Dosing ranged from 0.32-4.35g/kg/mo (1.7g/kg/mo average) in CIDP, and 0.58-3.75g/kg/mo (2.1g/kg/mo average) in myasthenia gravis without acute exacerbation. 47.5% of IVIg prescriptions were unbranded. Summary/Conclusion: The interim data illustrates that IVIg dosing strategies for the most common neuromuscular diseases are variable. Approximately half the prescribers had no IVIg brand preference. Study supported by: NuFactor Specialty Pharmacy. Elissa Ritt, Michelle Greer, and Leslie Vaughan are employed by NuFactor Specialty Pharmacy. S521. The Relationship between Pain and Clinical Features in Multiple Sclerosis Haluk Gumus, Zehra Akpinar and Osman Serhat Tokgoz. Konya, Turkey Purpose:Multiple Sclerosis (MS) is an autoimmuneneurodegenerative disease of the central nervous system.We aimed to analyse the relationship between pain and other clinical features in MS.Patients and the Method:100 MS cases who have complaints of pain.We examined the pain type and localization.We applied Visual Pain Scale (VPS), Ashworth Spasticity Scale and Beck Depression Scale.Findings:When female and male patients are compared, significant difference has not been observed statistically among age, disease period and EDDS scores.77% of the cases have suffered from neuropathic pain,21% of the cases have displayed Lhermitte symptoms and 55% of the cases have had complaints of neuropathic extremity pain.In 60% of the cases nociceptive pains, in 12% of the cases jointextremity-muscle pain, in 47% headache and in 1% pain-
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ful tonic spasms have existed.The pain score has been detected significantly on patients with spasticity and depression(p 5 0.008,p 5 0.001).While there has been reasonable positive correlation between age,EDDS score and VPS(p 5 0.01,p 5 0.002),poor correlation has been obtained between disease period and number of attacks(p 5 0.002, p 5 0.045).Result:These findings indicate that MS pain is related with spasticity, disability and depression and these clinical findings should be taken into account during pain treatment and the above factors should be treated. Study supported by: There is no conflict of interest. S522. HyperCKemia and Skeletal Muscle Pathology in Neuromyelitis Optica Yong Guo, Carrie Katherine Grouse, Margherita Milone, Hans Lassmann, Vanda A. Lennon, Sean J. Pittock, Dusan Stefoski, Jordan Topel, Roumen Balabanov and Claudia F. Lucchinetti. Rochester, MN; Chicago, IL and Vienna, Austria Neuromyelitis optica (NMO) is an inflammatory central nervous system disorder of aquaporin-4 (AQP4) autoimmunity preferentially involving optic nerve, spinal cord and AQP4-rich periventricular brain regions. AQP4 is also present in renal distal collecting tubules, gastric parietal cells and fast-twitch skeletal muscle fibers. HyperCKemia has been reported as an attack phenomenon in NMO. We report a 51-year-old AQP4-IgG-seropositive woman, with relapsing optic neuritis, transverse myelitis and recurrent rhabdomyolysis (CK 131-63,0001 IU/L). Skeletal muscle biopsies revealed scattered myofibers with internal nuclei, atrophy, regeneration, and no myofiber necrosis. There was mild endomysial and perivascular lymphohistiocytic inflammation, and scattered eosinophils. Sarcolemmal IgG and C9neo deposits were present in NMO skeletal muscle. No sarcolemmal immune complexes were observed in control muscle biopsies. AQP4 protein was lost in NMO myofibers. In contrast, sarcolemmal AQP4 immunoreactivity was normal in 4 healthy controls and variably reduced, but present in two inflammatory myopathy cases. Sarcolemmal immune complex deposition and AQP4 loss in this NMO case is compatible with an antibody-directed attack against sarcolemmal AQP4. Recurrent hyperCKemia accompanying AQP4-IgG-seropositivity is evidence for targeting of extraCNS AQP4 by pathogenic IgG and can be considered an NMO spectrum phenomenon which extends beyond the CNS. Study supported by: The Guthy Jackson Charitable Foundation (CFL). Drs. Lennon and Lucchinetti stand to receive royalties for intellectual property related to identification of NMOIgG and AQP4 autoantigen. S523. Intracellular IL33 in MS Fangling Zhang and Subramaniam Sriram. Nashville Interleukin-33 is a member of the IL-1 family of proinflammatory cytokines. IL33 is present mainly in the nucleus and released when the cell become necrotic or die. Our earlier study had shown that some of the genes which were induced in patients with clinically isolated syndrome
were those that were also induced by IL33.Using flow cytometry we quantified the amount of IL33 in CD3, CD14 and CD19 subset of cells in 36 MS patients, 17 healthy controls, 20 other neurological disorder (OND) in un-stimulated and in in vitro LPS stimulated cells. There was a constitutive increase in the number of IL33 positive cells in CD3, CD14 and CD19 subset of cells between MS and controls (p < 0.05). After stimulation with LPS, the number of IL331 CD141 cells were 12.3% and IL331 CD191 cells was 7.8% which was greater (p < 0.01) when compared to OND and HC. There was no difference in either the constitutive or inducible levels of IL1 between MS patients and controls suggesting that the IL33 response is relatively specific for MS. Our results suggest that IL33 is part of the inflammatory signature of MS. Study supported by: Departmental funds. S524. Extra-Cranial Neuronal Tumors Distinguish Cases with Anti-NMDA Receptor Encephalitis from Controls: Early Report of a Case-Control Study Gregory S. Day, Simin Laiq, David F. Tang-Wai and David G. Munoz. Toronto, ON, Canada Background: Ovarian teratomas are diagnosed in upwards of 60% of adult females presenting with anti-NMDA receptor encephalitis (ANMDARE). Identification of neuroglial elements (Dalmau et al. 2008; T€ uz€ un et al. 2009) and lymphoid aggregates (Dabner et al. 2012) within teratomas resected from patients with ANMDARE implies that the co-localization of nervous system tissue and inflammatory cells is integral to the formation of autoantibodies. We hypothesized that the organization of neuroglial elements within ANMDARE-associated teratomas may promote development of autoimmunity in affected patients. Methods: The cytoarchitectural features of ovarian teratomas resected from 2 consecutively-accrued ANMDARE cases were compared with those from 10 women without encephalopathy. Results: Dysmorphic neuronal elements were observed within teratomas resected from both cases, consistent with gangliocytomas (WHO, Grade I). Dysplastic neurons were surrounded by prominent lymphocytic inflammation. Neuroglial elements were observed in 60% (6/10) of control teratomas but neurons were scarce, contrasting with their abundance in cases. No neural tumors, dysplastic neurons or inflammatory infiltrates were seen. Conclusions: Dysplastic neurons within teratomas may be relevant to the pathogenesis of ANMDARE, promoting immune recognition, presentation of self-antigens and autoantibody formation. Study supported by: Unfunded, Investigator Driven. S525WIP. Sensitivity of Antibody Testing, Clinica-Titer Correlations, and Epitope Repertoire in Anti-NMDAR Encephalitis Nuria Gresa-Arribas, Maarten Titulaer, Frank Leypoldt, Myrna R. Rosenfeld, Francesc Graus and Josep Dalmau. Barcelona, Spain; Rotterdam, Netherlands and Philadelphia, PA In this observational study, the presence of NMDAR antibodies in paired serum/CSF of 250 patients with antiNMDAR encephalitis was determined using brain immuno-
histochemistry and cell-based assays. All 250 CSF, but only 214 sera were positive with both techniques (86%, p < 0.0001). Clinical/antibody-titer correlations were examined at 3 disease time points in 45 randomly selected patients (10 relapses, 25 good-outcome, 10 poor-outcome). Most episodes (14/19) of clinical relapses correlated well with increase-decrease of CSF titers, while this correlation was less frequent with serum titers (7/16, p 5 0.037). In multivariable analysis, CSF and serum titers were higher in patients with poor-outcome than in those with good-outcome (p 5 0.049, p 5 0.0025), and in patients with teratoma than in those without (p 5 0.0079, p 5 0.024). Serum and CSF titers decreased over time regardless of outcome (both p < 0.0001), but the median titer decrease during the first months (median 3.6 months, IQR 2.6-6.4) was greater and occurred faster in CSF of patients with good-outcome than in those with pooroutcome, or in patients’ serum. The epitope repertoire did not change with outcome/relapses. In summary, CSF testing is more sensitive and CSF antibody-titers correlate better with outcome/relapses than serum titers. Study supported by: The current work is supported in part by a KWF fellowship 2009–4451 of the Dutch Cancer Society (MT), an ErasmusMC fellowship (MT), Forschungsf€orderungsfonds Hamburg-Eppendorf (FL), the National Institutes of Health RO1NS077851 (JD), Fundacio la Marato TV3 (JD), and Fondo de Investigaciones Sanitarias (FIS, PI11/01780 JD). S526WIP. A Phase II Trial of Neuroprotection with Riluzole in Early MS Emmanuelle Waubant, Amir-Hadi Maghzi, Nisha Revirajan, Rebecca Spain, Laura J. Julian, Ellen Mowry, Shuang Liu, Chengshi Jin, Ari J. Green, Charles E. McCulloch and Daniel Pelletier. San Francisco; Portland; New Haven and Baltimore Background: Approved MS drugs have limited neuroprotective benefit. Aims: To determine the effect of riluzole 50 mg bid versus placebo added to weekly interferon beta-1a in early relapsing-remitting (RR) MS. Methods: Mixed model regression analysis was used to compare the changes over time between groups, while accounting for longitudinal data. Results: 43 subjects were randomized (22 riluzole, 21 placebo) within 7.5 months of disease onset. Baseline characteristics were similar between groups except for older age (p 5 0.042), higher nCSF volume (p 5 0.050) and lower nGMV (p 5 0.14) in riluzole subjects. In the primary analysis, brain volume (SIENA) in the placebo group decreased at a rate of 0.041% per month whereas the active group decreased at a rate of 0.072%, a greater decline (0.031% more per month; p 0.065). Secondary analyses showed no group differences for changes in nGMV, nWMV, MSFC, RNFL and SDMT (p> 0.30). Riluzole subjects developed more new T2 lesions than placebo (p 5 0.047). Conclusions: Riluzole does not reduce brain atrophy progression in early RRMS (class 1 evidence). It is unclear whether the faster pace of brain atrophy without clinical changes was related to riluzole treatment or to more active disease in the treatment group due to randomization imbalance.
Abstracts, American Neurological Association
Study supported by: This research was performed as a research grant funded by the National MS Society (PI Waubant, RG 3932-A-2). Sanofi Aventis and Biogen Idec provided riluzole and placebo, and interferon beta-1a. A.H.M. is supported by the International MS Federation (www.MSIF.org) through a McDonald fellowship. Dr. Waubant has received honorarium from Roche, Sanofi Aventis and Genentech for three educational lectures, and is on the advisory board for a trial of Novartis. Dr. Waubant has received free medication from Biogen Idec and Sanofi-Aventis for this trial. She is also supported by the Nancy Davis Foundation, the NMSS and the NIH (R01NS071463-01). S527WIP. Viral Infection as Trigger of Synaptic Autoimmunity: New Evidence That Relapses Post-Herpes Simplex Encephalitis Are Caused by NMDA Receptor Antibodies Frank Leypoldt, Thais Armangue, Ignacio Malaga, Miquel Raspall-Chaure, Itxaso Marti, Charles Nichter, Monica Vicente-Rasoamalala, Miguel Lafuente-Hidalgo, Alfons Macaya, Carol Glaser and Josep Dalmau. Barcelona, Spain; Hamburg, Germany; Oviedo, Spain; Albany, NY; San Sebastian, Spain; Richmond, CA and Philadelphia, PA An autoimmune etiology of relapsing symptoms post-herpes simplex-encephalitis (post-HSVE) has long been suspected. We recently suggested that NMDA receptor antibodies (antiNMDAR encephalitis) could account for some cases. We describe 4 children (median age 8 months, range 2–24) and a 24-year-old patient with post-HSVE related to CSF/serum NMDAR antibodies. Symptoms developed 7–41 days after HSVE (median 21); choreoathetosis was present in all children but not in the adult. Investigations during the viral and autoimmune stages showed that the new synthesis of CSF/ serum NMDAR antibodies started a few days after the viral infection when HSV-PCR became negative. The epitope repertoire was similar to that of paraneoplastic or idiopathic anti-NMDAR encephalitis. Two patients improved after immunotherapy, one spontaneously, and two are currently undergoing immunotherapy. In parallel experiments, evaluation of CSF of 34 patients with HSVE showed that between days 0–7 and days 8–100 after viral diagnosis 22% and 64% developed brain neuropil antibodies (4% and 18% against NMDAR). These findings show that HSVE is a robust trigger for synaptic autoimmunity which in a subgroup of patients evolves to anti-NMDAR encephalitis. Study supported by: FL is supported by Forschungsf€orderungsfonds Hamburg-Eppendorf, TA receives a personal grant from the Instituto Carlos III (FI12/00366). This work is supported by the National Institutes of Health RO1NS077851 (JD), Fundacio la Marato TV3 (JD), and Fondo de Investigaciones Sanitarias (FIS, PI11/01780 JD). S528WIP. Overlap of Anti-NMDAR Encephalitis with Demyelinating Disorders Maarten J. Titulaer, Romana Hoftberger, Takahiro Iizuka, Myrna R. Rosenfeld, Francesc Graus, Albert Saiz and Josep Dalmau. Barcelona, Spain; Philadelphia, PA; Rotterdam, Netherlands; Sagamihara, Japan and Barcelona, Spain
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Patients with anti-NMDAR encephalitis may develop clinical and/or MRI features suggesting a demyelinating disorder, but the overlapping symptoms and type of disorders have not been characterized. We studied 691 patients with antiNMDAR encephalitis and identified 23 with demyelinating features. Group 1 included 5 patients with anti-NMDAR encephalitis preceded or followed by episodes of NMOspectrum disorder (4 aquaporin-4 [AQ4]-positive, 1 definitive NMO AQ4-negative), and 6 patients with brainstem or multifocal demyelinating syndromes in association with myelin oligodendrocyte glycoprotein (MOG) antibodies. Group 2 included 12 patients in whom anti-NMDAR encephalitis occurred simultaneously with atypical symptoms and/or MRI features of demyelination (5 AQ4-positive, 3 MOG-positive). In contrast, among 50 randomly selected patients with anti-NMDAR encephalitis, 1 had AQP4 and 3 MOG antibodies, and among 56 with definite NMO, 0 had NMDAR and 1 MOG antibodies (p < 0.0001 for all comparisons). Only 1/23 patients had a tumor (teratoma). Most patients improved with immunotherapy, but compared with anti-NMDAR encephalitis the demyelinating episodes resulted in more residual deficits. In summary, patients with NMO or other demyelinating disorders with atypical findings may have anti-NMDAR encephalitis, and conversely patients with anti-NMDAR encephalitis may develop demyelinating features as concurrent or separate episodes. Study supported by: The current work is supported in part by a KWF fellowship 2009–4451 of the Dutch Cancer Society (MT), an ErasmusMC fellowship (MT), the Fonds zur F€orderung der wissenschaftlichen Forschung, Austria, Project J3230 (RH), the National Institutes of Health RO1NS077851 (JD), Fundacio la Marato TV3 (JD and AS), Fondo de Investigaciones Sanitarias (FIS, PI11/01780 to JD, and PS09/0193 to FG). Dr. Dalmau receives royalties from the editorial board of Up-To-Date; from Athena Diagnostics for a patent for the use of Ma2 as autoantibody test. Dr. Dalmau holds a patent application for the use of NMDA receptor as autoantibody test. Dr. Dalmau has received a research grant from Euroimmun. Behavioral and Cognitive Neurology S601. Does Dysregulation of MAPK/ERK Signaling Underlie the Developmental Pathology in 16p11.2 Patients?. Alireza Faridar, Brieana Fregeau, Polina Bukshpun, Nicholas Pojman, Simons VIP Investigators, Tony Thieu and Elliott Sherr. San Francisco, CA Deletion of a 593kb interval at 16p11.2 locus is the most common chromosomal change associated with autism. This locus not only contains the gene MAPK3, but also the gene MVP (major vault protein), a critical regulator of MAPK/ ERK pathway. In this study, we evaluated MAPK/ERK pathway in freshly isolated lymphocytes of patients with copy-number variants (CNVs) at 16p11.2 locus. In patients with deletion at 16p11.2 locus, phosphorylated ERK1/2(p-ERK1/2) was significantly amplified in comparison to controls(p-ERK/ERK:P-value < 0.0001), despite the observation that total protein levels of ERK1/2 were significantly decreased compared to controls. In
contradistinction, suppression of ERK1/2 activity was detected in 16p11.2 duplication patients versus controls(PERK/ERK:p-Value:0.02). To evaluate the role of MVP in this pathway, MVP translation was suppressed by transfecting MVP siRNA into normal fibroblasts; preliminary results shown that a decrease in MVP protein levels was associated with a significant increase in the abundance of phospho-ERK1/2. Interestingly, MVP steady-state protein levels also correlated significantly to a number of cognitive and neurologic measures including IQ and head circumference(HC). In conclusion, activity levels of MAPK/ERK pathway are dysregulated in patients with 16p11.2 deletion, that might relate to altered MVP expression levels. Study supported by: Simons foundation. S602. Association of Metabolic Syndrome and Inflammation with Cognitive Decline in Elderly Adults Zuolu Liu and Carol Lippa. Philadelphia, PA Objective: To test the hypothesis that metabolic syndrome (MetS) is significantly associated with cognitive decline (CoD) in elderly adults, and further assess whether MetS and inflammation have a significant joint effect on CoD. Methods: Data (n 5 2975) from the National Health and Nutrition Examination Survey (1999–2002) in participants aged 60 with Digit Symbol Substitution Tests (DSS) were studied. CoD was defined using the lowest quintile of DSS score. MetS was defined as having 3 of 5 MetS traits (waist circumference (WC), high BP, glucose, triglycerides, and decreased HDL). Results: Of 2975 participants, the prevalence of MetS and CoD were 37.5% and 12.1%. Multivariate analyses indicated that large WC, high BP, elevated glucose level, and MetS were significantly associated with CoD (p < 0.001). A significant dose-response relationship between an increased number of MetS traits and the odds of CoD, and a joint effect of MetS and CRP on CoD were observed. Conclusion: The study extends previous studies by highlighting a significant MetS–CoD relationship, and a joint effect of MetS and CRP on CoD. These novel findings add to our understanding of the association between neurometabolic disorders and CoD, and have implications in clinical practice. Study supported by: N/A. S603. fMRI and TMS Studies of Motor-Cognitive Interactions Diana A. Liao, Monica L. Faulkner, Jessica J. Rilee, Vahid Azimi, John E. Desmond and Cherie L. Marvel. Baltimore, MD Working memory (WM) is the ability to hold information temporarily in mind, and generally engages fronto-parietalcerebellar networks. However, functional MRI studies reveal activation of secondary motor areas during silent rehearsal of verbal content (e.g., letters, words), and this activity scales with load (Marvel, Brain and Language, 2012). The following studies aim to further elucidate interactions between
WM and the motor system, which have been understudied to date. Expt 1: Neural activity in healthy adults was examined using fMRI while subjects rehearsed verbal and non-verbal content. Increased left premotor cortex (BA 6) was observed during rehearsal of both types of content versus a baseline condition controlling for visual load and button press response. Expt. 2: Transient lesions (via TMS) were applied to the motor and visual cortices in healthy adults during rehearsal of verbal and non-verbal content. TMS applied to the motor cortex, but not visual cortex, impaired WM performance for both types of content. These findings suggest that the motor system supports WM, and a compromised motor system leads to WM deficits. This line of research can inform novel motor and nonmotor approaches to cognitive rehabilitation. Study supported by: NIH: K01 DA 030442; R01 MH 060234; Johns Hopkins University School of Medicine’s Institute for Clinical and Translational Research: Neurobehavioral Research Unit; NIH grants provided salary support for the presenting author and co-authors, except for VA. S604. Functional Cortical Biomarkers of Audiovisual Speech Processing in Developmental Stuttering Santosh A. Helekar, Blessy S. John and David B. Rosenfield. Houston, TX Developmental Stutterers (DS) are significantly more fluent when they speak or read simultaneously with normal (fluent) speakers. The neural basis of this “choral speech” phenomenon is currently unclear, but the fronto-parietal mirror neuron system has been implicated. In an ongoing brain fMRI investigation of DS, we query whether DS subjects have an altered responsiveness of this system to audiovisual observation of speech. We focus upon neural activation during perception of the movements of lips and mouth of a person reading a text passage. In the 8 DS and 16 matched control subjects we have scanned, we note in DS a selective increase in activation of superior and inferior parietal gyri, supramarginal gyri and angular gyri. Using a newly devised analytical approach, we also detect this increased sensitivity at the individual DS subject level, opening the possibility of using this difference as a biomarker for DS. Taken together, these findings demonstrate that DS is associated with significant reorganization of the activity of multimodal association and mirror neuron system areas during the processing of combined auditory, visual and visual motion information related to perception of speech. Study supported by: The M. R. Bauer Foundation. S605. Cerebrovascular Disease and Verbal Learning in a Multiethnic Stroke-Free Community Sample Hilary P. Glazer, Chuanhui Dong, Janet T. DeRosa, Mitchell S.V. Elkind, Ralph L. Sacco, Yaakov Stern and Clinton B. Wright. Miami, FL and New York, NY Background: Subclinical cerebrovascular disease (SCVD) and verbal learning have not been rigorously examined. Methods: 1,272 stroke-free subjects over age 55 from the Northern Manhattan Study underwent total brain volume
Abstracts, American Neurological Association
(TBV), subclinical brain infarction (SBI), white matter hyperintensity volume (WMHV) quantification and a verbal learning (VL) task. Group-based trajectory modeling identified distinct VL curves over five testing trials. Generalized linear regression correlated MRI findings with VL after adjusting for age, sex, education, race-ethnicity, and medical insurance status. Results: TBV was positively associated (b 5 0.11, p 5 0.04), and SBI (b 5 21.23, p 5 0.05) and WMHV (b 5 20.99, p 5 0.0001) were negatively associated, with total words learned. We identified three VL curves after correcting for trial 1 performance. A 1% greater TBV lowered the odds of a less steep VL curve (OR 5 0.95, p 5 0.07) independent of SBI and WMHV. In separate models, SBI and WMHV increased the odds of a less steep VL curve (SBI OR 5 2.2, p 5 0.03; WMHV OR 5 1.7, p 5 0.0004), independent of TBV. The inverse association of WMHV with VL was significant, independent of SBI. Conclusion: SCVD may impair learning and memory. Higher TBV may confer cognitive reserve. Study supported by: Study supported by grants from the National Institute of Neurological Disorders and Stroke (R01 NS 29993; K02 NS 059729). CBW: Dr. Wright’s current or recent grant support includes federal (K02 NS 059729, R01 HL 108623) and private (American Heart Association SDG 0735387N) sources. He serves on a DSMB for the NOCIP clinical trial and receives royalties from UpToDate for two chapters on vascular dementia. He has done legal consulting for the law firms of Abali, Milne and Faegre, Baker, Daniels. He is a consultant for Merck and does stroke adjudication for the NIH clinical trial SPRINT. S606. Early Cerebellar Degeneration Is Associated with Cognitive Decline in Ataxia-Telangiectasia Franziska Hoche, Emily Frankenberg, Jennifer Rambow, Luciana Porto and Matthias Kieslich. Boston, MA and Frankfurt, Hesse, Germany Objective: Determine the relationship between cognitive function and age, neurological presentation, CNS degeneration, and genotype in children with ataxia-telangiectasia (AT). Background: AT typically presents with early cerebellar ataxia and atrophy before extrapyramidal (EPM) or cortical disease signs set in. Cognitive impairment in AT has been described clinically but has not yet been analyzed in detail in relation to age and clinical and neuroradiological pathology. Methods: 23 patients with AT were assessed for neurological symptoms, neuroradiological pathology, and cognitive function. Results: Very young patients showed early cerebellar disease signs without clinical or neuroradiological evidence of EPM or cortical involvement (ATI; mean age 4.35 yrs). Patients aged > 7.5 yrs presented with EPM or cortical pathology (ATII; mean age 14.02 yrs). Most significant cognitive impairment was present in ATI for total IQ (F(1,11) 5 15.031, p 5 .003), verbal IQ
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(F(1,8) 5 34.182, p < .001), working memory (F(4.952, p 5 .050), and reaction speed (F(1,6) 5 18.210, p 5 .005). No significant differences were found for attention and digit span forward. AT1 and AT2 did, however, differ with regard to digit span and attention scores. Conclusion: Cognitive decline in AT occurs early and may be associated with early cerebellar disintegrity. Study supported by: The authors report no declaration of interest. S607. Increased Amyloid Burden Correlates with Cognitive Decline in Logopenic Progressive Aphasia Youngsin Jung, Jennifer L. Whitwell, Joseph R. Duffy, Edythe A. Strand, Mary M. Machulda, Matthew L. Senjem, Val Lowe, Clifford R. Jack and Keith A. Josephs. Rochester, MN Cortical b-amyloid deposition is seen in the logopenic variant of primary progressive aphasia (lvPPA). However, the effects of the underlying amyloid pathology on lvPPA are unclear. Here, we examined the relationship between cortical amyloid burden and cognitive and language impairments in patients with lvPPA by performing regression and multivariate correlation analyses using [11C]Pittsburgh compound B (PiB) positron emission tomography (PET), the Montreal Cognitive Assessment (MoCA), the Boston Naming Test (BNT), and the Western Aphasia Battery (WAB). There was a significant inverse correlation between the global PiB ratio and performance on the MoCA (p 5 0.02). However, the correlations between PiB ratio and measures of aphasia, including BNT, WAB aphasia quotient (WAB-AQ), and WAB repetition scores were not significant (p > 0.05). The present study demonstrates that increased cortical amyloid burden is associated with worse cognition in patients with lvPPA. The results suggest that amyloid burden may be in part responsible for cognitive decline in patients with lvPPA. Interestingly, language deficits in individuals with lvPPA were not significantly associated with degree of amyloid burden, suggesting that other pathologic mechanisms may contribute to progressive language decline in these patients. Study supported by: NIH R01-DC010367. Dr. Jung has no disclosures. Dr. Whitwell receives research support from the NIH (NIDCD and NIA) and the Alzheimer’s Association, and has served as a consultant for Bristol-Myers Squibb. Dr. Lowe serves as a consultant for Bayer Schering Pharma and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, the NIH (NIA, NCI), the MN Partnership for Biotechnology and Medical Genomics, the Leukemia & Lymphoma Society, and the Alzheimer’s Association. Dr. Duffy receives research support from the NIH (NIDCD). Dr. Strand receives research support from the NIH (NIDCD). Dr. Machulda receives research support from the NIH (NIDCD). Matthew Senjem has no disclosures. Dr. Jack serves as a consultant for Janssen, Bristol-Meyer-Squibb, General Electric, Siemens, and Johnson and Johnson and is involved in clinical trials sponsored by Allon and Baxter, Inc. He receives research funding from the National Institutes of Health and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Foundation. Dr.
Josephs receives research support from the NIH (NIDCD and NIA), and the Alzheimer’s Association. S608. Inhibition of Glutamate Carboxypeptidase II (GCPII) Activity as a Treatment for Cognitive Impairment in Multiple Sclerosis Kristen A. Rahn, Crystal C. Watkins, Jesse Alt, Rana Rais, Marigo Stathis, Inna Grishkan, Ciprian M. Crainiceau, Martin G. Pomper, Camilo Rojas, Mikhail V. Pletnikov, Peter A. Calabresi, Jason Brandt, Peter B. Barker, Barbara S. Slusher and Adam I. Kaplin. Baltimore, MD Cognitive impairment is a frequent comorbidity of multiple sclerosis (MS), but no treatments exist to target this aspect of disease. Human magnetic resonance spectroscopy data collected from MS patients demonstrated significant positive correlations between hippocampal N-acetyl aspartyl glutamate (NAAG) levels and performance on a battery of cognitive tests. Therefore, we hypothesized that pharmacological upregulation of NAAG, a peptide that is broken down by the enzyme glutamate carboxypeptidase II (GCPII), would be an efficacious method of reversing cognitive impairment in MS. Using the experimental autoimmune encephalomyelitis (EAE) model of MS and Barnes maze and fear conditioning behavior tests, we measured cognitive performance following chronic treatment of the GCPII inhibitor 2PMPA. While disability levels were unaffected, two independent experiments confirmed that 2-PMPA-treated mice exhibited a significant improvement in behavior test performances compared to vehicle-treated EAE controls. Postmortem analysis revealed that the 2-PMPA can penetrate the blood brain barrier and that treatment significantly increases NAAG levels in the brains of these mice. In summary, these data support inhibition of GCPII for the treatment of cognitive impairment in MS. Study supported by: This work was supported by the National Institutes of Health Grants K23 MH069702 (to A.I.K.), T32 MH015330 (to K.A.R.), and P41EB015909 (to P.B.B.); the Montel Williams Multiple Sclerosis Foundation; the Nancy Davis Multiple Sclerosis Foundation; the Transverse Myelitis Association; and the Johns Hopkins Brain Science Institute. The authors declare no conflict of interest. S609. Pure Apraxia of Speech from Stroke Jonathan Graff-Radford, David T. Jones, Edythe Strand, Joseph R. Duffy and Keith A. Josephs. Rochester, MN Background: Apraxia of speech (AOS) is a disorder whose neuroanatomical correlate is felt to be the left insula or Broca’s area, based on studies of patients with both AOS and aphasia due to stroke. In contrast, neurodegenerative studies suggest the supplementary motor and the premotor areas as the crucial regions. Objective: To describe the common area of infarction in AOS patients with no or equivocal aphasia. Methods: Patients with AOS were identified through a pre-existing database. Chart review identified cases of “pure” AOS (without aphasia) due to ischemic stroke. Results: Seven subjects were identified. Median age was 68 (range: 49–72). Two had mild right upper extremity
weakness; neurological examinations were otherwise unremarkable. Five had pure “AOS,” while two had equivocal aphasia. Lesional study revealed that all strokes occurred in the left hemisphere with the premotor cortex the largest area of overlap. Conclusions: In AOS with equivocal or no aphasia, the left premotor cortex is the region of greatest overlap. Our results differ from prior studies because we excluded coexisting aphasia which results in a larger lesion area. Our study links stroke-induced AOS to the neurodegenerative literature by demonstrating a common area of pathology, the left premotor cortex. Study supported by: None. S610. Topography of Spontaneous Activity Predicts Visuo-Spatial Neglect Antonello Baldassarre, Lenny Ramsey, Carl Hacker, Nick V. Metcalf, Jennifer Rengachary, Kristina L. Zinn, Abraham Z. Snyder, Alex R. Carter, Gordon L. Shulman and Maurizio Corbetta. St. Louis, MO and Chieti, Italy Spatial neglect is a neurological syndrome characterized by deficit in attending and responding to contralesional stimuli. The severity of spatial neglect has been correlated with reduced inter-hemispheric resting state functional connectivity (FC), between homologous regions of the fronto-parietal dorsal attention network. We examined whether the largescale topography of multiple brain networks defined by FC correlates with spatial neglect deficits in a large heterogeneous sample of stroke patients. 84 individuals (42 right /42 left) affected by a 1st stroke within 1–2 weeks were studied with structural, functional, and diffusion MRI. Attentional deficits were evaluated by the Posner task, Mesulam and BIT cancellation tests. Raw tests underwent a principal component analysis (PCA) that revealed a main factor (34% of variance): visual field bias (VFB), with higher factor scores indicating poorer performance for contralesional than ipsilesional targets. FC-behavior correlational analysis indicated that severe VFB is associated to two main patterns of FC: 1-low inter-hemispheric FC within dorsal attention, motor and auditory networks; 2-high connectivity from visual, dorsal attention and motor networks towards default mode network in the right hemisphere. Our data suggest that FC within and between large-scale functional networks predicts severity of neglect. Study supported by: NIH Grant R01_HD061117-05A2. Salary for post-doctoral position S611. Clinical and Neuropsychological Predictors of Rate of Decline in Alzheimer’s Disease Jagan Pillai, Aaron Bonner-Jackson, Esteban Walker and Lyla Mourany. Cleveland, OH Background: Progression of Alzheimer’s disease (AD) varies significantly. We examined whether early neuropsychological changes relate to dementia progression trajectory. We studied patients with autopsy-confirmed AD dementia from the National Alzheimer’s Coordinating Center (NACC) database. Methods: Model selection was used to construct parsimonious models to predict the rate of change on MMSE and
Abstracts, American Neurological Association
CDR using the baseline scores of the tests, along with age, gender, APOE status, and education as covariates. Role of disease duration, neuropsychiatric symptoms, and initial Hachinski score on rate of MMSE and CDR change were explored. Results: Longer symptom duration before first visit was associated with slower MMSE and CDR decline, whereas higher education was associated with faster decline. Higher initial object naming predicted slower decline on MMSE. Higher initial psychomotor speed predicted slower decline on both MMSE and CDR (trend levels). Poor initial MMSE and digit span scores were negatively correlated to final Braak pathology stage. Conclusions: Initial cognitive deficits may be informative regarding rate of cognitive and functional decline. Demographic and clinical variables also affect rate of change in individuals with suspected Alzheimer’s disease. Study supported by: Institutional research funding from Cleveland Clinic. S612. Course of Improvement in Sleepiness in OSA after Introduction of PAP Nazan Aksan, Jon Tippin, Jeffery Dawson, Steven Anderson and Matthew Rizzo. Iowa City, IA We studied the time course of excessive daytime sleepiness (EDS) in obstructive sleep apnea (OSA) over 3-months of positive airway pressure (PAP) treatment. EDS was measured by the Epworth Sleepiness Scale (ESS) in 58 OSA subjects and 26 matched controls. ESS scores were stable for controls and declined in OSA; levels of EDS became similar to controls by the end of the third month of PAP therapy. Indices of disease severity (AHI, RDI and SpO2 nadir; p’s < 0.05) but not average daily PAP use predicted rate of EDS decline in OSA. In severe OSA, EDS declines were steady and significant in consecutive months. In moderate OSA, EDS declines were only significant between month-1 and 3, and between month-2 and 3. In mild OSA, EDS declines were evident immediately at month-1 and held steady thereafter. These findings show that improvement in EDS occurs over time after introduction of PAP and improvement trajectories depend on disease severity. The results inform clinical practice in terms of expected course of improvement and timing of follow-up. Study supported by: NIH-R01 HL091917-01A1. All authors receive salary support from the NIH grant listed above that funds the study. The abstract is a product of that work. S613. The Moral/Conventional Distinction Task: Adaptation and Clinical Use in Multiple Sclerosis (MS) Patients Ehrle Nathalie, Potet Alexia, Chaunu Marie-Pierre, Tourbah Ayman and Bakchine Serge. Reims, France and Villeneuve d’Ascq, France The moral/conventional distinction task (Blair, 1995) is a test first used in developmental psychology and mainly applied in psychiatry. The subject has to judge whether a behavior featured in a scene is good or bad. If judged as a transgression, the seriousness and rationale of the answer are verbally explained. In a second part, in order to evaluate which social norm (moral versus conventional) contributed
Annals of Neurology Vol 74 (suppl 17) 2013
to the answer, the subject is requested to evaluate the same scene as if it was authorised by an authority. We designed a derived task, adapted both to French cultural references and to adults subjects, with normative data (150 healthy controls). We conducted a study in 46 patients with relapsing remitting MS and matched controls. Our results showed that MS patients judged the conventional transgressions less permissible than controls in the absence of rules, whereas no significant difference was observed for moral transgressions. Moreover, patients gave more incongruous reasons, with conventional justifications for moral transgressions and conversely. These preliminary results suggest that the moral/ conventional task can be a useful clinical tool for social cognition studies in adults with neurological diseases. Study supported by: None. S614. Self-Regulation of Real-World Driving Changes after PAP-Treatment in OSA Nazan Aksan, Mark Schall, Anthony McDonald, Jeffrey Dawson, Steven Anderson, John Lee, Jon Tippin and Matthew Rizzo. Iowa City, IA and Madison, WI Epidemiologic evidence shows that obstructive sleep apnea (OSA) significantly increases driver crash risk. The extent to which OSA patients self-regulate driving exposure to mitigate road risk is poorly understood. We examined behavioral markers of sleepiness, alertness, exposure to road risks, and safety from video event recorders in the personal vehicles of 52 drivers with OSA (pre- and post-PAP) and 22 comparison drivers. Driver performance over three-months was evaluated in relation to average daily PAP-use and disease severity. There were no significant differences in driving performance between controls and OSA drivers pre-PAP. Average daily PAP-use predicted changes in driver performance post-PAP, controlling for OSA severity). OSA drivers with higher average daily PAP-use showed lower rates of lethargic/sleepy appearance, and higher rates of alertness/vigilance toward roadway/driving tasks, and greater activity level during risk exposure (e.g., bad weather, slippery roads) (p < .05). However, higher rates of distracted driving and greater apparent willingness to take risks emerged after a month of starting PAP indicating that OSA drivers may continue to be at risk for a period of time after introduction of PAP despite seemingly “adequate” treatment. Study supported by: The study is support NIH, R01 HL091917-01A1. The abstract is a work product of all authors who receive salary support from this grant. All authors on the abstract receive salary support from the NIH grant that funds the research. S615. Laterality of Motor Control or Increased Intracranial Pressure: The Case of Congresswoman Gabielle Giffords Iraj Derakhshan. Beckley, WV Backgrounds: Apprehensions concerning midline shifts in supratentorial lesions have lead to adoption of craniectomy and removal of surrounding brain tissue (fear of herniation). Methods: Based on evidence indicating presence directionality in callosal traffic, I review cases showing that only lesions affecting the major hemisphere are likely to cause
life-threatening respiratory difficulty, regardless of the status of the intracranial pressure. I present data from my own indicating that craniectomy and tissue removal, particularly those affecting the nondominant hemisphere, is likely are deprive the patient from the benefits of future resumption of function by the removed tissue surrounding the (ischemic) lesions, thus resulting in post-surgical permanent hemiplegia. Conclusion: Using publicly available documents, I show that Giffords’ permanent right hemiplegia is the direct result of an aggressive posture in neurosurgery, often based on an unjustifiable fear of raised intracranial pressure. In will review neurophysiological evidence elucidating the role of one-way callosal traffic circuitry in enabling the major hemisphere to underpin consciousness and function as pacemaker for breathing. Cases such as that of Congresswoman Giffords, in whom neural and behavioral handedness did not match, will receive special attention. Study supported by: private funds. S616. Reversible Capgras Syndrome Due to Temporal Lobe Dysfunction Joel I. Shenker. Columbia, MO Patients with Capgras syndrome show a form of delusional misidentification. Such patients visually recognize a person well known to them, but believe the person is an imposter. One hypothesis for this phenomenon posits a disconnection, in both temporal lobes, separating brain regions supporting visual person recognition (e.g. fusiform face area) from regions supporting “feeling of knowing” (e.g. peri-amygdalar area). Supporting this view, most patients have bilateral temporal damage. Stronger support would come if removing temporal lobe dysfunction eliminated Capgras. Here I present such a case. A man presented for behavioral neurology evaluation. He had been healthy and cognitively functional for decades after traumatic brain injury. But, for several months, he said his wife was an imposter, but still looked like her, and he “recognized” her voice on the phone. Brain magnetic resonance imaging showed old right anterotemporal encephalomalacia. Electroencephalogram showed left temporal sharp transients. After starting levetiracetam, he visually recognized his wife again, and did so for years, on levetiracetam treatment. These findings suggest bilateral temporal lobe brain dysfunction caused Capgras phenomena, but the left sided dysfunction was a reversible interictal manifestation of an epileptiform disorder. Study supported by: No financial support. S617. Temporal Pole and the Language Network: Physiologic Evidence from Resting State fMRI Borna Bonakdarpour, Rob S. Hurley and Marsel Mesulam. Chicago, IL Although the temporal pole (TP) was not included in the classic neurological model of language, recent evidence suggests that it should be included as part of the left temporosylvian language network (Mesulam et al., 2013). Few studies (e.g. Liu et al., 2009) have used resting state fMRI (rs-fMRI) to investigate connectivity of the language network. In this study we investigate the nature of TP connec-
tivity with known language nodes compared to analogous regions in the right hemisphere. Thirty-three right-handed participants with average age of 63.5 were imaged with rs-fMRI. In the left hemisphere, spontaneous hemodynamic fluctuations in TP were correlated with activity in other language epicenters including the middle temporal gyrus and inferior frontal gyrus. In contrast, connectivity between these regions was sparse in the right hemisphere. This asymmetric pattern of connectivity suggests that modal-specific connections with TP differ in each hemisphere. This contradicts the semantic hub theory of TP function, which states that TP encodes amodal representations similarly in each hemisphere. Further investigations will reveal how TP connectivity may be disrupted in patients with the semantic variant of Primary Progressive Aphasia, who show substantial atrophy in TP. Study supported by: R01DC008552-06, NIDCD. S618. Distribution of the Corticobulbar Tract in the Internal Capsule Soo Hwan Yim, Jong Hun Kim, Jeong Hee Cho, Gyu Sik Kim, Sun-Ah Choi and Jun Hong Lee. Goyang, Korea It is generally thought that the corticobulbar tract descends through the genu of the internal capsule (IC). However, the precise ocation of the corticobulbar tract in the IC remains controversial. The purpose of our study is to assess whether the corticobulbar tract passes through the IC genu. We reviewed 26 patients with selective IC infarction and located the sites related to bulbar symptoms. In addition, using diffusion tensor imaging, we reconstructed tracts passing through the IC in ten subjects without cerebral infarction. Patients with genu infarction, which extended to more than half of the posterior limb of the IC, showed bulbar symptoms. However, patients with genu infarction, which was limited to the genu, did not have bulbar symptoms. In contrast, patients with lesions limited to the posterior limb may show bulbar symptoms. In diffusion tensor imaging of subjects without cerebral infarctions, the corticobulbar and corticospinal tracts did not pass through the IC genu. Our data provide evidence that the corticobulbar tract does not pass through the IC genu. The proposed location of the corticobulbar tract in the level of the IC lies beyond the midpoint of the posterior limb. Study supported by: The design and conduction of this study was supported by intramural funds from Ilsan Hospital, National Health Insurance Corporation and a grant of the Korea Health 21 R&D Project, Ministry of Health, Welfare, and Family Affairs, Republic of Korea (A102065). S619. Dalfampridine in Subjects with Chronic Deficits after Ischemic Stroke David M. Simpson, Michael J. Reding, James Goldenberg, Richard M. Zweifler, Gustavo A. Suarez, Ping Zhao, Herbert R. Henney III, Adrian L. Rabinowicz and Enrique Carrazana. New York; Atlantis; Norfolk and Ardsley Dalfampridine extended release tablets (D-ER; prolongedrelease fampridine in Europe) 10mg twice daily were evaluated in subjects with ischemic stroke 6 months
Abstracts, American Neurological Association
experiencing stable sensorimotor deficits; lower extremity Fugl-Meyer Assessment score 28; and ability to complete the Timed 25-foot walk (T25FW). This double-blind, placebo-controlled study consisted of a 2-week screening period, 2-week treatment (Period-1), 1-week placebo washout, crossover to 2 weeks of treatment (Period-2), and a 1-week safety follow-up. Safety was the primary endpoint; the pre-defined exploratory efficacy endpoint was change from baseline in walking speed (T25FW). Subjects (66.3% male, mean 6 SD age 59.5 6 1.1 years) were randomized to sequence A (placebo/D-ER; n 5 55) or sequence B (D-ER/placebo; n 5 28). Seventy subjects (84.3%) completed the study; 6 withdrawals were for adverse events (AEs). Four subjects (2/treatment) had serious AEs including 3 seizures; 1 placebo and 2 D-ER one of which was secondary to an intentional overdose (suicide attempt). The common AEs with D-ER were generally consistent with its known safety profile. Change in T25FW was significantly greater with D-ER relative to placebo (least square mean 0.21 vs 0.10 ft/sec; P 5 0.027). These data provide a foundation for larger studies of D-ER for functional recovery following ischemic stroke. Study supported by: Acorda Therapeutics, Inc. D.M. Simpson: Research Grant; Significant; Astra Zeneca, Pfizer, Allergan, Merz, Ipsen, Astellas, Viromed. Consultant/Advisory Board; Significant; NeurogesX, Astellas, Eli Lilly, Pfizer, Merz, Ipsen, Acorda Therapeutics, Inc., Depomed, Syntaxin, Viromed, Allergan. M.J. Reding: Research Grant; Significant; Acorda Therapeutics, Inc. Consultant/Advisory Board; Significant; Acorda Therapeutics, Inc. Other; Significant; American Society of Neurorehabilitation. J. Goldenberg: Has nothing to disclose. R.M. Zweifler: Has nothing to disclose. G.A. Suarez: Employment; Significant; Acorda Therapeutics, Inc. Ownership Interest; Significant; Acorda Therapeutics, Inc. P. Zhao: Employment; Significant; Acorda Therapeutics, Inc. Ownership Interest; Significant; Acorda Therapeutics, Inc. H.R. Henney: Employment; Significant; Acorda Therapeutics, Inc. Ownership Interest; Significant; Acorda Therapeutics, Inc. A.L. Rabinowicz: Employment; Significant; Acorda Therapeutics, Inc. Ownership Interest; Significant; Acorda Therapeutics, Inc. E. Carrazana: Employment; Significant; Acorda Therapeutics, Inc. Ownership Interest; Significant; Acorda Therapeutics, Inc. S620. Dementia-Related Epilepsy in Vascular Dementia & Alzheimer’s Disease Tyler Webb, David M. Thompson, Summer Frank, Jennifer Lippoldt and Linda A. Hershey. Oklahoma City, OK Objectives: 1) Is epilepsy more common in vascular dementia (VaD), Alzheimer’s disease (AD), or other dementias? 2) Do dementia-related epilepsy patients have more rapid cognitive decline than those who remain seizure-free? 3) Does epilepsy develop earlier in VaD than AD? Methods: We reviewed charts of 195 dementia patients, ages 50–90 yrs, including those diagnosed with epilepsy within 5 yrs of dementia onset. Two MMSE scores separated by greater than 9 months were used to estimate progression of dementia. This estimate was adjusted for time from dementia diagnosis.
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Results: The prevalence of epilepsy in VaD (20.0%; exact binomial 95% CI:7.7%, 38.6%) did not differ from AD (2.9%; exact binomial 95% CI: 0.6%, 8.3%). Patients with dementia-related epilepsy had a more rapid decline in MMSE scores (1.75 pts/yr; 95% CI:0.59, 2.91), compared to seizure-free group (0.51 pts/yr; 95% CI: 0.22, 0.80). Time to event analysis showed patients with VaD to develop epilepsy earlier than those with AD (log rank test p 5 0.0022). Interpretation: Epilepsy prevalence did not differ among the various dementia types. Cognitive decline was faster in dementia-related epilepsy than in seizure-free dementia patients. VaD patients developed epilepsy earlier than those with AD. Study supported by: No outside support. Neuroinfectious Disease S701. Host and Organism Factors in the Neuropathogenesis of Cryptococcal Meningitis. Jeffrey A. Rumbaugh, Angela Pool, Lindsey Lowder, Kelly Forrester and Yuhui Wu. Atlanta, GA Mechanisms by which cryptococcal meningitis causes morbidity and mortality are not clearly defined. We developed a murine model to address how the ability of a cryptococcal strain to cross the blood brain barrier (BBB) is critical to its neurovirulence, and how the host Th1 versus Th2 immune response is critical to host susceptibility. We used normocapsular, hypercapsular, and hypocapsular strains of C. neoformans, which differ from each other by only a single mutation in a single gene, affecting capsule production. We intravenously inoculated mice with these strains, and compared morbidity and mortality. We measured capsule volume both in vitro and in vivo. We measured organism load and calculated capsule load in the brain. Using a Luminex assay, we measured changes in Th1 and Th2 cytokines in brain over time after infection. We found that virulence of cryptococcus in this model associates with ability to cross the BBB, rather than with production of capsule. Virulence may also be related to host response, as the least virulent strain may produce a greater protective Th1 response. Future studies will determine the exact mechanism by which strains cause greater virulence despite smaller capsule. Study supported by: This research was funded by the Emory Center for AIDS Research (Grant #P30 AI050409) to JAR. The authors report no other disclosures. S702. Corticosteroids in Herpes Simplex Virus Encephalitis: Is Timing the Key for Safety and Efficacy? Karlo J. Lizarraga and Ciro Ramos-Estebanez. Miami, FL INTRODUCTION: In spite of antiviral therapy, herpes simplex virus encephalitis (HSVE) is associated with high morbidity and mortality rates. The adjuvant use of corticosteroids could benefit certain HSVE patients. We studied the relationship between the time of steroid initiation and the neurological outcome in HSVE. Methods: Medical record analysis of immunocompetent, neurologically intact, adult patients who were treated for
HSVE at our Institution in the last 10 years. The Fisher’s exact test was used to compare the six-month neurological outcomes of patients in whom adjuvant steroids were started in the first 72 hours of disease onset with those who had received them afterwards. Results: Nineteen patients with similar characteristics were selected. Six months after HSVE, eight patients had good neurological outcomes (i.e. normal or minor neuropsychological deficits) and eleven patients had poor outcomes (i.e. death, motor, speech, memory or epileptic disorders). Patients who had received adjuvant corticosteroids in the first 72 hours of disease onset were more likely to have good outcomes than those in whom steroids were started afterwards. (P 5 0.024) Conclusion: There is a significant relationship between the time of adjunctive corticosteroid administration and the neurological outcome in HSVE patients. As soon as an additional inflammatory burden is established in HSVE, the rapid addition of steroids to the antiviral treatment might improve outcomes. Study supported by: The authors. S703. Radiological Predictors of Poor Outcome in Herpes Simplex Encephalitis Pavan Bhargava, Garett Cox, Simon Bekker and Thomas Ala. Springfield, IL Objective: To determine radiological features predicting a poor outcome in Herpes Simplex Encephalitis (HSE). Background: HSE is a common encephalitis with high mortality and morbidity. Age, level of consciousness, and delay in initiating acyclovir are known predictors of poor outcome. Previous studies have not evaluated the utility of MRI in predicting outcomes. Methods: All patients hospitalized with HSE between 2005 and 2012 were included. Two radiologists blinded to clinical data independently assessed their admission MRI scan, counting the number of areas of brain involved out of a total of 20 specified areas and assigning a numerical severity score to each area based on a visual grading (Range 1– 3). The primary clinical outcome measure was the Glasgow Outcome Score (GOS) at discharge. Results: 13 patients were identified, mean age 61.8 6 18.5 years. Six patients had a poor outcome (GOS 1/2/3) and seven had a good outcome (GOS 4/5). Involvement of >8 brain areas on MRI correlated with poor outcome (v2(1) 5 3.90,p 5 0.048) as did a severity score >10 (v2(1) 5 6.96,p 5 0.008). Conclusions: MRI measures predict poor outcome in HSE patients. Larger studies are warranted to determine if such measures help with short term and long term treatment decisions. Study supported by: None. S704. Near-Infrared Fluorescent Imaging of Matrix Metalloproteinases as an Index of Brain Inflammation in Cerebral Malaria Fernando Pereira Bruno, Henry J. Shikani, Brandi D. Freeman, Minxian Dai, Fnu Jasmin, Herbert B. Tanowitz,
Louis M. Weiss, David C. Spray and Mahalia S. Desruisseaux. Bronx, NY and Rio de Janeiro, RJ, Brazil Introduction: Cerebral malaria (CM) is an aggressive neurological manifestation, which results from Plasmodium falciparum infection. CM is characterized, in part, by severe cerebrovascular damage and inflammation. The expression and activity of matrix metalloproteinases (MMPs) enzymes serves as a strong marker of inflammation and has been studied in the context of several CNS diseases. In this regard, in the present study, we examined MMPs during the course of CM. Method: We assessed MMP levels in our murine model of CM via near-infrared fluorescent (NIRF) imaging and compared our findings to mice with non-neurotropic malarial disease and uninfected mice. Results: We observed a significant increase in MMP expression in several brain regions of mice with CM compared to the other groups, including the brain stem, cerebellum, hypothalamus and cortex. Over time, there was also a significant progressive increase of MMPs’ levels, which correlated with the severity of disease and histological findings. Conclusion: NIRF provided a sensitive and reliable approach to monitor CM. It may prove to be a valuable tool to both analyze inflammatory changes during the course of disease as well as evaluate response to therapy. Study supported by: NIH National Institute of Neurological Disorders and Stroke (NS069577); the BurroughsWellcome Fund’s Career Awards for Medical Scientists; the NIH Global Infectious Disease Research Training Program (D43 TW007129). S705. Using PET-Scan To Monitor Brain Metabolism in a Murine Model of Cerebral Malaria Fernando Pereira Bruno, Brandi D. Freeman, Wade R. Koba, Minxian Dai, Linda A. Jelicks, Eugene J. Fine and Mahalia S. Desruisseaux. Bronx, NY and Brazil Introduction: Cerebral malaria (CM) is the deadliest complication of infection with Plasmodium falciparum. Despite successful antimalarial treatment, 25% of survivors develop long-term neurocognitive deficits. Human studies are restricted to postmortem observations, thus making the characterization of brain metabolic activity difficult. This raises the need for non-invasive diagnostic tools. We investigated cerebral metabolic changes in a mouse model of CM. Method: We used FDG-PET to longitudinally monitor tissular glucose alterations. We examined metabolic activity in mice with CM and uninfected mice. Results: We observed a significant effect of both infection and time, with a decrease in mean uptake of FDG in several brain regions of mice with CM compared to controls, including the cortex, hippocampus, brainstem and cerebellum. These findings correlated temporally with increased CM pathology and neurocognitive dysfunction, including memory and learning impairments. A similar decrease in FDG was observed in the eyes of mice with disease, correlating with the known retinopathy. Conclusion: With FDG-PET, we have established a novel imaging tool to non-invasively study brain metabolism
Abstracts, American Neurological Association
during CM. FDG-PET may prove to be a viable approach to understand the brain metabolism in human patients with disease. Study supported by: NIH National Institute of Neurological Disorders and Stroke (NS069577); the BurroughsWellcome Fund’s Career Awards for Medical Scientists; the NIH Global Infectious Disease Research Training Program (D43 TW007129). S706. Apolipoprotein E Genotype Influences the Expression of Innate Immune Response Genes by Differentiating Human Neuroepithelial Progenitors Exposed to HIV-1 Micheline McCarthy, Ricardo Martinez, Biju Issac, Roberto Perez and Rebeca Geffin. Miami, FL To investigate how HIV exposure affects neurogenesis, we used an in vitro culture system consisting of human neuroepithelial progenitor (NEP) cells that undergo directed differentiation into astrocytes and neurons in the absence of microglia. Changes in gene expression in differentiating NEP cultures exposed to HIV were investigated using Illumina HumanHT-12 v4 Expression BeadChip microarray. Genes upregulated by virus exposure were related to interferon-induced responses and antigen presentation. When the data were stratified by the NEP’s apolipoprotein E genotype, innate immune response gene expression was more robust in the apolipoprotein E3/E3 cultures compared to the apoliprotein E3/E4 cultures. Biological processes defined by gene ontology (GO) were also differently affected by virus exposure according to apolipoprotein E genotype, particularly processes related to antigen presentation and interferon action. Differences occurred in both the numbers of genes affected and their significance in the GO processes, with apolipoprotein E3/E3 more significant than apolipoprotein E3/E4. Thus maturing NEP cultures recognize HIV and express innate immune response genes with a vigor that is influenced by the apolipoprotein E genotype of the cells. Study supported by: Campbell Foundation, Fort Lauderdale, Florida and the Department of Veterans Affairs. S707. Eastern Equine Encephalitis in Setting of Rituximab: Clinical Presentation and Histopathology Shibani S. Mukerji, Pedro D.S.C. Ciarlini, Sandro Santagata, Umberto De Girolami and Sashank Prasad. Boston, MA Eastern equine encephalitis (EEE) is a virulent arboviral encephalitis with high mortality and severe neurological impairment in many survivors. EEE in an immunosuppressed patient has not been previously described. A 64year-old woman with a history of follicular non-Hodgkin’s lymphoma on Rituximab developed 103 F fever and confusion followed by respiratory decline requiring intubation. An encephalitis panel including EEE virus-IgM was negative. Peripheral CD201 B cells were absent; consistent with Rituximab. Her initial MRI brain was normal. A repeat MRI two days later revealed subtle T2-FLAIR hyperintensities in bilateral thalami and cervical cord. EEE virus-PCR serologies were positive and was treated with intravenous immunoglobulin. She was ultimately transitioned to comfort
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measures and an autopsy performed. Microscopic examination of the brain showed acute neuronal damage throughout the neuroaxis including spinal cord. These regions were associated with a robust inflammatory infiltrate comprised of CD3-positive T lymphocytes and macrophages. Immunohistochemistry of affected areas demonstrated EEE virus within neurons. This case highlights the clinical presentation of EEE in the setting of Bcell depletion with subtle and delayed imaging abnormalities and a T-cell mediated inflammatory response. Study supported by: None. S708. Atypical MRI Findings of Progressive Multifocal Leukoencephalopathy in a Patient with Sarcoidosis Bahareh Hassanzadeh, Sushanth Bhat, Karna Sherwood, Vahid Tohidi, David Nochlin and Ming He. Edison, NJ A 40 year-old African-American man with a prior diagnosis of sacroidosis, who had been on prednisone 10 mg daily for five years, presented with two weeks of confusion, ataxia, right-sided weakness, diffuse hyperreflexia and dysarthria progressing to aphasia. Brain MRI showed scattered nonenhancing lesions in the cortical/subcortical regions, corpus callosum and brainstem. CSF analysis was normal. He was HIV-negative. Intravenous methylprednisone was initiated for suspected neurosarcoidosis, but he deteriorated clinically. Repeat brain MRI a week later showed increased number and size of the previous lesions with mild enhancement and extensive periventricular and cerebellar involvement, but no parietooccipital or frontal predilection. Stereotactic brain biopsy with immunohistochemistry showed JC virusinfected oligodendrocytes. Serum and CSF PCR were positive for JC virus. Progressive multifocal leukoencephalopathy (PML) was diagnosed. PML occurs in up to 9% of patients with sarcoidosis, both treated and untreated. While MRI in PML generally shows large, subcortical, confluent lesions in the parietooccipital and frontal lobes, the lesions in our patient appeared to be more discrete, widespread and periventricular. It is possible that the nature of MRI lesions in PML may be atypical in patients with both PML and sarcoidosis. Study supported by: none. S709. Trends in Creutzfeldt-Jakob Disease: The Mayo Clinic Experience 1976–2013 Jeremy K. Gregory and Allen J. Aksamit. Rochester, MN Objective: To determine variance in the clinical characteristics of Creutzfeldt-Jakob disease over time. Methods: Retrospective review of 324 patients with CJD in a single clinic population over 37 years (1976–2013). Results: The review classified 98 patients as definite; 103, probable; and 123, possible CJD. Peak age of onset was in the seventh decade. Presenting findings at disease onset were dementia (42%), ataxia (36%), and behavioral manifestations (18%). Mean survival after symptom onset was 7.7 months. CSF was non-inflammatory, with mean total protein 44 mg/dL and normal nucleated cell count in 98%. Normal neuron specific enolase had a high negative predictive value. 14-3-3 protein was diagnostically elevated in 24%. EEG showed periodic sharp wave complexes in
37% of definite CJD patients. MRI showed CJD-specific abnormalities in 58% of all patients, though the specificity increased to 80% after the year 2000. Conclusions: The age of onset, spectrum of clinical features, and duration of illness of sporadic CJD were invariant over time. No cases of variant CJD were identified, yet psychiatric manifestations and dysesthesias were common. EEG was specific but insensitive for CJD. Improved DWI and FLAIR MRI has helped antemortem CJD diagnosis. Study supported by: N/A. S710. Reactivation of Cerebral American Trypanosomiasis (Chaga’s Disease) in the United States: An Emerging Neuroinfectious Disease Clay Goodman. Houston, TX Objective: To report two cases of cerebral American trypanosomiasis (Chaga’s disease) in AIDS patients. Background: Chaga’s disease is endemic in Central and South America. Initial infection may be asymptomatic, but encephalitis or myocarditis may occur. Immunocompromise may result in reactivation of cerebral Chaga’s disease. Design/Methods: Case report. Results: Case #1: A 38-year-old Honduran woman with AIDS presented to Ben Taub General Hospital in Houston with altered mental status due to multiple intracranial masses. Biopsy showed lymphocytic inflammation, gliosis and numerous amastigotic T. cruzi within astrocytes, neurons and macrophages. Case#2: A 50-year-old Guatemalan woman with AIDS presented to a community hospital with multiple contrast enhancing masses. Brain biopsy demonstrated intracytoplasmic T. cruzi and CSF examination showed trypanosomes. Conclusion: Cerebral Chaga’s disease pursues a fulminant course in immunosuppressed patients, and clusters of reactivation due to AIDS have been described. Physicians in the United States are less familiar with this disease, but it is estimated that 300,000 to 1 million infected individuals reside here. Clinical vigilance is warranted, as an increasing incidence of this infection is likely. Study supported by: None. S711. Recurrent Hypertrophic Neuroma in Treated Hansen’s Disease Christopher Parres, Christine Thomas, Winnie Ooi, David Bryan, Doreen Ho and Jayashri Srinivasan. Boston, MA and Burlington, MA Background: Peripheral nerve manifestations of leprosy (aka Hansen’s disease) range from asymmetric dermal involvement to bilateral symmetric distal neuropathies (Ooi & Srinivasan, Muscle Nerve, 2004). Neuritis can occur before, during, or following treatment with multiple drug therapy (MDT) and typically responds to steroids and/or thalidomide (Agrawal et al., Clin Neurol Neurosurg, 2005). Case Report: A 42 year-old man with lepromatous leprosy treated with MDT developed multiple episodes of neuritis involving facial, posterior tibial, and sural nerves. He was treated successfully with prednisone and thalidomide. Eight years later, he presented with painful paresthesias in the left calf. On
exam, he had sensory loss in a sural distribution and an enlarged, tender nerve. Steroids were ineffective. Nerve ultrasound and MRI revealed focal dilation of sural nerve. Sural nerve biopsy was diagnostic of hypertrophic regenerative neuroma. Discussion: Other case reports have described the copresence of schwannoma as well as neurofibroma/neurofibromatosis in leprosy (Angoori et al., Indian J Dermatol, 2010; Guedes et al., Acta Reumatol Port, 2011), but here the findings suggest a late manifestation of the natural course of disease. Conclusion: Recurrent nontraumatic neuroma in a patient with treated Hansen’s disease may clinically mimic perineuroma or neurofibroma. Study supported by: none. S712. Rhombencephalitis Due to Listeria Monocytogens in Immunocompetent Patient Ruchir Shah, Umang Shah and Thomas Bosley. Camden, NJ and Milwaukee, WI Introduction: Rhombencephalitis define as inflammatory diseases affecting the hindbrain. Usually demonstrated by neuroimaging,with pleocytosis in CSF. Case: 53 year old Caucasian male with PMH of hyperlipidemia developed abdominal pain, nausea, vomiting and diarrhea 5 days prior to admission. Symptoms persisted for 2 days and then develop headache, fever. He was taken to ER where he noted to have 105.4 temperature with HR of 132. Noted to have leukocytosis of 17000 and lactate of 3.7. His CSF analysis showed WBC of 440 with 40% polymorph, 58 % lymphocyte, protein 145 and glucose 62. He was empirically started on antibiotics. On neurological exam he had left lower motor neuron facial palsy,horizontal gaze palsy in right eye and abduction palsy on left eye. MRI brain was consistent with rhombencephalitis. His blood and CSF culture grew Listeria monocytogens. Work up for HIV, malignancy, diabetes came back negative. Discussion: L. monocytogenes is a common cause of CNS infections, especially in immunosuppressed patients, infants and elderly people.In contrast to other listerial CNS infections, the majority of listerial rhombencephalitis occur in previously healthy adults.The factor that most strongly correlates with survival is the timely use of appropriate antibiotics. Study supported by: None. S713. Haemorrhagic Encephalitis Caused by Mycoplasma Pneumoniae in an Eleven Year Old Boy Shweta Shweta, Surinder Kumar, Seema Kapoor and Sanjeev R. Saigal. New Delhi, India Mycoplasma pneumoniae (M.pneumoniae) frequently causes upper and lower respiratory tract infections and 25% of them may experience extrapulmonary complications including central nervous system (CNS) complications. We report a case of CNS disease associated with serologic evidence of acute infection with M.pneumoniae in an eleven year old boy documented in by serological investigations including ELISA for IgM antibodies and Gelatine particle agglutination test, though CSF for Mycoplasma pneumonie
Abstracts, American Neurological Association
polymerase chain reaction was negative. The child was managed with mannitol, ceftazidime, amikacin and acyclovir, following which his condition gradually improved and was hence discharged two weeks later. We conclude that M.pneumoniae should be considered as a potential cause of encephalitis. Study supported by: none. S714. Subacute Bulbar Failure with Blown Pupils Due to Wound Botulism – Case Report Mihai-Cosmin Sandulescu, David Roby, Sumeet Multami and Jonathan Dissin. Philadelphia A 47-year old male presented with open tibial and fibular fracture. Patient required multiple surgical interventions and extensive wound debridements. On the 20th day of hospitalization, he developed bilateral ptosis, facial weakness, dilated (7 mm) symmetrically sluggish pupils, nasal voice, dysphagia and dysarthria. He remained lucid. There was mild proxymal weakness of upper extremities, but DTRs were present and Babinski negative. EMG suggested neuromuscular disturbance with decremental response. The state lab performed the botulinum bioassays. They detected Clostridium botulinum toxin Type B from wound sample. Model of mouse assay was positive, too. No antitoxin was administered. He was treated initially with IVIG for presumed Miller Fisher syndrome variant of Guillain Barre syndrome. Patient required tube feeds for 2 weeks. Pupils normalized within 2 weeks. Speech improved, too. He was transferred to Rehab Service where his recovery has been uneventful. Botulism can be fatal and it is considered a medical emergency. Wound botulism is responsible for 20% of all cases. In about 50% pupils are involved. Main therapy is supportive care. Recognition of the case of bulbar failure along with the wound, should make you think about it. Study supported by: Not applicable. S715. Vascular and Metabolic Risk Factors Impact Neurocognitive Decline in HIV Infection Ahson Ghias, Ronald J. Ellis, Maria J. Marquine, Yu-Ting Kao, Reena Deutsch, Jennifer E. Iudicello, Pariya Lynne Fazeli, Patricia K. Riggs, Donald Franklin, Robert K. Heaton, Suzi Hong, J. Allen McCutchan and Igor Grant. San Diego, CA and La Jolla, CA We evaluated the impact of metabolic syndrome and vascular risk factors (MSVRF) on neurocognitive decline (NCD) in HIV1 and HIV- subjects. In multiple prospective cohorts, MSVRF (hypertension [HTN], diabetes mellitus [DM], tobacco smoking [TOB], coronary heart disease [CHD], body mass index [BMI] and hyperlipidemia [HL]) were ascertained at baseline. NC performance was evaluated at baseline and at least one follow-up visit 1 year later. Separate models for each MSVRF estimated subject-specific global mean NC scaled scores slopes with the following terms: MSVRF, time, HIV serostatus, HIV X MSVRF and MSVRF X time. Models were reduced by backwards elimination, retaining terms with p < 0.05. Subjects were 634 HIV1 and 107 HIV-, primarily men (80%) with mean ( 6 SD) age 42.1 ( 6 9.3) years and total follow-up 3,305 person-years. For HIV1 analyzed separately, HTN, DM,
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and CHD (all ps < 0.05), but not TOB, BMI or HL, were associated with worse NCD. In the combined sample, all models showed NCD worse in HIV1, and MSVRF effects were similar. HIV X MSVRF interactions were not significant. MSVRFs and HIV both contributed to worsening NCD, supporting future studies to aggressively manage MSVRF to ameliorate NCD. Study supported by: P30 MH62512; N01 MH22005; U01 MH83506; P01 DA12065. S716. Central Nervous System Involvement in Dengue Is a Marker of Severity of Illness Usha K. Misra, Jayantee Kalita and Prashant S. Chauhan. Lucknow, Uttar Pradesh, India We report the frequency and spectrum of neurological and muscle involvement in dengue and correlate these with dengue serotypes and prognosis. 75 Consecutive NS1 antigen/ IgM antibody positive dengue patients were clinically evaluated. Blood counts, coagulation parameters, serum chemistry, dengue serotypes and CSF were examined. Cranial MRI and electroneuromyography were done. The patients were categorized into encephalopathy/encephalitis, immune mediated and muscle dysfunction (MD) groups. Outcome at 1 month and prognostic predictors were evaluated. Their age ranged between 5 and 69y and 9 females. 50 had dengue fever(DF), 17 dengue hemorrhagic fever(DHF) and 8 dengue shock syndrome(DSS). 22 patients had neurological manifestations (encephalopathy 6, encephalitis 15, transverse myelitis 1), and MD in 30. The CNS involvement was more common in DHF/DSS than DF (44%vs22%). 4 patients died in CNS and 1 in MD group. CNS group had more frequent shock, renal failure, mechanical ventilation and poorer outcome than MD group but was not related to dengue serotypes. To conclude, dengue MD and CNS involvement represent a spectrum; CNS involvement suggests more serious illness and poorer outcome. Study supported by: NO
2013 Annual Meeting Monday, October 14, 2013 Poster Session Neuro-opthalmology M801. WITHDRAWN M802. Optic Neuropathy Caused by Digoxin Toxicity Bahareh Hassanzadeh, Sushanth Bhat, Vahid Tohidi, Emad Noor and Ming He. Edison, NJ An 81 year-old diabetic man with renal disease, atrial fibrillation/sick sinus syndrome and a cardiac pacemaker was on warfarin, amiodarone and digoxin. He presented with sudden-onset, progressive bilateral visual impairment for two days. Head CT showed old left parietal lobe infarction. His digoxin levels were high (5.1 ng/mL). Digoxin was held, but amiodarone was continued. Ophthalmological examination revealed bilateral cataracts and mild macular degeneration, with no relative afferent pupillary defect.
Fundoscopy revealed bilateral temporal pallor and macular discoloration. Visual acuity was 20/200 OD, 20/100 OS. He had difficulty distinguishing yellow color. Humphrey visual field testing 30-1 showed bilateral central scotoma, consistent with optic disc disease. Three days after stopping digoxin, the level decreased to 3.3 ng/mL, and vision improved to 20/70 OS, but was unchanged (20/200) OD. Antiarrythmic medications such as amiodarone and digoxin may cause acute visual impairment, especially when used in combination, requiring careful ophthalmological surveillance. In our patient, discontinuing digoxin alone, without any change in amiodarone dose, resulted in improvement of visual acuity. Digoxin toxicity is a potential cause of visual impairment, which can be dose related and may be the earliest or sole manifestation. Study supported by: N/A. Trauma/Injury M901. WITHDRAWN. M902. Subtle Post-Concussion Cognitive Impairment Is Under-Recognized, and yet Identifiable: Findings from the Concussion in Columbia University Sports Student (ConCUSS) Study Tanzid Shams, Adam M. Brickman, James Gossett, William Levine and James M. Noble. New York, NY Meaningful objective thresholds for cognitive impairment following sports concussion have not been established. We retrospectively studied psychometric testing in all Columbia University football players from 2000–2011. Each player completed baseline Concussion Resolution Index which assesses reaction time, object recognition, and recall. CRI was repeated in those with suspected incident concussion. 647 CRIs were performed on 439 players, including 208 serial post-concussion evaluations on 70 (15.9%) athletes with at least 1 concussion. Following concussion, median duration prior to return-to-play was 10 days (range 5–124 days). Players without prior concussion history had a slightly longer recovery (p 5 0.24). Additionally, 7 (10%) never returned to play. Using an average Z-score derived from 9 CRI tests, lowest post-concussion scores were on average 0.4 lower (range 11.1 to 22.6) (t-test for related samples, p < 0.001), and 28 of 71 (39.4%) athletes declined at least 0.5 units. Passing scores on psychometric testing can be useful in return to play strategies. However, these objective measures also highlight the degree of initial postconcussion decline and could serve as potential risk markers in longitudinal cohort studies of elite, tested athletes. Study supported by: The authors of this study have no financial relationships or conflict of interest to disclose. M903. Comparison of the Post-Concussion Syndrome (PCS) in OEF/OIF Veterans with Traumatic Brain Injury (TBI) Due to Blast Injury (BI), Direct Head Trauma (DHT), or Both for up to 8 Years after TBI James R. Couch, Kenneth Stewart and Peggy Wisdom. Oklahoma City, OK
BACKGROUND: TBI is a major problem of the military OEF/OIF campaigns. This study compares the PCS produced by BI, DHT, or a combination over 8 years after TBI. Methods: Veterans of OEF/OIF Campaigns with deployment TBI were evaluated with the Beck Depression Inventory (BDI) and a form for PCS using symptoms of: 1. Headache, 2. Dizziness, 3. Balance, 4. Poor Coordination, 5. Difficulty with decisions, rated none to very severe. Blast injury was divided into categories of: Primary/secondary (BI only), or Tertiary/Quarternary (BI 1 DHT). DHT subjects were those who had TBI related to falls, assaults or other circumstances without BI. Subjects were divided into groups 1–4 and 5–8 years post-TBI, Results: There were 309 in the 1–4 year and 186 in the 5–8 year groups. No significant differences were found in PCS or BDI symptoms among the these Conclusion: There is no difference in the PCS produced by BI, DHT or both. Study supported by: VA Education and Research Fund of the Oklahoma City Veteran’s Administration Medical Center, Oklahoma City, OK. M904. Prediction of a Favorable Functional Outcome by 12–15 Months after Severe Traumatic Brain Injury on Discharge from Inpatient Rehabilitation David S. Kushner and Doug Johnson-Greene. Miami, FL Case series evaluating usefulness of FunctionalIndependence-Measure (FIM) cognitive and sphincter score changes and return of bowel/bladder continence by discharge from inpatient rehabilitation(IR) to predict recovery of functional-independence at 12–15months in 10 patients having severe traumatic brain injury (STBI).Patients had initial Glasgow Coma Scale scores of 3–6, post-traumatic amnesia durations of 20–115 days, time to follow commands of 16–100 days, abnormal initial brain CT scans, and initial pupil abnormalities. IR ranged 18–73 days. IR FIM cognitive and sphincter score improvements were compared to national normative STBI FIM data from Uniform Data Systems for Medical Rehabilitation (UDSMR) for 2010(n 5 16,368). All 10 patients returned to functional independence by 12–15 months; 4 are now employed as a physician, accountant, lawyer and a bank manager. Cognitive-FIM scores improved an average of 14 points, compared to 5.9 points for UDSMR. Sphincter-FIM scores improved an average of 5.6 points, compared to 3 points for UDSMR. FIM cognitive and sphincter score improvements approximately twice the national average, and the return of bowel/bladder continence by discharge from IR, may be associated with favorable functional outcomes at 12–15months after a STBI. Study supported by: None. M905. Retraining of Existing Spinal Cord Circuitry: SCUBA Diving and Adaptive Skiing as Potential Novel Forms of Rehabilitation for the Spinal Cord Injured Adam Kaplin, Alison Riehm, Cody Unser, Kristen Rahn and Daniel Becker. Baltimore, MD and Washington, DC
Abstracts, American Neurological Association
The Cody Unser First Step Foundation (CUFSF) has been at the forefront of training individuals with SCI to go SCUBA diving. CUFSF asked us to pilot a study of the effects of SCUBA diving on subjects with chronic SCI. We conducted neurological and psychological evaluations before and after diving on 9 veterans with SCI and their 10 healthy “dive buddy” controls. Neurologic and psychologic testing included ASIA and modified Ashworth exams, and mood, anxiety and PTSD symptomatology. These evaluations were done prior to and after an average of 10 separate 30-minute open water dives required for certification. Our pilot results suggest that SCUBA potentially has a novel and robust therapeutic benefit for veterans with SCI. These results will also be compared and contrasted with those obtained in a cohort of individuals with SCI who engaged in a similar duration of skiing under the training and auspices of the Adaptive Sports Center in Crested Butte, CO. Potential mechanisms, future clinical and preclinical studies and implications for SCI rehabilitation will be discussed. Study supported by: Cody Unser First Step Foundation, Adaptive Sports Center, Bruce and Debra Downey. M906. Congresswoman Gabriella Giffords in Clinical Perspective: Contralateral Internuclear Ophthalmoplegia from Lesion Affecting the Minor Hemisphere Iraj Derakhshan. Charleston, WV Backgrounds: Prevost’s eye sign is specific to lesions affecting the minor hemisphere. There are examples, however, in which only one eye deviates to the affected side and the other falls behind or stops at the midline; a picture similar to internuclear ophthalmoplegia (INO). This occurred in one of Prevost’s 51 cases following a left hemisphere stroke (Case 50). None of Prevost’s cases had language deficits regardless of the laterality of the lesion. Method: I have explained elsewhere the basis of this laterality indexed phenomenon (Derakhshan: How Do the Eyes Move Together? CMAJ, 2005; 172: 171–173). Accordingly, diaschitic paralysis of contralateral pontine oculomotor apparatus, including the medial longitudinal bundle, prevents the yoking of the eye by the abducting eye, moved by the uninjured hemisphere. Conclusion: In the case of representative Giffords, an ostensibly right hander wired as a neural left hander, arrangements mentioned are in the reverse compared to a true right hander, indicating that her nondominant (minor) hemisphere is on left side. Published photographs of her hospitalization showed her displaying a lone abducting eye to the left, with the right eye remaining at the midline. Study supported by: entirely private fund. Sleep Disorders and Circadian Rhythm M1001. Glutamate-Containing Neurons of the Posterior Lateral and Supramammillary Hypothalamus Support Wakefulness. Nigel P. Pedersen, Patrick M. Fuller and Clifford B. Saper. Boston, MA Posterior hypothalamic lesions produce somnolence not accounted for by lesions of orexin or histamine neurons. We
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hypothesized that glutamate-containing posterior hypothalamic neurons, known to innervate the cerebral cortex, account for this discrepancy. In vglut2-Cre mice, we stereotaxically injected conditional adeno-associated viruses that expressed either excitatory modified human M3 receptor, or a modified inhibitory ivermectin receptor, agonized by otherwise inert clozapine-N-oxide (CNO) or low-concentration ivermectin (IVM), respectively. Fluorescent labels allowed delineation of projections and transfected cells. Headsets were affixed for sleep-wake recording. Mice receiving saline three hours after lights-on (ZT3) slept after 14 minutes, while mice injected with CNO, remained awake for nine hours (CNO: 540 6 208 (SD) versus saline: 13.7 6 5.42 minutes, t-test p 5 0.0142, n 5 4, 4; ANOVA p 5 0.0014, Bonferoni p < 0.05 eight of nine hours). Ivermectin (at lights out, normal wake period) suppressed wakefulness, resulting in a level of sleep that would be typical of the light (sleep) period (ANOVA p 5 0.0139, Bonferoni p < 0.01 for first hour, n 5 4, 4). This study demonstrates a novel population of glutamatergic hypothamic neurons that support wakefulness. Study supported by: Financial support was provided by NIH NINDS R25 Research Training Grant, 5R25NS070682-03 (NPP), R01NS073613 (PMF) and the Mathers Foundation (PMF and CBS). M1002. Descending Projections from the Basal Forebrain (BF) to the Melanin Concentrating Hormone (MCH) Neurons Minjee Kim, Lindsay J. Agostinelli and Thomas E. Scammell. Boston, MA Introduction: MCH, expressed by the neurons in the lateral hypothalamic area, seems to play an important role in regulation of rapid eye movement (REM) sleep. We examined afferents to the MCH neurons from the BF and found that innervations vary across different areas of the BF and different cell groups. Methods: Using lines of mice that express Cre recombinase selectively in GABA, glutamate, or acetylcholine (Ach) neurons, we microinjected the BF with an adeno-associated viral vector coding for a Cre-dependent red fluorescent protein (mCherry). Four weeks later, we mapped the injection sites and descending projections to the MCH neurons. Injection sites and cell types were confirmed by doublelabeling. Then, we mapped the innervation of the MCH neurons using double immunostaining for mCherry and MCH. Results: Robust and selective anterograde labeling of GABA, glutamate, and Ach BF neurons were found. GABAergic and glutamatergic neurons innervate MCH neurons more heavily than Ach neurons. Dense inputs to MCH neurons arise from caudal BF. Conclusion: Descending projections from the BF may play an important role in the regulation of MCH neuron activity and REM sleep. Study supported by: NINDS/R01 NS055367 and NHLBI/P01 HL095491; NINDS/R01 NS055367 and NHLBI/P01 HL095491.
M1003. Age-Related Healthcare Utilization and Comorbidity: Data from the Burden of Narcolepsy Disease (BOND) Database Jed Black, Nancy Reaven, Susan Funk, Karen McGaughey, Maurice Ohayon, Christian Guilleminault and Chad Ruoff. Stanford, CA; La Canada, CA and San Luis Obispo, CA No large database analyses of age-related patterns of narcolepsy burden of illness have been reported. Truven Health R Databases (>50 million covered Analytics MarketScanV lives) were accessed to identify adults with narcolepsy 1 cataplexy continuously insured between 2006 and 2010 (n 5 9,312; mean age 46.1 y; range, 18–93 y); controls without narcolepsy were matched 5:1 on multiple factors (n 5 46,559). Age categories (% of population) included: 18–24 y (3.8%), 25–34 y (16.8%), 35–44 y (24.7%), 45– 54 y (30.4%), 55–74 y (21.1%), and 751 y (3.2%). Within each age category, mean annual utilization rates for healthcare services and non-narcolepsy drugs were approximately doubled compared to controls, with the greatest excess noted among younger narcolepsy patients vs. controls. Among comorbid conditions previously associated with narcolepsy, the largest excess prevalence (narcolepsy over control) was found in persons 551 years for most conditions but in the youngest cohort (18–24 y) for anxiety/mood disorders. Within the narcolepsy cohort, diagnoses of anxiety disorders, mood disorders and hypersomnia declined with increasing age. Narcolepsy imposes substantial healthcare burden and medical comorbidity across all age categories, with the highest burden compared to controls observed in younger adult patients. Study supported by: Jazz Pharmaceuticals; J Black has served as a paid consultant for Jazz Pharmaceuticals, and is employed part time by Jazz Pharmaceuticals; N Reaven, S Funk, K McGaughey, M Ohayon, C Ruoff and E Mignot have served as paid consultants for Jazz Pharmaceuticals. M1004. Effect of Sodium Oxybate (SXB), Modafinil, and Combination on Disrupted Nighttime Sleep in Narcolepsy Yves Dauvilliers, Thomas Roth, Jed Black, Diane Guinta and Efim Dynin. Detroit, MI; Montpellier, France; Palo Alto, CA and Redwood City, CA Disrupted nighttime sleep (DNS) affects most narcolepsy patients. An expert consensus on DNS identified frequent shifts to lighter sleep and awakenings and reported poor sleep quality as important measures of DNS. In this study, data from a randomized trial retrospectively analyzed effects of three common narcolepsy treatments on DNS. Patient with narcolepsy (N 5 278) were randomized to placebo (PBO), 9g SXB/nightly, 200–600mg/day modafinil or a SXB/modafinil combination. Polysomnograms (PSGs) and sleep quality from the Pittsburgh Sleep Quality Index (PSQI) question 6 were obtained at baseline and 8 weeks. Analysis was performed for patients with evaluable sleep stage and PSQI data. SXB given alone or in combination with modafinil, significantly decreased shifts from S2,3,4 or REM to 1/Wake. Median change from baseline was 21.5(range 237–37),
213.0(274–20), 0.0(253–44), 211.5(258–45) shifts in the PBO, SXB, modafinil and SXB1modafinil groups, respectively (P 50 million covered Analytics MarketScanV lives) were accessed to identify individuals 18 years of age with narcolepsy 1 cataplexy continuously insured between 2006 and 2010 (n 5 9,312; 59.2% female); controls without narcolepsy were matched 5:1 on multiple factors (n 5 46,559). Rates of healthcare service utilization were significantly higher among narcolepsy patients compared to controls, regardless of sex (males, 17.6 vs 8.5 services/pt/yr; females, 24.0 vs 11.8 services/pt/yr; P < 0.0001), as were the mean number of annual drug transactions (males, 22.3 vs 11.5; females, 29.3 vs 14.5; P < 0.0001). Costs and drug utilization followed a similar pattern. Utilization of services was higher in female vs. male patients in both narcolepsy (36.4% excess) and control (38.8% excess) cohorts. Both male and female narcolepsy patients had a significantly greater number of comorbid diagnoses compared with controls, including many not previously associated with narcolepsy. Odds ratios for almost all comorbidity categories were
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higher in females vs. males; this finding was even more pronounced within the narcolepsy cohort, with the exceptions of obstetrics/fertility and perinatal categories. Study supported by: Jazz Pharmaceuticals; J Black has served as a paid consultant for Jazz Pharmaceuticals, and is employed part time by Jazz Pharmaceuticals. M1008. Different Timing of Light Exposure in Adults with Delayed Sleep Phase Disorder Phyllis C. Zee, Eunyeon Joo, Kathryn J. Reid and Joseph Kang. Chicago, IL To determine the daily light and activity levels of adults with Delayed Sleep Phase Disorder (DSPDs), 42 DSPDs and age/ gender matched 26 controls wore a wrist activity/light monitor and maintained a sleep diary for 7 consecutive days. Data was binned by 30 minutes in relation to clock time and to time since wake and analyzed for the 24 h light exposure and activity profile. DSPDs had significantly delayed bed and wake time than controls without a significant difference in total sleep time. DSPDs were exposed to more light between 24:00h and 6:00h and less between 6:00 h and 12:00h in clock time. DSPDs also had higher light intensity from 21st to 24th h time since wake than controls. Total amount of light and activity level were not different between the groups. Light exposure early in the morning by clock time and late evening since wake may play a role in phase delay in DSPD. Different timing of light exposure rather than the light amount appears to be the primary determinant factor to express the phenotype of DSPD. Study supported by: none. M1009. Patients’ Journeys to a Narcolepsy Diagnosis Christine Acebo, Lawrence P. Carter and Ann Y. Kim. Palo Alto, CA Narcolepsy is a lifelong disorder with debilitating symptoms, yet obtaining an accurate diagnosis is not always straightforward. This report describes results from a companysponsored survey regarding patients and their journeys to a narcolepsy diagnosis. Neurologists and other specialists (majority board-certified in sleep medicine) who treated 5 narcolepsy patients per month completed up to six surveys using patient charts. Data from 252 patients were collected from 77 physicians. Patients were primarily male (55%) and Caucasian (67%). Specialists rated patients’ initial symptoms as mild (15%), moderate (50%), or severe (35%). Most common initial symptoms were excessive daytime sleepiness (91%), trouble staying awake (44%), and trouble concentrating/functioning during the day (43%). On the Multiple Sleep Latency Test (MSLT) mean sleep latency was 4.2 min (SD 2.3); 91% of patients exhibited 2 sleep onset REM periods. Sixty percent of patients were previously misdiagnosed with disorders including depression (31%), insomnia (18%), and/or obstructive sleep apnea (13%); at least half saw 2 providers. The typical time from patient report of symptoms to diagnosis was nearly two years (median 22 months; range 0–126 months). These data highlight the need for increased awareness and better identification of narcolepsy and its symptoms.
Study supported by: Jazz Pharmaceuticals, Inc. Dr. Carter, Dr. Acebo, and Ms. Kim are employees of Jazz Pharmaceuticals and own stock and stock options in the company.
M1202. Abnormal Synchrony of Striatal Direct Pathway Neurons in a Mouse Model of Dystonia Alexandra B. Nelson and Anatol Kreitzer. San Francisco, CA
M1010. Advancing Our Understanding of Restless Legs Syndrome Genetics and Biology Guy A. Rouleau. Montreal, QC, Canada
Dystonia may be caused by abnormal neural activity, since the brain appears normal in patients with primary dystonias at autopsy. According to classical models of basal ganglia function, excess activity in the direct pathway may produce dystonia. To examine this hypothesis, we have studied neural activity in the basal ganglia of a transgenic mouse model of dystonia, paroxysmal non-kinesigenic dyskinesia (PNKD), which carries the single gene mutation found in the human disease. PNKD mice suffer dyskinetic attacks triggered by stress, caffeine, and alcohol, as do humans with the disease. We have made single-unit striatal recordings in awake-behaving mice, using an optogenetic method to label direct pathway striatal neurons. Direct-pathway striatal neurons in PNKD mice do not have higher firing rates than those in wild-type littermates, but are more likely to fire synchronously with their neighbors. Using slice electrophysiology, we find that direct pathway neurons in PNKD mice receive excess cortical excitatory inputs, suggesting an anatomic and physiological substrate for this abnormal synchronized striatal activity. Together, these findings suggest that dystonia may be characterized by excess correlated activity in the basal ganglia. Study supported by: NINDS.
Restless Legs Syndrome (RLS) is a sleep sensorimotor disorder characterized by an urge to move the legs and abnormal sensations in the legs; this happens in situations of rest (e.g. before falling asleep or at night). Epidemiological studies have shown it is a common neurological disorder (prevalence 5–10% in European and North American populations). Several GWAS were reported for RLS and a metaanalysis of the association signals for MEIS1 and LBXCOR1 highlighted the importance of these genes, P values were respectively 3.40x10–49 and 1.37x10–22. Our current results support a regulation of LBXCOR1 by MEIS1 and we hypothesize this regulation takes place upstream from key genes involved in the pathogenesis; various studies suggest that CNS iron metabolism plays important roles. To this day our group is amongst the few to have reported biological studies investigating the MEIS1 and LBXCOR1 in RLS. As we conduct these studies we are also using exome sequencing methods and large RLS families to identify novel genetic variants for RLS (these are likely to be rare and show medium to high penetrance). Study supported by: Canadian Institutes of Health Research. Movement Disorder M1201. Stabilization of Dopamine Responses in Striatal Neurons by Blockade of NMDA Receptor Transmission in Parkinsonian Monkeys. Arun Singh, Kenneth J. Burke, Jessica S. Whithear, Bhagya L.D. Shetty and Stella M. Papa. Atlanta In Parkinson’s disease, striatal projection neurons are hyperactive and exhibit abnormal dopamine responses characterized by unstable firing rate changes (“inversions”) that are associated with dyskinesias. It has been hypothesized that the baseline hyperactivity of medium spiny neurons (MSNs) is mediated by hyperglutamatergic NMDAR tone, and is responsible for the inversions of dopamine responses. To address this hypothesis, NMDAR was blocked in situ for MSN activity recordings during levodopa responses in three behaving parkinsonian monkeys (Rhesus). The reduction of baseline MSN firing by NMDAR antagonism (p < 0.0001) completely abolished the inverted responses to dopamine, stabilizing the firing rate changes throughout the “on” state. Stable responses were demonstrated consistently in all recorded neurons expressing either D1 or D2 dopamine receptor firing changes (p < 0.01). The extensive effects on all MSNs result in reversal of the pathological heterogeneity and imbalance of striatal outputs. These results support a critical role of the increased MSN firing/NMDAR signaling pathways in dysregulation of striatal function and abnormal motor responses to dopamine replacement. Study supported by: NS045962.
M1203. Dopaminergic Modulation of Sensorimotor and Central Executive Networks during Dual Motor Tasks in Parkinson’s Disease Cecile Gallea, David Benninger, Valerie Voon, Ryan Moore and Mark Hallett. Paris, France and Bethesda, MD Parkinson’s disease (PD) patients experience difficulties performing two tasks simultaneously. We investigated the influence of dopaminergic agonists on executive and sensorimotor networks during dual motor tasks with fMRI. Eighteen PD patients ON and OFF dopaminergic medication and eighteen healthy volunteers performed bimanual visuomotor tasks with two attentional modes (dissociated 5 two hands performing different tasks; coupled 5 two hands performing same task) and two planning loads (anticipative 5 high planning; reactive 5 low planning). Compared to healthy volunteers and ON-dopa patients, OFF-dopa patients had increased activation in preSMA and bilateral dorsolateral prefrontal cortex (DLPFC) during dissociated versus coupled; and in bilateral SMAproper and posterior dorsal putamen during anticipative versus reactive. Compared to OFF-dopa, ON-dopa increased connectivity between preSMA, bilateral DLPFC, and anterior cingulate cortex during dissociated versus coupled; SMAproper, insula and visual areas during anticipative versus reactive; and posterior dorsal putamen and ventral premotor cortex during anticipate versus reactive. ON-dopa decreased connectivity between posterior dorsal putamen and cerebellum during anticipative versus reactive. Dopaminergic agonists in PD enhance central executive network efficiency; improve information processing in motor planning network; and modulate interaction between striatum and cerebellum.
Abstracts, American Neurological Association
Study supported by: Intramural Research Program of NINDS, NIH. M1204. Altered Cerebrospinal Fluid Levels of aSynuclein and Ab in Parkinson Disease Paul T. Kotzbauer, Chandana Buddhala, Meghan C. Campbell and Joel S. Perlmutter. St. Louis, MO Accumulation of misfolded a-synuclein (a-syn) protein in Lewy bodies and Lewy neurites is the defining pathologic feature of Parkinson disease (PD). The development of dementia in PD is consistently associated with neocortical a-syn accumulation. In addition, 60% of PD participants with dementia have neocortical accumulation of Ab plaques. We analyzed cerebrospinal fluid (CSF) levels of a-syn and Ab to further investigate whether the metabolism of these proteins is altered in PD and whether these measures could be useful to monitor disease progression. Sixty PD and twenty control participants were included in the analysis. CSF levels of a-syn and Ab were significantly lower in PD compared to controls, but CSF tau levels were not different between the two groups. Furthermore, the levels of both Ab and a-syn were lower in PD with mild cognitive impairment (CDR 5 0.5) compared to those without cognitive impairment (CDR 5 0) and there was a significant positive correlation between the level of a-syn and the level of Ab in PD but not in controls. These results further support a connection between altered a-syn and Ab metabolism in PD. Study supported by: National Institutes of Health/ National Institute of Neurological Disorders and Stroke. M1205. Comparison of IPX066, a Carbidopa-Levodopa Extended Release Formulation with CD-LD IR1Entacapone in Patients with Advanced Parkinson’s Disease Fabrizio Stocchi, Ann Hsu, Sarita Khanna, Aaron Ellenbogen, Andreas Mahler, Grace Liang, U. Dillmann, Robert Rubens, Sherron Kell and Suneel Gupta. San Raffaele, Rome, Italy; Hayward, CA; Farmington Hills, MI; Niedersachsen, Deutschland, Germany; Sunnyvale, CA and Homburg, Saar, Germany Objective: To compare efficacy and safety of IPX066 to carbidopa-levodopa immediate-release1entacapone (CLE). IPX066, is an extended-released carbidopa-levodopa, is designed to rapidly attain and maintain therapeutic levodopa concentrations for prolonged duration. Methods: After open-label conversion to IPX066 (6 weeks), patients with 4 weeks stable CLE were randomized (double blind) to receive IPX066 followed by CLE or vice versa (2weeks/period, 1 week open-label IPX066 between periods). Primary endpoint was percent “off- time” during waking hours. Results: Of 110 patients 91 completed dose conversion, 84 completed the study. Percentage of “off-time” was 23.98% (IPX066) vs. 32.48% (CLE), p < 0.0001. “Offtime” was 5.88 hours at baseline, 3.72 hours after doseconversion; 3.82 and 5.22 hours at end of treatment for IPX066 and CLE, respectively. IPX066 provided 84 minutes less “off-time” and 83 minutes more “on-time” without troublesome dyskinesia than CLE at the end of treatment.
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Daily dosing frequency was 3.5 with IPX066 and 5.0 with CLE. AEs ( 2%) for IPX066 were dyskinesia (4.5%), confusional state (3.4%), and insomnia (3.4%); for CLE was fall (2.3%). Conclusions: This study showed IPX066 improved motor control in patients previously treated with CLE. Study supported by: This study was solely supported by Impax Laboratories. Drs. Hsu, Kell, Khanna, Reubens and Gupta are full time employees of impax. Drs. Stocchi and Ellenbogen have served as a consultant for Impax laboratories Inc. Ann Hsu –Dr. Hsu is a full time employee of Impax Laboratories. Within the past year she received personal compensation from Impax Labs as an employee. Dr. Hsu as an Impax employee received stock as part of her compensation. Dr. Hsu owns stock of other pharmaceutical companies, which include medical equipment or materials related to the practice of medicine, but has no controlling capacity of these companies. Sherron Kell- Dr. Kell is a full time employee of Impax Laboratories. Within the past year she received personal compensation from Impax Labs as an employee. Dr. Kell as an Impax employee received stock as part of her compensation. Dr. Kell owns stock of other pharmaceutical companies, which include medical equipment or materials related to the practice of medicine, but has no controlling capacity of these companies. Suneel Gupta- Dr. Gupta is a full time employee of Impax Laboratories. Within the past year he received personal compensation from Impax Labs as an employee. Dr. Gupta as an Impax employee received stock as part of his compensation. Dr. Gupta owns stock of other pharmaceutical companies, which include medical equipment or materials related to the practice of medicine, but has no controlling capacity of these companies. Sarita Khanna and Robert Ruebens are full time employees of Impax Laboratories. Within the past year they have received personal compensation from Impax Labs as an employee. As an Impax employee they have also recieved received stock as part of their compensation. M1206. Polymorphisms of the Aromatic L-Amino Acid Decarboxylase Gene Affect the Motor Response to LDopa in Parkinson’s Disease David Devos, Stephanie Lejeune, Florence Cormier-Dequaire, Fanny Charbonnier-Beaupel, Nathalie Rouaix, Khadija Tahiri, Marie Vidailhet and Jean-Chirstophe Corvol. Lille, France and Paris, France The major pathway for dopamine synthesis from L-dopa is decarboxylation by aromatic L-amino acid decarboxylase encoded by the DDC gene. Objective: to determine the motor response to L-dopa in PD patients as a function of the DDC gene promoter polymorphisms. Methods: 33 Parkinson’s disease patients underwent an acute L-dopa1benserazide challenge and were genotyped for rs921451 (DDCT/C) and rs3837091 AGAG del (DDCAGAG/) polymorphisms. The primary efficacy criterion was the motor response to L-dopa, as estimated by the area under the curve for the change in the UPDRS part III score (AUCDUPDRS) during the 4 hours following L-dopa.
Secondary endpoints were pharmacokinetic parameters of Ldopa and dopamine. Results: When adjusted for the L-dopa dose, AUCDUPDRS was significantly lower in DDCCC/CT patients (1095 6 890 UPDRS/100mgL-dopa, n 5 14) than in DDCCT/T patients (1369 6 574 UPDRS/100mgL-dopa, n 5 19, p 5 0.01) and in DDC-/- or DDCAGAG/- patients (874 6 800 UPDRS/ 100mgL-dopa, n 5 8) than in DDCAGAG/AGAG patients (1386 6 658 UPDRS/100mgL-dopa, n 5 25, p 5 0.01). There were no significant intergroup differences in pharmacokinetic parameters of L-dopa and dopamine. Conclusion: DDC gene promoter polymorphisms influence the motor response to L-dopa but do not significantly change peripheral pharmacokinetic parameters for L-dopa and dopamine. Study supported by: Assistance-Publique H^opitaux de Paris grant CRC-05–170. The research leading to these results has received funding from the program “Investissements d’avenir” ANR-10-IAIHU-06. M1207. Freezing of Gait in Parkinson’s Disease Is Related to Executive and Perceptual Dysfunction Stewart A. Factor, Michael K. Scullin, Ann B. Sollinger, Julia Land, Cathy Wood-Siverio, Lavezza Zanders, Raven Lee, Alan Freeman, Donald L. Bliwise and Felicia C. Goldstein. Atlanta, GA Freezing of gait (FOG), defined as brief, episodic absence or reduction of forward progression of the feet despite intention to walk, is a disabling symptom complex that occurs in advanced Parkinson’s disease (PD). The pathogenesis is unknown but hypothesized to relate to cognitive dysfunction. 148 patients with PD (mean age 57.8 1 9.5 years; disease duration 7.8 1 4.4 years) were prospectively recruited from the Emory Movement Disorders Clinic and completed a comprehensive neuropsychological battery and a FOG Questionnaire (FOG-Q). FOG-Q indicated that 47 (32%) patients experienced FOG. Regression analyses were performed to examine relationships of FOG with cognitive domains, controlling for potential confounders: age, education, gender, disease duration, motor severity, and PD medications. The presence and severity of FOG were significantly (p < .05) associated with lower global cognitive status (MMSE), auditory attention (Digit Span), poorer performance in executive functioning (Trails B, Wisconsin Card Sort Test), visuomotor sequencing (Trails A), visual memory (Brief Visuospatial Memory Task), and visuospatial processing (Judgment of Line Orientation). These findings support the hypotheses that attribute FOG to cognitive deficits, especially those involving executive function and visual perceptual processing. Study supported by: Consolidated Anti-aging Foundation. M1208. Identifying Gait Markers of Parkinson’s Disease Using a Full-Body Profiles Approach Guodong Liu, Nicholas W. Sterling, Joshua R. Baxter, Joseph M. Mahoney, Stephen J. Piazza, Joseph P. Cusumano, Mechelle M. Lewis and Xuemei Huang. Hershey, PA and New York, NY
Parkinson’s disease (PD) patients have altered posture and movement patterns. Whereas potential gait changes have been reported previously, few studies have evaluated comprehensively the entire gait pattern and its subunits in early PD patients. We derived a full-body gait profile, by which patterns of gait changes can be systematically and quantitatively evaluated, compared, and integrated to provide a potentially robust prediction model. Using 69 3D body markers, walking strides were acquired from 8 early stage PD and 10 control subjects. Analyses to identify changes over subsets of markers in movement magnitudes and asymmetry were conducted. Preliminary findings indicate no statistical difference in lower legs, feet, toes, and heels between PD and control subjects, although these areas were critical for postural balance and movement stability. In contrast, PD subjects demonstrated significantly reduced magnitude and inter-limb symmetry in upper limbs compared to control subjects (p-values 5 0.005 or less), particularly in distal arms, wrists, and hands, areas less critical for posture and movement stability. These results imply that early-stage PD is characterized more by upper-limb pattern changes during gait and these changes may provide utility for early and/or pre-diagnosis of PD. Study supported by: This work was supported by NS060722, and the HMC GCRC (NIH M01RR10732) and GCRC Construction Grants (C06RR016499). M1209. Environmental and Occupational Risk Factors for Progressive Supranuclear Palsy: A Case-Control Study Irene Litvan, Chris R. Cunningham, Peter S.J. Lees, Shesh N. Rai, Alex C. Cambon, Leila W. Jackson and ENGENE Study Group. La Jolla, CA; Louisville, KY; Baltimore, MD and Cleveland, OH Background: PSP-ENGENE is the first epidemiologic study to evaluate the hypothesis that PSP is associated with chronic exposure to complex I mitochondrial enzyme inhibitors. Methods: Incident PSP cases (n 5 150) and an equal number of age, sex, and geographically matched controls were administered a standardized interview to obtain data on demographics, residential history, lifetime occupational and medical history. An industrial hygienist and a toxicologist, unaware of case-control status, independently assessed occupational histories to determine past exposure to metals, pesticides, and organic solvents. Results: Cases and controls were similar on most demographic factors; however, cases were less likely to have obtained a college degree and more likely to have ever lived within one mile of an agricultural area, and ever resided in a home with well water. PSP was associated with high exposure to any chemical, as well as, high metal exposure. These associations remained after adjusting for education and living with 1 mile of agriculture. Conclusions: PSP is associated with exposure to occupational chemicals. Chronic exposure to chemicals inducing oxidative injury may have a role in the pathogenesis of this complex disorder.
Abstracts, American Neurological Association
Study supported by: National Institutes of Health, National Institutes of Aging, R01AG024040.
M1210. Efficacy of Levodopa-Carbidopa Intestinal Gel Versus Oral Levodopa-Carbidopa in Advanced Parkinson’s: Sensitivity and Responder Analyses James T. Boyd, Hubert H. Fernandez, John T. Slevin, Alberto J. Espay, David G. Standaert, Yili Pritchett, Wuyan Zhang, Krai Chatamra, Katherine L. Widnell and Janet Benesh. Burlington, VT; Cleveland, OH; Lexington, KY; Cincinnati, OH; Birmingham, AL and North Chicago, IL In a primary analysis, levodopa-carbidopa intestinal gel (LCIG) significantly improved the change from baseline in “Off” time, compared with optimized LC-Oral therapy. We assessed the consistency and robustness of the data with sensitivity and responder analyses. In a double-blind, doubledummy trial, patients received LCIG infusion 1 placebo capsules or encapsulated LC-Oral 1 placebo gel infusion for 12 weeks. Open-label LC-Oral could be used as rescue medication. Sensitivity analyses assessed the impact of rescue levodopa use on “Off” time. A responder analysis examined the proportion of patients who achieved a given level of reduction (0–100%) in average “Off” time. 62.9% of LCIG compared with 22.6% of LC-Oral patients had 50% reduction, and 25.7% of LCIG versus 3.2% of LC-Oral patients had 80% reduction in “Off” time (P 5 0.0026 across all thresholds). Total levodopa (mean [SD] mg/day: 1176.5 [431.6] vs. 1485.8 [621.0]), levodopa from doubleblind study drug (1116.0 [447.9] vs. 1415.6 [635.4]), and rescue levodopa (117.5 [76.2] vs. 187.3 [207.2]) were all lower with LCIG compared to LC-Oral. LCIG produced significantly greater improvement in “Off” time compared with LC-Oral irrespective of rescue levodopa use. Support: AbbVie. Study supported by: This study was sponsored by AbbVie Inc. AbbVie contributed to the study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. Nathan R. Rustay and Michelle M. Tangredi, of AbbVie, provided medical writing support. Boyd: JB was a study investigator and has received compensation from AbbVie for serving as a consultant, lecturer, and/or participating in scientific advisory boards. Fernandez: HF was a study investigator and has served as a consultant for AbbVie through a contract between AbbVie and Cleveland Clinic Foundation; he has not received any personal compensation from AbbVie. Slevin: JS was a study investigator and has received compensation from AbbVie for participating in scientific advisory boards. Espay: AE was a study investigator and has received compensation from AbbVie for serving as a consultant, lecturer, and/or participating in scientific advisory boards. Standaert: DS was a study investigator and has received compensation from AbbVie for serving as a consultant, lecturer, and/or participating in scientific advisory boards. Pritchett: YP was an employee of AbbVie at the time the study was conducted. YP is currently employed by Astellas. Widnell: KW was an employee of AbbVie at the time the
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study was conducted. KW is currently employed by Amgen. Zhang, Chatamra, Benesh: Current employees of AbbVie. M1211. Selective Activation of Excitatory Neurons in the Medial Medulla Induces Cervical Dystonia Veronique VanderHorst, Brian Ellison, Audrey Worley, Tamara Samardzic and Clifford B. Saper. Boston, MA The neural substrate that mediates the twisting movements so characteristic for the various types of dystonia is not fully understood. This is especially true for complex brainstem regions that may form a relay between forebrain/cerebellum and motoneurons that are abnormally activated during dystonia. We used a novel technology called Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology, to acutely, selectively and reversibly modulate subtypes of neurons in the medial medulla, a major relay between supraspinal motor regions and the spinal cord. Designer receptors and a fluorescent marker were incorporated into excitatory medullary neurons that express vesicular glutamate transporter 2 (VGlut2) by injecting a conditional, cre-dependent viral vector into this region of VGlut2- cre mice. Following administration of the designer drug, movements were analyzed using high speed video analysis and EMG. Connections from modulated neurons were traced using the fluorescent marker. The results show that activation of vglut21 neurons in the ventral medulla induces a phenotype that resembles cervical dystonia with rotation of the neck towards the side of injection, with overflow into the forepaw and dystonic tremor. Rotation is prominent during rest, and suppressed during walking and grooming. Study supported by: Bachmann-Strauss Dystonia and Parkinson Foundation; Judy Goldberg Foundation. M1212. Altered 14-3-3 Phosphorylation in Parkinson’s Disease Models Talene A. Yacoubian, John Shacka and Sunny R. Slone. Birmingham, AL Disruption of 14-3-3 function is implicated in Parkinson’s disease. 14-3-3 proteins play a key role in cell survival and interact with several PD-related proteins, including alphasynuclein, parkin, and LRRK2. Dimerization and ligand binding of 14-3-3s are regulated by phosphorylation at three phosphorylation sites: serine 58, 184, and 232. Here we investigate whether 14-3-3 phosphorylation is altered in models of PD. We found that phosphorylation of 14-3-3f at serine 58 is increased in M17 cells approximately twofold at 12 hours following 5 mM rotenone treatment. In addition, phosphorylation of 14-3-3h at serine 232 was increased twofold at 24 hours but then nearly eliminated 48 hours after rotenone treatment. This initial phosphorylation was reversed by the casein kinase inhibitor D4476. In a tetracycline-inducible alpha-synuclein cell line, we observed a threefold increase in 14-3-3h phosphorylation at serine 232 24 hours after alpha-synuclein induction. We also observed increased S232 phosphorylation in an adenoassociated virus alpha-synuclein mouse model. Cells expressing a serine to aspartate phosphomimetic 14-3-3h mutant
failed to reduce rotenone toxicity compared to cells overexpressing 14-3-3h with serine or alanine at S232. We are currently investigating whether phosphorylation changes are observed in human PD brain. Study supported by: NINDS, Parkinson Association of Alabama; Talene Yacoubian has a US Patent # 7,919,262 on the use of 14-3-3s in neurodegeneration. M1213. Changes in “On” Time with LevodopaCarbidopa Intestinal Gel Infusion in Advanced Parkinson’s Disease Patients with Troublesome Dyskinesia Angelo Antonini, Victor S.C. Fung, James T. Boyd, John T. Slevin, Coleen Hall, Katherine L. Widnell, Krai Chatamra and Janet Benesh. Padua, Italy; Syndey, Australia; Burlington, VT; Lexington, KY and North Chicago, IL There is currently no effective pharmacological strategy to manage troublesome dyskinesia (TSD) in advanced Parkinson’s disease (PD) with motor complications. We assessed the effect of levodopa-carbidopa intestinal gel (LCIG) in advanced PD patients with 1 hour/day TSD at baseline. In a 12-week, double-blind, double-dummy study, patients received LCIG infusion 1 placebo capsules, or encapsulated LC-Oral 1 placebo gel infusion. In an independent, 54week, open-label study, patients all received LCIG infusion. Changes in “On” time with or without TSD were analyzed based on diary assessment. LCIG patients with TSD in the double-blind study (N 5 10) reported a significant decrement (mean [SD]) in “On” time with TSD from baseline (3.13[1.65]) to final, change 5 21.76[1.83], P 5 0.014. This was accompanied by an increase in “On” time without TSD (baseline 5 7.35[2.15], change 5 4.43[3.64], P 5 0.004). In the open-label study (N 5 139), LCIG treatment significantly reduced “On” time with TSD (baseline 5 3.37[1.81], change 5 21.83[2.92], P < 0.001) and extended “On” time without TSD (baseline 5 6.84[2.44], change 5 5.31[3.88], P < 0.001). LCIG produced increased “On” time without TSD and reduced “On” time with TSD in advanced PD patients. Support: AbbVie. Study supported by: This work was funded by AbbVie Inc. AbbVie participated in the study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. Michelle M. Tangredi, of AbbVie, provided medical writing assistance in the development of this publication. Angelo Antonini: Dr. Antonini has received compensation for consulting and scientific advisory board services from AbbVie. Victor SC Fung: Dr Fung was a Site Principal Investigator for Open Label study, and has served on Advisory Boards for AbbVie. AbbVie contribute to funding for a PD Nurse Specialist in the form of an unrestricted grant to his institution. (Dr. Fung was a study investigator, has served on advisory boards for AbbVie, and AbbVie contributed to funding for a PD Nurse Specialist in the form of an unrestricted grant to his institution.); James Boyd: Dr. Boyd was a study investigator (for both the open-label and double-blind studies) and has received compensation from AbbVie for serving as a consultant, lecturer, and/or participating in scientific advisory
boards. John Slevin: JS was a study investigator and has received compensation from AbbVie for participating in scientific advisory boards. Katherine Widnell: KW was an employee of AbbVie at the time the study was performed, receiving compensation and stock. KW is currently an employee of Amgen, receiving compensation and stock and/ or stock options; Coleen Hall, Krai Chatamra and Janet Benesh are employees of AbbVie Inc. and hold AbbVie stock and/or stock options.
M1214. Effect of Prolonged Medication and DBS Washouts on UPDRS-III Scores in Early Stage Parkinson’s Disease Anna L. Molinari, Chandler E. Gill, Amanda D. Currie, Maxim Turchan and David Charles. Nashville, TN and Maywood, IL Background: We conducted a prospective, randomized, single-blind clinical trial testing the safety and tolerability of deep brain stimulation (DBS) in early stage Parkinson’s disease (PD) (IDE G050016, IRB 040797). Prolonged therapy washouts were utilized to discern the effects of DBS on the underlying disease and monitor the safety of the intervention. Methods: Thirty subjects with early stage PD were randomized to optimal drug therapy (ODT) or DBS1ODT. Subjects underwent 7 day medication and stimulation (if applicable) washouts every 6 months for 24 months. UPDRS-III ratings were conducted daily. Results: UPDRS-III scores in subjects with DBS1ODT increased during the washouts. No plateau effect was observed towards the end of the washouts. From Day 1 to Day 8, scores increased an average of 11.6 points at baseline, 11.9 points at 12 months, and 11.7 points at 24 months. No subjects developed neuroleptic malignant-like syndrome. Conclusions: This study demonstrates that the therapeutic effects of DBS1ODT take longer than 7 days to fully washout. Although a longer washout period would be desirable from a study design standpoint, asking subjects to withdraw from therapy longer than 7 days may be unreasonably burdensome. Study supported by: The research reported in this abstract was supported by Vanderbilt CTSA grant 1 UL RR024975 from the National Center for Research Resources, National Institutes of Health, by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH), by a research grant from Medtronic, Inc., and by gifts from private donors. Vanderbilt University receives income from grants or contracts with Allergan, Ipsen, Merz, Medtronic, and UCB for research or educational programs led by Dr. Charles. Dr. Charles receives income from Allergan, Ipsen, Medtronic, and the Alliance for Patient Access for education or consulting services. Ms. Molinari, Ms. Gill, Ms. Currie, and Mr. Turchan have no conflicts to disclose.
Abstracts, American Neurological Association
M1215. Deep Brain Stimulation for Dystonia Is Associated with Shorter Pulse Generator Longevity Than for Parkinson’s Disease and Essential Tremor Pawan V. Rawal, Luke Smelser, Leonardo Almeida, Barton Guthrie, He Huang and Harrison Walker. Birmingham, AL Objective: To investigate the longevity of deep brain stimulator (DBS) implanted pulse generators (IPG) across different movement disorders. Background: DBS is effective for medically refractory movement disorders, yet it is invasive, complex, and costly. Although stimulation intensity and surgical target relate to IPG longevity, prior studies frequently do not evaluate this outcome across diseases. Methods: With IRB approval, we retrospectively analyzed 470 consecutive Soletra IPGs (280 Parkinson’s disease, 129 essential tremor, 49 idiopathic dystonia, 12 cerebellar tremor). IPG longevity was compared using Kaplan-Meier analysis with group-wise comparisons by diagnosis, using p < 0.05 as the significance threshold. Results: The mean IPG longevity was 44.7 6 1.4 months across diagnoses. Globus pallidus interna and thalamic stimulation for dystonia and cerebellar tremor, respectively, were both associated with shorter IPG longevity than DBS for essential tremor and Parkinson’s disease (28.1 6 2.0 and 26.5 6 4.3 versus 47.8 6 2.6 and 47.2 6 1.8 months, p < 0.001). Conclusions: In this large, single center retrospective study, IPG longevity was shorter for patients with dystonia and cerebellar tremor versus other indications. Optimization of surgical targeting, programming strategies, and battery technology are needed to decrease the morbidity and cost of DBS. Study supported by: This work was supported by the United States National Institutes of Health / National Institutes of Neurological Disorders and Stroke (K23 NS067053 [H.W.]). M1216. Predictors of Apathy in Parkinson’s Disease Whitney Fitts, Rachel G. Gross, Jacqueline Rick, Howard Hurtig and Nabila Dahodwala. Philadelphia, PA Objective: Apathy is common in Parkinson’s disease (PD), impacting functional status and caregiver burden. We examined predictors of apathy in PD. Methods: We conducted a longitudinal study of initially non-apathetic PD patients over a one-year period. At baseline, the Unified Parkinson’s Disease Rating Scale motor subscale, Dementia Rating Scale (DRS), and Geriatric Depression Scale (GDS) were collected. Apathy was assessed using the Neuropsychiatric Inventory apathy sub-scale. We performed t-tests, Wilcoxon rank-sum and multivariate regression to identify baseline characteristics associated with becoming apathetic. Results: Of 171 PD patients, 53 (31%) developed apathy after one year. Those who became apathetic had greater depressive symptoms (median GDS 1.5 vs 2; p 5 0.02) and worse cognitive function (mean DRS 9.0 vs. 7.7; p 5 0.04) at baseline than those without apathy. There were no significant differences in age, motor scores, disease duration or
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levodopa dosing between groups. After controlling for age and disease duration, depressive symptoms (OR 1.16, 95%CI 1.01-1.34) and cognitive function (OR 0.90, 95%CI 0.81-0.99) remained independently associated with developing apathy. Conclusions: There was a high incidence of apathy in this cohort. Non-motor features of cognitive impairment and depressive symptoms preceded apathy development, whereas primarily dopaminergic-mediated features did not. Study supported by: Morris K. Udall PD Research Center of Excellence; NS053488. M1217. Peripheral Blood Gene Expression as a Possible Biomarker for Parkinson’s Disease Stephen J. Walker, Cesar Santos, Xiaojin Li, Elizabeth McKee, Charles Wang and Mustafa S. Siddiqui. Winston-Salem, NC; Washington, DC; Ave Duarte, CA and Winston-Salem Currently there are no definitive biomarkers for the diagnosis or staging of Parkinson’s disease (PD). This pilot study tested the hypotheses 1) peripheral blood gene expression in PD patients differs significantly from non-PD controls 2) peripheral blood gene expression profiles are significantly different in various stages (H & Y) of PD. Forty subjects with PD diagnosed per UK Brain Bank criteria (10 in each H & Y stage) and 10 controls (without PD) were included. Gene expression was measured in peripheral blood taken from each individual using human whole genome microarrays and the resulting blood transcriptome profiles were compared. Results supported the hypothesis that transcriptome profiles differ significantly between PD and non-PD individuals. In PD versus non-PD gene ontology analysis, neurological disease was the most significantly overrepresented category from the Diseases and Disorders ontology. Biological pathways that were significantly overrepresented in this comparison included vascular smooth muscle contraction, notch signaling and dopamine receptor signaling. Furthermore, results showed that PD patients can be delineated, based on stage, by molecular profiling. These findings suggest that gene expression profiling in peripheral blood may be a useful diagnostic tool for Parkinson’s disease. Study supported by: Hanes Foundation. M1218. Deep Brain Simulation of the Internal Globus Pallidus for Generalized Dystonia Associated with Spinocerebellar Ataxia Type 1 Brian J. Copeland, Timothy M. Ellmore, Albert Fenoy and Mya C. Schiess. Houston, TX and New York, NY Spinocerebellar ataxia type 1 (SCA1) is an inherited form of ataxia associated with abnormal CAG repeats on the ataxin 1 gene on chromosome 6. The highly variable clinical features of this disorder are well documented and may include dystonia, parkinsonism, cognitive dysfunction, and other movement disorders in addition to ataxia. We present a case of deep brain stimulation (DBS) of the internal globus pallidus (GPi) for primary generalized dystonia in a patient with SCA1. A 35-year-old woman with SCA1 developed craniocervical dystonia as a manifestation of her disease. Over a period
of 18–24 months, her dystonia became more generalized and required multiple hospitalizations for dystonic crises. Oral medications and botulinum toxin injections were no longer effective despite escalating dosages. The decision was made to proceed with DBS and the patient underwent implantation of electrodes in the bilateral GPi. She had immediate improvement in her dystonic symptoms and had near complete resolution sustained at nine-month follow-up. Diffusion tensor imaging (DTI) tractography seeded from the therapeutic DBS contacts implicated a widespread network including the cerebellum. GPi DBS is an effective treatment for generalized dystonia associated with SCA1. Study supported by: NA. M1219. Efficacy and Safety of IPX066, a CarbidopaLevodopa, Extended-Release Formulation, in Early Parkinson’s Disease Rajesh Pahwa, Aaron Elllenbogen, Sherron Kell, Martin O’Conell, Robert Hauser, Stanley Fahn, Joseph Jankovic, Emmanuelle Pourcher, Ann Hsu and Suneel Gupta. Kansas City, KS; Farmingto Hills, MI; Hayward, CA; Tampa, FL; New York, NY; Houston, TX and Quebec City, QC, Canada Objective: To assess the efficacy and safety of IPX066 in levodopa (LD) naive Parkinson’s disease (PD) patients. IPX066, an extended-released carbidopa-levodopa, is designed to rapidly attain and maintain therapeutic LD concentrations for a prolonged duration. Methods: This double-blind, placebo-controlled, 30-week study randomly assigned 381 LD-na€ıve patients to IPX066 145, 245, 390 mg LD or placebo TID. The primary efficacy measure was Unified Parkinson’s Disease Rating Scale (UPDRS) Parts II1III. Other UPDRS outcomes, Patient and Clinical Global Impression (PGI and CGI), and the Parkinson’s Disease Questionnaire (PDQ-39) were also assessed. Results: The mean improvement in the UPDRS Parts II1III was 11.7, 12.9, and 14.9 units for 145, 245, and 390 mg LD IPX066 TID, respectively, compared to 0.6 units for placebo (P < 0.0001, all doses). PGI, CGI and PDQ-39 all showed a similar pattern of individual IPX066 treatments superior to placebo (all P < 0.034). With the fewest side effects reported among the active treatments, the 145 mg dose provided the best balance of efficacy and safety. Conclusions: IPX066 provides clinical benefit (UPDRS scores/PGI/CGI and PDQ-39) and appeared to be well tolerated in early PD patients. Study supported by: This study was solely sponsored by Impax Laboratories Inc. Drs. Ann Hsu, Sherron Kell, Martin O’connell, and Suneel Gupta are full time employees of Impax Laboratories Inc. The following non-Impax individuals have recieved grants, honoraria or consulting fees including Drs. Pahwa, Hauser, and Fahn. Ann Hsu- Dr. Hsu is a full time employee of Impax Laboratories. Within the past year she received personal compensation from Impax Labs as an employee. Dr. Hsu as an Impax employee received stock as part of her compensation. Dr. Hsu owns stock of other pharmaceutical companies, which include medical equipment or materials related to the practice of medicine,
but has no controlling capacity of these companies. Martin O’Connell- Dr. O’Connell is a full time employee of Impax Laboratories, Inc. Within the past year he received personal compensation from Impax Labs as an employee. Dr. O’Connell as an Impax employee received stock as part of his compensation. He also owns stock of other pharmaceutical companies, which include medical equipment or materials related to the practice of medicine, but has no controlling capacity of these companies. Sherron Kell- Dr. Kell is a full time employee of Impax Laboratories. Within the past year she received personal compensation from Impax Labs as an employee. Dr. Kell as an Impax employee received stock as part of her compensation. Dr. Kell owns stock of other pharmaceutical companies, which include medical equipment or materials related to the practice of medicine, but has no controlling capacity of these companies. Suneel Gupta- Dr. Gupta is a full time employee of Impax Laboratories. Within the past year he received personal compensation from Impax Labs as an employee. Dr. Gupta as an Impax employee received stock as part of his compensation. Dr. Gupta owns stock of other pharmaceutical companies, which include medical equipment or materials related to the practice of medicine, but has no controlling capacity of these companies. M1220. Restless Limbs Syndrome (RLS), Migraine and Bruxism: A Common Clinical Triad David J. Dickoff and Stephanie M. Dontje. New York Overview: The literature supports an association of RLS and migraine. We reported a 35.7% coincidence of bruxism in 676 patients with RLS and responsiveness of bruxism to dopamine agonists. We now analyze this population for associated migraine headaches. Methods: 700 patients with IRLSSG criteria for RLS completed a survey investigating demographics, symptoms, associated conditions, family history and response to therapy. Charts were reviewed and interviews conducted to complete the data. These patients are part of an ongoing study. Results: Of 700 respondents with RLS, 438 had migraines (62.57%); 249 had bruxism (35.57%); and, 209 had all three conditions (29.86%). Of 413 for whom data was complete, 317 had migraines (76.76%); 241 had bruxism (58.35%); and, 209 had the full triad (50.61%). Family data showed that 60.71% of patients had at least one first degree relative with RLS, migraines, or bruxism. Conclusion: These data suggest a strong clinical association of RLS, bruxism, and migraine. If supported by prospective studies, this knowledge will improve identification and diagnosis of all 3 conditions. The data also suggest that headaches associated with bruxism, previously attributed to TMJ dysfunction, may be migraines and responsive to appropriate therapies. Study supported by: No disclosure. M1221. Anxiety and Depression Are Co-Morbid Features of Psychosis in Parkinson’s Disease Felicia C. Goldstein, Michael K. Scullin, Ann B. Sollinger, Julia Land, Cathy Wood-Siverio, Lavezza Zanders, Raven Lee, Alan Freeman, Donald L. Bliwise, William McDonald and Stewart A. Factor. Atlanta, GA
Abstracts, American Neurological Association
Hallucinations and delusions are troublesome non-motor features of Parkinson’s disease (PD). We examined for the presence of affective co-morbidities of psychosis. 144 PD patients (mean age 64.7 1 8.9 years; disease duration 7.8 1 4.4 years) were prospectively recruited from the Emory Movement Disorders Clinic. Comprehensive evaluation included administration of the Scale for the Assessment of Positive symptoms (SAPS) and measures of anxiety and depression including the Structured Clinical Interview for DSM-IV (SCID). SAPS revealed that 37 (26%) patients experienced hallucinations, mostly visual (15%) and auditory (12%), and 23 (16%) experienced delusions. Regression analyses were performed, controlling for potential confounders: age, education, gender, disease duration, motor severity, and PD medications. The presence, number of types, and severity of hallucinations were significantly (p < .05) associated with greater anxiety as measured by Beck Anxiety Inventory. The presence of hallucinations was significantly associated with a diagnosis of current depressive disorder by SCID. The presence of delusions was associated with anxiety. These findings highlight the association of psychosis in PD to anxiety and depression and the need to assess and treat these co-morbidities. Study supported by: Consolidated Anti-Aging Foundation. M1222. The Pimple Sign of Progressive Supranuclear Palsy Hugo Botha, Jennifer L. Whitwell and Keith A. Josephs. Rochester, MN Background Some patients with progressive supranuclear palsy (PSP) demonstrate a focal area of midbrain hypometabolism on FDG-PET scans which we call the ‘pimple sign’. We assessed its association with midbrain atrophy, its reliability and its ability to differentiate PSP from corticobasal degeneration (CBD) and multiple system atrophy (MSA). Methods We identified 67 patients with PSP, CBD or MSA who had volumetric MRI as well as FDG-PET imaging. Midbrain volume was corrected by expressing it as a percentage of total intracranial volume. Two independent, blinded specialists rated the ‘pimple sign’ as ‘absent’, ‘possible’ or ‘definite’. Midbrain volumes were compared across these groups and reliability assessed with the kappa statistic. Sensitivity and specificity was calculated using CBD and MSA patients as controls. Results Midbrain volume was decreased in the ‘definite’ group (0.47%) compared to the ‘absent’ (0.54%) and ‘possible’ (0.51%) groups. Inter-rater reliability for the pimple sign was high (j 5 0.90). A ‘definite pimple sign’ had a high specificity (97%) but low sensitivity (32%) for PSP. Conclusion The ‘pimple sign’ of PSP serves as a marker of midbrain atrophy, and is a reliable and specific sign helpful in differentiating PSP from CBD and MSA. Study supported by: Dr. Botha has no disclosures. Dr. Whitwell receives research support from NIH grants R21AG38736 (PI), R01-DC010367 (Co-I), and R01AG037491 (Co-I), and the Dana Foundation (Co-I). Dr.
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Josephs is funded by R01-DC010367 (PI), R01-AG037491 (PI), R21-AG38736 (Co-I), and the Dana Foundation (PI). M1223. The PREQUEL Multi-Center Phase II Study of Coenzyme Q10 in Pre-Manifest Huntington Disease Annie Killoran, Kevin M. Biglan, Flint Beal, Wayne Matson, Elaine Julian-Baros, Nadine Yoritomo, Wendy R. Galpern, Shan Gao, Michael P. McDermott and Christopher A. Ross. Morgantown, WV; Rochester, NY; New York, NY; Bedford, MA; Baltimore, MD and Bethesda, MD Background: PREQUEL represents the first multi-center interventional trial in Huntington disease (HD). Objective: To assess the safety and tolerability of three dosages (600 mg,1200 mg and 2400 mg per day) of coenzyme Q10 (CoQ) in subjects with pre-manifest HD, and the feasibility of conducting therapeutic trials in this population. Methods: PREQUEL is a phase II randomized, doubleblind, 20-week trial of CoQ. Participants were 90 adults with the HD CAGn expansion and a UHDRS diagnostic confidence score 3. The primary outcome was CoQ tolerability, defined as 75% of subjects completing the study on the randomized treatment assignment. Serum CoQ and 8OHdG were measured. Results: PREQUEL had 93% retention. 90%, 93% and 84%, respectively, completed the trial on the assigned CoQ dosages. The prevalence of adverse events (45%, 50% and 63%, respectively) was not significantly different among the treatment groups; most were mild to moderate and GIrelated. Four of the six withdrawals were on the 2400 mg dose. Serum CoQ levels increased similarly for all dosages. There were no changes in 8-OHdG with any dosage. Conclusion: CoQ was well-tolerated. The study shows the feasibility of conducting clinical trials in this population. Study supported by: National Institute of Neurological Disorders and Stroke (NINDS). M1224. Using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) To Assess Deficits in Patients with and at Risk for Huntington’s Disease Elizabeth Breen, Jody Goldstein, Shea Gluhm, Diane Nicoll, Paul Gilbert and Jody Corey-Bloom. La Jolla, CA and San Diego, CA The RBANS is a brief instrument that assesses five cognitive domains (attention, language, visuospatial abilities, immediate and delayed memory) and has been used to examine cognitive performance in various populations. However, studies examining its utility in HD, and especially premanifest HD (preHD), are limited. The RBANS was administered to 27 HD and 28 preHD subjects. One sample t-tests were used to compare RBANS scores for each group to normative data using z-scores. HD patients showed significant differences in total and all index scores (all p < 0.0001) compared to norms. In addition, list and story learning figure copy, semantic fluency, coding, list recall, story recall, figure recall, and list recognition subtests for the HD group were significantly different from controls (p 5 0.01 to < 0.0001). Even preHD patients showed significant
differences (p 5 0.02 to < 0.0001) with regard to figure copy, list recall, and figure recall. We conclude that the RBANS may be useful for assessing cognitive performance in patients with, and at-risk for, HD. Further studies will be needed to confirm and extend these findings. Study supported by: This study was supported by the UCSD Huntington’s Disease Society of America Center of Excellence and the UCSD Shiley-Marcos Alzheimer’s Disease Research Center NIH P50 AG 005131. M1225. Subthalamic Deep Brain Stimulation Synchronizes Cerebral Cortical Activity: Non-Invasive, Intraoperative Findings in Parkinson’s Disease Harrison C. Walker, Christopher L. Gonzalez, He Huang and Barton L. Guthrie. Birmingham, AL Although subthalamic brain stimulation (STN DBS) is superior to medications for the motor symptoms of Parkinson’s disease (PD), its therapeutic mechanism is unknown. Precise targeting of the stimulating electrode is critical to ensure the efficacy and tolerability of DBS. Here we evaluate how stimulation alters cortical activity during intraoperative targeting of the DBS electrode using noninvasive electroencephalography (EEG). With IRB approval, we studied 8 PD subjects undergoing DBS for routine care. Using our prior methods to eliminate the stimulus artifact, we generated event related potentials (ERPs) to 20 Hertz stimulation at different voltages and depths relative to the anticipated target, and then evaluated changes in cortical potentials at approximately one millisecond latency after stimulus onset. Our results demonstrate ERPs in 8/8 subjects which showed amplitude dependence on stimulation voltage and location (ANOVA for voltage, p < 0.001). We conclude that cortical synchronization by subthalamic DBS can be detected reliably and non-invasively with EEG in patients with PD. Better understanding the systems physiology DBS could eventually yield models to predict clinical outcome and guide intraoperative electrode targeting in real time. Study supported by: National Institutes of Health / National Institutes of Neurological Disorders and Stroke K23-NS067053 [to HCW]. M1226. Tremors in Progressive Supranuclear Palsy Shinsuke Fujioka, Avi Algon, Melissa E. Murray, Zbigniew K. Wszolek and Dennis W. Dickson. Jacksonville, FL Objective: Recently, Louis et al. reported that essential tremor (ET) may be associated with pathology of progressive supranuclear palsy (PSP) (J Neuropathol Exp Neurol 2013;72:8–17). The present study focused on the frequency of tremor in autopsy-confirmed PSP and a comparison of patients with and without tremor. Methods: Medical records were reviewed in a consecutive series of patients with autopsy-confirmed PSP in the Mayo Clinic Brain Bank. Clinical features were recorded in a database. All cases had neuropathologic evaluation with phospho-tau immunohistochemistry. Results: There were 304 patients with documented presence or absence of tremors (patients in which tremor was not specifically addressed were excluded), including 135
(44%) with tremor at some point during their illness. The frequency of tremor type was as follows: resting tremor (n 5 17); postural and/or action tremor (n 5 105); and mixed resting and other tremor type (n 5 13). There were no significant differences in demographic or genetic features between PSP patients with and without tremors. The tremor group tended to have more frequent atypical pathology; however, no differences were detected in average tau pathology lesion scores between the two groups. Conclusion: Tremor is relatively common in PSP. Its relationship to ET requires further investigation. Study supported by: None. M1227. Stuttering in Parkinson’s Disease Provoked by Levodopa and STN-DBS Bjorg J. Waro, Krisztina K. Johansen and Jan O. Aasly. Trondheim, Norway Stuttering is a speech disorder in which speech flow is disrupted by involuntary repetitions or prolongations of sounds/syllables. It is occasionally present in patients with Parkinson’s disease (PD). Levodopa is the most widely used treatment for PD. However, long-term medication is often complicated by dyskinesias and fluctuating motor function. Deep brain stimulation (DBS) relieves motor fluctuations effectively. DBS of the subthalamic nucleus (STN-DBS) is the most common surgical procedure in PD. We report the emergence of stuttering in two male patients treated for advanced PD. Patient 1 started stuttering shortly after initiation of levodopa. Patient 2 acquired stuttering six years after STN-DBS. Patient 1 has improved fluency in “off”-state, while patient 2’s dysfluency increases with increased neurostimulation. The role of dopamine and the basal gangliathalamocortical circuitry in stuttering is complex. Stuttering following levodopa treatment may be viewed as a dyskinesia. STN-DBS can induce speech disturbances, but reduces levodopa doses. DBS of the globus pallidus internus (GPi-DBS) leads to better tolerance of levodopa, but the effect on speech function is inconclusive. Patient 1 now suffers from severe dyskinesias and motor fluctuations. Should he be offered DBS? Which nucleus should then be targeted? Study supported by: Liaison Committee between the Central Norway Regional Health Authority (RHA) and the Norwegian University of Science and Technology (NTNU). M1228. Evaluation of Vigilance in Parkinson’s Disease Using a Virtual Reality Street-Crossing Task Kristin J. Ford, David C. Schwebel, Anna Johnston, Gary Cutter, David G. Standaert and Amy W. Amara. Birmingham, AL Parkinson’s disease (PD) patients commonly experience sleep dysfunction, including daytime sleepiness. Excessive sleepiness affects vigilance, which can impact safety in tasks like street-crossing. Twenty-five subjects with PD completed the Epworth Sleepiness Scale, a virtual reality street-crossing task, and Useful Field of View (UFOV), a measure of visual processing. The primary outcome measure was the number of looks/minute, with higher values indicating better vigilance. We hypothesize a negative correlation between looks/
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minute (visual attention) and subjective sleepiness. Preliminary analysis shows a non-significant trend toward a negative correlation (r 5 -0.06) between visual attention and sleepiness. Adjusted for UFOV scores, subjective sleepiness still cannot predict visual attention. However, sleepiness is strongly correlated with near misses (r 5 0.46, p 5 0.021). Additionally, UFOV is strongly predictive of and significantly negatively correlated with visual attention (r 5 -0.56, p 5 0.005). Preliminary data indicate no significant correlation between subjective sleepiness and vigilance. Interestingly, sleepiness did correlate with close calls to pedestrian crashes. Visual processing negatively correlated with visual attention, indicating that subjects with PD may not correct for visual processing deficits. Failure to reject the null hypothesis may indicate that PD patients underestimate their daytime sleepiness. Study supported by: NIH/NINDS (1K23NS080912-01); Francis and Ingeborg Heide Schumann Fellowship in Parkinson’s Disease Research; American Sleep Medicine Foundation; Center for Clinical and Translational Science (CCTS) (UL1 TR000165); UAB Center for Aging. M1229. Neurophysiological Distinction between Pyschogenic and Organic Myoclonus Vahid Tohidi, Bahareh Hassanzadeh, Sudhansu Chokroverty, Sushanth Bhat, Phillip A. Hanna, Nancy Gadallah, Rony Dekermenjian and Sumaiya Z. Salim. Edison, NJ Polymyographic studies with EEG-EMG correlation and back-averaging distinguish psychogenic and organic myoclonus. Cortical myoclonus has rostrocaudal propogation (duration 20–100 milliseconds). Subcortical myoclonus propogates up the brainstem and down the spinal cord (100–150 milliseconds). Propriospinal myoclonus propogates up and down the spinal cord (150–250 milliseconds). Spinal myoclonus is localized (150–250 milliseconds). Psychogenic myoclonus is generally rostrocaudal with variable, prolonged duration. Only cortical myoclonus has EEG-EMG correlation on back-averaging (positive-negative transient preceding jerks by 20 milliseconds in upper limbs, 35–40 milliseconds in lower limbs). We studied four patients (47M, 50F, 60M, 48F) with sudden onset of jerking movements in various limbs, not conforming to known movement disorders, but resembling myoclonus, tremor, choreoathetoid or ballismic movements, Psychogenic etiology was suspected. Polymyography using surface EMG electrodes was performed in multiple cranially and spinally innervated muscles. EEG-EMG correlation was performed with backaveraging; 40–50 EEG responses, consisting of potentials occurring 1000–1500 milliseconds before both spontaneous and simulated jerks, were averaged. Variable patterns of muscle recruitment within each jerk, without specific patterns of propogation, and the presence of Bereitschaftspotential (slowly rising negative potential 1000–1500 msecs before the jerks) confirmed the voluntary nature of these myoclonic jerks and supported the diagnosis of psychogenic myoclonus.
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Study supported by: n/a. M1230. Distinct Progression of Dysphagia between Hereditary and Sporadic Ataxias Involving Multiple Systems Chiharu Isono, Makito Hirano, Hikaru Sakamoto, Shuichi Ueno, Susumu Kusunoki and Yusaku Nakamura. Sakai, Osaka, Japan and Osakasayama, Osaka, Japan Multiple system atrophy of cerebellar type (MSA-C) is a sporadic type of ataxia affecting the cerebellum, brainstem, basal ganglia, and autonomic nervous systems. Dysphagia is frequently observed, and may lead to aspiration pneumonia, a major fatal complication. Spinocerebeller ataxia (SCA) type 1 (SCA1) and type 3 (SCA3) are major hereditary ataxias affecting multiple systems. To date differential features of dysphagia between hereditary and sporadic ataxias remain largely unknown. The aim of this study was to compare extent and progression of dysphagia between MSA-C (n 5 10) and SCAs 1 (n 5 2) and 3 (n 5 8), using videofluoroscopic examination of swallowing (VF). The evaluation was based on the scale established by the Japanese Society of Dysphagia Rehabilitation, which can evaluate oral and pharyngeal phase separately, and on dysphagia outcome severity score (DOSS), a scale used world-widely. We also used arbitrary scores, the aforementioned swallowing scores divided by durations of disease (points/yr), which may at least partly reflect progression of dysphagia. The result suggested that extents of dysphagia did not differ between two groups, but that progression was faster in MSA than in SCAs 1 and 3. Study supported by: N/A. M1231. Usefulness of the Montreal Cognitive Assessment (MoCA) in Detecting Cognitive Change in Mild, Moderate, and Severe Huntington’s Disease Shea Gluhm, Jody Goldstein, Daniel Brown, Charles Van Liew, Paul Gilbert and Jody Corey-Bloom. La Jolla, CA and San Diego, CA The Montreal Cognitive Assessment (MoCA) is a brief screening instrument for dementia that is sensitive to executive dysfunction. Although the MoCA has been examined in a variety of neurological conditions, studies in subcortical dementia are limited. This study examined the usefulness of the MoCA for assessing cognitive performance in mild, moderate, and severe Huntington’s disease (HD), as compared to the Mini-Mental State Examination (MMSE). Nonparametric Mann-Whitney U tests were used to examine MoCA and MMSE total scores and the number of correct answers in five cognitive-specific domains (attention/ executive functioning, visuospatial, language, memory, orientation) in 104 manifest HD patients and 100 matched controls. For the total HD cohort, and for moderate and severe patients compared to normal controls, significant differences between MoCA and MMSE total scores (p < 0.001) and almost all cognitive-specific domains (p < 0.001) emerged. Even mild HD subjects showed significant differences with regard to total score (p < 0.001) and several cognitive domains on each instrument (p < 0.01). We conclude that the MoCA, although not necessarily superior to the MMSE,
is a useful instrument for assessing cognitive performance over a broad level of functioning in HD. Study supported by: This study was supported by the UCSD Huntington’s Disease Society of America Center of Excellence and the UCSD Shiley-Marcos Alzheimer’s Disease Research Center NIH P50 AG 005131. M1232. Physical Activity and Risk of Comorbid Depression with Parkinson Disease Rui Liu, Daivd Umbach, Yikyung Park, Xuemei Huang, Albert Hollenbeck, Aaron Blair and Honglei Chen. Research Triangle Park, NC; Hershey, PA and Washington, DC Objective: To prospectively examine physical activity in relation to risk of comorbid depression with Parkinson Disease (PD). Methods: Participants comprised 934 PD cases and 264,533 individuals without PD. Physical activity was assessed via questionnaires in 1995–1996 and in 1996– 1997. Physician-diagnosed depression and PD after 2000 were reported in 2004–2006. Multivariate odds ratios (OR) and 95% confidence intervals (CI) were estimated from logistic regression models. Results: There were a total of 136 depression diagnoses among PD cases and 11,159 among those without PD. Increasing frequency of physical activity at baseline was associated with lower risk of depression in both future PD cases (5 times/week vs. never/rarely, OR 0.53; 95%CI 5 0.271.04; p-trend 0.02) and those without PD (0.65; 0.61-0.69; p-trend < 0.0001). Light to heavy lifting/carrying vs. mostly sitting was associated with lower risk of depression among those with future PD (0.35; 0.15-0.81) and those without (0.74; 0.68-0.80). Both “light” and “moderate to vigorous activities” in the past 10 years before baseline predicted lower risk of comorbid depression with future diagnosis of PD. Conclusion: Our results suggest active participation in several domains of physical activity contribute to lower risk of comorbid depression with PD. Study supported by: Supported by the intramural research program of the National Institute of Environmental Health Sciences and the National Cancer Institute. None of the authors have a conflict of interest for this research. M1233. Primary Dystonia Misinterpreted as Parkinson Disease: A Case Presentation and Practical Clues Alexander Neuwelt, Tam Nguyen, Maureen Leehey and Olga Klepitskaya. Albuquerque and Aurora Background Dystonic tremor is a significant source of erroneous diagnosis of Parkinson disease (PD) and Essential Tremor (ET). Case History A 46-year-old man with a history of tremor and diagnosis of PD was referred to the movement disorders clinic. His initial symptom was left (dominant) hand tremor at rest and with action. Examination showed an irregular head tremor that changed direction, frequency and amplitude with changing of head position. A dystonia was suspected based on the atypical presentation, and genetic testing revealed a GAG946 deletion in the DYT1 gene.
Discussion A dystonic tremor is a focal tremor that is postural and kinetic, has irregular amplitude and variable frequencies, is not seen during complete rest, and is frequently reduced by “gestes antagonists.” The head tremor characteristics were typical for dystonic tremor: The tremor was influenced by a sensory cue (touching his chin temporarily decreased his tremor), and a partial null point (improvement of the tremor when holding a certain position). Conclusion Our case illustrates typical challenges in the recognition and diagnosis of dystonia, and serves to increase clinicians’ awareness of this disabling, but treatable, condition. Study supported by: None. M1234. Progressive Supranuclear Palsy: Diagnosis through Skin Biopsy Ildefonso Rodriguez-Leyva, Jose Renan-Perez, Ana L. CalderonGarciduenas, Martha E. Santoyo, Erika Chii and Maria E. Jimenez-Capdeville. San Luis Potosi, Mexico and Veracruz, Mexico Objective: Skin biopsy as a supportive method to evaluate a patient with parkinsonism. Backgound: The only definitive diagnosis for neurodegenerative parkinsonism is an autopsy. Exploring the terminal nerve endings could yield a good assessment method for PD and AD. Methods: We report a 59-year-old male, presenting, with four years of evolution: frequent falls, slurred speech, rigidness (mostly in the trunk), emotional lability, excessive drooling and dysphagia. Exam showed a 15/30 MMSE, vertical gaze palsy, optokinetic nistagmus absent, slow pursuit movements, dysphagia, dysphonia, parkinsonism, snouting, glabelar and grasping reflexes, cog-wheel and axial dominant rigidity, retrocollis, severe bradikinesis, with apraxia of the upper left extremity, dysmetric and disdiadokinetic. MRI showed severe atrophy within cerebellar peduncles, humming bird and morning glory sign. Patient fulfilled the mandatory PSP diagnostic and supportive criteria. With the patient’s and his caregivers’ authorization we underwent skin biopsy. Immunoreactive Tau protein was evidenced by the monoclonal antibodies recognizing two phosphorylation sites, characteristic of AD, and a polyclonal antibody against non-phosphorylated tau, aggregates of alpha-synuclein, was mild positive. Results: Immunoreactive Tau-positive inclusions in the terminal nerve endings, melanocytes, vessels and glands in the skin. In our knowledge this is the first report of PSP supporting his taupathy in life. Study supported by: The principal author is speaker for Novartis, UCB, Boehringer Ingelheim Mexico. M1235. Posterior Column Disease in the Setting of Falsely Elevated Vitamin B12 Levels Due to AntiIntrinsic Factor Antibodies Sui Li, Subhashie Wijemanne, M. Elfahal, C. Dunn, G. Abel and Michal Vytopil. Burlington, MA and Boston, MA Vitamin B12 deficiency causes degeneration of the posterior columns resulting in diminished proprioception and vibratory sense. We report a patient with megaloblastic anemia
Abstracts, American Neurological Association
and severe pancytopenia for eight months who had serum B12 levels >1200 pg/ml on repeated testing. He was thought to have a hematologic malignancy until he presented with a rapidly progressive gait disorder. MRI of the spinal cord revealed T2 hyperintensity of the posterior columns. Methylmalonic acid and homocysteine levels were both elevated. Endoscopy revealed significant atrophy of the antral mucosa. Anti-intrinsic factor antibodies were positive. Vitamin B12 levels were falsely elevated due to the presence of anti-intrinsic factor antibodies which interfered with the immunoassay via competitive binding. We subsequently used polyethylene glycol to precipitate immunoglobulins from the patient’s plasma and discovered the true B12 level to be much lower. His hematologic abnormalities and gait disorder were successfully treated with B12 injections. This case illustrates the importance of recognizing the potential limitations of laboratory tests in order to avoid misdiagnosis and delay in diagnosis of easily reversible conditions. Study supported by: Lahey Clinic. M1236. Glutathione and Lipid Peroxidation in Neurologic Wilson Disease: Clinical, Biochemical and MRI Correlation Jayantee Kalita, Vijay Kumar, Satish Chandra and Usha K. Misra. Lucknow, Uttar Pradesh, India The role oxidative injury by free copper in neurologic Wilson disease(NWD) has not been evaluated. We report glutathione and lipid peroxidation in NWD and correlate these with clinical, MRI and biochemical changes. 28 NWD patients whose median age was 16 years were included. Their clinical severity (0–3 grade), MRI changes,blood counts,hemoglobin, liver and kidney function tests,ultrasound abdomen, serum ceruloplasmin, serum free copper and 24hour urinary copper were noted. Plasma glutathione(GSH) and malonodialdehyde(MDA) were measured in NWD and 64 matched controls. GSH was reduced (2.26 6 0.49 Vs 2.6 6 0.39 mg/dl, p 5 0.001) and MDA increased (4.90 6 0.74 Vs 3.21 6 0.69 nmol/ml, p 5 0.0001) in NWD compared to controls.The GSH had positive correlation with ceruloplasmin (r 5 0.54) and negative correlation with free serum copper (r 5 20.52) and urinary copper(r 5 20.75). MDA level on the other hand had negative correlation with ceruloplasmin(r 5 20.61) and positive correlation with serum free copper(r 5 0.41) and urinary copper(r 5 0.61). The clinical severity and hematological, liver, renal and MRI changes however did not correlate with GSH and MDA levels. Lower GSH and higher MDA suggest copper induced oxidative injury in NWD. The role of adjunctive antioxidant in the treatment of NWD needs to be explored. Study supported by: No. M1238. The Use of Neural Stem Cells for the Treatment of Parkinson’s Disease in a Non-Human Primate Model Rodolfo Gonzalez, Ibon Garitaonandia, Alina Ostrowska, Tatiana Abramihina, Gerald Wambua, Alexander Noskov, John S. Craw, Maxim Poustovoitov, Andrew Crain, Francesca S. Boscolo, Louise C. Laurent, D. Eugene Redmond, Evan Y.
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Snyder and Ruslan A. Semechkin. Carlsbad, CA; La Jolla, CA and New Haven, CT Parkinson’s disease can potentially be treated with neural stem cells (NSC) derived from human pluripotent stem cells including parthenogenetic stem cells which may confer additional immunogenetic benefits. The primary goal of this non-human primate study is to determine the therapeutic benefits and pharmacological profile of NSC implanted in the MPTP-lesioned African green monkeys with Parkinsonism. Immunosuppressed animals were given bilateral stereotaxic injections of NSC into the striatum and substantia nigra, substantially the same route and locations proposed for the phase I clinical study. Behavioral changes as well as potential motoric side effects were evaluated using Parkinson scores. To determine the safety profile clinical pathology, necropsy, histopathological analysis of multiple organs and biodistribution of the cells were performed on all experimental animals. These results represent a first, but significant step toward a safe and effective treatment of Parkinson’s disease with a histocompatible stem cell derived NSC. Study supported by: International Stem Cell Corporation; employment, salaries, ownerships. M1239. Evaluating the Relationship between Dopamine Transporter Imaging (DATSCAN) Characteristics and Clinical Ratings of Parkinson Disease Shnehal Patel, Michael Georgiou, Corneliu Luca, Efrosyni Sfakianaki and Fatta B. Nahab. Miami, FL and La Jolla, CA INTRODUCTION: Efforts to identify an objective biomarker of dopaminergic neurodegeneration in Parkinson’s disease (PD) are ongoing, with existing methods serving to separate PD from non-PD. Reliability of visually rated DATSCAN has not been well studied, along with correlation of rater severity of DAT and clinical severity of PD. Methods: Informed consent was obtained for all subjects under a natural history protocol. Data collection included clinical rating by a movement disorder neurologist (Modified Hoehn & Yahr scale (mHY), demographics, and clinical findings pertaining to symmetry and presence of cardinal signs of PD), and rating of DAT by two trained readers. We hypothesized that ratings by the trained DAT readers would not be significantly different and that DAT scores would correlate with the HY. Results: 64 sequential subjects were studied from 10/ 2011 to 6/2013 (mean age 5 66.8, median HY 5 1). Interrater kappa statistic showed excellent agreement (k 5 0.83). DAT ratings were also correlated with HY on Spearman non-parametric testing (r 5 0.54, p < 0.01). Conclusions: Findings suggest that visual DAT ratings having high interrater reliability and correlate moderately with mHY. Further work is needed to correlate regional DAT indices with particular symptom subsets. Study supported by: N/A. M1240. Localization of Alpha-Synuclein in the Retina in Parkinson Disease (PD) Piotr B. Kozlowski, Sofya Glazman and Ivan Bodis-Wollner. New York, NY and Brooklyn, NY
Braak and his collaborators demonstrated misfolded alphasynuclein (AS) as a marker in the olfactory bulb, in the gut and in the nucleus vagus dorsalis in postmortem material in PD. Vision is also affected in PD and at least part of the visual impairment is linked to abnormal retinal processing and imaging techniques reveal retinal thinning. We evaluated the possible presence of AS in the postmortem PD and aged matched control retina. Commercially available AS immune staining, paraffin embedding and HE staining was used. Some retinae were in poor condition. However dark AS staining was clearly evident in abundance in two PD subjects retinae, mostly in the inner plexiform layer. Discrete, largish cells were easily detectable, at the border of the inner nuclear and inner plexiform layer. We saw 2–3 such cells per HPF. No staining was evident in the photoreceptor layer. Very faint staining was noticeable in one control retinae. We conclude the retina contains AS labeling in PD in the inner pexiform layer and in some distinct cells in the location usually associated with amacrine cells. Further quantification and identification is needed to establish the presence and relevance of AS to visual processing deficits in PD. Study supported by: the Parkinson Study Group and by the Michael J. Fox Foundation. M1241. Long-Term Dosing Trends of Intrathecal Baclofen Therapy for Spasticity in Adults with Intellectual and Developmental Disabilities Amanda D. Currie, Anna L. Molinari, Maxim Turchan and David Charles. Nashville, TN Background: No studies have investigated the long-term (>2 years) dosing trends for intrathecal baclofen (ITB) in adults with intellectual and developmental disabilities (IDD). Methods: Retrospective chart review of subjects who previously participated in a prospective outcomes study of spasticity treatment for 54 adults with IDD. Nine subjects who received ITB were included. ITB dose was recorded at 3, 6, 9, 12, 18, and 24 months and annually thereafter. Results: Mean follow-up was 6.4 years (1.0 - 8.6 years). All subjects received therapeutic benefit from ITB as evaluated by their physical and/or occupational therapist throughout follow-up. Mean baclofen dose increased from 176 mg/day at 3 months to 440 mg/day at one year postimplantation and remained relatively constant thereafter, decreasing slightly to 405 mg/day at 72 months. Conclusions: ITB provided long-term benefit in this population. The trends observed in this analysis are consistent with published reports of ITB dosing trends. Although adults with IDD have unique medical needs and often require unique treatment considerations, the results of this analysis suggest that ITB dosing trends do not need to be modified greatly for this population. Study supported by: Allergan; Vanderbilt University receives income from grants and contracts with Allergan and Medtronic for research led by Dr. Charles. Dr. Charles
receives income from Allergan and Medtronic for consulting and education services. M1242. A Crossover Study of DM-1992, A Gastroretentive Formulation of Carbidopa/Levodopa in PD Patients with Motor Fluctuations L. Verhagen Metman, N. Stover, C. Chen, V.E. Cowles and M. Sweeney. Chicago, IL; Birmingham, AL and Newark, CA To compare the efficacy and tolerability of DM-1992, an extended-release formulation of carbidopa/levodopa (CD/LD) with an immediate-release (IR) formulation in PD patients. This study included a 3-day baseline period and two 10day treatment periods. Patients with OFF time 2.5 hrs/day taking 400–1600 mg LD/day in 4 doses were titrated to stable regimens of DM-1992 twice/day or IR-CD/LD 3–8 times/day. Rescue medication was permitted. %OFF time, derived from patient home diaries was the primary outcome measure, which was compared between DM-1992 and IRCD/LD for all patients and for patients using LD 1000 mg/ day at baseline. Thirty-four patients with baseline LD of 968 mg/day were enrolled. After titration, IR-CD/LD was dosed 4.8 times/day. Mean (SD) daily %OFF time at baseline was 32.5% (10) and at day 10, 27.2% (18.2) with DM-1992 vs 33.5% (12.7) with IR-CD/LD (p 5 0.047). Patients with baseline LD 1000 mg/day (n 5 23) benefited more from DM-1992 than all patients with 21.62 hrs OFF time and 12 hrs ON time vs IR-CD/LD. There was no AE pattern and no discontinuations due to AEs. Twice-daily DM-1992 reduced OFF time significantly more than IR-CD/LD dosed 3–8 times/day. Study supported by: Depomed. M1243WIP. Transgenic Mice Expressing a Human C9orf72 Transcript Containing an Expanded Hexanucleotide Repeat Develop Intranuclear RNA Foci Owen M. Peters, Helene Tran, Peter Sapp, Debra Cameron, RuJu Chian, Jake Meterville, Christine J. Jung, Yuko Yoshinaga, H. Robert Horovitz, Pieter J. de Jong and Robert H. Brown. Worcester, MA; Oakland, CA and Cambridge, MA The expansion of a normally non-coding GGGGCC hexanucleotide repeat motif in the C9orf72 gene represents the most common heritable mutation in familial ALS and FTLD. Because the mechanism by which this mutation gives rise to pathology is undefined, relevant model organisms to aid its study are urgently required. We have generated a BACtransgenic mouse line heterozygously expressing the C9orf72 transcript with an expanded hexanucleotide sequence of approximately 500 repeats and have characterized the phenotype of young adult mice. qPCR analysis confirmed abundant expression in the CNS of C9orf72 pre-mRNA and mRNA transcripts containing the hexanucleotide repeat motif. Up to 6-months of age, the mice failed to show any obvious signs of ill health, nor was a substantial motor phenotype manifest. However, in concurrence with data reported from human C9orf72-positive patient tissues, intranuclear RNA foci containing the GGGGCC motif were observed in disease-relevant regions of the brain, including cortex, hippocampus and cerebellum. We are continuing to characterize an aging cohort and
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believe the BAC-transgenic C9orf72 mouse will be an important tool in determining disease mechanisms and developing therapeutics for ALS/FTLD. Study supported by: ALSA, NIH (NINDS), Angel Fund, Project ALS, P2ALS, ALS Therapy Alliance, Gaffin Family Trust, Howard Hughes Medical Institute. M1244WIP. Genome-Wide RNAi Screen for Modifiers of DYT1 Pathology Changrui Xiao, Zachary Caffall, Anna Liu, James Pearson and Nicole Calakos. Durham, NC DYT1 dystonia is one of the most common primary inherited dystonias, and dystonia, in all forms, is among the top 3 movement disorders in prevalence. While the genetic etiology of the human disease is known, both our understanding of cellular mechanisms and the efficacy of current treatments for DYT1 dystonia are limited. The causative mutation (inframe GAG deletion of the TOR1A gene) is associated with several cellular phenotypes including: abnormal TorsinA localization in the nuclear envelope forming a punctate pattern (“inclusions”), abnormal secretion, and increased ER stress. To identify genes and pathways that will advance our understanding of dystonia pathogenesis and provide novel therapeutic targets, we developed a high-throughput assay to monitor DYT1-genotype specific cell pathology. Using the assay, we performed a human genome-wide RNAi screen for modifiers of inclusion pathology and secondary assays to identify genes that also normalize ER stress and secretion. We identified 151 candidate genes enriched for cellular pathways related to mRNA processing, unfolded protein response, and fatty-acid metabolism. These results can now be applied to further mechanistic and preclinical animal model studies to identify novel genes, pathways, and drugs for the treatment of dystonia. Study supported by: The authors wish to acknowledge financial support by the Tyler’s Hope foundation for Dystonia Cure, the Duke University School of Medicine Core Facility Voucher program to N.C., and the National Institute of Health. Interventional Neurology M1301. Simultaneous Endovenous Hypothermia and Intra-Arterial Thrombectomy Is Feasible in Patients with Acute Ischemic Stroke Cynthia Kenmuir, Kees Polderman, Edilberto Amorim, Ashutosh Jadhav, Ramesh Grandhi, Brian Jankowitz, Lawrence Wechsler, Tudor Jovin and Guillermo Linares. Pittsburgh, PA Background: Hypothermia is a promising neuroprotectant and may ameliorate reperfusion injury. Easy access to the femoral vein allows it to be combined with intra-arterial therapy. Methods: Consecutive patients with acute ischemic stroke receiving intra-arterial therapy were studied. A femoral arterial sheath and femoral venous catheter were placed for hypothermia induction with cold saline infusion. Goal temperature prior to reperfusion was 35 , followed by 32 for a total of 24 hours. Patients were rewarmed at 0.2 /hour.
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Results: Twenty-two patients were studied, five women. Median age 62 (range 47–80), NIHSS 15 (13–32), time from last known well 4 hours (1–10), ASPECTS 8 (7–10). No groin complications, four intubations unrelated to the procedure, five pneumonias, one DVT and one PE occurred. Symptomatic hemorrhage occurred in two patients (7.6%). Six patients died (27%), four after withdrawal of care, eleven were discharged to rehabilitation (50%) and five to skilled nursing facilities (22.7%). Conclusions: Combined endovenous hypothermia and intra-arterial therapy for acute ischemic stroke is feasible. There is no increase in symptomatic hemorrhage rates. This data supports the planning of a phase 2 trial to optimize temperature goals and length of the intervention. Study supported by: not applicable - no financial disclosures to report. M1302. Texas Stroke Intervention Pre-Hospital Stroke Severity Scale (aka LEGS Score): A Novel Triaging Tool for Interventional Stroke Therapy Sherman H. Chen, Lauren A. Carlson, Ryan M. Gianatasio, Stewart R. Coffman, Mark Gamber, W. Tim Hartman, John H. Myers and Vallabh Janardhan. Plano, TX and Dallas, TX Background: A pre-hospital stroke severity scale that correlates well with an NIHSS of 10 or greater (given a correlation of NIHSS 10 with large vessel occlusions), but is easier and faster to perform, would be a useful triaging tool for emergency medical services (EMS). Methods: The LEGS score is a shortened NIHSS-5. LEGS score stands for Leg strength, Eyes/visual fields, Gaze, Speech/language. LEGS score (0–16) as well as the full NIHSS (0–42), were performed in the emergency department over a 6-month period. Results: A total of 182 consecutive ischemic stroke patients were evaluated. LEGS score of 4 or greater was a good predictor of an NIHSS of 10 or greater (59/182; positive predictive value 92%; specificity 95%); false positives noted was 5/182. LEGS score of less than 4 was a good predictor of an NIHSS of less than 10 (108/182; negative predictive value 91%; sensitivity 95%); false negatives noted was 10/182. Conclusion: LEGS score of 4 or greater is a useful indicator to triage moderate to severe stroke patients (NIHSS 10) to a comprehensive stroke center for consideration for Interventional Stroke therapy. Study supported by: None. M1303. Canine Endovascular Reperfusion Stroke Model Dileep R. Yavagal, Amanda Torress, Alessandra Giannini, Philip Garza and Fernando Vinuela. Miami, FL and Los Angeles, CA Background: A large number of novel stroke therapies failed in clinical trials after showing effectiveness in the rodent middle cerebral artery occlusion (MCAo) models. The STAIR criteria to maximize success of translation of stroke therapies therefore recommend testing of such therapies in large animal stroke models. We report an endovascular reversible MCAo stroke model in canines to bridge this translational gap.
Methods: A total of 28 mongrel dogs, age between 1–4 years, average wt. 23.25kg14.7, underwent transfemoral microcatheterization and occlusion of the MCA with a platinum detachable embolization coil for 1–3 hours. MCA reperfusion was established by coil retraction and the dogs were survived. Results: Successful MCAo with reperfusion was achieved in 26/28 dogs. MCA territory infarction was seen in all dogs with successful MCAo. 100% feasibility of achieving MCAo in the last consecutive 25 dogs. Perioperative mortality occurred in 10/28 dogs (35.7%) and decreased from 50% in the first 14 animals to 21% in the subsequent 14 animals. Conclusions: We report the successful development and high feasibility of an endovascular reversible MCAo model in the dog. A learning curve is seen in the successful implementation of this survival model. Study supported by: 1. Leo G. Rigler Center for Radiologic Research, UCLA, 2002–2004; 2. Department of Neurology, University of Miami Miller School of Medicine (UMMSM), 2008–2009; 3. Interdiscriplinary Research Development Initiative Grant, UMMSM, 2009–2010; 4. Anderson Family Gift to Division of Interventional Neurology, Dept of Neurology, UMMSM, 2009–2011. M1304. Poor Natural History of Large Vessel Acute Ischemic Stroke Underscores the Need for Mechanical Thrombectomy: Natural History FIRST Stroke Study Interim Results Vallabh Janardhan, Lauren A. Carlson, Ryan M. Gianatasio, Sherman H. Chen, Parita Bhuva, Mark M. Murray, Madhu B. Vijayappa, Paul A. Hansen, Anita Guthmann, Raymond Cheung, Thomas Leung, Iris Grunwald, Heather Hernandez, Leticia Barraza, Hope Buell, Sophia S. Kuo, Arani Bose and Siu Po Sit. Plano, TX; Hong Kong, China; Oxford, United Kingdom and Alameda, CA Background: Limited information is available on the natural history of the mechanical thrombectomy-eligible stroke cohort. Therefore, FIRST aims to collect real-world data in an appropriate population. Methods: The FIRST Trial is a prospective natural history study of a stroke cohort eligible for but untreated by endovascular therapy presenting with a large vessel occlusion and ineligible for or unresponsive to IV rtPA. The primary endpoint is 90-day mRS 0–2. Results: Sixty-one patients met analysis criteria. Mean age was 68; median NIHSS score was 18. Occlusions were in the ICA (28%), MCA (67%) and other (5%). The admission TIMI 0–1 rate was 98% and TICI 0–1 was 98%, in which 10% and 12% spontaneously recanalized. Good 90-day outcome was achieved in 22%; 41% died, 54% had SAEs and 56% were IV rtPA-refractory. Compared to PROACT II, the FIRST cohort has substantially different entry criteria, less recanalization and worse outcome. Conclusion: If untreated, 78% of patients with large vessel acute ischemic stroke will die or suffer long-term disabilities. Results suggest FIRST data could provide a benchmark for future thrombectomy trials. Study supported by: Penumbra, Inc.
M1305. Developing a Comprehensive Stroke System of Care Positively Impacts Stroke Volumes in Primary Stroke Centers Madhu B. Vijayappa, Debbie Roper, Lauren A. Carlson, Lori Lemay, Anita Guthmann, Jeff Coulson, Mark Whitley and Vallabh Janardhan. Plano, TX and Irving, TX Background: With the advent of certifications for primary as well as comprehensive stroke centers and the development of stroke systems of care, there is concern that there will be a significant decrease in stroke volumes within primary stroke centers in the stroke network as a consequence of growth of comprehensive stroke programs. Methods: Stroke volume defined as ischemic and hemorrhagic stroke inpatient discharge diagnoses (ICD-9 codes) across 9 hospitals within a regional stroke network were analyzed retrospectively two years (2008–2009) prior to developing a comprehensive stroke program within the network and for the subsequent two years (2011–2012). Results: Stroke volume increased steadily over time across the entire regional stroke network. Before becoming a comprehensive stroke program, the hospital’s stroke volume in 2008 was 350 and the other eight primary stroke centers’ combined volume was 2530. In 2012, the comprehensive stroke program’s volume increased to 1095 and the primary stroke centers’ volume increased to 2846. Conclusion: Establishing a comprehensive stroke system of care increases stroke volumes in the primary stroke centers as well as the comprehensive stroke program within a regional stroke network of community hospitals. Study supported by: None. M1306. Implementation of an ED-Based Rapid BrainAttack Triage Algorithm in a Regional Tele-Stroke Network Positively Impacts Treatment Rates for Acute Ischemic Stroke Lauren A. Carlson, Ryan M. Gianatasio, Sherman H. Chen, Paul A. Hansen, Mark M. Murray, Parita Bhuva, John Myers, Stewart Coffman, John Saad, Chris Fanale, Brandon Meek, Traci Oberg, Matthew Bush, Scott Robins, Anita Guthmann, Debbie Roper, Mark Whitley and Vallabh Janardhan. Plano, TX; Dallas, TX and Irving, TX Background: A simplified algorithm for evaluating and triaging brain-attack patients in the emergency department (ED) similar to heart-attack triage can potentially improve treatment rates. Methods: A simplified 2-step ED-based Rapid BrainAttack Triage Algorithm was developed. The process begins with a non-contrast head CT to distinguish a hemorrhagic stroke from an ischemic stroke. The second step involves identifying the time “last known normal (LKN)”. The Texas Stroke Institute Rapid Brain-Attack Triage Algorithm was implemented for all Tele-stroke consultations within the regional stroke network. Data was prospectively collected during a 1-year period from January to December 2012. Results: 907 Tele-stroke consultations were performed via telephone or camera. Two-thirds were ischemic stroke patients (603/907; 66.7%) and one-third were hemorrhagic stroke patients (304/907; 33.3%). Among the ischemic
Abstracts, American Neurological Association
stroke patients, 64% (386/603) presented within 12 hours from LKN (283 of these within 4.5 hours). 43% of timeeligible patients (165/386) received intravenous r-tPA and/ or catheter-based mechanical thrombectomy. Conclusion: A simplified ED-based Rapid Brain-Attack Triage Algorithm as part of a regional Tele-stroke Network is feasible and helps significantly increase treatment rates in patients with acute ischemic stroke. Study supported by: None. M1307. Community Hospitals within a Regional Stroke Network Can Safely Administer Intravenous Recombinant Tissue Plasminogen Activator (IV r-tPA) in Acute Ischemic Stroke Paul A. Hansen, Lauren A. Carlson, Ryan M. Gianatasio, Debbie Roper, Alex Rolland, Jeff Coulson, Scott Robins and Vallabh Janardhan. Plano, TX and Irving, TX Background: Despite FDA approval in 1996, the use of IV r-tPA in acute ischemic stroke remains relatively low (3– 4%), partly because of the concerns for symptomatic intracerebral hemorrhage (6–12%). Methods: A Comprehensive Stroke System of Care was developed in 2010 and included 5 certified stroke centers. Standardized emergency department-based (ED) algorithms were implemented and stroke coordinators tracked protocol violations. ED physicians administered IV r-tPA with vascular neurology consultation via telephone or camera. IV rtPA usage was identified based on procedure codes for intravenous thrombolytic administration on inpatient hospital discharges from 2008 to 2012. Symptomatic intracerebral hemorrhage was defined based on the ECASS criteria. Results: A total of 6,311 patients were hospitalized with acute ischemic stroke over a 5-year period. The IV r-tPA usage rates increased from 7.10 % in 2008 to 13.13 % in 2012 and the associated symptomatic intracerebral hemorrhage rate dropped from 4% in 2008 to 1% in 2012. Conclusion: Community hospitals within a regional stroke network can safely administer IV r-tPA with low rates of symptomatic intracerebral hemorrhage comparable to the results of controlled clinical trials. Study supported by: None. M1308. Effect of Pregabalin on Glycemic Control and Serum Lipids in Patients with Diabetic Peripheral Neuropathy Bruce Parsons and Birol Emir. New York, NY Objective: To examine whether pregabalin is associated with loss of glycemic control (HbA1c) or change in lipids (cholesterol and triglycerides) in patients with diabetic peripheral neuropathy (DPN). Methods: Data were pooled from 11 placebo-controlled (2 collected lipids) and 3 open-label trials of pregabalin. For placebo-controlled trials, changes from baseline to endpoint were compared between and within treatment groups using analysis of covariance. For open-label trials, changes were summarized descriptively. Results: Placebo n 5 1050; Pregabalin 150 mg/d n 5 176, 300 mg/d n 5 559, 600 mg/d n 5 705, and flexible 150–600 mg/d n 5 521. Pregabalin was not associated
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with clinically meaningful changes in HbA1c (%) compared to placebo (150 mg/d 5 0.09, 300 mg/d 5 0.11, 600 mg/ d 5 0.01, and flexible 5 0.10), and intragroup changes were not statistically significant. Pregabalin was also not associated with clinically meaningful changes in total (fasting) cholesterol (mg/dL) compared to placebo (300 mg/ d 5 0.72, 600 mg/d 5 21.50, and flexible 5 24.64), and intragroup changes were not statistically significant. This was similar for HDL, LDL cholesterol, and triglycerides. In open-label studies, HbA1c increased by 0.14 (n 5 160), 0.26 (n 5 102), and 0.16 (n 5 290). Conclusions: Pregabalin does not appear to be associated with loss of metabolic control in DPN patients. Funded by Pfizer Inc. Study supported by: Pfizer Inc. Dr Parsons and Emir are full-time employees of Pfizer Inc and own stock in Pfizer Inc. M1309. Intraprocedural Parenchymal Blood Volume for Acute Ischemic Stroke Intervention Vinodh T. Doss, Heike Theessen, Adam Arthur and Lucas Elijovich. Memphis, TN and Hoffman Estates, IL Introduction Parenchymal blood volume (PBV) is a non-quantitative cerebral tissue perfusion imaging technique used during cerebral angiography. PBV may help determine initial infarct core and also provide intraprocedural information regarding reperfusion. Methods: Retrospective review of patients presenting from March to June 2012 who received pre & postintervention PBV. Data was collected to determine recanalization (TICI score), reperfusion, and clinical outcome. Successful reperfusion was defined as a > 1/3 improvement in the PBV deficit. Results: Six patients with an average NIHSS of 16 underwent endovascular treatment for acute stroke. Two patients had no recanalization or reperfusion. Infarct volume was similar to the initial PBV deficit with poor clinical outcome – mRS of 4 and 6. In the four patients with recanalization, three had successful reperfusion with smaller final infarct volume in comparison to initial PBV deficit and with mRS of 1–3 at discharge. The fourth patient had a large final infarct volume without reperfusion with mRS of 1. Conclusion: PBV normalization/reperfusion may be a marker for tissue salvage and good outcome. PBV does not appear to be a marker of initial infarct core and should not be used to exclude patients from treatment. Study supported by: no outside support. M1310. A Combination of Covered Stents and Percutaneous Thrombin Injection in the Management of Carotid Blowout Syndrome Karthikeyan M. Arcot, Jean Delbrune and Jeffrey Farkas. Brooklyn, NY An 86 year old male with a history of HTN, CAD, COPD, PVD, Right Carotid Endarterectomy (2 years ago) presented with a mass on the right side of his neck and difficulty swallowing for three days. On exam a tender pulsatile mass was
noted on the right side of his neck. A CTA revealed a giant pseudoaneurysm (6 3 5 3 7 cm) arising from a large rent in the right internal carotid artery(ICA). At emergent angiography two covered stents were placed to span the rent in the carotid artery and only minimal residual leak was noted. A repeat CTA performed the next morning revealed recurrence of the pseudoaneurysm. Angiography was repeated. An additional covered stent was placed but the leak persisted through the stents. At this time a balloon was inflated in the right ICA for protection against intravascular coagulation and thrombin was injected percutaneously (750 IU distributed over two sites). There was no residual pseudoaneurysm. Serial carotid dopplers demonstrated a reduction in hematoma volume with no residual pseudoaneurysm. Study supported by: None. M1311. Establishing a Comprehensive Stroke System of Care Increases Acute Ischemic Stroke Volume and Intravenous Recombinant Tissue Plasminogen Activator (IV r-tPA) Usage Ryan M. Gianatasio, Debbie Roper, Lauren A. Carlson, Scott Robins, Anita Guthmann, Jeff Coulson, Mark Whitley and Vallabh Janardhan. Plano, TX and Irving, TX Background: Comprehensive Stroke Systems of Care are needed across the country. However, there is limited information on the growth of acute ischemic stroke volumes within hospitals in a regional stroke network and the associated IV r-tPA rates. Methods: A Comprehensive Stroke System of Care was developed in 2010 and included 5 hospitals that were certified primary stroke centers. Acute ischemic stroke volume was identified based on inpatient hospital discharges (ICD-9 codes) from 2008 to 2012. IV r-tPA usage was identified based on procedure codes for intravenous thrombolytic administration and data collected by hospital stroke coordinators. Results: A total of 6,311 patients were hospitalized with acute ischemic stroke over a 5-year period. Acute ischemic stroke volumes grew from 902 in 2008 to 1493 in 2012, representing a 65.5% growth rate. The IV r-tPA usage rates increased from 7.10 % in 2008 to 13.13 % in 2012 with a growth of 6.03%. Conclusion: A Comprehensive Stroke System of Care positively impacts stroke volumes in all the hospitals within the regional stroke network and is associated with increased IV r-tPA rates. Study supported by: None. M1312. Impact of Posterior Communicating and Vertebral Artery Size on Recanalization in Endovascular Treatment of Acute Basilar Artery Occlusion Sushrut S. Dharmadhikari, Diogo C. Haussen, Ajith J. Thomas, Mohammad A. Aziz-Sultan, Mohamed Samy A. Elhammady and Dileep R. Yavagal. Miami, FL and Boston, MA Objective: We assessed if posterior communicating (PCommA) or vertebral artery (VA) diameter and/or pat-
ency influence recanalization in patients with acute basilar artery occlusion (BAO) treated with endovascular therapy. Methods: Retrospectively reviewed patients with acute ischemic stroke and BAO that underwent intervention. BAO classified into proximal, middle or distal. PCommA and VA diameters measured. PCommA atretic if diameter < 1mm. VA’s that end-in-PICA or unilateral VA occlusion classified ‘unilateral perfusing vertebrobasilar junction’ (UPVBJ). Recanalization classified using TICI scale. Univariate linear regression performed for recanalization. Variables with p < 0.2 included in multivariate linear regression analysis. Results: 30 BAOs. 11 proximal, 7 middle, 12 distal. PCommA diameter 1.43( 6 1.0) mm. VA diameter 2.51( 6 1.6) mm, and 14 UPVBJ. TICI 0 5 24%, 2a 5 13%, 2b 5 33%, 3 5 30%. In univariate linear regression, atretic PCommA or PCommA diameter not associated with recanalization (p 5 0.981 and p 5 0.781). Diabetes (p 5 0.168), UPVBJ (p 5 0.073) and mechanical thrombectomy (Merci and/or Penumbra versus IA-tPA; p 5 0.02) included in multivariate linear model. UPVBJ (unstandardized beta 21.233; p 5 0.047) associated with lower and mechanical thrombectomy (unstandardized beta 1.886; p 5 0.009) with higher recanalization rates. Conclusions: UPVBJ independently associated with worse BAO recanalization rates. Mechanical thrombectomy predicted better reperfusion. Study supported by: Department of Neurology, University of Miami.
M1313. Stroke Center Certification and Performance Metrics Task Forces Help Reduce Door-to-Needle (D2N) Times in Community Hospitals within a Regional Stroke Network Andre Fredieu, Sherman H. Chen, Debbie Roper, Sharon Eberlein, Andrea McManus, Lauren A. Carlson, Scott Robins and Vallabh Janardhan. Plano, TX; Irving, TX and Fort Worth, TX Introduction: The number of stroke centers being certified by The Joint Commission or Det Norske Veritas is rapidly growing. The importance of stroke centers becomes relevant when performance metrics such as D2N times improve. Methods: We evaluated the relationship between stroke center certification and D2N times in 4 hospitals undergoing certification (non-certified hospitals) compared with 5 certified stroke centers. D2N times were compared one year before (year 1) and one year after (year 2) establishing a performance metrics task force. Results: The non-certified hospitals had mean D2N times of 86 minutes in year 1 and 83 minutes in year 2 (Decrease in D2N time of 3 minutes); the certified hospitals had mean D2N times of 92.8 minutes in year 1 and 78.2 in year 2 (Decrease in D2N time of 14.6 minutes). Conclusion: The certified stroke centers had a more dramatic lowering of D2N times. This highlights the importance of stroke center certification, need for establishing stroke performance metrics task forces, having dedicated
Abstracts, American Neurological Association
stroke coordinators and implementing standardized stroke algorithms in improving the quality of stroke care. Study supported by: None. M1314. Does Antiplatelet Resistance Effect Stroke Severity? Ghulam Mustafa, Haris Kamal, Aaron McMurtray, Abdelrahman Beltagy, Rabia Ghazi, Ping Li and Bijal K. Mehta. Buffalo, NY and Torrance, CA Background: Antiplatelet resistance in stroke patients remains a clinical problem to neurologists. Our study reviewed whether being antiplatelet sensitive or resistant resulted in differences in stroke severity using the NIHSS. Methods: This study was a retrospective cross-sectional cohort study of all patients presenting with a new ischemic stroke between 1/2009-12/2011; a total 381patients were included.Study participants were analyzed in groups consisting of those sensitive, resistant and not treated with either clopidogrel or aspirin. The group being treated with both clopidogrel and aspirin was compared to those not being treated with any antiplatelet therapy. Results: The distribution of rank NIHSS scores significantly differed between those sensitive to clopidogrel versus those that were not (p 5 0.049). Patients on both aspirin and clopidogrel who were sensitive to both were compared to those that were not sensitive to either and those not treated with either aspirin or clopidogrel. A direct correlation was detected between increasing NIHSS score and antiplatelet resistance (p 5 0.014, correlation coef 5 0.157). Differences in vascular territories effected is discussed. Discussion: Our study shows that clopidogrel sensitivity appears to result in a decreased stroke severity. Our study did not show a similar finding with aspirin. Conclusion: This retrospective study provides evidence that antiplatelet resistance to clopidogrel results in differences in stroke severity. Study supported by: none relating to this study. M1315. Safety of Extracranial Carotid Stenting in Acute Ischemic Stroke Shahram Khalid and Andrew Xavier. Detroit Objective: To determine the safety and efficacy of carotid artery stenting (CAS) in the setting of acute ischemic stroke. Methods: The departmental database of patients with ischemic stroke from 2 metropolitan hospitals over last 5 years was reviewed. Outcomes were successful carotid revascularization (20% residual stenosis), revascularization of associated intracranial occlusion (TICI 2b), in-hospital mortality and discharge status. Results: 15 patients (6 Females, 5 African Americans) underwent CAS within 24 hours of ischemic stroke onset. Mean age was 61 (range 42–82) and mean NIHSS 16.1 6 7.60. Four patients had received IV tPA. No antiplatelets were used 24 hours after tPA administration. Suction thrombectomy was used at the extracranial location in 4 patients. Revascularization after stenting was successful in 14 patients (93.33%). Eight patients showed additional intracranial occlusion and revascularization was successful in seven patients (87.5%). Two patients had intracranial hem-
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orrhage (one symptomatic). Three patients with age 70, and NIHSS20 died during the hospitalization (20%). NIHSS at discharge was 5.75 6 4.11 in other patients. Conclusion: CAS can be performed successfully with good outcomes in patients with moderate neurological deficits from an acute ischemic stroke. Study supported by: No sponsor. M1316. Comparison of Outcomes with Pipeline and SILK Flow Diverters for the Treatment of Intracranial Aneurysms: A Systematic Review of Literature Santosh B. Murthy, Shreyansh Shah, Chethan P. Venkatasubba Rao, Eric Bershad and Jose I. Suarez. Houston Background: Emerging endovascular treatment options for complex intracranial aneurysms include flow diverters such as Pipeline Embolization Device (PED) and SILK Flow Diverter (SFD), with no head to head comparisons between them. We present a comparative analysis of published literature on PED and SFD. Methods: A literature was performed using the keywords “pipeline embolization device”, “SILK flow diverter”, or “flow diverters”, with inclusion criteria: n>10 patients, either PED or SFD use, 6-month follow-up. Results: We identified 21 studies. Demographics of PED vs SFD are as follows: n 5 905 vs 285, number of aneurysms 5 1043 vs 317, mean age 5 53.8 vs 52.7 years, females 5 76.3% vs 78.6% respectively. For PEDs, rates of mortality, stroke and ICH were 2.3%, 1.4%, and 1.6% respectively. The 6-month aneurysm occlusion rate (AOR) was 79.7% (95% CI: 0.78-0.83). For SFDs, the rates of mortality, stroke and ICH were 5%,7.7% and 1.4% respectively. The cumulative 6-month AOR was 79% (95% CI: 0.73-0.84). Conclusions: This systematic review suggests a higher incidence of stroke and mortality with SFD, with comparable AORs in the two groups. Study supported by: None. M1317. Severe Delays in Switch from Transfemoral Access to Transradial Access in Intra-Arterial Cerebral Thrombolysis Dileep R. Yavagal, Diogo C. Haussen, Keith G. DeSousa, Sophia Janjua, Raul G. Nogueira and Johnny Chung-Huan Sun. Miami, FL; New York, NY; Brooklyn, NY and Atlanta, GA Background: Trans-femoral access (TFA) for intra-arterial cerebral thrombolysis (IACT) in acute ischemic stroke may fail because endovascular devices can not reach the lesion. Although trans-radial access (TRA) has been reported in neuroendovascular procedures, TRA in IACT has not been studied. Hypothesis: While TRA is feasible for IACT, switching from TFA to TRA entails a significant delay. Methods: Patients undergoing TRA for IACT were analyzed retrospectively at 3 stroke centers. Results: Amongst the 3 centers, TRA was successful in 6/ 7 patients. The mean age was 72.6 6 9.0 years (5 male/1 female). TRA failed once because of small arm arteries. TFA failed because of aortic arch unfolding. Merci and/or Penumbra or Solitaire devices were deployed in the basilar artery (5 patients) or ICA (1 patient) through 6F guide
systems. The mean time to switch (mins.) from TFA to TRA were 151.6 6 78.5 and from TRA to procedure completion was 133 6 70.1. 5/6 cases achieved TICI 2b. Conclusion: TRA in IACT is feasible and beneficial in some cases but the time to switch from TFA is unacceptably long. Better strategies to select patients requiring TRA are needed. Study supported by: None. M1318. Analysis of Clinical Characteristics in Patients with NON-Hemorrhagic Reversible Cerebral Vasoconstriction Syndrome Aman Dabir, Ghulam Mustafa, Haris Kamal, Aaron Mcmurtray and Bijal Mehta. Buffalo, NY and Torrance, CA Background: Reversible Cerebral Vasoconstriction Syndrome(RCVS) is associated with subarachnoid and intracerebral hemorrhage. It is characterized by multisegment intracranial vasospasm, which can result in ischemia. However, recently there have been many cases in the literature of RCVS without intracranial hemorrhage. Blood in the subarachnoid and perivasculature spaces are known to induce vasospasm. The mechanism of vasospasm associated with these nonhemorrhaghic cases remains unknown. The treatment for these vasospastic events often involves endovascular administration of medications. Methods: Our study was a review of the literature describing RCVS in patients without intracranial or subarachnoid hemorrhage. Notation of demographic data, past medical history, social history, and presenting symptoms were collected. Commonality of these characteristic were analyzed and compared to those patients who present with RCVS associated with hemorrhage. Results: Multiple clinical characteristics and clinical scenarios will be discussed that may distinguish nonhemorrhagic RCVS patients. This may help in clinical diagnosis of patients and selecting patients for cerebral angiograms as conventional imaging (CTA/MRA) may appear normal in these patients; who also may have a LP for CSF that is negative for blood or xanthochromia. Conclusion: A preliminary description of clinical characteristics and “risk-factors” for non-hemorrhagic RCVS is discussed. Study supported by: none relating to the study. M1319WIP. ASCEND Study of Natalizumab Efficacy on Disability in Patients with Secondary Progressive Multiple Sclerosis (SPMS): Baseline Demographics and Disease Characteristics Daniel Mikol, Mark S. Freedman, Myla D. Goldman, HansPeter Hartung, Eva Havrdova, Douglas Jeffery, Raj Kapoor, Aaron Miller, Finn Sellebjerg, Sophia Lee, Yun Chen, Diego Cadavid and Barry Ticho. Weston, MA; Ottawa, ON, Canada; Charlottesville, VA; D€ usseldorf, Germany; Prague, Czech Republic; Advance, NC; London, United Kingdom; New York, NY and Copenhagen, Denmark Background: ASCEND is a fully enrolled, international, multicenter, randomized, placebo-controlled study of natalizumab’s effects on disability progression in SPMS patients.
Methods: Natalizumab-na€ıve adults with SPMS and Expanded Disability Status Scale (EDSS) score 3.0–6.5 were enrolled. Patients (N 5 889) were randomized 1:1 to receive intravenous natalizumab 300 mg or placebo (double-blind) every 4 weeks for 2 years. Assessments include disability progression and changes in walking ability, dexterity, cognition, quality of life, and brain volume. Results: Baseline mean patient age was 47.2 years; 62% female, 77% prior MS medications, 27% prior immunosuppressant therapy, 83% relapse-free in the prior year, and 55% anti-JC virus antibody positive at screening. Times (mean/ median) since first MS symptom, MS diagnosis, and SPMS diagnosis were 16.5/16.0, 12.0/11.0, and 4.8/3.7 years, respectively. Baseline assessment scores (mean/median) were EDSS 5.6/6.0; Multiple Sclerosis Severity Score 6.3/6.4; Timed 25Foot Walk 13.7/11.2 seconds; 9-Hole Peg Test (9HPT) dominant hand 34.8/28.6 seconds; 9HPT nondominant hand 37.2/29.7 seconds; 12-item MS Walking Scale 68.6/72.9. Conclusions: Baseline functional disability test scores are consistent with a disabled SPMS population. Results will be presented by low/high EDSS subgroups. Study supported by: Biogen Idec, Inc. Drs. Cadavid, Chen, Lee, Mikol, and Ticho are employees of Biogen Idec. Dr. Freedman has received research or educational grants from Bayer HealthCare and Genzyme; honoraria or consulting fees from Actelion, Bayer HealthCare, Biogen Idec, Celgene, EMD Canada, Genzyme, Glycominds, Hoffman LaRoche, Novartis, Opexa, sanofi-aventis, and Teva Canada Innovation; is a member of a company advisory board, board of directors, or other similar group for Actelion, Bayer HealthCare, Biogen Idec, Celgene, Hoffman La-Roche, Merck Serono, Novartis, Opexa, and sanofi-aventis; and has participated in a company-sponsored speaker bureau for Genzyme. Dr. Goldman has received honoraria for consulting from Novartis. Dr. Hartung has received honoraria for consulting and speaking at symposia from Bayer HealthCare, Biogen Idec, BioMS, Genzyme, Merck Serono, Novartis, Roche, sanofi-aventis, and Teva. Dr. Havrdova has received consulting and speaker honoraria from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, Sanofi, Genzyme, and Teva. Dr. Jeffery is a consultant for Acorda, Bayer, Genzyme, GlaxoSmithKline, Novartis, Pfizer, Questcor, Serono, and Teva and has received research support from Berlex, Biogen Idec, Novartis, Pfizer, Serono, and Teva. Dr. Kapoor has received honoraria for consulting and speaking from Biogen Idec, Genzyme, Novartis, and Teva. Dr. Miller has received consulting honoraria from Acorda, Biogen Idec, EMD Serono, Genzyme/Sanofi, GlaxoSmithKline, Novartis, Nuron Biotech, ONO, Questcor, and Teva Neuroscience and research support from Acorda, Biogen Idec, Genentech, Genzyme, Genzyme/Sanofi, Novartis, Osmotica, and Roche. Dr. Sellebjerg has served on scientific advisory boards for Biogen Idec, Genzyme, Merck Serono, Novartis, sanofi-aventis, and Teva; has been on the steering committee of a clinical trial sponsored by Merck Serono; has served as consultant for Biogen Idec and Novo Nordisk; has received support for congress participation from Biogen Idec, Novartis, sanofi-aventis, and Teva; and has received speaker honoraria from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis,
Abstracts, American Neurological Association
sanofi-aventis, and Schering-Plough. His laboratory has received research support from Bayer Schering, Biogen Idec, Merck Serono, Novartis, and sanofi-aventis. Neurodegenerative disorders M1401. CGG Repeat Associated Translation Drives Neurodegeneration in Fragile X Tremor Ataxia Syndrome Peter K. Todd, Seok Yoon Oh, Amy Krans, Fang He and Henry L. Paulson. Ann Arbor, MI Fragile X-associated Tremor Ataxia Syndrome (FXTAS) results from a CGG repeat expansion in the 5’UTR of FMR1. This repeat is thought to elicit toxicity as RNA yet disease brains contain ubiquitin-positive neuronal inclusions, a pathologic hallmark of protein-mediated neurodegeneration. We explain this paradox by demonstrating that CGG repeats trigger repeat associated non-AUG initiated (RAN) translation of a cryptic polyglycine-containing protein, FMRpolyG. FMRpolyG accumulates in ubiquitin-positive inclusions in Drosophila, cell culture, mouse disease models and FXTAS patient brains. CGG RAN translation occurs in at least two of three possible reading frames at repeat sizes ranging from normal (25) to pathogenic (90), but inclusion formation only occurs with expanded repeats. In Drosophila, CGG repeat toxicity is suppressed by eliminating RAN translation and enhanced by increasing polyglycine protein production. These studies expand the growing list of nucleotide repeat disorders, including C9orf72 associated FTD/ ALS, where RAN translation occurs and provide the first evidence that RAN translation can contribute directly to neurodegeneration. Study supported by: Support to PKT related to this project: AAN clinical Reserach Fellowship, NINDSK08KNS069809A, and Patti Harris Professorship. Support to FH related to this project: National Ataxia Foundation Post-doctoral fellowship. Support to HLP related to this project: RO1 NS038712 and RO1 AG034228. M1402. Sense and Anti-Sense RNA Foci in c9ALS/FTD: More Light in a House of Mirrors Michael W. Baughn, Clotilde Lagier-Tourenne, Shuying Sun, Frank Rigo, Frank Bennett, Don Cleveland and John Ravits. La Jolla, CA and Carlsbad, CA Background: Expanded repeats in the C9orf72 gene is a major cause of ALS and FTD. Of the proposed disease mechanisms, two could be treatable with gene knockdown therapy: toxicity of the RNA repeat, and non-ATG initiated translation of a dipeptide repeat. Methods: In ongoing FISH studies using locked nucleic acid probes, we localized foci from sense and antisense repeat expanded RNA strands in patient cell lines and tissues. Nucleases and targeted antisense oligonucleotides (ASO) tested specificity. Results: RNA foci were specific to repeat expanded C9orf72 carriers and were not found in a variety of controls. They were seen from both the sense and antisense strands. ASO knockdown indicated hybridization specificity.
Annals of Neurology Vol 74 (suppl 17) 2013
Isoform-specific ASOs could reduce foci without affecting overall transcript levels. siRNA treatment did not reduce foci. Discussion: RNA foci of the expanded repeat in the C9orf72 gene are a hallmark of c9ALS/FTD. Targeted ASO treatment is a viable therapeutic approach if disease mechanism is related to primary RNA toxicity or non-ATG initiated translation of the repeat RNA. Additional work defining the function of the strands in the disease process is needed. Study supported by: ALSA, P2ALS, UCSD. M1403. The Swedish Nerve Growth Factor Mutation (NGFR100W): Signaling Mechanisms and Its Potential Use for Treating Neurodegenerative Diseases Kijung Sung, William C. Mobley and Chengbiao Wu. La Jolla, CA The clinical application of NGF in treating Alzheimers disease and diabetic neuropathies has been severely constrained due to significant pain caused by NGF. Recently, a point mutation in NGF (NGFr100w) was identified in patients with hereditary sensory and autonomic neuropathy, type V (HSAN V), who suffered from loss of deep pain perception but had normal mental functions. We examined if signaling through TrkA or p75 is altered by NGFr100w. We show that NGFr100w bound to and activated TrkA receptor. It activated the MAP kinase and the PI3KAkt pathway to support neuronal survival and differentiation. However, NGFr100w did not bind to and stimulate p75-mediated signaling cascades. Further, NGFr100w lost the ability to induce hyper-potentiation of DRG sensory neurons. Finally, intraplantar injection of NGFr100w into the paw of adult rats induced neither thermal nor mechanical hyperaglgesia. Therefore, NGFr100w retains trophic support capability through TrkA, but no longer engages the p75-mediated signaling pathways, leading to an increase in pain threshold. We speculate that this is one of the major reasons for the loss of pain perception in HSAN V patients. Study supported by: NIH, Down Syndrome Research and Treatment Foundation, Larry L. Hillblom Foundation. M1404. Novel Mutations in the SQSTM1 gene Encoding p62 in Japanese Patients with Sporadic Amyotrophic Lateral Sclerosis Makito Hirano, Yusaku Nakamura, Kazumasa Saigoh, Hikaru Sakamoto, Shuichi Ueno, Chiharu Isono and Susumu Kusunoki. Sakai, Osaka, Japan and Osakasayama, Osaka, Japan Amyotrophic lateral sclerosis (ALS) mostly occurs sporadically, but 5%-10% of cases are familial. Mutations in genes for familial ALS have been found occasionally in apparently sporadic cases. Recent reports have suggested that the SQSTM1 gene encoding p62 is a causative gene for familial and sporadic ALS, accounting for 4.4% of all cases of sporadic ALS in the United States. In this study, we sequenced the SQSTM1 gene in 70 Japanese patients with sporadic ALS. We found two novel missense mutations (p.Ala53Thr and p.Pro439Leu) in two
patients. Cultured skin fibroblasts from one of the patients, but not those from controls, had cytoplasmic aggregation of p62 under oxidative stress, and ultimately died later. Accumulating evidence demonstrates that p62 plays a role in protein degradation. For example, this protein aggregates in neuronal inclusions of Alzheimer disease, Parkinson disease, and ALS. The previous and preset reports demonstrate that p62 is not only an aggregation marker, but is directly involved in neurodegeneration. Our finding also suggests worldwide, common involvement of this gene in ALS. Study supported by: A research grant from Kinki University. M1405. Immunohistochemistry and Confocal Laser Microscopy of Amyloid Plaques in Kuru Pawel P. Liberski, Pawel P. Liberski, Beata Sikorska and Beata Sikorska. Lodz, Poland Kuru was the first prion disease to be identified in humans, occurring in the Fore of Papua New Guinea; it was fatal and stereotyped cerebellar ataxic syndrome. Neuropathologically, kuru-affected brains were characterized by a neuronal loss, astrogliosis and spongiosis and the presence of numerous amyloid plaques. We performed electron microscopy, immunohistochemistry and confocal laser microscopy on brain material from a kuru case. The fine structure of plaques was surprisingly well preserved with compact core and radial fibrils at the periphery. Immunohistochemistry and confocal laser microscopy revealed that the plaques were built of PrPSc with abundant astroglial reaction around the core of the plaque. Dystrophic neurites characterized by MAP-tau, APP and p62 immunoreactivity were present. Additionally we performed 3D reconstruction of the kuru amyloid plaque using confocal laser microscope The proteins involved in dystrophic changes in neurites: APP, p62 and MAP-tau were present at the periphery of the amyloid plaques more frequently than in other areas of the cortex. We speculate that the amyloid fibrils influence the appearance of dystrophic neurites. Moreover, 3D reconstruction revealed the presence of astrocytic processes, partially intermingled with amyloid inside the plaques. Study supported by: no applicable. M1407. Method for Widespread microRNA-155 Inhibition Prolongs Survival in ALS-Model Mice Erica D. Koval, Carey Shaner, Peter Zhang, Xavier duMaine, Kimberlee Fishcer, Jia Tay, Nelson Chau, Greg Wu and Timothy M. Miller. St. Louis, MO and San Diego, CA microRNAs (miRNAs) are dysregulated in a variety of disease states, suggesting that this newly discovered class of gene expression repressors may be viable therapeutic targets. A microarray of miRNA changes in ALS model SOD1G93A rodents identified 12 miRNAs as significantly changed. Six miRNAs tested in human ALS tissues were confirmed increased. Specifically, miR-155 was increased 5 fold in mice and 2 fold in human spinal cords. To test miRNA inhibition in the central nervous system as a potential novel therapeutic, we developed oligonucleotide-based miRNA
inhibitors (anti-miRs) that could inhibit miRNAs throughout the central nervous system and in the periphery. AntimiR-155 caused global derepression of targets in peritoneal macrophages and, following intraventricular delivery, demonstrated widespread functional distribution in the brain and spinal cord. After treating SOD1G93A mice with antimiR-155, we significantly extended survival by 10 days and disease duration by 15 days (38%) while a scrambled control anti-miR did not significantly improve survival or disease duration. Therefore, antisense oligonucleotides may be used to successfully inhibit miRNAs throughout the brain and spinal cord, and miR-155 is a promising new therapeutic target for human ALS. Study supported by: This work was supported by the National Institute of Neurological Disorders and Stroke [K08NS074194 to T.M.M., R01NS078398 NINDS to T.M.M., F31 11022783 to E.D.K.]; The Robert Packard Center for ALS Research to T.M.M.; Project5 for ALS to T.M.M.; and the Edward Mallinckrodt, Jr. Foundation to T.M.M. Regulus Pharmaceuticals has provided the antisense oligonucleotides used in these studies. Washington University has filed a use patent on inhibiting miR-155 as a potential therapy for ALS. Regulus Therapeutics has filed a patent regarding the method of miR-155 inhibition using antisense oligonucleotides.
M1408. Trophic Factor Treatment Is Associated with Increased Alpha Synuclein Expression John R. Konen, Emeline Tolod-Kemp, Chris J. Kemp, Timothy J. Collier, Kathy Steece-Collier and Caryl E. Sortwell. Grand Rapids, MI Alpha-synuclein (a-syn) has been linked to Parkinson’s disease (PD) with over-expression and aggregation inducing toxicity. Thus an increase in a-syn expression is presumed detrimental. However, other studies suggest that some level of a-syn is required for normal survival of nigral dopamine (DA) neurons. We investigated the relationship between dopaminotrophic factors and endogenous a-syn protein expression in mesencephalic DA neurons in vitro. Primary E14 rat ventral mesencephalic cultures were treated with four neurotrophic factors: basic fibroblast growth factor (bFGF), brain derived neurotrophic factor (BDNF), pleiotrophin (PTN) and glial cell line-derived neurotrophic factor (GDNF). Cultures were labeled using immunofluorescently tagged antibodies against tyrosine hydroxylase (TH) and a-syn, individual neurons were measured for levels of TH and a-syn immunofluorescence intensity. Cultures treated with BDNF, bFGF, and PTN exhibited a 5–10 fold increase in endogenous a-syn expression compared to control and GDNF-treated cultures and exhibited greater TH fluorescence intensity. Our findings indicate that trophic factor signaling known to support nigral DA survival can be associated with increased a-syn expression suggesting that increased levels of a-syn within a certain physiological range should not be viewed as detrimental. Study supported by: NS058682 (CES) and The Morris K. Udall Center for Excellence in Parkinson’s Disease Research at Michigan State University NS058830 (TJC).
Abstracts, American Neurological Association
M1409. Novel Role of Depression-Associated Transcription Factor GATA1 in Aging and Alzheimer’s Disease Giulio M. Pasinetti and Wei Zhao. New York, NY Recent evidence suggests decreased expression of synapticrelated genes in major depressive disorder coincides with increased depression-associated transcription factor GATA1 (Kang et al.,2012). Depression is also linked to cognitive decline during aging and synaptic loss in Alzheimer’s disease (AD); however, this relationship is poorly understood. In this study, we explored GATA1 expression in frontal cortex of post-mortem AD brain (n 5 24). We examined the causal effect of GATA1 on expression of synaptic genes in neuronal cells experimentally and in relation to AD neuropathology. We found significant elevation of GATA1 in frontal cortex of AD patients with a history of depression which correlated inversely with synaptic gene expression (e.g. synapsin1) and correlated positively with the content of AD amyloid plaques. Exogenous expression of GATA1 in neuronal cells resulted in decreased expression of pre-synaptic genes. Feasibility evidence suggests exogenous GATA1 expression promotes beta-amyloid generation in HEK cells expressing mutant amyloid precursor protein. Our study for the first time suggests GATA1 expression may negatively influence brain synaptic plasticity and causally promote the transition from normal cognitive function during aging to AD cognitive deterioration and dementia through mechanisms involving amyloid neuropathology. Study supported by: Discretionary funding to GMP. M1410. IRX4204 in Preclinical Parkinsonism: Experimental Evidence and Clinical Implications Giulio M. Pasinetti. , NY Currently there is no disease-modifying treatment for Parkinson’s disease (PD). Activation of the nuclear Rexinoid X Receptor (RXR) may protect against PD by providing trophic support for dopaminergic neurons, which is thought to be mediated by signal transduction involving activation of the heterodimeric RXR-Nurr1 nuclear receptor complex by interaction with RXR-activating ligands. Currently available RXR ligands are not selective to RXRs, significantly limiting their potential application to treat PD. IRX4204 is a second-generation RXR agonist with high potency and selectivity. We found IRX4204 accumulated in the brain following repeated dosing in rodents. Using primary mesencephalic culture, we also found IRX4204 can significantly improve dopaminergic neuron survival, in part by activating Nurr1-RXR heterodimerization in vitro. Using a conventional rodent model of PD, we found administration of IRX4204 can significantly improve PD-like phenotype in unilateral 6-hydroxydopamine lesioned rats. Our in vitro studies also demonstrated that IRX4204 is a potent inhibitor of a-synuclein aggregation. Thus, IRX4204 is effective in modulating several mechanisms relevant to PD. Our ongoing studies continue to examine mechanisms by which IRX4204 may protect against PD and will provide scientific impetus for the application of IRX4204 in treating PD patients. Study supported by: Io Therapeutics, Inc. Io Therapeutics, Inc. provides us with the compound IRX4204 for our
Annals of Neurology Vol 74 (suppl 17) 2013
studies. There is a SRA between Mount Sinai and Io Therapeutics, Inc. M1411. Randomized Trial of Rifampicin in MSA: Effect on Autonomic Function Wolfgang Singer, Robert D. Fealey, Paola Sandroni, Eric J. Ahlskog, Joseph Y. Matsumoto, James H. Bower, Melinda S. Burnett, Jay Mandrekar, Tonette L. Gehrking, James D. Schmelzer, David M. Sletten, Jade A. Gehrking, Adam J. Loavenbruck, Eduardo E. Benarroch and Phillip A. Low. Rochester, MN Objective: To determine the effect of rifampicin on progression of autonomic failure in multiple system atrophy (MSA). Background: We undertook an oligocenter, randomized, double-blind, placebo-controlled trial of rifampicin in MSA which failed to demonstrate efficacy for primary and secondary clinical outcome measures after 12 months. Autonomic deficits occur typically early in MSA with rapid progression. Methods: Patients enrolled at Mayo underwent standardized autonomic testing in addition to clinical and laboratory evaluations at baseline and study completion. Sudomotor, cardiovagal, and adrenergic deficits were quantified on a composite autonomic severity scale (CASS, range 0–10). Thermoregulatory sweat test was performed to derive anterior body anhidrosis (TST%, 0–100). Autonomic symptoms were quantified in patients at all centers using a validated instrument (COMPASS_select). Results: Of the patients enrolled at Mayo, 10 received rifampicin, 9 placebo. CASS was 6.5 6 2.8 versus 6.4 6 2.3 at baseline and 7.2 6 2.7 versus 6.9 6 2.0 following treatment (rifampicin versus placebo, change p 5 0.96). TST% was 31.4 6 30.5 versus 48.4 6 32.5 at baseline and 34.7 6 27.6 versus 53.8 6 38.6 following treatment (change p 5 0.44). COMPASS_select was 32.9 6 21.9 versus 34.5 6 18.5 at baseline and 41.2 6 20.3 versus 36.2 6 18.6 following treatment (change p 5 0.61). Conclusions: There was no significant effect of rifampicin on progression of autonomic deficits and symptoms. Study supported by: NIH (P01NS44233, U54NS065736, K23NS075141, UL1RR24150) and Mayo Funds. M1412. Randomized Clinical Trial of Rifampicin in MSA Phillip Low, David Robertson, Sid Gilman, Horacio Kaufmann, Wolfgang Singer, Italio Biaggioni, Roy Freeman, Susan Perlman, Robert Hauser, Stephanie Lessig, Steven Vernino, Jay Mandrekar, William Dupont, Thomas Chelimsky and Wendy Galpern. Rochester, MN; Nashville, TN; Ann Arbor, MI; New York, NY; Boston, MA; Los Angeles, CA; Tampa, FL; La Jolla, CA; Dallas, TX; Milwaukee, WI and Bethesda, MD Objective: To determine efficacy of rifampicin on MSA progression. Background: In a mouse model of MSA, rifampicin inhibits formation of a-synuclein fibrils, the neuropathological hallmark of MSA, and improves behavioral and neuropathological changes.
Methods: We undertook a randomized, double-blind, placebo-controlled trial of 100 MSA patients recruited from 10 US sites and followed for 12 months. Subjects were randomized to rifampicin 300 mg BID or matching placebo. The primary outcome measure was rate of change from baseline to 12 months in UMSARS I score. Results: Subjects had possible (48%) or probable (52%) MSA; 38% were women. The mean age was 61.0 6 8.5 (mean 6 SD); 11 subjects withdrew prematurely. The study was stopped after pre-planned interim analysis met futility criteria. The UMSARS I slopes were 0.50 6 0.50 and 0.50 6 0.70 in the placebo and rifampicin arms, respectively (P 5 0.817). UMSARS II slopes were 5.4 6 6.6 and 7.0 6 6.3 in placebo and rifampicin groups (P 5 0.225). Slopes for Total UMSARS(I1II) were 10.6 6 12.1 and 11.0 6 11.6 in placebo and rifampicin subjects (P 5 0.806). Compass_select at baseline was 34.5 6 18.5 for placebo and 32.9 6 21.9 for rifampicin subjects. At 12 months compass_select was 36.2 6 18.6 and 41.2 6 20.3 in placebo and rifampicin subjects (P 5 0.610). Conclusions: Rifampicin is ineffective in modifying disease progression in MSA. Study supported by: NS 44233 Pathogenesis and Diagnosis of Multiple System Atrophy; U54 NS065736 Autonomic Rare Disease Clinical Consortium.
M1413. Presence of Phosphorylated Tau Protein in the Skin of Patients with Alzheimer Disease Ildefonso Rodriguez-Leyva, Martha Santoyo, Erika Chii, Veronica Medina-Mier, Bertha M.B. Torres, Juan P. Castanedo and Maria E. Jimenez-Capdeville. San Luis Potosi, Mexico Objective: The presence of misfolded proteins is the hallmark of neurodegeneration, the specific biomarker was identified through brain tissue evaluation. Now we know that proteinopathies could be systemic, enabling the possibility to find them in several tissues. Our quest is to demonstrate their presence in skin. Methods: Tau protein was evidenced by means of monoclonal antibodies recognizing two phosphorylation sites characteristic of AD and a polyclonal antibody against nonphosphorylated tau. The immunohistochemical technique was performed in paraffin-included tissues and validated in parallel analysis of brain and skin tissue from a death AD patient. Biopsies from both control and diseased subjects (AD, LBD, PSP, CBD) were processed and analyzed in blind way. Results: Aggregates of phosphorylated tau protein were abundant in the hippocampus and neocortex of AD. Scattered aggregates of phosphorylated tau protein were found, in the epidermis, dermis fibroblasts and skin appendages from patients with neurodegenerative diseases. The study is ongoing. Conclusions: Aggregates of phosphorylated tau are present in the skin of AD patients and non-detectable in control subjects. These findings require further confirmation, but have the potential of improving the diagnostic accuracy using a minimally invasive modality.
Study supported by: The principal author is speaker of Novartis, Genzyme (Sanofi), UCB, Boehringer-Ingelheim. M1414. RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention Christopher J. Donnelly, Pingwu Zhang, Svetlana Vidensky, Elizabeth Daley, Benjamin Hoover, Bryan Traynor, Frank Rigo, Frank Bennett, Blackshaw Seth, Rita Sattler, Jeffrey D. Rothstein and Jeffrey D. Rothstein. Baltimore, MD; Bethesda, MD and San Diego, CA A hexanucleotide ‘GGGGCC’ repeat expansion in the noncoding region of the C9ORF72 gene has recently been identified as the most common known genetic cause of sporadic and familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While the pathogenic mechanism behind this mutation is unclear, repeat expansion disorders are the known causes of other neurological/ neuromuscular disorders, with some due to expansions in non-coding regions including myotonic dystrophy 1 and 2 (DM1, DM2). In non-coding repeat expansion disorders, pathogenesis may be due to the accumulation of expanded repeat-containing RNA transcripts that sequester RNA binding proteins (RBPs). Since animal models are still being generated, to elucidate the pathogenic mechanism behind the C9ORF72 mutation, we have generated iPS cells from C9ORF72 ALS patient fibroblasts. Using iPS-differentiated neurons and astrocytes, we have 1) identified intranuclear (GGGGCC)exp RNA foci in vitro similar to those found in vivo, 2) described dysregulated gene expression in C9ORF72 ALS tissue that match iPS cell lines, and 3) have identified two (GGGGCC)exp RNA binding partners, ADARB2 and TRIM32. Importantly, all of these pathogenic characteristics can be mitigated with RNase H-based antisense therapeutics to the C9ORF72 transcript. Taken together, these data point to a toxic RNA gain-of-function mechanism for C9ORF72 ALS. Study supported by: Funded by grants from NIH (NS33958; , P2ALS, Muscular Dystrophy Association and the Robert Packard Center, for ALS Research and from Maryland Stem Cell Research Fund. M1415. Disease Progression Model To Characterize the Amyotrophic Lateral Sclerosis Time-Course in Patients Treated with Placebo Roberto Gomeni and Maurizio Fava. La Fouillade, France and Boston, MA Aims: To develop a longitudinal model for describing the time-course of the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) in patients with amyotrophic lateral sclerosis (ALS) treated with placebo and to estimate the presence of clusters in the trajectories describing the progression of ALS during 9 months of treatment. Methods: 338 patients treated with placebo from the PRO-ACT database (https://nctu.partners.org/ProACT/) were included in the analyses. The ALS disease progression was described by a 4-parameter model: baseline ALSFRS-R, rate of ALS progression, rate of change in response and lower ALSFRS-R bound. The presence of clusters in
Abstracts, American Neurological Association
ALSFRS-R trajectories was investigated using a mixture model. Results: A Weibull model accurately described ALS progression. The mixture model identified two clusters: cluster_1 (75% of patients) and cluster_2 (35% of patients) characterized by a decline in ALSFRS-R of 15% and 50% from baseline after 9 months respectively. Conclusion: Results showed that the rate of ALS progression quantified by symptomatic change on placebo at 9 months is highly heterogeneous. This finding indicates the interest for implementing a disease-progression-based population enrichment strategy to control the level of heterogeneity in new trials. Study supported by: none. M1416. Are the Mechanisms of the Oxidative Stress in Alzheimer and Parkinson’s Disease Different? Andrzej Friedman and Jolanta Galazka-Friedman. Warsaw, Poland Background: Iron-mediated oxidative stress plays an important role in the neurodegeneration. It is not known if the specific pathway leading to the oxidative stress is similar in all neurodegenerations. This oxidative stress is triggered by an excess of divalent iron, which may produce free radicals. The concentration of this iron depends on iron-storage capacities of ferritin. Aim: to compare the concentration of iron and the structure of ferritin in parkinsonian (PD) substantia nigra (SN) and Alzheimer (AD) hippocampal cortex (Hip) Methods: The concentration of the total iron was determined by M€ossbauer spectroscopy or atomic absorption and the structure of ferritin by ELISA method. The obtained results were compared to the control tissues. Results: In PD no difference in the total iron compared to control was found but the ELISA study revealed an important decrease of the concentration of L-ferritin. In AD Hip a significant increase of both L and H ferritin without an important increase of the total iron concentration, compared to control, was found. Conclusion: Our results suggest that the way, by which the oxidative stress is triggered in these two diseases is different. Study supported by: No financial support. M1417. Th2-Type Cytokines in the Plasma of Parkinson’s Disease Patients Are Up-Regulated Keri C. Smith, Mary F. McGuire, Diane L. Bick and Mya C. Schiess. Houston Peripheral and intra-cranial immune cells have been implicated in the pathoetiology of Parkinson’s disease (PD), therefore the molecular profile of patients with PD shoulld be distinctly different from that of controls and patients with atypical PD like Mulitple System Atrophy (MSA). Plasma samples from 3 PD, 3 MSA and 3 control patients were added to MILLIPLEX Map Human Cytokine/Chemokine assay (Millipore, Billerica, MA); 38 different analytes measured and analyzed using a Bio-Plex 200 equipped with Bio-Plex Manager software; calculated values
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of each analyte collected from individual patients at baseline, 6,18 and 24 months. Significant changes were not seen over time for individual patients. Between group differences for cytokine/chemokines were based on median values. Th2 pathway cytokines were all up-regulated in PD ; Th17 associated cytokines unchanged from controls; IL-12p70 associated with Th1 significantly increased in PD vs control; IFNgamma unchanged; IL-12 p40 markedly increased in PD. IL-2 considered an early T cell activation cytokine increased in PD. Hematopoietic growth factors all increased in PD, suggests mobilization and maturation of immune cells. This pilot study suggests T cell activation occurs in PD compared to controls and MSA patients. Study supported by: Adriana Blood Endowed Chair; Kanaly Fund for Parkinson’s Research. M1418. Three Dimensional Volumetric Analysis of Skin Biopsies Confirm Intraepidermal Nerve Fiber Densities Chelsea N. Lindblad, John M. Hayes, Eva L. Feldman and Stephen I. Lentz. Ann Arbor, MI Counting nerves in skin sections stained using chromogenbased immunohistochemistry is a common methodology to determine the intraepidermal nerve fiber density (IENFD) and diagnose small fiber neuropathy. However, this method may not portray the actual volume of nerve fibers in the epidermis. We developed a three dimensional (3D) analysis technique for fluorescently stained nerves to assess cutaneous innervation. Immunohistochemistry was performed on 20 control subjects, and entire skin sections were visualized using confocal microscopy. Images were processed with the 3D computer software, Imaris, to generate the nerve and epidermal volumes. Ratios of these volumes were calculated to find the IENFDs. These ratios were then compared to the IENFDs measured by the traditional chromogen-based immunohistochemistry protocol to determine the relationship. Initial results demonstrate that volumetric ratios correlate with IENFDs generated using bright field microscopy (R-squared 5 0.721, P < 0.0001). The average volumetric ratio of these samples is 0.284 and the average IENFD is 15.955 fibers/mm, which is within the normative range for healthy patients of this age. These results verify that using the standard protocol is an accurate way to diagnose small fiber neuropathy. Study supported by: The Program for Neurology Research and Discovery. M1419. Identification of Factors Associated with Sural Nerve Regeneration and Degeneration in Diabetic Neuropathy Junguk Hur, Kelli A. Sullivan, Rodica Pop-Busui, Brian C. Callaghan and Eva L. Feldman. Ann Arbor, MI Patients with diabetic neuropathy (DN) demonstrate variable degrees of nerve regeneration and degeneration. To identify risk factors associated with sural nerve regeneration in DN, we retrospectively examined demographic, anthropometric and biochemical data of diabetic subjects from a clinical trial of acetyl-L-carnitine. Based on the change of sural nerve myelinated fiber density (DMFD%), subjects
were divided into three groups: Regenerator (top 16%, n 5 67), Intermediate (n 5 290), and Degenerator (bottom 16%, n 5 67). HbA1c at baseline was the only risk factor significantly different between Regenerator (8.3 6 1.6%) and Degenerator (9.2 6 1.8%), p 5 0.01 with other factors adjusted. Support Vector Machine classifier using HbA1c alone demonstrated 62.4% accuracy classifying subjects into Regenerator or Degenerator. Microarray analysis revealed that upregulated genes in Regenerator are enriched in cell cycle and myelin sheath functions, while downregulated genes are enriched in immune/inflammatory responses. In conclusion, these data, based on the largest available DN patient cohort with MFD information, suggest that HbA1c level predicts myelinated nerve fiber regeneration and degeneration in patients with DN, and that maintaining optimal blood glucose control is essential in patients with DN to prevent continued nerve injury. Study supported by: Program for Neurology Research & Discovery; A. Alfred Taubman Medical Research Institute; JDRF Postdoctoral Fellowship to JH (JDRF grant number: 3–2011-237). M1420. Effects of Acetyl-DL-Leucine in Patients with Cerebellar Ataxia: A Case Series Michael Strupp, Katharina Feil, Maximilian Habs, Thomas Klopstock and Julian Feil. Munich, Germany Background: New drugs that effectively treat cerebellar ataxia are required. Objective: Perform a case series of patients with degenerative cerebellar ataxia to evaluate the severity of impairment based on ataxia scores (Scale for the Rating and Assessment of Ataxia (SARA) and Spinocerebellar Ataxia Functional Index (SCAFI)) before and during treatment with acetylDL-leucine (Tanganil). This agent has been shown to stabilize membrane potential in neurons. Design/Methods: Twelve patients (7 females, median age 49) with degenerative cerebellar ataxia of different etiology (SCA1/2, ADCA, AOA, SAOA) were treated with acetylDL-leucine (5 g/d) for at least 1 week. Motor function was evaluated by changes in the SARA and the SCAFI after 7 days of treatment compared to baseline values. Quality of life and side effects were also assessed. Results: The SARA decreased from a baseline of 16.3 6 7.4 (mean 6 SD) to 13.0 6 7.0 (p 5 0.003, Wilcoxon signed-rank test). There was an improvement in the 8 m walking test (p 5 0.003), speech task (PATA, p 5 0.005), the 9-hole peg test (p 5 0.011), and in the subscore testing of the SCAFI. No side effects were reported. Conclusions: Acetyl-DL-leucine significantly improved ataxic symptoms, suggesting a beneficial risk-benefit profile. Study supported by: Federal Ministry of Research. M1421. Diabetes and Neuropathy-Induced Alterations in Sensory Neuron Mitochondria Colin M. Mervak, Alexandra E. Munch, Hussein S. Hamid, Nicholas J. Robell, John M. Hayes, J. Robinson Singleton, A. Gordon Smith, Eva L. Feldman and Stephen I. Lentz. Ann Arbor, MI and Salt Lake City, UT
Diabetic peripheral neuropathy (DPN) is characterized by length-dependent degeneration of sensory nerves. This study focused on altered mitochondrial dynamics as a potential mechanism for DPN by measuring the size distribution of mitochondria within intraepidermal nerve fibers (IENFs). Cutaneous punch biopsies from distal thigh and distal leg were obtained from patients with diabetes and no DPN, patients with diabetes and confirmed DPN, and healthy controls. Fluorescent immunohistochemistry, confocal microscopy and 3D analysis software was used to isolate and quantify nerve-specific mitochondria signals. Mitochondria distributed within distal thigh IENFs were increased in diabetic and DPN patients compared to controls, represented by a significant shift in size frequency distribution of mitochondria towards larger mitochondria within distal thigh nerves of diabetic and DPN patients. Interestingly, there was a length-dependent difference in mitochondria within IENFs of healthy controls. Distal leg IENFs significantly shifted towards larger volumes of mitochondria signal compared to distal thigh IENFs. This shift towards larger mitochondria signals was also observed in distal leg IENFs in diabetic patients with and without DPN. Results of this study support the hypothesis that altered mitochondrial dynamics may contribute to DPN pathogenesis. Study supported by: This work was supported by National Institutes of Health Grants NS-38849 and DK076160, the Juvenile Diabetes Research Foundation Center for the Study of Complications in Diabetes, the Program for Neurology Research and Discovery and the A. Alfred Taubman Medical Research Institute at the University of Michigan. This work used the Morphology and Image Analysis Core of the Michigan Diabetes Research and Training Center funded by National Institutes of Health Grant 5P60 DK-20572 from the National Institute of Diabetes and Digestive and Kidney Diseases. CMM, AEM and NJR were supported by a Howard Hughes Medical Institute (HHMI) Summer Fellowship and HSH received a Biomedical and Life Sciences Summer Fellowship through the Undergraduate Research Opportunity Program that was funded in part by the HHMI. M1422. Neuronal Progenitor Markers Are Increased in Dorsal Root Ganglia of Diabetic Mice Tatsuhito Himeno, J. Simon Lunn, Carey Backus, Catrina Robinson, Crystal Pacut, John M. Hayes, SangSu Oh, Jacqueline R. Dauch, Lisa L. McLean, Lucy M. Hinder, Junguk Hur, Phillipe D. O’Brien and Eva L. Feldman. Ann Arbor, MI Regenerative therapies employing endogenous progenitor cells have potential applications in many diseases. In the peripheral nervous system, neural and glial progenitor cells are evident in dorsal root ganglia (DRG); however, their cellular distribution has not been explored. Using the leptin receptor-deficient BKS-db/db mouse model of type 2 diabetes, we observe an increase in nuclear staining of the neural progenitor cell markers Musashi1 and SOX2 in DRG satellite cells in db/db mice compared to controls. Musashi1expressing cells significantly increased in middle-aged (16
Abstracts, American Neurological Association
week) mice compared with young (4 week) mice. Unexpectedly, we observed these increases not only in satellite cells, but also in mature neurons. To determine the implications of this observation, we examined Notch signaling, which modifies the cell cycle and accelerates proliferation. Mature neurons in 16 week mouse DRG expressed activated Notch2, but not activated Notch1. Activated Notch2 expression levels increased with age, and the number of activated Notch2-expressing cells significantly increased in db/ db mice compared to controls, suggesting that Notchdependent signaling is increased in DRG neurons under diabetic stress. Future work aims to elucidate the importance of neural progenitors in DRG in diabetes. Study supported by: Support provided by the National Institutes of Health (NIH 1DP3DK094292), the Program for Neurology Research and Discovery, and the Manpei Suzuki Diabetes Foundation (fellowship to TH). M1423. Hyperlipidemia-Induced Neuropathy in a Murine Model of Type 2 Diabetes Phillipe D. O’Brien, Nick J. Robell, John M. Hayes, Jacqueline R. Dauch, SangSu Oh, Junguk Hur, Yu Hong and Eva L. Feldman. Ann Arbor, MI Diabetic neuropathy is the most common complication associated with diabetes. Apart from strict glucose control in type 1 diabetes, effective therapeutic interventions do not exist. The leptin-deficient BTBR ob/ob type 2 diabetes mouse model develops severe early-onset diabetes accompanied with an array of diabetic complications similar to the human condition, including diabetic retinopathy, nephropathy, cardiomyopathy, and steatohepatitis. Here, for the first time, we characterize the neuropathic phenotype of the BTBR ob/ob mouse. We observed significant deficits in motor and sensory nerve conduction velocities, thermal hyperalgesia, and increased small fiber loss in BTBR ob/ob mice. This early onset and severity of neuropathy suggest that BTBR ob/ob mice are ideal to assess neuropathy pathogenesis and gain insight into key events in disease progression; therefore, we performed microarray analyses on dorsal root ganglia and sciatic nerve of juvenile and adult BTBR ob/ob mice. We discovered that key biological processes, including inflammation and lipid/cholesterol synthesis, are dysregulated at different stages of diabetic neuropathy pathogenesis. Further analyses are underway to identify molecular pathways that may be targeted to develop novel therapeutic interventions for diabetic neuropathy. Study supported by: This work is supported by the Program for Neurology Research and Discovery (PNR&D), American Diabetes Association, Milstein, Nathan and Rose Research Fund, Sinai Medical Staff Foundation Neuroscience Scholar Fund 2, Robert C Graham Fund, and the Walbridge Aldinger Graduate Fellowship Fund. M1424. Activation of Mitochondrial Bioenergetics by a Novel PGC-1alpha/PINK1 Signaling Pathway in Diabetes-Induced Neurodegeneration Joungil Choi, Vera V.K. Batchu, Manfred Schubert, Rudolph J. Castellani and James W. Russell. Baltimore, MD and Bethesda, MD
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PGC-1alpha and PINK1 are key molecules in the maintenance of mitochondrial integrity in neurodegeneration. PGC-1alpha downregulation is associated with mitochondrial dysfunction and impaired lipid metabolism in obesity and diabetes, which increase the risk of neurodegenerative disease. Polymorphisms in PINK1 are associated with altered plasma fatty acids and oxidative energy metabolism in diabetes. Loss-of-function mutations in PINK1 are linked to Parkinson’s disease. We report that a previously unrecognized, novel 35-kDa PGC-1alpha localizes to the mitochondrial inner membrane and matrix in brain. The 35-kDa PGC-1alpha protein is significantly decreased in human Alzheimer disease (AD) and in diabetic animal brains. Immunoelectron microscopy of mouse mitochondria and import experiments in vitro revealed that 35-kDa PGC-1a colocalizes and interacts with the voltage-dependent anion channel (VDAC), and its import depends on VDAC. The 35-kDa PGC-1alpha binds and colocalizes with PINK1 in brain mitochondria. Overexpression of PGC-1alpha increases mitochondrial fatty acid oxidation upon exposure to lipid overload; down-regulation of PINK1 abolishes these effects. These results provide new insights into 35-kDa PGC-1alpha’s role in mitochondrial beta oxidation in a PINK1-dependent manner and implicate impaired mitochondrial signaling in the pathogenesis of diabetic neurodegeneraton. Study supported by: Office of Research Development (Biomemedical and Laboratory Research Service), Department of Veterans Affairs, NIH RR024888. M1425. Selective Up-Regulation of TRiC Subunit(s) Ameliorates mHtt Toxicity Xiaobei Zhao, Eugene Han, Rotem Fishel Ben Kenan, William Mobley and Chengbiao Wu. La Jolla, CA The molecular chaperonin TRiC (CCT) plays a critical role in maintaining cellular proteostasis. Mutant huntingtin protein in Huntington’s disease (HD) is a client protein of TRiC. An attractive therapeutic strategy is to identify means that can significantly increase the level/activity of TRiC within affected cells to sequester mutated proteins. We have constructed all eight individual human CCT1–8 subunits with their C-terminus tagged with mCherry or HA to facilitate imaging and biochemical analysis. Our preliminary data show that expression of a single CCT subunit(s) is sufficient to induce upregulation of both the level and activity of TRiC in multiple cell lines as well as in primary neurons. Overexpression of CCT3-mCherry or CCT5-mcherry is sufficient to induce upregulation of cellular TRiC complex. Co-transfection of CCT3- or CCT5-mCherry with wildtype Huntingtin exon 1 with 25 polyQs (HttQ25-GFP) or the mutant form with 97 polyQs (mHttQ97-GFP) in PC12 cells demonstrate that the level of mHttQ97-GFP is significantly decreased while wtHtt25-GFP is not altered. We believe that selective upregulation of a single CCT subunit is sufficient to increase the level/activity of the TRiC complex, which will enhance cells’ ability to ameliorate toxicity in HD. Study supported by: NIH 5PN2EY016525-06.
M1426. Use of a Disease Progression Model To Enrich the Study Population in Clinical Trials Conducted in Patients with Amyotrophic Lateral Sclerosis Roberto Gomeni and Maurizio Fava. La Fouillade, France and Boston, MA Aims: To evaluate the predictive performances of the amyotrophic lateral sclerosis (ALS) disease progression model, to develop models for estimating the degree of symptomatic change of ALSFRS-R scale at 9 months given measurements at weeks 2–4, to use this model for implementing population enrichment strategies. Methods: 338 patients treated with placebo from the PRO-ACT database (https://nctu.partners.org/ProACT/) were analyzed. The database was randomly split in learning (n 5 228, model development) and test datasets (n 5 110, model validation). ROC-curve analyses estimated the optimal cut-off for classifying patients as slow (change in ALSFRS-R < 15% in 9 months) or fast disease progressors (otherwise) given ALSFRS-R measurements at 2–4 weeks. Results: The comparison between observed and Bayesian estimates of ALSFRS-R trajectories in the validation dataset provided a measure of model predictive performances. The area under ROC-curves, (week 2 5 0.90, week 4 5 0.88), indicated the prognostic power of early ALSFRS-R measures. Conclusion: Results showed that ALS disease progression at 9 months can be accurately anticipated using ALSFRS-R at 2–4 weeks and that the classification rule of patients in slow/fast disease progressors can be used for implementing an enrichment strategy. Study supported by: None. M1427. Characterization of Cancer Drug IRX4204 as a b-Sheet Breaker for Treatment of Neurodegenerative Disorders Jun Wang and Giulio M. Pasinetti. New York, NY Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease of aging with an estimated prevalence of 5.3 million in the U.S. alone. Currently, there is no cure for AD; therefore, developing novel therapeutic agents to prevent or slow AD progression and possibly delay onset of dementia is of immediate importance. IRX4204 is a potent retinoid X receptor-specific agonist with an extensive track record of safety in oncology trials. We have designed a study to elucidate the novel role of IRX4204 to attenuate abnormal tau processes associated with neurodegenerative conditions known as tauopathy. Recent evidence from our laboratory supports the hypothesis that IRX4204 may neuroprotect in AD and other tauopathies by acting as a bsheet breaker preventing or reversing the formation of fibrillar tau oligomers, and potentially preventing synaptotoxicity early in AD prior to neuronal loss. Our study will be the first to explore the mechanism of the preclinical therapeutic role of IRX4204 in preventing cognitive deterioration using the THMT tau mutant mouse model. The results from our study will support development of IRX4204 for preventative and long-term therapeutic application in tauopathies including AD.
Study supported by: Io Therapeutics, Inc.; Io Therapeutics, Inc. supported the study by providing our laboratory with the compound being tested. M1428. Dysregulation of miRNAs in Sporadic ALS Claudia Figueroa-Romero, Junguk Hur, Diane E. Bender, Michael D. Cataldo, Andrea L. Smith, Raymond Yung, Brian C. Callaghan and Eva L. Feldman. Ann Arbor, MI Amyotrophic lateral sclerosis (ALS) is a progressive and terminal neurodegenerative disease. The majority (90–95%) of ALS cases are sporadic (sALS) with unknown causes. Longterm influences of environmental factors may alter epigenetic mechanisms, such as miRNAs, leading to aberrant gene expression that culminates in sALS. Our goal is to address the role of miRNAs in the pathogenesis of sALS. We hypothesize that differential expression of miRNAs in human sALS spinal cord promotes dysregulation of key genes and biological pathways leading to sALS. Systems biology analyses combining TaqMan OpenArray and Affymetrix GeneChip Human Genome U133 Plus 2.0 on postmortem human spinal cord tissue identified 90 differentially expressed miRNAs and 1,182 differentially expressed genes (DEG). Since miRNAs negatively regulate gene expression, we identified the inverse correlation between differentially expressed miRNAs and mRNAs. Potentially relevant miRNA DEG targets were obtained by compiling multiple miRNA prediction target databases. Gene and miRNA expression was confirmed by qPCR. We identified miR577, members of the let-7 family, miR-133b, and miR140b-5p as potential regulators of FAS, CD4, EIF2C4, and CCL2. We contend that changes in miRNA and their corresponding targets may represent pathogenic mechanisms leading to sALS. Study supported by: NIEHS P30 Pilot Grant U035448, the Katherine Rayner Fund, and the A. Alfred Taubman Medical Research Institute. M1429. Alcohol Suppresses PGC-1a Expression, Impairs Mitochondrial Function and Enhances Cell Toxicity by Interfering with the cAMP-CREB Pathway Zilong Liu, Yongping Liu, Rui Gao, Tiffany Dunn, Glenn R. Smith, Ping Wu, Parthar S. Sarkar and Xiang Fang. Galveston, TX Alcohol intoxication results in neuronal apoptosis, neurodegeneration and manifests as impaired balance, loss of muscle coordination and behavioral changes. One of the early events of alcohol intoxication is mitochondrial dysfunction and disruption of intracellular redox status. Proliferatoractivated receptor gamma co-activator 1-alpha (PGC-1a) plays critical roles in the regulation of mitochondrial biogenesis/respiration, cellular antioxidant surveillance mechanism, and maintenance of neuronal integrity and function. In this study, we examined the role of PGC-1a in eliciting alcohol-induced mitochondrial dysfunction, disruption of redox homeostasis and neurodegeneration. Our data suggest that alcohol suppresses PGC-1a expression, impairs mitochondrial function and perturbs redox homeostasis in human neuroblastoma SH-SY5Y cells and in human fetal brain neural stem cell-derived primary neurons. Moreover,
Abstracts, American Neurological Association
we found that over-expression of PGC-1a significantly ameliorated alcohol-induced mitochondrial dysfunction and cellular toxicity in cultured SH-SY5Y. Furthermore, we found that alcohol dramatically attenuated phosphorylation of cAMP-response element binding protein (CREB) and PGC1a promoter activity. These data suggest that alcohol inhibits transcription of PGC-1a by interfering with the cAMP!PKA!CREB signaling pathway. These data support an important protective role for PGC-1a in alcoholinduced apoptosis and/or neurodegeneration. Study supported by: UTMB Junior Faculty Start-up Fund. M1430. MoCA vs. MMSE in Mild Cognitive Impairment and Early-Stage Alzheimer’s Disease Helen M. Hochstetler, Brett Walker, Shufang Wang, Paula Trzepacz, Elizabeth Stiegelmeyer, Michael Witte and Andrew J. Saykin. Indianapolis, IN Objective: We compared the Montreal Cognitive Assessment (MoCA) to the Mini-Mental State Examination (MMSE) for detecting early cognitive impairment. Methods: We analyzed 279 healthy control (HC), 419 mild cognitive impairment (MCI) and 133 Alzheimer’s dementia cases from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database to compare MoCA (cutoffs of 17, 19 and 23) and MMSE (cutoff 24) for capturing HC and MCI cases. We used descriptive statistics, scatterplots and Pearson correlations. Results: Correlations between scales were higher for dementia (r 5 .83) than for HC (r 5 .44) and MCI (r 5 .58). The MoCA ( 17) captured 100% of HC and 97.4% of MCI, whereas the MMSE (24) captured 99.6% of HC and 98.1% of MCI. HC and MCI cases had a broader score range on the MoCA than MMSE where many more scored from 28 to 30 on the MMSE (71.5%) than on the MoCA (17.5%). Conclusions: There was a greater ceiling effect with the MMSE than with the MoCA for HC and MCI. MoCA appears to detect a broader score range within the MCI population. Additional memory and functional measures will help identify at-risk HC and dementia cases, respectively, scoring 17. Study supported by: Avid Radiopharmaceuticals, a wholly-owned subsidiary of Eli Lilly and Company; Employee of Lilly USA, LLC, a wholly owned subsidiary of Eli Lilly and Company. M1431. Long-Chain Acyl Coenzyme A Synthetase 1 (Acsl1) Overexpression in Primary Cultured Schwann Cells Prevents Fatty Acid-Induced Oxidative Stress and Mitochondrial Dysfunction Lucy M. Hinder, Crystal Pacut, Claudia Figueroa-Romero, Anuradha Vivekanandan-Giri, Subramaniam Pennathur and Eva L. Feldman. Ann Arbor, MI Diabetic neuropathy (DN), characterized by progressive loss of peripheral axons, results in pain and eventual loss of sensation. Poor efficacy of glycemic control on DN development suggests the involvement of factors in addition to hyperglycemia. Clinical epidemiologic studies show a strong association of dyslipidemia with DN. Microarray analysis on
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peripheral nerve biopsies from human diabetic patients and diabetic mice identified an overlapping cluster of lipid metabolism genes regulated in DN. Of these, long-chain acyl coenzyme A synthetase 1 (Acsl1) exhibited the greatest fold-change in expression. Acsl1 activates 16–18 carbon FA, those elevated in diabetic plasma, for entry into betaoxidation or lipid synthesis pathways. Acsl1 overexpression in cultured Schwann cells protected against FA-induced oxidative stress and apoptosis, and improved mitochondrial function. These data suggest Acsl1 upregulation in diabetic mouse nerve may improve Schwann cell function and survival, but is insufficient to prevent the development of DN in the complex in vivo environment. Study supported by: This work was supported by the National Institutes of Health [NIH 1RC 1NS068182, NIH 1 UO1 DK076160, NIH 1 R24 DK082841, NIH 1 DP3 DK094292 to ELF], the A. Alfred Taubman Medical Research Institute and the Program for Neurology Research & Discovery. LMH is funded by the Juvenile Diabetes Research Foundation Angelika Bierhaus Postdoctoral Fellowship in Diabetic Complications. This work utilized Core Services supported by grants DK089503 (Seahorse) and DK097153 (Lipidomics) of the National Institute of Diabetes and Digestive and Kidney Diseases to the University of Michigan; and the Mouse Metabolic Phenotyping Center Core at the University of Washington, Seattle, Washington (U24 DK076126). M1432. Macrophages Promote a Pro-Inflammatory Microenvironment in the Peripheral Nervous System in a Murine Model of Type 2 Diabetic Neuropathy Diane E. Bender, Jacqueline R. Dauch, Wilson Hsieh, Brandon M. Yanik, Zachary A. Kelly, Yu Hong, Hsinlin T. Cheng and Eva L. Feldman. Ann Arbor, MI Diabetic neuropathy (DN) is the most common complication associated with diabetes. We contend that inflammation drives DN development and progression, and hypothesize that macrophages populating the peripheral nervous system induce neuronal damage in type 2 diabetes. The leptin receptor-deficient C57BKS-db/db mouse, a model of type 2 diabetes and DN, develops allodynia at 8–10 weeks followed by sensory loss and nerve conduction deficits at 21–24 weeks of age. Examination of sciatic nerve from non-diabetic control (db/1) and diabetic (db/db) mice revealed no significant changes in macrophage number at 5, 8, 16, 21, and 24 weeks; however, the pro-inflammatory cytokine tumor necrosis factor alpha (TNFa) is elevated in diabetic sciatic nerve as early as 16 weeks, and remains significantly increased through 24 weeks. We also observed enhanced TNFa expression in diabetic sciatic nerve macrophages by 21 weeks, suggesting that functional differences in diabetic macrophages that promote a pro-inflammatory microenvironment, not their total number, may contribute to nerve injury and DN progression. Current studies are assessing the therapeutic efficacy of blocking TNFa as a treatment for DN. Study supported by: Support provided by the Program for Neurology Research & Discovery. DEB is supported by the National Institutes of Health (T32 NS07222).
M1433. Speech Dysfluencies Induced by Deep Brain Stimulation in Parkinson’s Disease Albert J. Fenoy, Monica McHenry, Timothy M. Ellmore and Mya C. Schiess. Houston, TX and New York, NY
depleting inhibitory dopaminergic neurons. Is PD a neurodegenerative or neuro-entanglement disorder? Study supported by: Nil.
Patients with Parkinson’s disease (PD) who undergo subthalamic nucleus deep brain stimulation (STN-DBS) often develop a deterioration in speech performance. We analyzed fiber tract modulation by the active DBS contact that could implicate a causative structure in speech effects. Acoustic conversational speech data were obtained both ON and OFF STN- DBS in 2 PD patients of different subtypes. Deterministic tractography was used to identify the likely fiber tracts and end structures involved by the active contact of stimulation. Left STN-DBS ON resulted in increased hesitation dysfluencies, decreased syllables on target, deceased intensity variation in one tremor-dominant patient; tractography revealed involvement of the left premotor cortex (PMC) and supplementary motor area (SMA). Left STN-DBS ON in an akinetic rigid patient resulted in increased conversational speaking rate as well as increased fluid dysfluencies, less effect in syllables on target and intensity variation; there was involvement of SMA, not PMC. We highlight 2 contrastive cases of STN –DBS and their effects on conversational speech through specific fiber and end structure involvement. Dysprosody, dysfluency, and overall intelligibility may be due to variable left SMA and/ or PMC involvement, which may be anticipated depending on contact choice. Study supported by: Adriana Blood Endowed Chair.
M1434. Peripheral Triggering Factors for Sporadic Parkinson’s Disease – Neuro-Entanglement of Muscle Spindles and Remission Devathasan Gobinathan and Lea Dosado. Singapore, Singapore Although PD is considered as a relentless neurodegenerative brain disorder we probed for peripheral, preceding, localized, extracranial factors. 120 patients (& relatives), over 10 years with early PD (L dopa responsive), were interrogated with regards to sleep posture or position (classified : habitual >70% sleep-time in either right/left/supine/prone positon or non habitual/ turning slumberers). Other factors asked were trauma, persistent pain, peculiar motor habits, intense sports. Muscle U/S was used to assess tone in both brachioradialis and hamstrings in 30 cases. In 112 patients a triggering peripheral cause can be identified preceding onset of disease by at least 3 years. Of the 30 U/S cases 27 showed showed 4–7 Hz discharges even in the clinically unaffected side. Factors (in %) identified were habitual sleep position 56 (72 if overlapping), peculiar motor habits 18, persistent pain/trauma of one limb or trunk 16, extreme sports 4, and unidentified 6. 15 cases of remission noted (off medication for > 6 months) when the triggering cause was eliminated. We postulate that quantum entanglement at a macro level induces massive muscle spindle discharges diffusely
M2201. Enhancement of AMPA Receptor-Mediated Neurotransmission during Established Status Epilepticus. Karthik Rajasekaran, Suchitra Joishi and Jaideep Kapur. Charlottesville, VA We tested whether AMPA receptor (AMPAR) -mediated transmission is enhanced 10 (early) and 60 (late) after onset of benzodiazepine resistance in status epilepticus. AMPARmediated excitatory postsynaptic currents (EPSCs) were recorded from CA1 pyramidal neurons (CA1-PN). The frequency of action-potential independent EPSCs (m-EPSCs) increased with increasing seizure duration. The amplitude was unchanged. Compared to controls, the cell surface expression of GluA1 subunit was increased in early and late ESE animals. The increased surface expression of the GluA1 subunit was confined to CA1 region as demonstrated by BS3 assay. Treatment of hippocampal slice cultures with NMDA and high extracellular potassium increased the surface expression of GluA1 subunit. Further, treatment of animals with NMDAR open-channel blocker, MK-801 after 10 min of continuous electrographic seizures prevented increase in GluA1 surface expression in the CA1 region. Phosphorylation of the AMPARs at the Ser831 and Ser 845 residue on the C-tail of the GluA1 subunit was not increased during late ESE. AMPAR-mediated synaptic transmission on CA1 PNs is strengthened associated with an increased surface expression of the GluA1 subunit. Study supported by: NIH. M2202. Defining the Cellular, Transcriptional, and Molecular Networks Underlying Human Epileptic Brain Activity with Systems Biology Jeffrey A. Loeb, Fabien Dachet and Shruti Bagla. Chicago, IL and Detroit, MI We have developed a systems biology approach to determine the ‘Molecular Interactome’ of human cortical brain activity. Taking advantage of electrically mapped human neocortex removed as part of the surgical treatment of patients with refractory epilepsy, we have integrated high-throughput genomics from 15 paired human brain samples comparing high and low amounts of epileptic activities. These data are integrated with long-term quantitative electrophysiology, 3dimensional brain anatomy, brain histology, neuropsychology, and clinical variables into a web-based relational database. We built statistical interactomes merging these data together and predicted both cellular and pathway-specific changes in electrically active cortical regions that were subsequently validated on adjacent brain tissue regions. Thus far we have shown, (i) increased levels and size of microglia with a reciprocal decrease in neurons, (ii) increase in vascularity, and (iii) activation of a number of signaling pathways including the MAPK/CREB pathway leading to transcription of Immediate Early Genes (IEGs) and changes in
Abstracts, American Neurological Association
synaptic plasticity. Biomarkers and possible drug targets from these studies are now being evaluated in animal models for the treatment of patients with epilepsy. Study supported by: NINDS/NIH R01 NS058802, R01 NS045207, P20 NS080181. M2203. Response to Clobazam in Relationship to Baseline Seizure Frequency Jouko Isojarvi and Deborah Lee. Deerfield, IL We conducted post-hoc analyses of the Phase III CONTAIN trial to determine if clobazam was efficacious even for the most severe Lennox-Gastaut syndrome (LGS) patients. CONTAIN compared 3 clobazam dosages with placebo. Following a 4-week baseline, patients were randomized to placebo or 1 of 3 clobazam dosages (0.25, 0.5, and 1.0 mg/ kg/day). Treatment included a 3-week titration, followed by a 12-week maintenance phase. Patients were grouped by quartile based on average baseline weekly drop-seizure frequencies. Each quartile had 40 patients. Ranges (seizures/ week) were: < 10 (Quartile 1), 10–30 (Quartile 2), 32–86 (Quartile 3), and 86–1,077 (Quartile 4). Mean percentage decreases in average weekly seizures were similar for all quartiles for drop and total seizures. >50% in all 4 quartiles demonstrated 50% decreases in weekly frequency of drop and total seizures. Decreases in percentages achieving 100% reductions in drop and total seizures were observed for patients with greater baseline seizure frequencies (5% in Quartile 4 still achieved 100% reduction in drop seizures). Using baseline seizure counts as surrogates for disease severity, we determined clobazam was efficacious for patients with the most severe disease. A small percentage still achieved drop-seizure–freedom. Study supported by: Lundbeck LLC; Drs. Isojarvi and Lee are full-time Lundbeck employees. M2204. Thalamo-Hippocampal Connectivity in Medial Temporal Lobe Epilepsy Daniel S. Barron, Nitin Tandon, Jack L. Lancaster and Peter T. Fox. San Antonio, TX and Houston, TX Background: In MTLE, neuronal loss has been detected in structural MRI studies in the epileptogenic hippocampus and the thalamus. Wallerian degeneration has been detected with diffusion MRI with indirect measures of axonal integrity. Here we quantify neuronal damage in the thalamus and hippocampus via volumetric analysis; more directly test Wallerian degeneration via quantification of ipsilateral thalamo-hippocampal connections; and investigate reorganization of thalamo-hippocampal connectivity in the thalamus. Methods: 25 unilateral MTLE patients with hippocampal sclerosis and 20 controls underwent a diffusion-weighted and T1 MRI session. FreeSurfer (recon-all, dt-recon) was used to create ROIs for subsequent probabilistic tractography (FMRIB). Individual thalamic seed-to-target outputs were used to quantify thalamic voxels with >20% probability of connectivity with each MTL target. Center of gravity of maximal thalamo-hippocampal connectivity (MxTHC) was reported in MNI305 space.
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Results: Both R- and L-MTLE vs control groups reported volume loss (P < 0.004) in epileptogenic hippocampus and bilateral thalami, decreased (P < 0.02) number of thalamo-hippocampal connections in the thalamus, but no change in the MxTHC. Conclusion: We provide evidence that notwithstanding neuronal and axonal loss, connectivity does not reorganize. To our knowledge, this is the first time MTLE Wallerian degeneration has been reported in terms of probable connections. Study supported by: NINDS, 1 F31 NS083160-01 (PI: Barron, Daniel); NIMH, R01 MH074457 (PI: Fox, Peter). M2205. Myoclonin 4 Causes Childhood Absence Epilepsy Persisting with Eyelid Myoclonia and Convulsions into Adulthood Miyabi Tanaka, Julia N. Bailey, Jenny Wight, Rayna Duron, Dongsheng Bai, Maria E. Alonso, Iris Martinez-Juarez, Adriana Ochoa, Aurelio Jara-Prado, Marco T. Medina, Laura M. Ferreira-Guilhoto, Elza M. Yacubian and Antonio V. DelgadoEscueta. Los Angeles, CA; Tegucigalpa, Honduras; Mexico City, Mexico and San Paulo, Brazil We identify the causal gene of persisting childhood absence epilepsy with eye lid myoclonia (CAE/EM) evolving to juvenile myoclonic epilepsy (JME). After we analyzed results of linkage mapping and genome scan with 440 microsatellites, we “whole exome sequenced” 5 affected members and “one married-in” person belonging to a large family. Of 51 members, 8 were epilepsy affected and 2 symptomatics had EEG poly spike waves. LOD score (2.41 for D12S1042, q 5 0, m 5 f ) identified 8 more microsatellites on chr 12p11.23 to form a haplotype that segregated with 8 CAE/EM-affecteds and 2 EEG affected across four generation. Whole exome sequencing isolated R638W missense mutation of Myoclonin 4 on chr 12p11.23. The same mutation is absent in 342 controls matched for ethnicity and ancestral origin. Five other missense mutations (Q332K, I640V, G1016V, S486T, R879K) of Myoclonin 4 were observed in nine families with CAE/ EM and two singleton with CAE/EM evolving to JME. Our results strongly suggest that Myoclonin 4 is a causal gene of childhood absence epilepsy with eyelid myoclonia persisting to adulthood with tonic- clonic and myoclonic convulsions. Study supported by: NIH grant NS055057; salaries. M2206. White Matter Development in Children with Benign Epilepsy of Childhood with Centro-Temporal Spikes Carolina Ciumas, Mani Saignavongs, Faustine Ilski, Nathalie Bedoin, Vania Herbillon, Agathe Laurent, Julitta de Bellescize, Eleni Panagiotakaki, Salem Hannoun, Dominique Sappey Marinier, Karine Ostrowsky-Coste and Philippe Ryvlin. Lyon, France Purpose DTI studies of new onset epilepsy, mixing various syndromes, have reported changes in white matter architecture. Conversely, no series has specifically investigated the presence of such abnormalities in benign epilepsy of childhood with centro-temporal spikes (BECTS), a condition
which is likely to be associated with altered or delayed brain maturation. Methods: We performed DTI in 25 children suffering from BECTS and 25 age matched controls, and explored changes in white matter anisotropy and diffusivity. We used a voxel-based analysis to detect abnormalities at both the group and individual levels. Results: Significant differences of DTI-derived parameters were observed between BECTS and controls, with the former presenting decreased anisotropy and increased diffusivity, mainly within the areas that surrounded the left central sulcus and correlated with the duration of epilepsy. Individual analysis showed similar significant abnormalities of anisotropy in 9 patients (36%), all located on the side of the EEG focus, and of diffusivity in 15 patients (60%), 11 of which corresponded to the location of the EEG focus. Conclusion White matter integrity is compromised in BECTS, and appears to progress over time as a function of disease duration. Study supported by: The study was supported by a grant from Picri (Partenariats institution-citoyens pour la recherche et l’innovation) Ile-de-France, Epilepsy France Foundation, Fondation Le Roch-Les Mousquetaires and Institute Des Epilepsies. Dr Ciumas received financial support from Fondation pour la Recherche Medicale. Dr Laurent received financial support from Picri. M2207. WITHDRAWN M2208. D-Leucine Protects Against Kainate-Induced Seizures Adam L. Hartman, Polan Santos and J. Marie Hardwick. Baltimore, MD Rationale. Some D-amino acids have biological activity (e.g., D-serine). It is unknown whether results from prior Lleucine studies (showing modest seizure protection) were due to L- or D-isomers. We investigated whether D-leucine protected against kainate-induced seizures. Methods: NIH Swiss male mice (5 weeks) were injected intraperitoneally with L- or D-leucine or water 3 hours before kainate injection. Blood glucose and betahydroxybutyrate levels were measured prior to seizure testing. Results: D-leucine treatment (300 mg/kg) led to lower mean seizure scores (one-way ANOVA, P < 0.0007; Tukey, P < 0.001 D-leucine vs H2O) but no difference in latency to stage 2 seizure onset, compared to L-leucine and water. Similar findings were noted with low-dose D-leucine (3 mg/ kg). Blood glucose levels after low-dose D-leucine were lower than controls (P 5 0.01). Conclusions: The beneficial effects of L-leucine may be due to D-leucine contaminants (0.5% in commercial preparations). Protection at a low dose suggests that Dleucine may act as a signaling molecule. The late effect in seizure protection without a difference in latency to seizure onset suggests D-leucine may have a more subacute mechanism than current anticonvulsants. Because blood glucose was lower, D-leucine may mediate cellular responses to mild hypoglycemia, shown previously to protect against seizures.
Study supported by: K08NS070931 (ALH) and RO1NS037402 (JMH); Salary support for all authors by NINDS/NIH.
M2209. Hypothermia for Refractory Status Epilepticus Claude G. Wasterlain, Roger A. Baldwin, Jerome Niquet and Lucie Suchomelova. Los Angeles, CA We need better treatments for drug-refractory status epilepticus (RSE). Deep hypothermia is used routinely during cardiac/aortic surgery and neurosurgery, but has received only cursory attention for the treatment of acute seizures. We used a lithium-pilocarpine model to study the effects of deep hypothermia on RSE. After midazolam failed to stop RSE, cooling stopped all seizure activity. Brain temperature was maintained at 20 C. for 30 min., then rewarming proceeded at 0.24 C./min. until normothermia was re-established. Seizure activity did not return. Behavioral recovery was rapid. Complete neuroprotection was achieved. Blood-brain barrier breakdown was prevented, and cell-mediated inflammation which was prominent in normothermic brains 48 hrs after SE, was minimal or absent. These results suggest that deep hypothermia differs markedly from mild hypothermia in its effects on neuronal excitability and status epilepticus, and deserves more attention as a possible treatment of RSE. Study supported by: the Research Service of the Veterans Health Administration, the James and Debbie Cho Foundation and grant 1 UO1 NS074926 from NINDS (NIH).
M2210. The Role of Quality Improvement Measures in Epilepsy Related Hospitalization Reduction Daniel J. Pomerantz, Travis R. Ladner, Clinton D. Morgan, Vanessa E. Kennedy and Amir M. Arain. Nashville, TN In 2011, the American Academy of Neurology (AAN) established eight quality mprovement (QI) measures for chronic epilepsy treatment to address deficits in quality of care. This study assesses the role of adherence to these eight AAN QI measures plays in reducing Epilepsy Related Adverse Hospitalizations (ERAH). A retrospective chart review of 477 new epilepsy patients with an ICD-9 code 345.1–9 seen at the Vanderbilt Epilepsy Clinic between 2010 and 2012 was conducted. Patient demographics, adherence to AAN guidelines, and annual number of ERAHs were analyzed from patient records. No relationship between AAN guideline adherence and ERAHs in the general patient population was observed. Patients with intellectual disability were less likely to have an MRI/CT requested, reviewed, or ordered on first visits; receive annual safety counseling; or have a documented seizure type/ etiology at each visit. Patients with intellectual disability who did have an MRI/CT requested, reviewed, or ordered on first visits were less likely to have ERAHs (OR 0.105, 95% CI: 0.012-0.929). Adherence to the eight AAN QI measures is associated with reduced likelihood of ERAHs in the intellectually disabled but not in the general patient population. Study supported by: Vanderbilt Department of Neurology.
Abstracts, American Neurological Association
M2211. Use of Rescue Medications by Lennox-Gastaut (LGS) Patients Treated with Clobazam Deborah Lee, William Rosenfeld and Jouko Isojarvi. Deerfield, IL and St. Louis, MO We conducted post-hoc analyses of the Phase III CONTAIN trial to evaluate degrees to which patients received rescue medications during maintenance therapy. CONTAIN compared 3 dosages of clobazam with placebo. Following a 4week baseline, patients were randomized to placebo or 1 of 3 clobazam dosages (0.25, 0.5, and 1.0 mg/kg/day). Treatment included a 3-week titration, followed by a 12-week maintenance phase. Patients were permitted 1 rescue/day, with 4 days of rescue medications in 4 weeks (average of 1 rescue dosage per week). 238 were randomized, and 217 comprised the mITT population. Percentages who received rescue medications at least once was < 20% in all treatment groups and lower in each clobazam group than for placebo (differences not statistically significant). Numbers (percentages) in each group were 7 (13.2), 5 (8.6), and 4 (8.2) for low-, medium, and high-dosage clobazam, and 11 (19.3) for placebo. Overall, rescue medications were used infrequently. There were no clinically important or statistically significant differences between treatment groups in the percentage who received rescue medications on multiple occasions. We observed a trend toward less frequent use of rescue medications in the low-, medium- and high-dosage clobazam groups. Study supported by: Lundbeck LLC; Drs. Lee and Isojarvi are full-time Lundbeck employees. Dr. Rosenfeld has been a Lundbeck study investigator and has received an honorarium for presenting at a Lundbeck Scientific Exhibit. M2212. USL255 Is Well Tolerated and Demonstrates Dose-Proportional Pharmacokinetics at High Doses Annie M. Clark, Tricia L. Braun, James C. Cloyd and Mark B. Halvorsen. Maple Grove, MN and Minneapolis USL255, once-daily extended-release topiramate, is being evaluated for the treatment of epilepsy. Previously, administration of USL255 25–400mg resulted in dose-proportional AUC with Cmax approaching proportionality over 100– 400mg. The objective of this study was to evaluate singleascending doses of USL255 from 600–1600mg to determine maximum tolerated dose (MTD) and dose proportionality. In this Phase 1, randomized, placebo-controlled, doubleblind study, 60 healthy subjects were planned for enrollment into 6 dose cohorts (600, 800, 1000, 1200, 1400, 1600mg), each with 10 subjects randomly assigned 8:2 to a single dose of USL255 or matching placebo. Blood samples were collected and tolerability was evaluated for 14 days post-dose. If a priori dose-limiting criteria were met, dose escalation would cease and the previous dose would be declared MTD. USL255 was generally well tolerated from 600–1200mg, with no serious or severe adverse events. Dose escalation ceased at 1400mg, thus 1200mg was determined to be MTD. AUC and Cmaxwere dose proportional from 600– 1400mg. Additionally, USL255 provided consistent topiramate plasma concentrations over 24 hours with low intersubject variability in total and maximum exposures.
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These data further support the favorable tolerability and consistent, predictable pharmacokinetic profile of USL255. Study supported by: Upsher-Smith Laboratories, Inc; Drs. Clark, Braun, and Halvorsen are employees of UpsherSmith Laboratories, Inc. M2213. Pharmacokinetics of N-Desmethylclobazam – Clobazam’s Active and Primary Metabolite Dwain Tolbert and Ihor Bekersky. Deerfield, IL To provide N-desmethylclobazam’s pharmacokinetics following clobazam administration, in vitro and ex vivo protein binding studies were conducted via spiked plasma and blood samples from participants dosed to steady state with clobazam. Plasma concentrations from single- and multiple-dosage trials (healthy volunteers) were used to calculate absorptive and post-absorptive parameters, and N-desmethylclobazam accumulation at steady state. Population pharmacokinetics were used to calculate elimination rate constants and clearance values. In vitro clobazam and N-desmethylclobazam plasma protein binding ranged from 78%–89% (concentration-independent). Ex vivo binding of both was 90%. In vitro, N-desmethylclobazam was a substrate (but not inhibitor) of the P-glycoprotein transport system and was unlikely a substrate for organic cation or anion systems. After initial dosing, clobazam was the predominant moiety (mean AUC0– inf range: 8,890–11,600 hr* ng/mL; Cmax range: 310–402 ng/mL). Following repeated administrations, N-desmethylclobazam became the major circulating moiety. N-desmethylclobazam steady-state concentrations were attained 2 weeks. Steady state, mean clobazam AUC and Cmax were 10,350 hr* ng/mL and 1,076 ng/mL. Corresponding parameters for N-desmethylclobazam were 30,350 hr* ng/mL and 2,783 ng/ mL. Clobazam’s and N-desmethylclobazam’s median half-lives were 36 and 79 hours. N-desmethylclobazam’s disposition wasn’t significantly affected by renal or hepatic dysfunction, or concomitant medications. Study supported by: Lundbeck LLC; Dr. Tolbert is a fulltime Lundbeck employee. Dr. Bekersky was a Lundbeck employee at the time the analyses were conducted. M2214. Safety and Efficacy of a Reduced Electroencephalography Electrode Array for Detection of Seizures Mark N. Rubin, Oliver Jeffery, Jennifer E. Fugate, Jeffery Britton, Gregory D. Cascino, Gregory Worrell, Sara Hocker, Eelco F.M. Wijdicks and Alejandro A. Rabinstein. Rochester, MN Background: The expertise required for EEG setup can make the 10–20 array unwieldy. There may be a role for an EEG array with reduced leads to improve efficiency. Methods: Clips from 100 EEG records, 50 “ictal” and “non-ictal,” in adult inpatients from 1/1/2007-1/1/2012 were selected for digital lead reduction and blind review. Two epileptologists reviewed these tracings and documented the presence of seizures and severe disturbance of background. The array included seven leads spanning the scalp; three different montages were available. Sensitivity and specificity calculations were determined by comparing results of
the blind review of the reduced array tracings to the EEG report of the corresponding full array tracings. Results: The reduced array EEG had a sensitivity of 70% for seizure of any kind and a specificity of 96%. Sensitivity for identifying encephalopathic patterns was 62% with a specificity of 86%. Focal seizures were more readily identified by the reduced array (20/25) than were generalized ictal patterns (13/25). Conclusion: The reduced electrode array demonstrated insufficient sensitivity for seizure detection. These findings suggest that reducing EEG leads might not be a preferred means of optimizing hospital EEG efficiency. Study supported by: N/A. M2215. Immune Therapy Can Improve Objective and Subjective Memory Problems in VGKC ComplexMediated Epilepsy Matthew T. Hoerth, Katherine H. Noe, Dona E. Locke, Kristin A. Kirlin and Joseph F. Drazkowski. Phoenix, AZ Although autoimmune causes for epilepsy are still considered rare, one of the most frequently associated neuronal antibodies is to the voltage-gated potassium channel (VGKC) complex. This antibody has been classically associated with paraneoplastic limbic encephalitis, a syndrome characterized by seizures and cognitive dysfunction. Since this has a predilection to the temporal lobes, specifically memory is affected. A series of three patients presenting with VGKC complex antibody-mediated epilepsy were reviewed. Neuropsychometric profiles for of these patients were analyzed. All three patients had left temporal or bilateral temporal lobe seizures documented, as well as nonlesional MRI scans of the brain. In addition, all patients were treated with immunosuppressive therapy (IV methylprednisolone) in addition to standard antiepileptic drug therapy. Two patients had specific retrospective memory complaints, difficult to measure in standardized testing. Some relatively mild abnormalities were noted on initial neuropsychometirc testing as compared to the patients’ complaints. Both subjective and objective improvements occurred post-immunotherapy. The findings in these patients suggest that the unique mechanism of epilepsy allows for improvement in not only seizure control, but also cognitive status after immune therapy. Study supported by: No study support. M2216. Relative Bioavailability of Clobazam Oral Suspension after a Single 20-mg Dose in Healthy Volunteers Dwain Tolbert, Axel Juan, Ihor Bekersky and Eleanor Sales. Deefield, IL and Miami, FL This randomized, open-label, two-way crossover study investigated the relative bioavailability, safety, and tolerability of clobazam oral suspension (2.5 mg/mL) vs. oral tablets following a single 20-mg dose to healthy participants (N 5 30) on Days 1 and 15. Each administration was separated by 14-day washouts. Pharmacokinetic profiles of clobazam and N-desmethylclobazam were obtained from serial plasma concentrations collected over 312 hours post-doses. The relative bioavailability of suspension vs. tablet was evaluated
using bioequivalence criteria. The suspension/tablet ratio point estimate and 90% CIs for clobazam were: Cmax 5 1.19 (1.12 to 1.27); AUC0–last 5 0.997 (0.977 to 1.02); and AUC0–inf 5 0.995 (0.976 to 1.01). Thus, bioequivalence criteria were met for AUC0–last and AUC0–inf. However, for Cmax, the upper boundary of 90% CI was just above the bioequivalence limit of 1.25. All other parameters were similar. The slight increase observed in Cmax is a consequence of the physicochemical properties of the suspension form (designed to deliver drug faster than tablet) and was not considered clinically meaningful. The 20-mg oral suspension was functionally bioequivalent to 20-mg tablets. Clobazam has a wide therapeutic window and is intended for long-term administration for LGS patients. Study supported by: Lundbeck LLC; Dr. Tolbert and Ms. Sales are full-time Lundbeck employees. Dr. Bekersky was a Lundbeck employee at the time the analyses were conducted. Dr. Juan is a Lundbeck consultant. M2217. Role of Vagal Nerve Stimulation in the Management of Intractable Epilepsy in Children with Static Encephalopathy Andrea Wenner, Jose Aceves, Diana Mungall, Richard Castillo and Batool F. Kirmani. Temple, TX Vagal nerve stimulation is approved for medically refractory partial epilepsy in children greater than 12 years of age. Authors report a case series of children less than 12 years of age who responded well to vagal nerve stimulation. A retrospective review was conducted at our institution for pediatric patients less than 12 years of age with pharmacoresistant epilepsy and brain anomalies resulting in static encephalopathy from 1997 to 2013. The study was approved by hospital’s institutional review board. Three patients were identified who received vagal nerve stimulator between 6–9 years of age. Two of these patients have generalized epilepsy and one had Lennox-Gastaut syndrome. The etiologies include lissencephaly, cortical dysplasias and asymmetry of the cerebral hemispheres respectively in our three patients. They were on average two to three anticonvulsants and have failed at least two anticonvulsants. The patients showed marked decrease in the seizure frequency during the 6 and 1 year follow-up. Vagal nerve stimulation was found to be efficacious in this subgroup of difficult pediatric patients with pharmacoresistant generalized epilepsy and epileptic encephalopathy. Study supported by: none. M2218. II Knowledge, Beliefs, and Health Care Perceptions of Epilepsy in Minnesota’s Native American Nations Miguel E. Fiol and Kirk C. Allison. Minneapolis, MN While epilepsy is a disease disproportionately affecting ethnic minorities, little research has been conducted on Native Americans (NA). We surveyed 58 NA, 26 with epilepsy and 32 without regarding knowledge, care barriers, stigma, spiritual beliefs, education, income and insurances.
Abstracts, American Neurological Association
We employed Fisher’s exact test for categorical variables, and t-tests for interval variables (1- or 2-tailed). Significance is reported p < .10. Results: Respondents were significantly more female and urban. Age, education and definitional knowledge were not significantly different. Affected had less etiological (p < .10) and medication management knowledge (p < .05), viewed community seizure understanding lower (p < .01), care providers fewer (p < .10), care barriers higher (p < .10) had lower trust (p < .01) and more hospital based care (p < .05). Both rated family least stigmatizing; but affected viewed work (p < .05) and school (p < .01) as significantly more stigmatizing in ascending order. Educational levels did not differ, but affected unemployment was sharply higher (p < .001), income lower (p < .05), driving less (p < .01), but driving rule knowledge was higher (p < .10). Conclusions: NA need: education on epilepsy causes/ management; addressing stigma in family/schools/workplace; care barriers corrections and addressing transportation and employment deficits. Study supported by: Mdewakenton Sioux Tribe, Shakoppe, Minnesota. M2219. Aggression in LGS Patients Treated with Clobazam during the CONTAIN Trial Juliann Paolicchi, Jouko Isojarvi and Deborah Lee. New York, NY and Deerfield, IL We conducted post-hoc analyses of aggression-related AEs from a Phase III RCT (CONTAIN) of clobazam in Lennox-Gastaut Syndrome. Following a 4-week baseline, patients who had 2 drop seizures/week were randomized to placebo or 1 of 3 dosages of clobazam (0.25, 0.5, and 1.0 mg/ kg/day). Treatment included a 3-week titration, followed by a 12-week maintenance phase. The safety population included all 238 randomized patients who received 1 dose of study drug or placebo. Four patients discontinued because of aggression (1 medium- and 3 high-dosage patients). 37/238 (15.5%) experienced 43 aggression-related events, occurrence of which was dosage-related. Time to onset for the majority of events in the medium- and high-dosage groups was during the 3-week titration, while in the placebo- and low-dosage groups, time to onset was distributed throughout the 15-week study. Resolution occurred for 43%, 40%, 63%, and 73% of events in the placebo, and low-, medium-, and high-dosage groups respectively. >50% of events resolved within 40 days, and all patients who received high-dosage clobazam who resolved did so within 60 days. Onset of aggression-related events was dosage-related, onset of majority of events was during titration, and the majority resolved. Study supported by: Lundbeck LLC; Dr. Paolicchi has been a Lundbeck study investigator and has received an honorarium for presenting at a Lundbeck Scientific Exhibit. Drs. Isojarvi and Lee are full-time Lundbeck employees. M2220. Treatment-Emergent Adverse Events (TEAEs) by Age for Patients with Lennox-Gastaut Syndrome (LGS) Treated with Clobazam Jouko Isojarvi, Deborah Lee and Jeffrey Buchhalter. Deerfield, IL and Calgary, AB, Canada
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We conducted pooled analyses of clobazam LGS studies to determine if safety events varied by age. In a Phase II trial, following a 4-week baseline, LGS patients were randomized to 1 of 2 clobazam dosages (0.25 and 1.0 mg/kg/day). Treatment included a 3-week titration, followed by a 4-week maintenance period. CONTAIN (Phase III) compared 3 dosages of clobazam with placebo. Following a 4-week baseline, patients were randomized to placebo or 1 of 3 clobazam dosages (0.25, 0.5, and 1.0 mg/kg/day). Treatment included a 3-week titration, followed by a 12-week maintenance phase. We evaluated safety results from baseline to maintenance phase for patients 2 to < 12 years of age; 12 to < 16 years; and 16 years. In the two studies, respectively, 68 and 238 patients comprised the safety populations (all who received 1 dose of study drug or placebo). Patients (%s) with 1 TEAE were 174 (90.6), 43 (84.3), and 53 (94.6) for those 2 to < 12 years of age (n 5 192), 12 to < 16 years of age (n 5 51), and 16 years of age (n 5 56), respectively. We observed no clinically important differences in TEAEs by age. Study supported by: Lundbeck LLC; Drs. Isojarvi and Lee are full-time Lundbeck employees. Dr. Buchhalter has been a Lundbeck study investigator, received an honorarium for an AAN Webinar within the past year, and has received an honorarium for presenting at a Lundbeck Scientific Exhibit. M2221. Response to Clobazam in Vagus Nerve Stimulation (VNS) vs. Non-VNS Patients Deborah Lee, Jouko Isojarvi and Selim R. Benbadis. Deerfield, IL and Tampa, FL We conducted post-hoc analyses of a Phase III trial to evaluate responses to clobazam for patients who were undergoing VNS during the study vs. those who were not. CONTAIN compared 3 clobazam dosages with placebo as adjunctive LGS therapy. Following a 4-week baseline, patients were randomized to placebo or 1 of 3 clobazam dosages (0.25, 0.5, and 1.0 mg/kg/ day). Treatment included a 3-week titration, followed by a 12week maintenance phase. Both VNS and non-VNS groups experienced significant mean percentage decreases in average weekly drop and total seizure rates vs. placebo. Least-square mean percentage decreases in average weekly rates of drop and total seizures were 51.7 and 47.9 for VNS patients receiving clobazam (vs. 221.5 and 25.8 for placebo, p < 0.01). For nonVNS patients, these percentages were 53.3 and 47.9 for clobazam (vs. 25.9 and 15.4 for placebo, p < 0.01). >50% of clobazam patients in both the VNS and non-VNS groups demonstrated 50% decreases in average weekly drop and total seizure frequencies, and >10% of clobazam-treated patients in both groups achieved drop-seizure–freedom. These results suggest clobazam is efficacious not only for less severe LGS, but also for more refractory LGS. Study supported by: Lundbeck LLC; Drs. Lee and Isojarvi are full-time Lundbeck employees. Dr. Benbadis has been a Lundbeck study investigator and has served in a consulting/advisory capacity for Lundbeck. M2222. Design and Implementation of a Test Model To Assess Standards for Comparing Brand Name and Generic Antiepileptic Drug Bioequivalence Allan Krumholz, Tricia T. Ting, Wenlei Jiang, Elizabeth Barry and James Polli. Baltimore, MD and Rockville, MD
Rationale: Therapeutic equivalence of generic antiepileptic drugs (AEDs) is questioned. The current approach to evaluate bioequivalence (BE) is a pharmacokinetic (pK) study in healthy adults, but BE is rarely assessed in clinical patients. We implemented a study to assess such BE for lamotrigine (LTG) in epilepsy patients. Method: This study replicates typical elements of a conventional BE study in healthy adults, but incorporates the unique aspect of performing a BE study in patients taking LTG for epilepsy. Results: This study is in process at our center as a double-blind, multiple-dose, full replicate design, pK study of LTG 100 mg tablets in patients with epilepsy. Subjects each receive the brand name and generic product twice, allowing for three switches between products. Each arm is two weeks in duration. Conclusion: A study has been designed and initiated to evaluate the BE of generic and brand name LTG in patients with epilepsy. Given the lack of available prior study designs to assess BE in patients under clinical use conditions, this design may serve as a prototype for assessment of brand and generic equivalence. Study supported by: Federal Drug Administration. M2223. Familial Incidence of Transient Global Amnesia: Case Report and Review of Literature Sudeepta Dandapat and Pavan Bhargava. Springfield, IL Objective: To describe two sisters with Transient Global Amnesia (TGA) and review the literature regarding familal cases of TGA. Background: TGA is a syndrome consisting of acute and temporary anterograde and retrograde memory loss without other focal neurological signs or alteration of consciousness. The etiopathogenesis of this disorder is unknown. Vascular, epileptic and migranous etiologies have been proposed. Familial cases have been rarely described and may provide an opportunity to better understand this disorder. Case: Two sisters aged 57 and 71 years, had episodes of TGA separated by a few months. Both had symptoms of anterograde and retrograde amnesia with resolution in 24 hours. One had a precipitating factor of sexual intercourse and the other complained of sleep deprivation. MRI brain in the older sibling demonstrated diffusion restriction in the left hippocampus. Discussion: Summarizing data from previous published familial TGA reports we found 24 cases including ours. There was a female predominance (F:M 5 2:1). There was a history of migraine or headaches in eight patients (33%). Familial occurence of TGA suggests a possible genetic influence and highlights the importance of obtaining a family history in patients with TGA. Study supported by: None. M2224. Somnolence and Sedation Were Transient AEs for Most Patients Receiving Clobazam during a Phase III Study in Lennox-Gastaut Syndrome (LGS) Jouko Isojarvi, Deborah Lee and J. Ben Renfroe. Deerfield, IL and Gulf Breeze, FL
Post-hoc subanalyses evaluated incidence and time to resolution of somnolence and sedation for LGS patients treated with clobazam. The CONTAIN trial compared 3 dosages of clobazam with placebo as adjunctive therapy for LGS. Following a 4-week baseline, patients were randomized to placebo or 1 of 3 dosages of clobazam (0.25, 0.5, and 1.0 mg/ kg/day). Treatment included a 3-week titration, followed by a 12-week maintenance phase. Incidence, time to onset, duration, and time to resolution of somnolence-related AEs were analyzed. Incidence of somnolence and/or sedation was greater for clobazam patients (26%) than placebo patients (15%). The incidence increased with greater dosages of clobazam (low-dosage, 17%; medium-dosage, 27%; and highdosage, 32%). For most patients, onset of these events was within the first 3 weeks of treatment (during titration). The majority of these events resolved (placebo, 73%; low-dosage, 82%; medium-dosage, 63%; and high-dosage, 83%). Median duration of these somnolence-related adverse events was within 2–3 weeks for all clobazam groups. Somnolence and sedation were relatively common AEs during clobazam treatment, and were dosage-related. However, most were transient and resolved within a few weeks. Study supported by: Lundbeck LLC; Drs. Isojarvi and Lee are full-time Lundbeck employees. Dr. Renfroe has been a Lundbeck study investigator, and has received an honorarium for presenting at a Lundbeck Scientific Exhibit. M2225. WITHDRAWN M2226. Human Herpes Virus 6 in Human Epilepsy: Data from Surgical Resections Jeanne Billioux, Emily Leibovitch, Giovanna Brunetto, Irene M. Dustin, Sara Inati, John Schreiber, Chigolum Eze, Kareem Zaghloul, Steven Jacobson and William H. Theodore. Bethesda Background: Previous studies suggested a possible role for HHV-6B in mesial temporal lobe epilepsy (MTLE). HHV6B is the etiologic agent of roseola, while HHV-6A is associated with central nervous system (CNS) disorders and may be more neurotropic than HHV-6B. Methods: Using digital droplet PCR (ddPCR) to examine HHV-6A and HHV-6B viral DNA, we studied a new cohort of 10 MTLE patients and six with focal cortical dysplasia (FCD). DdPCR is a highly sensitive and precise novel PCR technology that enables absolute quantification of target DNA molecules. Results: Viral DNA was detected in 60% of MTLE patients. This positivity frequency is consistent with our previous findings. In addition, we detected HHV-6A as well as HHV-6B. Moreover, HHV-6A and HHV-6B DNA also were detected in a subset of FCD patients. The detected viral copy numbers varied across a wide range between patients and even within a given patient, depending on regional sampling. Conclusions: Our new data suggest viral presence in patients with FCD and extend our findings in patients with MTLE, with detection of HHV-6A not previously reported. Study supported by: NINDS NIH Division of Intramural Research.
Abstracts, American Neurological Association
M2227. Quantification of PET Hypometabolism for “Non-Lesional” Refractory Epilepsy Pearce J. Korb, Bhawana Rathore, Hulegar Abhishek, Vina Ravichandran, James Galt, Jonathon Nye, Schuster David and Gross E. Robert. Atlanta, GA Introduction: One-third of patients with epilepsy are refractory to medical management and could benefit from surgical resection. Some cases are “non-lesional” without a target for surgery. These patients undergo invasive intracranial EEG monitoring (ICM) to identify the epileptic onset zone. We reviewed the novel use of a quantitative technique to identify foci of hypometabolism in these “non-lesional” patients. Methods: We reviewed patients with refractory epilepsy who underwent ICM at Emory University Hospital from 01/2003 to 12/2012. Patients with non-localizing MRI and PET were included (N 5 16). Using customized software (MIMneuro, Cleveland, Ohio) we computed the 10 most hypometabolic regions on PET. The statistical rank-ordered list of computed foci was compared to the ICM onset-zone. Results: Of the 16, 13 had regional localization on ICM whereas 3 did not. Of the 13 with well identified onsetzones, all (100%) had quantitative hypometabolic foci in the top 5 ranked order that correlated with the ICM onsetzone. For 7/13 (54%) the top-ranked foci correlated with the onset-zone on ICM. Conclusion: Quantification of hypometabolic foci may give additional information for seizure localization and provide potential surgical targets for resection in patients who are “non-lesional” on MRI. Further prospective studies are warranted. Study supported by: None. M2228. Vigabatrin in Status Epilepticus Uma Menon, Fawad Khan and Eugene Ramsay. New Orleans, LA Objective: Vigabatrin has been in use in various parts of the world since 1980s and was approved by the FDA in the United States in 2009 for refractory complex partial seizures. Multiple clinical trials have been conducted in Europe and in the United States but limited information is available regarding the use of Vigabatrin in status epilepticus. Methods: We present a series of 6 patients who had refractory status epilepticus from various causes and had prolonged stay in the intensive care unit. All of the patients required multiple anti-seizure agents and sedation with unresolved status epilepticus when Vigabatrin was started. Results: All of our patients had resolution of status epilepticus on starting Vigabatrin. Three patients subsequently demised from underlying severe medical conditions that resulted in status epilepticus. With the resolution of status epilepticus, at least one of the patients had significant improvement in quality of life from baseline state. Conclusion: Status epilepticus results in high mortality rates despite appropriate management. However, there still exist no standardized management options for status epilepticus. We recommend Vigabatrin as an option perhaps ear-
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lier in the management than later as it was successful in resolving status epilepticus in at least this cohort of patients. Study supported by: None. Co-author Dr.Eugene Ramsay has received personal compensation for activities with Lundbeck. M2229WIP. Altered Intrathalamic GABAergic Circuitry in an Absence Epilepsy Syndrome Chengwen Zhou, M. Elizabeth Deel, Li Ding and Martin J. Gallagher. Nashville, TN Heterozygous mutations and deletion (Heta1KO) of the GABAA receptor (GABAAR) a1 subunit cause absence seizures in humans and mice. In thalamus, GABAergic feedback inhibition from the reticular nucleus (nRT) to the ventrobasal nuclei (VB) contributes to aberrant thalamic oscillations in absence seizures. GABAAR a1 and a3 subunits are not expressed in the same cells in these nuclei; VB expresses the a1 subunit and nRT expresses the a3 subunit. Here we determined the effects of Heta1KO on the expression and physiology of a1 and a3 subunit-containing GABAAR in VB and nRT. Immunofluorescence and biotinylation/Western blot assays demonstrated that, in VB, Heta1KO reduced the total and surface a1 subunit expression to 62% and 73%, respectively, that of wild type (wt). Electrophysiological recordings in VB showed that Heta1KO reduced peak mIPSC amplitudes (57% wt) and did not alter their current kinetics. Unexpectedly, in nRT, Heta1KO increased the total (172% wt) and surface (205% wt) expression of the a3 subunit. Because nRT neurons do not express the a1 subunit, our results suggest that Heta1KO alters intrathalamic circuitry that indirectly increases a3 subunit expression. This increased intra-nRT inhibition may represent a partial compensation for VB disinhibition. Study supported by: National Institute of Neurological Disorders and Stroke R01 NS064286
2013 Annual Meeting Tuesday, October 15, 2013 Poster Session Neurotechnology T1501. Demonstration of the Use of Epidermal Electronics in Neurological Monitoring. Mary J. Harbert, Sheila S. Rosenberg, Diego Mesa, Mridu Sinha, Navaz P. Karanjia, Mark Nespeca and Todd P. Coleman. San Diego, CA Objective: Conventional electroencephalography (EEG) electrodes are bulky and require scrubbing and gluing of the skin. Patients find this uncomfortable and the data is easily contaminated by movement artifact. We demonstrate the first clinical use of “epidermal electronics” in the detection of electroencephalography. Epidermal electronics consist of thin circuitry that moves with the skin and is applied in the same manner as a temporary tattoo. Study Design Electroencephalography recordings were obtained from newborn and adult human subjects. Each subject received
two EEG recordings: one using conventional EEG electrodes and another using epidermal electronic electrodes. The two recordings were de-identified and interpreted by a blinded neurophysiologist. Results: EEG interpretation in all age groups was the same for recordings obtained from either epidermal electronics or conventional EEG electrodes. Epidermal electronic EEG recordings demonstrated age-specific EEG features, such as the posterior dominant rhythm. For the majority of the recordings, the blinded neurophysiologist could not identify which had been acquired using epidermal electronics. Conclusions EEG quality acquired by epidermal electronics is indistinguishable to a neurophysiologist from that of conventional electrodes. Epidermal electronics provide an attractive approach to unobtrusive EEG acquisition. Study supported by: The Gerber Foundation T1502. Neural-Oscillatory Intervention for AutoCalibration Improves EEG Asymmetry and HRV Charles H. Tegeler, Catherine L. Tegeler, Sung W. Lee, Hossam A. Shaltout and Nicholas M. Pajeswki. Winston-Salem, NC and Scottsdale, AZ Reduced vagal tone, inferred from lower heart rate variability (HRV), is associated with neurological and psychophysiological conditions including TBI, insomnia, PTSD, anxiety, and hot flashes. Cross-sectional data show negative correlation between high frequency temporal lobe EEG asymmetry (HFTLA: rightward dominance) and HRV. We tested the effects of high-resolution, relational, resonance-based electroencephalic mirroring (HIRREM), a novel, noninvasive, EEG-based technology for auto-calibration of neural oscillations, on HFTLA and HRV in 31 subjects enrolled in an open-label study for such conditions. Baseline asymmetry scores were calculated from log-transformed high frequency amplitudes (23–36 hertz) at the bilateral temporal lobes (T3/T4: one minute, eyes closed). Subjects, mean age 49.6 ( 6 16.7 SD), received 16 ( 6 6.7 SD) ninety-minute HIRREM sessions to explore efficacy and effect sizes. HRV was obtained pre- and post-intervention. Greater temporal lobe asymmetry at baseline strongly predicted reduced asymmetry during the penultimate minute of the penultimate HIRREM session (r 5 20.579, p < 0.001). As a group, the median value for standard deviation of the R-R intervals (SDRR) increased post-intervention (median change 5 4ms, p 5 0.037). Improved HFTLA and HRV suggest a potential role of HIRREM for disorders associated with hemispheric EEG asymmetry and autonomic dysregulation. Study supported by: The Susanne Marcus Collins Foundation, Inc.; Sung W. Lee, MD, MS, receives salary support from Brain State Technologies, LLC. T1503. High-Resolution, Relational, Resonance-Based Electroencephalic Mirroring (HIRREM) Reduces Symptoms and EEG Asymmetry in an Individual with PTSD Charles H. Tegeler, Charles H. Tegeler, Sung W. Lee and Jared F. Cook. Winston-Salem, NC and Scottsdale, AZ Studies link PTSD to right hemispheric over-activation. The right hemisphere manages sympathetic activity. HIRREM is a
novel, noninvasive technology for neural-oscillatory auto-calibration, designed to facilitate greater hemispheric symmetry and more optimized spectral power ratios through highresolution (0.001 hertz) EEG analysis and auditory tonal resonance. We report the use of HIRREM in a 55 year old woman with PTSD following a transportation accident, without physical injury, enrolled in an open-label pilot trial. Baseline scores on the civilian PTSD Symptom Checklist (PCLC), Insomnia Severity Index (ISI), and CES-D (depression scale) were 73, 22, and 47, respectively, each exceeding clinical diagnostic thresholds. Baseline temporal lobe (T3/T4: one minute, eyes closed) high frequency (23–36 hertz) EEG asymmetry (TLHFA) was 128.2% (rightward dominance). After sixteen 90-minute HIRREM sessions, over three weeks, scores decreased to 31, 10, and 9, reflecting clinically relevant improvements, which dropped below clinical thresholds. In the penultimate minute of the penultimate HIRREM session, TLHFA was reduced to 18.1%. This supports a model of hemispheric asymmetry in PTSD. Decreased asymmetry may relate to reduced PTSD symptoms. Controlled clinical trials of HIRREM for PTSD are needed. Study supported by: The Susanne Marcus Collins Foundation, Inc.; Sung W Lee, MD, MS, receives salary support from Brain State Technologies, LLC. T1504. Ongoing Prospective Multicenter Clinical Studies of Non-Invasive Absolute Value Pressure Measurements Arminas Ragauskas, Rolandas Zakelis, Laimonas Bartusis, Vytautas Petkus, Romanas Chomskis, Gediminas Daubaris, Daiva Rastenyte, Kestutis Petrikonis and Vaidas Matijosaitis. Kaunas, LT, Lithuania Background: An innovative non-invasive absolute intracranial pressure (aICP) measurement method, based on twodepth transcranial Doppler technology has been proposed in previous works. Material and Methods: The aim is to validate the accuracy, precision, sensitivity and specificity of proposed noninvasive aICP measurement method. Ongoing prospective multicenter clinical studies of simultaneous non-invasive aICP and “gold standard” invasive ICP measurements have been conducted on neurological and intensive care unit (ICU) patients. Data were collected from 110 patients (171 independent paired data points). Bland&Altman and ROC analyses have been performed. Results: Accuracy of non-invasive aICP meter (expressed by the mean systematic error D) is D 5 0.03 mmHg, CL 5 0.97. Precision of aICP meter (expressed by SD of random error) is SD 5 2.65 mmHg (CL 5 0.97). ROC analysis showed an area under ROC curve AUC 5 0.94 with sensitivity 73.7 % (CL 5 0.95) and specificity 94.7 % (CL 5 0.95). Conclusions: Negligible systematic error and low enough SD of random errors were observed in a wide range of aICP values from 5 mmHg to 30 mmHg. Validated method shows clinically acceptable accuracy, precision, sensitivity and specificity. Study supported by: Clinical studies and technology development were funded by European Commission EC
Abstracts, American Neurological Association
Framework Project FP7 projects “TBIcare”, “BrainSafe”, “BrainSafe II”, by Lithuanian-Swiss Cooperation Programme “BrainCare”, by the US Dept. of the Army and partially by NASA. Neuroinformatics T1601. Applying Biomedical Informatics to Electronic Health Records for Monitoring Brain Volume and Disease Activity in Multiple Sclerosis. Zongqi Xia, Lori Chibnik, Tanuja Chitnis, Howard Weiner, Issac Kohane and Philip De Jager. Boston, MA To optimally leverage the sample size and the unique features of electronic health records (EHR) for research that would improve patient outcomes in multiple sclerosis (MS), we developed algorithms using EHR data to derive measures of MS disease activity, including brain volume. Using the medical informatics framework of Partners HealthCare and MS patients who receive neurological care at the Partners MS Center, we derived from the EHR data brain parenchymal fraction (BPF, a measure of whole brain volume) and multiple sclerosis severity score (MSSS). EHR algorithms provide reasonable correlation between derived and true BPF and MSSS (R2 5 0.22 for BPF, R2 5 0.38 for MSSS). To illustrate their clinical relevance, disease activity derived from EHR algorithms capture the difference between progressive and relapsing-remitting MS patients (p 5 7.37 3 1027 for BPF, p 5 1.56 3 10212 for MSSS). Thus, informatics approach using EHR data provides reasonable estimates of disease activity outcomes in MS (including brain volume) that are not part of the routine medical records but highly useful to guide patient management. Similar approaches could be applied to other neurological disorders. Study supported by: The study was supported by NIH U54-LM008748 from the National Institutes of Health Office of the Director, National Library of Medicine and the National Institute of General Medical Sciences. Dr. Xia was a recipient of the Clinician Scientist Development Award from the National Multiple Sclerosis Society and the American Academy of Neurology and is supported by NIH K08-NS079493. T1602. An Open-Source Semi-Automatic Detector and Viewer of Epileptiform Discharges and High Frequency Oscillations Danilo Bernardo, Tim Pluta and Hae-won Shin. Chapel Hill, NC and Raleigh, NC High frequency oscillations (HFOs) have been implicated in normal neurodevelopment and cognition. Interictal epileptiform discharges (EDs) and HFOs have also been implicated as biomarkers of epileptogenic cortex. Manual visual detection of HFOs and EDs is time-consuming, particularly with large multichannel intracranial EEG datasets. Automated HFO and ED detection methods are time-saving, however have high false detection rates. Thus, expert (e.g. neurologist) supervision of these algorithms is required. There is a paucity of visualization tools that allows for efficient, usersupervised detection and analysis of HFOs and EDs in large EEG datasets. We present HFOVIS, an open-source semi-
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automatic HFO and ED detector. It automatically detects HFOs and EDs and contains a heatmap view that allows for rapid visual inspection of putative events. Users can explore areas of interest on the heatmap by clicking on them to examine them in more detail for verification. The GUI contains a module utilizing FIR filter and the complex Morlet wavelet for verification of putative HFOs and EDs. We have developed the GUI to be open-source and extensible. Thus, we expect it to evolve into a beneficial tool for clinical and research purposes. Study supported by: Employment as a resident physician by the UNC department of neurology. Headache and Pain/Neuro-otology T1701. Interictal Visual Discomfort and Visual Cortex Hyperresponsivity in Migraine with Aura. Brett L. Cucchiara, Rito Datta, Geoffrey K. Aguirre, Quan Zhang, Scott E. Kasner and John A. Detre. Philadelphia, PA and Tianjin, China Background: Interictal cortical hyperresponsivity has been demonstrated in migraine, but it’s correlation with symptoms is unknown. Methods: Migraine with aura (MWA), migraine without aura (MwoA), and control subjects were enrolled in a 1:1:1 ratio for multimodal MRI including interictal BOLD fMRI with an alternating checkerboard stimulus. The visual discomfort scale (VDS) was used to assess interictal photophobia. Results: 160 subjects were studied. VDS scores were similar in MWA and MwoA subjects, and both were markedly higher than controls: MWA 32 (IQR 28–39), MwoA 31 (IQR 28–37), controls 26 (IQR 24–29), p < 0.001 for both MWA and MwoA vs. controls. BOLD fMRI responses within primary visual cortex were greater in MWA compared to controls (2.7% vs 2.3%, p 5 0.006) but similar between MwoA and controls (2.2% vs. 2.3%, p 5 0.38). VDS and BOLD correlated significantly in MWA (r 5 0.29, p 5 0.04) but not in MwoA (r 5 20.06, p 5 0.69) or control subjects (r 5 20.14, p 5 0.38). Conclusions: Despite similar interictal VDS scores in MWA and MwoA, only MWA subjects showed BOLD hyperresponsivity and a correlation between cortical responsivity and VDS score. Cortical function appears to differ between MWA and MwoA. Study supported by: NIH grant NS061572. T1702. Headaches and Neuroimaging: High Utilization and Cost of Guideline Discordant Care Brian C. Callaghan, Kevin A. Kerber, Rob Pace, Lesli Skolarus and James F. Burke. Ann Arbor, MI Objective: To describe the use of neuroimaging in outpatient headache visits, expenditures attributable to these tests, and determine factors associated with their use. Methods: Using data from the 2007–2010 National Ambulatory Medical Care Surveys (NAMCS), we estimated neuroimaging utilization in United States outpatient headache visits (defined by ICD-9 and reason for visit codes). Multivariable logistic regression was used to explore
associations between patient level factors and neuroimaging utilization. Results: Of 50.3 million outpatient headache visits, 12.5% resulted in a neuroimaging study. Neuroimaging accounted for $977 million in annual health expenditures. Patients with a migraine diagnosis (OR 5 0.6, 95%CI 0.40.9) and chronic headaches (routine, chronic OR 5 0.3, 95%CI 0.2-0.5, flare up, chronic OR 5 0.5, 95%CI 0.30.9) were associated with lower utilization, but testing in these populations remained high (5.6–13.6%). Risk factors for intracranial pathology did not increase use of neuroimaging studies (OR 5 1.0, 95%CI 0.6-1.6). Conclusions: Multiple guidelines indicate that neuroimaging in patients with chronic headaches, especially those with migraines, should be avoided. However, neuroimaging utilization occurs in a substantial number of visits. Efforts to reduce neuroimaging in this population have the potential to improve guideline-concordant care and reduce costs. Study supported by: ADA Junior Faculty Award.
severe right greater than left leg weakness, right lower extremity hyperesthesia to T10, absent lower extremity reflexes, and bilateral extensor plantar responses. MRI spine demonstrated extensive T2/DWI hyperintensity in central spinal cord from T1-L1 with mild cord enlargement and enhancement at T7– 9 (sites of injection). At 1 month after presentation the patient showed significant improvement and was ambulating with a walker. Repeat MRI spine demonstrated near complete resolution of the T2 signal abnormality. Interpretation: Phenol is a viscous and destructive substance. The temporal and anatomic relationship of our patient’s symptoms to her phenol injection strongly suggests the injection as the etiology of her symptoms. The likely mechanism was diffusion of phenol from the intercostal space into the epidural space causing toxic injury. Given the severity of injury, our case highlights the importance of avoiding intercostal blocks containing phenol. Study supported by: No financial support required as this is a case report.
T1703. High Fat Diet Induces Impaired Glucose Tolerance and Painful Peripheral Neuropathy Jacqueline R. Dauch, Hsinlin T. Cheng, John M. Hayes, SangSu Oh and Eva L. Feldman. Ann Arbor, MI
T1705. Retrospective Analysis of Headache Pattern and Other Epidemiological Data in Adults with Chiari Malformation-1 Undergoing Posterior Fossa Decompression Rahul Khanna, Gauravjot Sandhu, Niranjan Singh, Gulshan Uppal and Natasha Kataria. Columbia, MO
Impaired glucose tolerance (IGT) is a common condition that causes idiopathic neuropathy and pain. Our understanding of the mechanisms causing IGT-induced neuropathic pain is very limited and effective treatment is lacking. In order to study IGT-induced neuropathy, we treated male C57BL/6 mice with high fat (HF, 45% fat calorie) and control chow (CC, 13% fat calorie) starting at 5 wk of age. IGT development was assessed by a weekly 2 hour-glucose tolerance test. Mechanical and thermal thresholds, as well as nerve conduction velocities, were measured periodically. By 36 wk of age, HF mice developed obesity, hyperlipidemia and hyperinsulinemia; however, the fasting glucose and glycosylated hemoglobin levels remained within control ranges. We detected IGT in HF mice starting at 11 wk of age. In parallel, mechanical allodynia and thermal hyperalgesia were detected at 12 wk in HF mice. Impaired sciatic motor and sural sensory nerve conduction velocities, along with significantly higher levels of oxidative stress in peripheral nerves, were detected in HF mice at 36 wk, indicating the presence of peripheral neuropathy. Our findings suggested that HF mice could serve as an animal model for studying painful neuropathy from IGT. Study supported by: Program for Neurology Research & Discovery; A. Alfred Taubman Medical Research Institute; NIH 1K08NS061039 (to HTC). T1704. Phenol Induced Paraparesis Narayan R. Kissoon, Jonathan Graff-Radford and Ruple S. Laughlin. Rochester, MN Objective: To report a case of phenol induced myelopathy. Case: A 53 year-old female was transferred from her local facility for acute onset of lower extremity paresis beginning shortly after right intercostal nerve injection of preservativefree phenol at the T7, 8, 9 levels. She had previous intercostal blocks without sequelae. Admission examination revealed
Introduction: Chiari Malformation-I (CM-1) is characterized by Cough Headaches(HA) and posterior fossa decompression(PFD) is the accepted treatment modality. Methods: We did retrospective chart review of 94 patients who underwent PFD for CM1 and demographic data with patterns of HA before and after surgery were recorded. Pediatric patients were excluded(n 5 36). Results: Out of 58 adults who underwent PFD, Male: Female ratio 1:3,67% of the patients had BMI >30 while 17% had normal BMI. The commonest presenting complaint and the indication of surgery was HA in 78% pts. Post op 55% patients reported no HA. 41% patients had Chiari HA preoperatively while only 3% had chiari HA postoperative, contrary to that 17% had migrainous HA preoperative but postoperative this number increased to 32%. Conclusion: Study suggests that 3/4th of adults who underwent surgery were female&more than half ofthe patients were obese.Data also indicates that patients who benefitted from surgery had typical Chiari HA, while patients with other components like migranous/mixed didnt improve significantly. We propose that candidates for surgery should undergo extensive preoperative evaluation in a headache clinic and aggressive management of non-chiari HA might eliminate the need for surgery. Study supported by: department of neurology, university of missouri, columbia, mo. Neurology Critical Care T1801. Association of Guillain-Barre Syndrome (GBS) with the Development of Diabetes Mellitus (DM) Ifeanyi Iwuchukwu, Sandi Lam, Jefferey Frank and Agnieszka Ardelt. New Orleans, LA and Chicago, IL
Abstracts, American Neurological Association
Objectives: The endocrine function of the pancreas is also regulated by the autonomic system. Severe GBS affects the autonomic system. We investigated an association between new onset DM(NODM) after severe GBS. Methods: A cohort of patients in the Marketscandatabase with claims of GBS were classified by the presence or absence of NODM, defined as new DM >90days after the GBS claim. Variables suggesting severity of GBS were collected for analysis by univariate and multivariate methods. Results: 3282 patients with GBS were included and of these 199 (6.1%) had NODM. Older age(50.2years vs 42.1years, p < 0.0001), longer hospital stay(14.3 vs 9.5, p 5 0.005), tracheostomy(9.6% vs 4.3%, p 5 0.007), arrhythmia(5% vs 1.2% p 5 0.008) and rehab discharge(25.6% vs 19.3%, p 5 0.024) were associated with NODM. A point each was assigned to age>45yrs, length of stay>10days, trachesotomy, arrhythmia and rehab discharge, with higher scores reflecting inreasing GBS severity. Using the total points, risk of NODM was stratified as 0–1 low, 2–3 moderate and 4–5 high risks. The frequency of NODM in low risk group was 4.9%, moderate 8.8% and high 15.5%. Conclusion: Amongst patients with GBS features suggestive of severe disease is associated with NODM. Study supported by: National Center for Advancing Translational Sciences of the National Institutes of Health through Grant Number UL1 TR000430. T1802. Intracerebral Hematoma Location Predicts Domain Specific Quality of Life at Follow-Up Andrew M. Naidech, Neil F. Rosenberg, Adam R. Kosteva, Kelly L. Brandstatt, Matthew B. Maas and Joel L. Voss. Chicago, IL Background: In patients with intracerebral hemorrhage (ICH), supratentorial hematoma location is not accounted for by severity scores. Quality of life (QOL) in specific domains (e.g. applied cognition, fatigue, mobility, etc.) may provide a more detailed assessment than functional outcomes (e.g. ambulation). We tested the hypothesis that hematoma location predicted QOL at follow-up. Methods: Hematomas from CT scans of 32 patients who survived ICH were mapped onto normalized stereotactic space. Neuro-QOL (with online computer adaptive questionnaires) and functional outcomes (modified Rankin Scale [mRS], a validated scale from 0, no symptoms to 6, death, with a standardized interview) were assessed at one and three months. Results: Hematoma location was associated with QOL scores for the domains of depression (right thalamus), fatigue (right thalamus and basal ganglia), and applied cognition (including executive function and general concerns, left temporal lobe) (P < 0.05 for all). Hematoma location was not associated with the mRS. Conclusions. In survivors of ICH, hematoma location predicted domain-specific QOL at follow-up. Neuro-QOL may be more sensitive to differences in outcomes vis-a-vis the mRS. The mechanisms underlying ICH’s affect on
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applied cognition, depression and fatigue require further study. Study supported by: in part by NIH to grant to Dr Voss. T1803. Variability of Physician Treatment Recommendations for Intracerebral Hemorrhage Darin B. Zahuranec, Angela Fagerlin, Andrea Fuhrel-Forbis, Meghan E. Roney, Peter A. Ubel and Lewis B. Morgenstern. Ann Arbor, MI and Durham, NC Background: There is substantial variability in early donot-resuscitate orders after intracerebral hemorrhage (ICH), though it is unknown whether this is due to physician recommendations, or patient/family wishes. Methods: Neurology and neurosurgery faculty and residents from an academic institution completed a pilot survey describing three cases of adults with spontaneous ICH (ages 61–83, Glasgow coma scale range 4–11). Each case included exam findings, CT images, and the following standardized background information: patient independent at baseline, no advance directive, previously stated generally that they “did not want to be a vegetable”. Participants provided a recommendation to the family for initial treatment intensity (scale from “1-comfort care only” to “6-full intensive care”, reported as comfort (1–2), moderate (3–4), or full (5–6)). Results: Response rate was 58/115 (50%). Despite standardized background information, treatment recommendations varied widely by physician: Case 1 comfort 14%, moderate 36%, full 50%; Case 2 comfort 29%, moderate 38%, full 33%; Case 3 comfort 43%, moderate 28%, full 29%. Conclusions: Some of the observed variability in end-oflife treatment for ICH may be due to heterogeneity between physicians in initial treatment recommendations. A national survey is planned to understand factors underlying this variability. Study supported by: NIH NIA K23AG038731; Salary support provided as a part of NIH career development award. T1804. Levetiracetam Is an Effective Postoperative Seizure Prophylaxis for Patients Undergoing Brain Tumor Surgery at High Risk for Seizures Sankalp Gokhale and David McDonagh. Durham, NC Background: The risk of developing immediate postoperative seizures (within 7 days) in patients undergoing supratentorial brain tumor surgery without AED (anti-epileptic drug) prophylaxis is 15–20%. Patients with pre-operative seizure, patients with supratentorial meningioma or supratentorial low grade gliomas are at significantly higher risk. There is little data regarding efficacy of levetiracetam in these patient populations. Methods: A retrospective chart review of 165 adult patients classified as higher risk for postoperative seizures who underwent brain tumor resection within last 2 years was carried out. All patients had received levetiracetam in dose of 1000–3000 mg/day in immediate postoperative period. Results: We identified 165 patients with following tumor locations: frontal 83 (50.3%), temporal 43 (26.1%), parietal 36 (21.8%) and occipital 2 (1.2%). Histology revealed:
gliomas 98 (59.4%), meningioma 57 (34.5%) and brain metastasis 6 (3.6%). 12 out of 165 patients (7.3 %) developed seizures (generalized 10, partial 2) in immediate postoperative period. Other than somnolence in 7 patients (4.2 %), no major side effects were noted. Conclusions The incidence of seizures was significantly lesser in patients treated with levetiracetam (7.3 %) as compared to expected (15–20%) risk without AED prophylaxis. Study supported by: None. T1805. The Use of EEG Reactivity in Predicting Outcome in Patients after Cardiac Arrest in Presence of Therapeutic Hypothermia Sameer Sharma and Julius Gene Latorre. Syracuse, NY Therapeutic hypothermia has been incorporated as a recommendation by the International Liasion Committee on Resuscitation as part of management for adult patients with spontaneous circulation after out of hospital cardiac arrest when the initial rhythm was ventricular fibrillation with an indication towards possible benefit for other cardiac rhythms Subsequent studies provide evidence to support that traditional prognostic markers such as motor examination,serum neuron-specific enolase,early myoclonus and pupillary or corneal cannot provide fool-proof prognostication after cardiac arrest in cases therapeutic hypothermia.The same studies support the absence of EEG reactivity as a potential novel marker for poor prognosis when hypothermia is used.We present a case of a 66 year old male who was put under hypothermia after a witnessed cardiac arrest out of the hospital,had absence of EEG reactivity alongwith traditional markers of poor prognosis,but went on to have good neurological recovery.Inclusion of EEG reactivity as a marker of poor prognosis needs further studies and should not be used.We need a new conglomerate of clinical, biochemical and neurophysiological markers with a false positive rate of 0 for better prognosis after therapeutic hypothermia. Study supported by: None. T1806. Asymptomatic Central Pontine Myelinolysis Syed O. Shah, Arthur Wang, Lakshmi Mudambi, Nasreen Ghuznavi and Robert Fekete. Valhalla, NY Introduction: Central pontine myelinolysis (CPM) is an acquired demyelinating lesion of the basis pontis that typically occurs after rapid correction of hyponatremia. Case Presentation: 26-year-old male with history of alcoholism was transferred to our medical center for acute onset abdominal pain. Abdominal CT scan demonstrated large pancreatic mass. He underwent endoscopic guided biopsy which demonstrated aggressive lymphoma. Laboratory values were consistent with hyponatremia, which the medical team gently corrected. MRI brain revealed findings consistent with CPM. A full neurological exam demonstrated no deficits. Materials and Methods: We conducted a Pubmed search using following keywords: asymptomatic, central, pontine, and myelinolysis in order to find other case reports of asymptomatic CPM.
Results: Of the 29 results, only 6 previous case reports with English language abstracts of asymptomatic CPM were present since 1995. Conclusion: Despite slow correction of hyponatremia, CPM can be an important consequence, especially in patients with chronic alcoholism. Although this patient did not demonstrate any neurological deficits, the fact that there were changes seen on MRI should caution physicians in aggressively treating hyponatremia. Furthermore, if there is a decision to treat, then fluid restriction and reversal of precipitating factors (i.e. diuretics) should be used initially, unless there is concern for hypovolemia. Study supported by: None; Dr. Fekete received honoraria from Medlink, Inc., and served as a consultant for Lundbeck, LLC, and Teva Neuroscience, Inc. T1807. Recurrent Posterior Reversible Encephalopathy Syndrome (PRES) in a Patient with HIV Mohankumar Kurukumbi, Frehiwot Temesgen and Mohammed Amine Achhal El Kadmiri. Washington, DC Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological syndrome in which patients present with an acute or subacute clinical presentation of seizures, visual disturbances, headache, and altered mental status. The pathophysiology of PRES may be explained by endothelial dysfunction that leads to transudation of fluids and protein, resulting in vasogenic cerebral edema. PRES is typically associated with many conditions such as hypertension, uremia, immunosuppressive drugs, and sepsis. PRES recurrence has been previously described but is a rare entity. This is a case report of a 40-year-old woman with untreated HIV infection and end-stage renal disease (ESRD) who developed a recurrence of PRES with a normal blood pressure and no other known causes of PRES. Untreated HIV is associated with known endothelial dysfunction and we believe that this, in combination with her untreated ESRD, caused her recurrence. To the best of our knowledge, this is the first report of recurrent PRES in a normotensive patient with untreated HIV and ESRD as the only precipitating factors. Study supported by: None. Neurogenetics T1901. Genetic Analysis of Motor Progression in Parkinson’s Disease Marie Davis, James Leverenz, John Trojanowski, Daniel Weintraub, Howard Hurtig, Rachel Goldman Gross, Alice Chen-Plotkin, Vivianna Van Deerlin, Stewart Factor, Cathy Wood-Siverio, Joseph Quinn, Kathryn Chung, Dora Yearout, Taryn Hall, Karen Edwards, Thomas Montine and Cyrus Zabetian. Seattle, WA; Philadelphia, PA; Atlanta, GA and Portland, OR We sought to determine whether susceptibility genes for Parkinson’s disease (PD) identified in recent genome-wide association studies also predict rate of motor progression in PD. We genotyped 26 markers from 14 susceptibility loci (BST1, CCDC62/HIP1R, GAK, HLA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, RIT2, SNCA, SPRY2, STK39,
Abstracts, American Neurological Association
SYT11/RAB25, TMEM163) in 433 PD patients who had undergone longitudinal assessments of motor performance (UPDRS). The mean disease duration in the sample was 11.3 6 5.9 years and the average duration of follow-up was 2.7 6 1.2 years. Patients were classified as fast or slow progressors, defined as a change of greater or less than 5 points per year in total motor UPDRS score. Regression analysis was used to test for association between progression category or mean annual change in UPDRS score and genotype in an additive model, adjusting for sex, disease duration, and age at onset. None of the markers examined were associated with progressor status, but rs10847864 within CCDC62/HIP1R was associated with rate of change in UPDRS score (p 5 0.004). Our data suggest that variation within CCDC62/HIP1R might influence rate of motor progression in PD, but these results require replication in independent studies. Study supported by: P50NS062684, P50NS053488, R01NS065070; 1) Department of Veterans Affairs; 2) Consolidated Anti-aging Foundation. T1902. Identification of Candidate Molecules Involving Axonal Degeneration in SPG6 Hereditary Spastic Paraparesis Rodent Model Yaz Y. Kisanuki, Fumihiro Watanabe, Rachael Hardison, Moti Harmeet, Robert E. Hammer, Jeremy Keirsey and Kari B. Green. Columbus, OH and Dallas, TX Length-dependent axonal degeneration is a common pathologic process in a variety of neurologic diseases affecting the central and/or peripheral nervous systems. Inherited forms of length-dependent axonal degeneration are associated with mutations in genes expressed in either neurons or glia, suggesting that dysfunction in either cell type can produce a similar histopathologic phenotype. We recently developed transgenic rats (Thy1.2-hNIPA1G106R) in which the SPG6/NIPA1 mutation, which causes an autosomal dominant form of hereditary spastic paraparesis, is specifically expressed in central and peripheral nerves. These rats show length-dependent axonal degeneration in both central and peripheral nerves, with corresponding behavioral and electrophysiologic phenotypes. We applied proteomics analysis on sciatic nerve protein extracts from transgenic rats at a very young age, prior to histologic onset of axonal degeneration to compare with samples from the age-matched wild-type rats. We identified 59 different proteins differentially expressed between transgenic and wild-type sciatic nerves. Of note, some of these proteins are expressed in Schwann cells and not neurons/axons. Our preliminary result suggests that SPG6 mutant protein in nerve cells may trigger dysfunction of axon-Schwann cell interactions even before histologic onset of axonal degeneration. Study supported by: Spastic Paraplegia Foundation. T1903. MAPT Haplotypes Associate with Alzheimer’s Disease Risk and Brain Gene Expression Mariet Allen, Michaela Kachadoorian, Zachary Quicksall, Fanggeng Zou, High Seng Chai, Curtis Younkin, Julia Crook, V. Shane Pankratz, Minerva Carrasquillo, Siddharth
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Krishnan, Thuy Nguyen, Li Ma, Kimberly Malphrus, Sarah Lincoln, Gina Bisceglio, Christopher Kolbert, Jin Jen, Ronald Petersen, Neill Graff-Radford, Dennis Dickson, Steven Younkin and Nilufer Ertekin-Taner. Jacksonville, FL and Rochester, MN MAPT encodes for tau, the constituent of neurofibrillary tangles, a hallmark of Alzheimer’s disease (AD) neuropathology. Common variation at the MAPT locus associate with risk for tauopathies, although the evidence for genetic association with late-onset AD (LOAD) is inconsistent. This is likely due to insufficient power and/or lack of detailed investigations of haplotypic variability at this locus. In this study we investigated associations of MAPT haplotypes with LOAD risk in a large case-control cohort and with brain expression levels of MAPT. We genotyped six MAPT haplotype-tagging SNPs in >5,400 subjects. We measured MAPT expression levels in the cerebellum and temporal cortex of 200 autopsied AD subjects. MAPT H2 haplotype was significantly associated with decreased risk of LOAD and decreased brain MAPT expression. The most common H1 sub-haplotype (H1b) had nominally significant association with increased risk of LOAD and a global test for the 19 haplotypes was also significant, with a number of additional significant or suggestive subhaplotypes. Our results strongly suggest that MAPT has regulatory variants which confer LOAD risk by influencing its brain expression. These findings require replication in additional cohorts. Study supported by: NIH/NIA: R01AG032990, P50AG16574, KL2RR024151. T1904. Utilization of Genetic Testing Prior to Subspecialist Referral for Cerebellar Ataxia Brent L. Fogel, Barbara G. Vickrey, Jenny Walton-Wetzel, Eli Lieber and Carole H. Browner. Los Angeles, CA Objective: Evaluation of laboratory testing for cerebellar ataxia, including initial standard testing for acquired causes, early genetic testing, and associated clinical and non-clinical factors, among patients referred for subspecialty consultation. Methods: Data from 95 consecutive ataxia patients referred to one neurogenetics subspecialist were used to analyze unique associations of clinical and non-clinical factors via multivariable logistic and linear regression models. Results: 27 of 95 patients lacked any of 14 laboratory studies suggested for initial acquired ataxia work-up. In contrast, 92% underwent brain MRI. Overall, 41% (n 5 39) had genetic testing but no association between family history of ataxia and genetic testing prior to referral was observed (p 5 0.39). 32% had early genetic testing, primarily due to an incomplete laboratory evaluation for acquired causes and no family history. Positive family history was associated with less laboratory testing (p 5 0.004) and referral by a neurologist was associated with increased early genetic testing (p 5 0.04). Conclusions: Among consecutive referrals to one center, a substantial proportion of sporadic cases had genetic testing without a work-up for acquired causes. Better strategies for decision-making and subspecialty referrals in rare neurologic
disorders are needed, given the cost and consequences of genetic testing. Study supported by: Support provided by NIMH K08MH86297 (BLF) and the UCLA Committee on Research Faculty Research Grant (CHB). T1905. Functional Consequences of Presenilin 2 Mutations on CNS Cells Derived from Patient iPSCs Amanda Case, Aravind Ramakrishnan, Bryce Sopher, Jane Sullivan, Mark Bothwell, Gwenn Garden and Suman Jayadev. Seattle, WA Alzheimer disease (AD) pathogenesis is multifactorial. Autosomal dominant AD (ADAD) is caused by mutations in the presenilin 1 and 2 (PSEN1, PSEN2) genes and APP. We hypothesize that combinatorial dysfunction in multiple CNS cell types expressing the causative mutation contributes to AD development. To investigate the proposal that both autonomous and non-cell autonomous dysfunction impairs neuronal function, we created induced pluripotent stem cells (iPSC) from ADAD patients carrying either the “Volga German” PSEN2N141I mutation or a 2bp deletion leading to a premature termination sequence in PSEN2. IPSCs were created through reprogramming by retroviral infection. We have developed mature neurons that express synaptic proteins, SV2 and synaptotagmin, and are characterizing the cell autonomous impact of PSEN2 mutations on their electrophysiological properties. We are concurrently characterizing microglia derived from ADAD iPSCs. To genetically correct PSEN2 mutations in isogenic lines, we are employing the CRISPR system to revert mutations and fluorescently label the derived cells. Furthermore, through co-culturing microglia and neurons from different genotypes we are studying the non-cell autonomous consequences of PSEN2 mutation on neuronal function in a human CNS model system. Study supported by: NIH, Friends of Alzheimers. T1906. ATP1A2 Gene Polymorphism rs2070704 and Acute Ischemic Stroke Risk: The Ischemic Stroke Genetics Study (ISGS) Andrea M. Harriott, Owen A. Ross, John W. Cole and James F. Meschia. Jacksonville, FL and Baltimore, MD Migraine is a disabling headache disorder. Acute ischemic stroke (AIS) is also a major source of disability. While migraineurs are at increased stroke risk, the mechanisms underlying this association remain unknown. One explanation is that both conditions share similar genetic factors. Familial hemiplegic migraine (FHM) is an inherited syndrome with focal neurological deficits. The ATP1A2gene of FHM type-2, encodes a neuronal/glial Na1-K1ATPase. We recently published an association between the rs2070704 polymorphism of the ATP1A2gene and AIS in young individuals. Based on these data, we hypothesized that there may be a stronger association in the general stroke population (average age 76). We therefore examined the association between rs2070704 and AIS in the ISGS population. In Caucasians, rs2070704 was associated with AIS in an additive (OR: 1.33, CI 1.02-1.72, p 5 0.034) and recessive model (OR: 2.32, CI 1.13-4.76, p 5 0.021) accounting for age, gender, coronary-artery disease, diabetes, hypertension,
and smoking. It was associated with cardioembolic stroke in an additive (OR: 1.62, CI 1.10-2.37, p 5 0.014) and recessive model (OR: 4.50, CI 1.81-11.21, p 5 0.0012). The results suggest that the ATP1A2gene maybe associated with AIS, validation of these findings is needed. Study supported by: R01 NS42733 NIH Grant, American Heart Association. T1907. The Contribution of Common Variants to Earlyand Late-Onset Alzheimer’s Disease Thomas S. Wingo, Noah Zaitlen and David J. Cutler. Atlanta, GA and San Francisco, CA Background: Previously, we used resemblance among relatives to show early-onset AD (EOAD; AD occurring on or before 60 years) does not appear to be substantially polygenic. In contrast, late-onset AD (LOAD; AD occurring on or after 65 years) appears perfectly polygenic, but our data suggested that a large proportion of EOAD is due to recessive causes and 10% is due to dominant ones. Here, we test those hypotheses using whole-genome genotying. Methods: The additive and dominance variance for LOAD and EOAD were found using pair-wise estimates of relatedness from whole-genome genotyping on 6,070 individuals genotyped by the Alzheimer’s Disease Genetics Consortium. Results: For LOAD, we found that the additive variance explains 34%, implying common markers account for 40% of the heritability, and dominance variance accounts for < 1% of the disease. For EOAD, we found that additive variance accounts for 17% but the dominance variance explains 26% of the disease. Discussion: Our results confirm LOAD is a polygenic disease with a substantial amount of the heritability due to common markers; however, we provide further evidence that EOAD is not substantially polygenic and alternative mechanisms should be investigated. Study supported by: Data was generated by the Alzheimer’s Disease Genetics Consortium supported by NIH/NIA grant 5U01AG032984; phenotype data was obtained through the National Alzheimer’s Coordinating Center supported by NIH/NIA grantU01AG016976); T.S.W is supported by a VA Career Development Grant 2 (1IK2BX001820). T1908WIP. Neurological and Endocrine Involvement in Women with the Fragile X Premutation Deborah A. Hall, Kristina Todorova-Koteva, Maura Walsh, Cory Deburghraeve and Elizabeth Berry-Kravis. Chicago, IL FMR1 premutation (PM) carrier women frequently report neurological or endocrine symptoms, but this has not been studied systematically. PM and normal control (NC) women were recruited and evaluated by a neurologist, neuropsychologist, endocrinologist and with molecular measures.The mean age of the women (n 5 37) was 50.9 years. Average FMR1 CGG in the PM women was 88 and 89% had a family history of fragile X syndrome. Forty-eight percent of the PM women had an abnormal neurological examination compared to controls (p 5 0.001). PM women had higher scores on the FXTAS Motor Rating Scale: 8.2 6 6.6 compared to controls at 2.8 6 3.0 (p 5 0.02), evidenced by
Abstracts, American Neurological Association
dystonia and difficulties with tandem gait (p 5 .03), which correlated with a lack of AGG interspersions. The Total Neuropathy Score was higher in the PM women (1.9 6 1.66) compared to controls (0.5 6 0.92; p 5 0.03). Central sensitivity syndromes, premature ovarian insufficiency, hypothyroidism, and prediabetes were more common in the PM women compared to controls, but only central sensitivity syndromes were significant (p 5 0.04). This first neurological study of PM women shows that they have mild ataxia, dystonia, and neuropathy; warranting a larger study to better define this potentially new phenotype. Study supported by: Rush University Translational Science Consortium. Pediatric Neurology and Developmental Disorders T2001. p75 Neurotrophin Receptor and Autism Louis T. Lotta, Jr., Katherine Conrad, Deborah Cory-Slechta and Nina F. Schor. Rochester, NY Autism is a developmental disorder characterized by difficulty responding appropriately to the social environment; diminished interest in interaction with others; and stereotyped, repetitive movements. Molecular biomarkers for and mediators of autism are not currently known, although oxidative stress and inflammation, and diminution of cerebellar Purkinje cell number and arborization are implicated. We demonstrated that p75 neurotrophin receptor (p75NTR) transitions from global to anatomically restricted expression in the human brain at the time at which developmental behavioral disorders like autism first become clinically apparent; serves as a redox regulator, gating and facilitating generation of reactive oxygen species in the cytoplasm and mitochondria; and regulates expression of endoplasmic reticulum stress- and inflammation-related proteins in neurons and extracellular matrix components in brain. We hypothesized that p75NTR is a redox regulator of importance in autism. We have produced a cerebellar Purkinje cell p75NTR cre-lox knockout mouse and have demonstrated that the phenotype of this mouse includes excessive jumpiness (p < 0.05); diminished exploratory behaviors in a foreign environment (p < 0.01); diminished social interaction and increased submissive behavior relative to cre-only control (p < 0.05) and wild type mice (p < 0.001), all murine analogues of human autism. Study supported by: Strong Children’s Research Center at the University of Rochester; William H. Eilinger Endowment of the Department of Pediatrics, University of Rochester. T2002. Electrographic Status Epilepticus While in the Pediatric Intensive Care Unit Is Associated with Worse Long-Term Outcome Katie Wagenman, Alexis A. Topjian, Robert A. Berg, Dennis J. Dlugos and Nicholas S. Abend. Philadelphia, PA We aimed to determine whether electrographic seizures (ES) and status epilepticus (ESE) in critically ill children were associated with worse long-term outcome. 300 children with an acute neurologic condition underwent EEG monitoring.
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We collected acute care clinical and EEG data and longterm outcome data including the pediatric extended Glasgow outcome scale (GOS-E-Peds). 137 of 300 of subjects were neurodevelopmentally normal prior to PICU admission and not deceased. Follow-up data was obtained for 56 of 137 (41%) at a median duration of 2.6 years (IQR 1.2– 3.8). There were no differences in acute characteristics between subjects with and without follow-up data. During the PICU admission, the 56 subjects with follow-up data were a median of 4.4 years old (IQR 1.1–13.0), 11 (20%) had ES and 12 (21%) had ESE. GOS-E-Peds was favorable in 37 (66%) and unfavorable (severe disability or vegetative state) in 19 (34%). In an adjusted model that included seizure category, age, acute neurologic disorder, and EEG background category, ES were not associated with unfavorable outcome (OR 0.42, 95%CI 0.06-2.85) while ESE was associated with unfavorable outcome (OR 6.54, 95%CI 1.3531.71). Study supported by: NINDS K23NS076550. T2003. Granger Causality Predicts Seizure Directionality in Patients with Epilepsy Edgard Andrade and Zhao Liu. Gainesville We prospectively studied seizure directionality in twenty-five patients with non-lesional pharmaco-resistant partial epilepsy utilizing Pairwise Granger Causality (PGC) to test the hypothesis of contra-lateral ictal spread (inter-hemispheric theory) versus no contra-lateral ictal spread (intra-hemispheric theory) using human ictal EEG raw data. Bootstrapping was used to address the issue of testing statistical significance of using PGC to evaluate network interactions before the onset of the seizure and during the seizure. Bayesian information criteria were used to select the model order. Time frequency distribution was plotted for each seizure and compared with controls. PGC was statistically significant within the hemisphere for seizure ictal onset over the left frontal (p 0.0028), left temporal (p 0.0548), right frontal (p 0.0558), and right temporal lobes (p 0.0257). Furthermore, there were no significant differences when looking at inter-hemispheric PGC directionality measures tested for seizures emanating over the left frontal (p 0.2882), left temporal (p 0.1572), right frontal (p 0.6772) and right temporal lobes (p 0.7795). Although the findings indicate an intra-hemispheric ictal spread, is still possible that the results are affected by limitations of the autoregressive PGC model and/or causal relations of more than two neuronal networks (hidden element theory). Study supported by: None. T2004. Clinical Review of Childhood Tourette’s Syndrome Matthew J. Eremita and Francis J. DiMario. Hartford, CT Tourette’s syndrome (TS) is a lifelong neurological disorder characterized by involuntary movements and vocalizations. There are several common co-morbidities often associated with TS; Attention-Deficit Hyperactivity Disorder (ADHD/ ADD), Obsessive-Compulsive Disorder (OCD), Oppositional Defiant Disorder (ODD) and Learning Disabilities
(LD). Typical antipsychotics used for treatment include pimozide however there is limited data on its efficacy and side effects in children. We undertook a retrospective review of all children diagnosed with TS using the diagnostic criteria set out in the DSM IV-TR evaluated between 2001 to 2011. We categorized their clinical manifestations, comorbidities and treatment effects with attention to the subset of patients treated with pimozide. There were 53 subjects (40 boys; mean age 9.7 years) of whom 10 (19%) were treated with pimozide. Co-morbid symptoms were identified in 81% of the cohort. There were 66%- ADHD/ADD; 51%-OCD; 34%-ODD and/or behavior/social conduct problems; 26%-with anxiety; 25%-LD and/or the requirement of an individualized learning plan and 17% reported being depressed. There were 7/10 subjects treated with pimozide who experienced adverse effects (2- prolonged QTc, 1-dystonic reaction, 5-weight gain). However, all remained on the drug with dose modification or concomittant treatment due to perceived benefit. Study supported by: None. T2005. Colpocephaly with Agenesis of Corpus Callosum in Adult Presenting with Frequent Falls Grerk Sutamtewagul, Pavis Laengvejkal, Kunut Kijsirichareanchai and Kenneth Nugent. Lubbock, TX Colpocephaly is a congenital malformation defined as a disproportionate dilatation of occipital horns of the lateral ventricles, which is usually found in association with agenesis of corpus callosum. Patients with colpocephaly can be asymptomatic or present with a variety of symptoms – motor or sensory deficit, visual disturbance, headache, seizure, and developmental delay since their infanthood. Colpocephaly in adults was usually detected as an incidental finding during the investigation of new-onset seizure in previous case reports. We report a 50-year-old woman without significant past medical history who presented with frequent fall secondary to diabetic neuropathy. The detailed neurological examination found no significant deficit. The magnetic resonance imaging of the brain found colpocephaly with agenesis of corpus callosum. Further neuropsychological evaluation revealed age-appropriate intelligence and normal developmental milestones. This patient adds an asymptomatic variant to the clinical spectrum of this developmental disorder in adult. Study supported by: None (case report). Neuro-oncology. T2102. Everolimus for Tuberous Sclerosis Complex (TSC)-Subependymal Giant Cell Astrocytoma (SEGA): EXIST-1 Update David N. Franz, Elena Belousova, Michael Frost, Rachel Kuperman, Martina Bebin, Bruce Korf, Robert Flamini, Michael Kohrman, Steven Sparagana, Joyce Y. Wu, Helene Cauwel, Noah Berkowitz and Sergiusz Jozwiak. Cincinnati, OH; Moscow, Russian Federation; Minneapolis, MN; Oakland, CA; Birmingham, AL; Atlanta, GA; Chicago, IL;
Dallas, TX; Los Angeles, CA; Basel, Switzerland; Florham Park, NJ and Warsaw, Poland EXIST-1 (NCT00789828), a double-blind phase 3 trial, evaluated everolimus for treating SEGA associated with TSC. Randomization was 2:1 for everolimus 4.5 mg/m2/d (titrated to blood trough levels of 5–15 ng/mL [n 5 78]) or placebo (n 5 39). SEGA response rate (primary endpoint) was defined as the proportion of patients with 50% reduction in sum of volumes of all target SEGA (1 SEGA 1 cm in longest diameter) compared with baseline. Adverse events (AEs) were monitored at every visit. Everolimus was superior to placebo for SEGA response rate (34.6% vs 0.0% P < 0.0001; original cut-off 03-02-11). As of 07–18-11 (90-day update) median treatment duration was 52 and 47 weeks for everolimus and placebo, respectively. Everolimus continued to demonstrate superiority over placebo for SEGA response rate: 38.5% (95% confidence interval [CI], 27.7–50.2) vs 0.0% (95% CI, 0.0–9.0). Discontinuations were the same in the everolimus arm, but had increased by 2 patients in the placebo arm since the initial analysis (n 5 2 disease progression). AEs were consistent with the original analysis; no patient discontinued therapy due to an AE. Everolimus continued to reduce SEGA volume with no new safety findings. Study supported by: Novartis Pharmaceuticals Corporation; From Novartis: Honoraria and travel support for lectures; Research support granted to me and my institution. Compensation from various attorneys for expert testimony and legal work. T2103. 3-Year Update for Everolimus for Tuberous Sclerosis Complex (TSC)-Subependymal Giant Cell Astrocytoma (SEGA) David N. Franz, Marguerite Care, Katherine Holland-Bouley, Karen Agricola, Cindy Tudor, Severine Peyard, Noah Berkowitz and Darcy Krueger. Cincinnati, OH; Rueil-Malmaison Cedex, France and Florham Park, NJ Long-term safety and efficacy data for the prospective, open-label, phase 2 trial (NCT00411619) of everolimus for SEGA-associated with TSC were available 12-14-2011 (original cut-off 12-09-2009). Patients received everolimus starting at 3 mg/m2/day (titrated to blood trough levels of 5–15 ng/mL). The primary endpoint was safety, and measures of efficacy were reduction from baseline in primary SEGA volume. Of 28 patients enrolled, 24 were continuing treatment at the time of this update. Median dose was 5.22 mg/m2/day (range, 2.0–11.8), and median treatment duration was 45.7 months (range, 4.7–58.5). After 36 (n 5 23), 42 (n 5 16), and 48 (n 5 10) months of everolimus, there was 30% reduction from baseline of the primary SEGA volume in 78.3%, 75.0%, and 90% of patients, respectively, and 50% reduction of the primary SEGA volume from baseline in 43.5%, 37.5%, and 50.0% of patients at the same time points. There were 6 patients with 1 drugrelated grade 3 adverse event (AE) and no drug-related grade 4 AEs. No patient discontinued treatment due to an AE. These results confirm maintenance of reductions in SEGA volume, with no new safety concerns identified.
Abstracts, American Neurological Association
Study supported by: Novartis Pharmaceuticals Corporation; From Novartis: Honoraria and travel support for lectures; Research support granted to me and my institution. Compensation from various attorneys for expert testimony and legal work. T2104. Multimodal MRI Performance Comparison between 1.5T and 3.0T in Recurrent GBM Lara J. Ronan, Thomas Hampton, Clifford Eskey and Camilo Fadul. Lebanon, NH Glioblastoma multiforme is the most common primary brain tumor. CE MRI is gold standard to determine response to treatment/tumor recurrence. We hypothesized that multimodal MR techniques providing tissue signatures obtained at 3T will be more accurate than 1.5T to characterize tumor recurrence. Materials and Methods: We prospectively acquired multi-parametric MR variables from GBM patients with pathologically confirmed recurrence. We compared the values of signatures acquired at 1.5T and 3T, to evaluate the predictive strength with the differing MR machines. Correlations between MRS ratios Cho/Cr,NAA/Cr,Lip/Cr, total metabolites T-NAA and T-Cho, ADC ratio and CBV were determined. Results: The confidence intervals for mean ADC, CBV and MRS were similar with both machines. There was poor correlation between metabolite variables on either 1.5T or 3.0T MRI.CBV showes a trend towards higher accuracy with the 3.0T MRI. Conclusion: We were unable to discern a clear benefit to the use of 3.0 T MRI in the tissue characterization using ADC ratio and MRS. over the standard 1.5 T machine in common clinical use. A trend towards better accuracy with the 3.0 T MRI was seen for CBV. A larger sample may determine if statististically significant. Study supported by: Norris Cotton Cancer Center Developmental Funds 2009–2011. T2105. Spectrums of Neurologic Presentations of Intravascular Lymphoma (IVL) Paul Bricker, Eric T. Wong and Ekokobe Fonkem. Temple, TX and Boston, MA Neurologic complications are frequently seen in cases of intravascular lymphoma (IVL), however the full spectrum and frequency with which these symptoms are seen has not been characterized. A comprehensive meta-analysis of 654 cases of IVL published between 1957 and 2012 was performed to provide better insight into the neurologic presentations of this disease. Neurologic complications were divided into central nervous system (CNS) symptoms and peripheral nervous system (PNS) symptoms. CNS symptoms were seen in 42% of all cases. The most common being cognitive impairment/dementia (61%), paralysis (22%), and seizures (13%). PNS complications were seen in 10% of cases while muscle weakness/numbness (60%), neurogenic bladder (37%), and paresthesias (16%) were the most common symptoms. Neurologic complications of IVL present with a broad spectrum of symptoms and represent a
Annals of Neurology Vol 74 (suppl 17) 2013
large source of morbidity in patients with intravascular lymphoma. Study supported by: No funding agency. T2106. WITHDRAWN T2107. Quantitative Measures of Tumor Enhancement Richard Leigh, Prakash Ambady and Jaishri Blakeley. Baltimore, MD and Bethesda, MD Patterns of enhancement of intracranial neoplasms can be homogeneous or heterogeneous. We hypothesized that qualitative differences between tumor types can be characterized in a quantitative manner using a novel imaging technique. Two tumor types (GBM and meningioma) with very different qualitative enhancement patterns were evaluated. Four typical patients, two with each tumor type, were studied. Regions of interest (ROIs) were drawn within the enhancing region. Using a novel imaging technique (Leigh et al., PLoS One 2012), the amount of contrast leakage was measured for every voxel in the ROIs. Mean, variance, median and interquartile range were measured. For the first GBM patient: mean 9.68, variance 222, median 5.30 and IQR 7.10. For the second GBM patient: mean 3.50, variance 28.7, median 1.80 and IQR 2.45. For the first meningioma patient: mean 0.96, variance 0.09, median 0.90, and IQR 0.40. For the second meningioma patient: mean 0.41, variance 0.08, median 0.30 and IQR 0.40. We concluded that our quantitative method of measuring enhancement pattern yielded similar results to those predicted by qualitative evaluation. The amount of enhancement was quite different between the tumor types, a finding that was not predicted with qualitative measures. Study supported by: R01DC05375. T2108. Neurological Manifestation of Erdheim Chester Disease Shri K. Mishra, Hermelinda Abcede and Bhavesh Trikamji. Los Angeles, CA; North Hills, CA and Irvine, CA Erdheim Chester Disease (ECD) is a rare non-Langerhans histiocytic disorder commonly characterized by multifocal osteosclerotic lesions of the long bones. It’s frequently associated with complications of bones, heart and lungs. Although, neurological complications can occur in up to 40% of the cases, it rarely presents as the primary manifestation. We report a 63 year male who initially presented with a three year history of progressive neurological symptomatology in 2002. His symptoms included seizures (intermittent spasms) lasting for about 20 seconds on right side of his body involving face, arm and legs. In 2005, he presented with worsening diplopia, dysphagia, dysarthria and weakness on left side of his body of 6 months duration. In 2002, MRI was significant for diffuse contrast enhancing medial temporal and brainstem lesions. CSF analysis for infection and EEG for seizures were negative. The serological workup for infections, autoimmune disorders, inflammatory disorders and malignancy was inconclusive. In 2005, bone and PET scans revealed multiple sclerotic lesions involving the brain and vertebral bodies. After multiple lung and bone biopsies, he was found to have non- Langerhans
histiocytosis confirming the diagnosis of ECD. The primary neurological manifestation makes this case unique and rare. Study supported by: None. T2109. Objective Response in Recurrent Glioblastoma from Adjuvant NovoTTF-100A and TCCC after Temozolomide and Bevacizumab Failure Eric T. Wong, Grace Elzinga, Amy Chung, Loretta Barron, Julianne Bloom and Kenneth D. Swanson. Boston, MA NovoTTF-100A is a novel, FDA-approved treatment for recurrent glioblastoma. It works by perturbing tumor cells during mitosis resulting in aneuploidy, asymmetric chromosome segregation and cell death. Clinical trial data have shown equivalent efficacy when compared to salvage chemotherapies and responders had lower dexamethasone requirement and higher rate of prior low-grade histology. We report response in a 56-year-old woman with glioblastoma after failure of adjuvant temozolomide, PLX-3397 and bevacizumab. Baseline MRI revealed a 5.5 3 3.6 cm right frontal glioblastoma with extensive dural invasion and an extracranial tumor mass measuring 2.4 3 1.9 cm. She was then placed on NovoTTF-100A. Bevacizumab was restarted and her daily dexamethasone was weaned from 6 to 0.5 mg. The 4-week interval MRI showed minimal change. However, after 6 weeks of adjuvant NovoTTF-100A and TCCC (6-thioguanine, lomustine, capecitabine and celecoxib), repeat MRI demonstrated partial response and shrinkage of both intracranial and extracranial tumors to 4.6x2.8 cm and 1.5x1.4 cm respectively. Tumor perfusion measured by arterial spin labeling had decreased to undetectable level. This case illustrates the possibility of achieving a response by the combination of NovoTTF-100A, cytotoxic chemotherapy, COX-2 inhibitor and possibly immune recovery. Study supported by: A Reason To Ride research fund; Research grant from Novocure, LTD. T2110. Paraneoplasticcerebellar Degeneration Associated with an Onconeural Antibody Against Creatine Kinase, Brain-Type Syuichi Tetsuka, Kaoru Tominaga, Kenji Kuroiwa, Mitsuya Morita and Hitoshi Endo. Shimotsuke, Tochigi, Japan Onconeural immunity, a cancer-stimulated immune reaction that cross-reacts with neural tissues, is considered to be the principal pathological mechanism for paraneoplastic neurological syndromes (PNS). A common PNS is paraneoplastic cerebellar degeneration (PCD). We had encountered a PCD patient with urothelial carcinomas (US) of the urinary bladderwho was negative for the well-characterized PNS-related onconeural antibodies. In the present study, we aimed to identify a new PCD-related onconeural antibody, capable of recognizing both cerebellar neurons and cancer tissues from the patient, and applied a proteomic approach using mass spectrometry. We identified creatine kinase, brain-type (CKB) as a new autoantigen in the serum and cerebrospinal fluid from the patient. Immunohistochemistry indicated that anti-CKB antibody reacted with both cerebellar neurons and US of the urinary bladder tissues. However, antiCKB antibody was not detected in sera from over 30 donors, including bladder cancer patients without PCD,
indicating that anti-CKB antibody is required for onset of PCD. We also detectedanti-CKB antibody in sera from three other PCD patients. Our study demonstrated that anti-CKB antibody may be added to the list of PCD-related autoantibodies and may be useful for diagnosis of PCD. Study supported by: nobody. T2111. Novel CNS Imaging Options with Ferumoxytol (A Superparamagnetic Iron Oxide Nanoparticle) as a MR Contrast Agent Edward A. Neuwelt. Portland The current standard gadolinium based contrast agents (GBCA) have limitations in measurement of relative cerebral blood volume (rCBV) which is emerging to be an important component in accurately diagnosing patients with CNS inflammatory disorders and especially CNS tumors. Ultrasmall superparamagnetic iron oxide (USPIO) agents such as ferumoxytol (Feraheme) are virus-sized, carbohydrate-coated particles that not only serve as contrast agents for MRI, but localization of the iron particles can also be easily identified histologically and ultrastructurally by standard and electron microscopy, respectively. Ferumoxytol is both a high molecular blood-brain barrier imaging agent and is taken up by inflammatory cells. MRI using ferumoxytol shows a good correlation with GBCA enhanced scans 24h post ferumoxytol injection. USPIO-based MRI provides relevant information in CNS inflammatory, vascular, and neoplastic diseases (Farrell BT, Neurology 2013). Recent advancements include using USPIO in measuring steadystate-CBV in patients (Varallyay CG, Journal of Cerebral Blood Flow & Metabolism 2013). Importantly, USPIO imaging provides a safe alternative for MRI in patients with renal failure. Our group is working with the US FDA to further the use of USPIO agents in the setting of MRI. Study supported by: a VA Merit Review Grant, National Institutes of Health grants NS44687, NS53468, NS076353, CA137488, and CA137488-15S1, in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. Some of the ferumoxytol USPIO nanoparticles donated by AMAG Pharmaceuticals. T2112WIP. Small Molecules Kill Proliferating and NonProliferating Hypoxic Glioma Cells by Novel Drug Mechanism of Action Fredric Gorin, Nagarekha Pasupuleti, Anthony Valenzuela, Leonardo Leon and Kermit L. Carraway III. Davis, CA and Sacramento, CA High-grade gliomas (HGGs) are infiltrative primary brain cancers characterized by hypoxic and necrotic regions from inefficient tumor vascularization. Hypoxic tumor regions harbor subpopulations of glioma-initiating cells (GICs) that self renew and contribute to the high recurrence rate of HGGs. Hypoxic GICs are resistant to RT, anti-mitotic and anti-angiogenic agents. HGGs, demonstrate elevated expression of urokinase plasminogen activator system components (uPAS), notably urokinase plasminogen activator (uPA), its receptor (uPAR) and the serpine PAI-1. We designed small molecules that selectively kill proliferating and nonproliferating GICs in hypoxic-ischemic tumor regions. The
Abstracts, American Neurological Association
lead molecules are cytotoxic to glioma cell lines in the single micromolar range, transported across the blood brain barrier, and target hypoxic GICs in human glioma intracerebrally implanted in NGS mice. These compounds target hypoxic GICs by a newly identified drug mechanism triggered by intracellular relocalization of uPAS components. Cell-permeant small molecules disrupt intracellular uPAS protein complexes expressed only in chronically hypoxic GICs. Disruption triggers relocalization of uPAS to perinuclear mitochondria causing mitochondrial AIF release and nuclear translocation PMID:23241369. AIF triggers irreversible caspase-independent necrotic cell death that is independent of cell cycle progression. Study supported by: NIH NS060880 NS040489 (Gorin PI); Komen for Cure KG090626 (Carraway PI); Pre doc fellowship W81XWH-10-1-0138 (Leon); FG is founder of D3G Inc a California based biotech focused on the preclinical development of compounds for the treatment of primary and metastatic cancers. FG serves as scientific advisor and holds stock options in D3G Inc. Dementia and Aging T2301. Damage to the Speech Production White Matter Tracts in Primary Progressive Aphasia Is Unique to the Non-Fluent Variant Maria Luisa Mandelli, Eduardo Caverzasi, Richard Binney, Bagrat Amirbekian, Miranda Babiak, Christa Watson, Nik Block, Maya L. Henry, Roland G. Henry, Bruce L. Miller and Maria Luisa Gorno-Tempini. San Francisco, CA Apraxia of speech and agrammatism are the characteristic clinical features of the non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA). NfvPPA is most often caused by FTLD-tau pathology with typical tau inclusions in white matter (WM). Changes in WM connections could provide an early marker for differential diagnosis. However, WM tracts within the frontal speech production network have never been investigated in PPA. We used a residual-bootstrapped q-ball tractography on HARDI images to reconstruct the WM pathways underpinning speech production. The tractography results were then used to define WM pathways for a novel assessment of speech production tract alterations across the three PPA variants using classical Diffusion-Tensor-Imaging derived WM metrics. In line with our hypothesis, we demonstrated WM alterations across all of the speech production tracts in nfvPPA relative to controls, but not in the other two variants. Moreover, we provide a unique demonstration of correlations between the WM metrics obtained and a score of speech production. Our findings demonstrate a role of WM tracts in language production as potential biomarker for differential, early diagnosis and longitudinal assessment of nfvPPA in clinical trials. Study supported by: National Institutes of Health (NINDS R01 NS050915, NIA P50 AG023501, NIA P01 AG019724, NIA R01 AG033017). Alzheimer’s Disease Research Centre of California (03-75271 DHS/ADP/ ARCC). Larry L. Hillblom Foundation; John Douglas French Alzheimer’s Foundation; Koret Family Foundation; and McBean Family Foundation.
Annals of Neurology Vol 74 (suppl 17) 2013
T2302. Efficacy of Memantine with and without Donepezil in Moderate-to-Severe Alzheimer’s Disease: Pooled Analysis of Four Randomized Trials Stephen M. Graham, Suzanne Hendrix, Michael L. Miller, Vojislav Pejovio and Michael Tocco. Jersey City, NJ; Salt Lake City, UT and Chicago, IL Treatment of Alzheimer’s disease (AD) typically involves therapy with a cholinesterase inhibitor (eg, donepezil), followed by the addition of memantine, an NMDA receptor antagonist, as the disease progresses. To investigate the effects of add-on vs monotherapy in moderate-to-severe AD, we pooled data from four randomized trials of memantine (monotherapy, N 5 567; added to donepezil, N 5 841) and compared Baseline-to-Endpoint changes in cognition (SIB), function (ADCS-ADL19), behavior (NPI), and global clinical status (CIBIC-Plus), between treatment regimens, using a mixed-effects model with repeated measures (observed cases). At Endpoint, memantine/donepezil-treated patients significantly outperformed those treated with placebo (P < 0.001), memantine (P < 0.05), and placebo/donepezil (P < 0.05) on all four efficacy measures. Comparing placebo/donepezil versus memantine monotherapy, the only significant difference was higher cognitive scores in the placebo/donepezil group (P < 0.001). Both monotherapy regimens were significantly better than placebo on the measures of cognition, function, and global status (P < 0.01). This pooled analysis is in agreement with evidence suggesting that memantine added to donepezil in patients with moderate-to-severe AD is superior to either monotherapy alone, across several clinical domains. Appropriately powered, long-term, prospective studies of add-on therapy in AD are warranted. Study supported by: Forest Laboratories, Inc.; Dr. Michael is employed by and receives a salary from Forest Research Institute. T2303. A Differential Effect of Amyloid Deposition and Neuroinflammation on Post-Stroke Cognitive Decline? Alexander Thiel, Shawn Whitehead, David Cechetto, WolfDieter Heiss and Vladimir Hachinski. Montreal, QC, Canada; London, ON, Canada and Cologne, Germany Stroke and the deposition of amyloid in the cerebral cortex are both known risk for developing dementia. While animal models suggest that stroke-induced inflammation and amyloid deposition both act synergetically this relationship remains to be established in human stroke. Cognitive performance was assessed in 7 Patients (55– 85y) with first supratentorial ischemic stroke using the Montreal Cognitive Assessment within 2 weeks (MOCA1) and 5–7 months post stroke (MOCA2). Patient underwent two PET –scans between 5 and 7 months post stroke to assess amyloid deposition (11C-PIB) and microglia activation (11C-[R]-PK11195). Standardized uptake value ratios (SUVRpib) for 11C-PIB and 11C-[R]-PK11195 (SUVRpk) were analyzed for gray and white matter. Cognitive performance 5–7 months after the stroke (MOCA2) was negatively correlated with gray matter SUVRpib. when controlling for MOCA1 (adjusted R2 5 0.979,
P < 0.01). Similarly microglia activation in the stroke-affected white matter (SUVRpk) was highly correlated with MOCA2 (adjusted R2 5 0.932, P < 0.01). No significant relationship was found between gray matter SUVRpib and SUVRpk. These results suggest that cortical amyloid deposition and post-stroke white matter inflammation independently contribute to post-stroke cognitive impairment and may thus constitute separate pathomechanisms to explain cognitive decline. Study supported by: Institutional Funding Lawson Health Research Institute. T2304. Assessment of Florbetapir-PET Versus Cerebrospinal Fluid Biomarkers in ADNI Subjects Paula Trzepacz, Ann Hake, Peng Yu, Shufang Wang, Michael Case, Helen Hochstetler, Michael M. Witte and Robert Dean. Indianapolis, IN We assessed relationships between florbetapir positron emission tomography (FBP-PET) scans and cerebrospinal fluid (CSF) biomarkers in clinically diagnosed healthy control (HC), mild cognitive impairment (MCI), and demented Alzheimer’s disease (AD) subjects. Data: Alzheimer’s Disease Neuroimaging Initiative (ADNI) Grand Opportunity and ADNI-2 (downloaded August 2012); all HC, MCI, or AD subjects with clinical and CSF data collected 6 90 days of their FBP-PET scans. Pearson correlation analysis was examined among 13 clinical, 5 CSF, and 7 FBP-PET variables. Multinomial logistic regression modeling (reference: HC subjects) assessed associations between diagnosis and CSF/FBP-PET variables. Likelihood ratio test examined whether adding CSF biomarkers to the model regressing clinical diagnosis on FBP-PET standard-uptake value ratios (SUVRs) significantly improved model fit, and vice versa. Highest correlations (|r|>0.60) observed in HC and MCI subjects: FBP-PET anterior and posterior cingulate and composite SUVRs with CSF beta-amyloid, tau/beta-amyloid, and phosphorylated tau/beta-amyloid; in AD subjects: FBP-PET anterior cingulate and composite SUVRs with CSF beta-amyloid. In multinomial logistic regression modeling, neither CSF biomarkers (p 5 0.096) nor FBP-PET SUVRs (p 5 0.675) improved prediction by the other. FBP-PET and CSF similarly distinguished among HC, MCI, and AD subjects, and combining measures offered no additional information. Study supported by: Eli Lilly and Company; salary and stock ownership.
lized. Effect size and power analyses were performed on FBP-positive subjects only or on all subjects regardless of FBP-PET status, based on 1-year changes of ADAS-Cog11, ADAS-Cog13, and CDR-SB. Sample size calculation was based on a hypothetical 25% reduction in decline rate with treatment (t-test: 80% power, 5% significance). Results: Amyloid based inclusion greatly reduced sample sizes for all clinical measurements in all groups (except CDR-SB in ADNI-2 mild AD and trial moderate AD). The greatest reduction in sample size was achieved with ADAS-Cog11 in ADNI-2 late MCI (58%), ADNI-2 mild AD (10%), and trial moderate AD (34%), compared with ADAS-Cog13 in trial mild AD (63%). For mild AD, sample size estimates based on ADNI-2 were smaller than those based on global clinical trials. Conclusion: Amyloid imaging selection may greatly improve statistical power in AD trials using ADAS-Cog regardless of disease stage. Study supported by: Eli Lilly and Company; Salaries. T2306. Aggregations of Small Nuclear Ribonucleic Acids (snRNAs) in Alzheimer’s Disease Chadwick M. Hales, Hong Yi, Eric Dammer, Nicholas T. Seyfried, Marla Gearing, Allan I. Levey and James Lah. Atlanta, GA
T2305. Amyloid-Based Patient Selection: Comparison of ADNI and Clinical Trial Data Peng Yu, Ferenc Martenyi, Jia Sun, Eric R. Siemers, Adam J. Schwarz and John R. Sims. Indianapolis, IN
Neurodegenerative diseases often involve pathologic aggregation of various proteins. Recent studies in amyotrophic lateral sclerosis (ALS) identified accumulations of small nucleolar RNAs (snRNAs), core components of RNA splicing machinery, in spinal cord motor neurons. Alterations in RNA splicing have been described in Alzheimer’s disease (AD), however the etiology for these changes remains unclear. We therefore hypothesized that aggregations of snRNA may also be present in AD. Immunohistochemical staining of postmortem human brain identified cytoplasmic tangle shaped aggregations of snRNA in both sporadic and familial AD cases. The aggregations were not present in aged controls or in other tauopathies like corticobasal degeneration or subjects with a familial microtubule associated protein tau (MAPT) mutation. Transmission electron microscopy demonstrated snRNA localization with paired helical filaments, the main component of neurofibrillary tangles (NFTs). These findings suggest that snRNA pathologic aggregations are not specific for ALS and may be a more general feature of neurodegeneration. In addition the findings suggest an association of snRNA with NFTs. Study supported by: This research project was supported in part by the Robert P. Apkarian Integrated Electron Microscopy Core of Emory University. A.I.L-Emory Alzheimer’s Disease Research Center-NIA-AG025688, J.J.L.-NIAP01AG1449, Emory Neuroscience NINDS Core FacilityP30NS055077.
Objective: This work evaluates the impact on AD clinical trials by recruiting only patients with positive florbetapir (FBP)-PET scans. Methods: Late MCI and mild AD subjects from ADNI2 and mild and moderate AD patients from placebo arms of two phase 3 global clinical trials (IDENTITY) were uti-
T2307. [18F]-Florbetapir PET in Alzheimer’s Disease and Frontotemporal Dementia Tobias C. Langheinrich, Christopher Kobylecki, Rainer Hinz, Emma R. Vardy, Maria E. Martino Casado, Cathleen Schmidt, Anna M. Richardson, Julie Snowden, Jose Anton Rodriguez, David Neary, David D. Mann, Alex Gerhard and
Abstracts, American Neurological Association
Karl Herholz. Manchester, United Kingdom; Salford, United Kingdom; Newcastle, United Kingdom and Madrid, Spain
of the Investigators and the funds for this research are provided by the National Institute on Aging.
Background: Deposits of fibrillar amyloid b (Ab) protein are important in the pathophysiology of Alzheimer’s disease (AD), but not frontotemporal dementia (FTD) and can be detected with amyloid PET. Pathological and imaging studies have reported FTD patients with Ab deposition. Apolipoprotein E (APOE) status and age are risk factors for amyloid deposition. We report a PET study using the novel Ab ligand [18F]-florbetapir in patients with AD and FTD. Methods: Ten healthy controls, ten AD patients and eight FTD patients were recruited. All patients were genotyped for APOE status. All participants underwent florbetapir PET, FTD patients also [18F]-fluorodeoxyglucose (FDG) PET. Grey matter uptake values were sampled from cortical and subcortical areas. Group differences were analysed using Kruskal-Wallis test. Results: Florbetapir target-to-reference ratios were significantly higher in AD compared to FTD patients and controls. One FTD patient (homozygous for APOE e4) displayed high grey matter florbetapir retention, with prominent mesiofrontal hypometabolism on FDG PET. Discussion Florbetapir PET can distinguish between AD and FTD. Our data are consistent with previous findings of positive amyloid PET scans in a small number of FTD patients. APOE status should be taken into account when interpreting the results of amyloid PET scans. Study supported by: AVID pharmaceuticals.
T2309. Dissipation of Slow Wave Activity in Sleep: A Marker of Neurocognitive Function in Older Adults Phyllis C. Zee, Lori L. McGee Koch, Roneil Malkani and Kathryn J. Reid. Chicago, IL
T2308. CSF IL-12 and Cognitive and Functional Status in Early AD Dimitrios Kapogiannis, Susan M. Resnick, Dennis Taub, Luigi Ferrucci and Edward J. Goetzl. Baltimore, MD Interleukin-12 (IL-12) contributes to AD pathology in APP/PS1 mice (Vom Berg et al., 2012). Elevated plasma IL-12 is associated with AD in humans (Swardfager et al., 2010). In 17 patients with probable AD and CDR 0.5 - 1, we examined the association of cognition (ADAScog) and function (CDRsob) with CSF cytokines, Ab42, tau and p181tau. Only IL-12 among CSF biomarkers correlated with ADAScog (R 5 - 0.61, p 5 0.02) and showed a trend for CDRsob (R 5 - 0.49, p 5 0.06). Linear regression models including predictors step-wise predicted: ADAS-cog (F 5 4.32, p 5 0.03) by including age (Beta 5 0.5, p 5 0.04) and IL-12 (Beta 5 -0.59, p 5 0.02); and CDRsob (F 5 4.18, p 5 0.03) by including Ab42 (Beta 5 0.58, p 5 0.01) and IL-12 (Beta 5 -0.5, p 5 0.04). Conclusions: Only IL-12 among CSF cytokines was associated with ADAScog and CDRsob in an early AD cohort. Higher CSF IL-12 predicted better status. These findings cast doubt over the proposed therapeutic potential of blocking IL-12 signaling and raise the possibility that IL-12 signaling is beneficial, at least early in AD. Study supported by: This research is supported entirely by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. Both the salary
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The amount of slow wave activity (SWA) and its dissipation during sleep is thought to reflect the restoration of physiological functions. Since aging is commonly accompanied by an altered distribution of SWA and changes in cognitive performance, it is plausible that SWA could link the relationship between sleep disruption and cognitive deficits in older adults. The aim of this study was to examine the relationship between the distribution of SWA across sleep with neurocognitive functioning in older adults. Twenty-four healthy older adults (mean 62.7; SD 6.9, 2 males) where included. Each participant underwent sleep evaluation with polysomno:graphy. In addition, all participants completed a repeated test battery during wake to assess working memory (WM), simple reaction time (SRT) and overall cognitive performance as a composite measure. Neurocognitive perfor:mance measures were com:pared with total SWA and SWA distribution during sleep. Higher amounts of SWA and the smaller rate of exponential decay of SWA predicted poorer neurocognitive performance on all measures. These results indicate that the distribution of SWA across sleep may prove to be a useful biological marker of cognitive functioning in older adults. Study supported by: R01 HL090873; NIH/NHLBI T32, Training Grant in Sleep Research NIH/NHLBI HL090873. National Institute of Aging grant P01 AG11412; General Clinical Research Center grant M01 RR00048, K23 HL091508, T32AG020506. T2310. Association of Hemoglobin with Cognition and Dementia: The Atherosclerosis Risk in Communities (ARIC) Study Andrea L.C. Schneider, Charles Jonassaint, A. Richey Sharrett, Thomas H. Mosley, Brad C. Astor, Elizabeth Selvin, Josef Coresh and Rebecca F. Gottesman. Baltimore, MD; Jackson, MS and Madison, WI Objective: To examine the shape of the association of hemoglobin levels with cognition and dementia. Methods: Cross-sectional (1990–1992, cognition) and prospective (through 2009, dementia) analyses of 12,594 participants in the ARIC Study. Hemoglobin was analyzed categorically (anemia: < 13 g/dL in men, < 12 g/dL in women) and continuously (restricted cubic splines). Cognition was measured by: Delayed Word Recall (DWR), Digit Symbol Substitution (DSS), and Word Fluency (WF). Dementia was defined using ICD-9 codes. Linear regression and Cox proportional hazards models were adjusted for demographic, lifestyle and cardiovascular risk factors. Results: Mean age was 57 years, 56% were female and 24% were black. Mean hemoglobin was 14.6 mg/dL for men and 13.0 mg/dL for women. Anemia was significantly associated with lower DSS (21.31 points [21.87, 20.76]) and WF (20.72 words [21.35, 20.09]), but not DWR
scores. Hemoglobin had a U-shaped association with DSS and WF, but only lower hemoglobin levels were significantly associated with lower scores. There was a marginally significant U-shaped association for increased dementia risk. Conclusion: Our results suggest that only low levels of hemoglobin (anemia) were associated with slower processing speed and poorer verbal fluency. Study supported by: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN-268201100006C, HHSN 268201100007C, HHSN268201100008C, HHSN2682011 00009C, HHSN268201100010C, HHSN 268 201-100 011C, and HHSN268201100012C). The authors thank the staffand participants of the ARIC study for their important contributions. T2311. Latent Information in Verbal Fluency Lists Predicts Functional Decline in MCI David G. Clark, Puneet Kapur, David S. Geldmacher, John C. Brockington, Lindy Harrell and Daniel C. Marson. Birmingham, AL and Augusta, GA Objective: To evaluate new methods for scoring fluency word lists, we built classifiers incorporating two types of scores and evaluated the ability of these classifiers to make prognostic determinations in individuals at risk of developing Alzheimer disease (AD), especially those with mild cognitive impairment (MCI). Method: Fluency lists from 44 cognitively normal elderly, 80 MCI patients, and 41 AD patients were transcribed electronically and scored by four methods: traditional raw scores, clustering and switching scores, “generalized” versions of clustering and switching, and a method based on independent components analysis (ICA). Random forest classifiers based on raw scores were compared to “augmented” classifiers that incorporated newer scoring methods for predicting conversion to AD. ROC curves were constructed for each classifier and the area under the curve (AUC) was calculated. Results: Augmented classifiers outperformed classifiers based on raw scores, improving the AUC for MCI conversion to 0.91 from 0.77. Conclusion: Modern machine learning methods may enhance the diagnostic value of semantic fluency raw scores. Latent information in semantic fluency word lists is useful for predicting cognitive and functional decline among elderly individuals at increased risk for developing AD. Study supported by: This study was supported by grants from the Department of Veterans Affairs [Career Development Award E6553W (PI)] and the NIH [NIA 2R01 AG021927-06A1]. No author has any other financial relationship relevant to this abstract. T2312. Efficacy of 13.3 mg/24 h Rivastigmine Patch on Global Functioning and Behavior in Severe Alzheimer’s Disease Martin R. Farlow, Steven Ferris, Monique Somogyi and Xiangyi Meng. Indianapolis; New York and East Hanover The 24-week, randomized, double-blind ACTivities of daily living and cognitION study demonstrated significantly less
deterioration with 13.3 versus 4.6 mg/24 h rivastigmine patch on cognition and activities of daily living in severe Alzheimer’s disease (AD). This current analysis investigates efficacy of 13.3 mg/24 h patch on secondary measures of global functioning and behavior. Patients had probable AD and Mini Mental State Examination scores of 3–12. Week 24 ADCS-Clinical Global Impression of Change (ADCS-CGIC) and change from baseline–Week 24 on Neuropsychiatric Inventory (NPI-12) was assessed, as was safety. Overall, 356 patients were randomized to 13.3 and 360 to 4.6 mg/24 h patch. Between-group differences in ADCSCGIC rating distribution was significant (p 5 0.0023). A higher proportion of 13.3 versus 4.6 mg/24 h group improved in clinical status (p 5 0.0094). At Week 24, the proportional odds ratio (1.65, 95% confidence interval 1.23, 2.21) favored 13.3 mg/24 h patch. Between-group differences on NPI-12 were insignificant (p 5 0.1437). Adverse events were similar between groups (13.3 mg/24 h, 74.6%; 4.6 mg/24 h, 73.3%). 13.3 mg/24 h patch showed significant benefit over 4.6 mg/24 h patch on global functioning in this population. Study supported by: The ACTION study was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Medical writing and editorial support in the development of this abstract were provided by Fishawack Communications Ltd, Oxford, UK; this service was sponsored by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Monique Somogyi and Xiangyi Meng are full time employees and stockholders of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Martin Farlow has served as a consultant Novartis Pharma, is a paid speaker for Novartis, and receives research support from Novartis Pharma. Steven Ferris has served as a consultant to Novartis. T2313. Transcranial Direct Current Stimulation Improves Verbal Fluency in Healthy Older Adults Tracy D. Vannorsdall, David J. Schretlen, Rasika Jayatillake, J. Jason van Steenburgh, Julia Hernandez, Jill Kessler, Patrick Chambers, Mark Varvaris and Barry Gordon. Baltimore, MD Transcranial direct current stimulation (tDCS) is a noninvasive intervention in which weak electrical current applied to the scalp modulates neural activity of the underlying cerebral tissue. The technique has shown promise as a tool for ameliorating language, motor, and working memory deficits resulting from cerebrovascular accidents and other neurological disorders. However, it is unknown whether tDCS can enhance cognitive functioning in healthy adults experiencing normal age-related declines in word-finding efficiency. We investigated this by administering 1.5mA of active anodal tDCS and sham stimulation in counterbalanced order to the left temporoparietal region of 20 healthy adults aged 55 to 85 years while they engaged in verbal fluency tasks. Relative to sham tDCS, active anodal stimulation increased lettercued verbal fluency performance by an average of 2.1 words (SD 5 3.7; t (19) 5 2.49, p 5 0.02). No effect of tDCS was found for category-cued word fluency. While the
Abstracts, American Neurological Association
underlying basis of this effect and the difference is unclear, these results suggest that left temporoparietal tDCS might prove to be a safe method to improve verbal generativity in older adults. Study supported by: This work was supported by the Therapeutic Cognitive Neuroscience Research Fund. Drs. Vannorsdall and Schretlen receive royalties from the sale of one of the cognitive tests used in this research (CIFA). T2314. Down Regulation of 5-HT6 Receptor Expression in Hippocampal CA1 Subfield of Vascular Dementia Rats Xiaodong Chen, Yan Liu and Yuanyuan Li. Guangzhou, Guangdong, China It was known that neurotransmitters such as serotonin played an important role in cognitive plasticity in cerebral vascular dementia. The rat permanent bilateral common carotid arteries occlusion model (BCCAo) was used to investigate the behavioral and the 5-HT6 receptor expression in hippocampus. The spatial learning and memory deficiencies were assessed by Morris Water Maze (MWM) test. The immunohistochemistry were applied to evaluate the expression of 5-HT6 in hippocampus at 2 days, 1 week, 4 weeks, 8 weeks post-BCCAo. The VaD rats showed the poor performances in MWM test reflecting on markedly prolonged escape latency to locate the hidden platform in spatial acquisition trials and shortened searching time in target quadrant in retrieval trials. The 5-HT6 receptors expression in hippocampal CA1 subfield began to decrease from 1 week post-surgery and an evident reduction was detected in 48 weeks post-BCCAo. We concluded that the vascular dementia rats showed a remarkable down-regulation of 5HT6 receptor in hippocampal CA1 subfield, which may participate in the potential mechanism of ischemia brain damage induced cognitive impairment. Study supported by: Guangzhou Science and Technology Key Project (No. 122732961131543). T2315. Cognitive Improvement in Hospitalized Patients with Decompensated Congestive Heart Failure Rebecca F. Gottesman, Mona Bahouth and Zainab Bahrainwala. Baltimore, MD Background: Cognitive dysfunction has been described in patients with congestive heart failure (CHF), but it is neither clear whether this cognitive impairment is transient nor how cognitive symptoms relate to other measures of CHF symptom resolution. Methods: Neuropsychological tests were administered to 26 patients hospitalized with acute decompensated CHF, twice: within a day of admission and 1–5 days later. Weight change over this interval was evaluated (as a marker of improvement in CHF status), as a predictor of improvement on cognitive tests. Results: For digit span backwards, using ordinal logistic regression, each additional one pound weight loss was independently associated with a 1.62-fold increased odds (95% CI 1.07-2.45) of remembering one additional number on retesting, compared to initial testing, in an adjusted model.
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Other tests, including Trails B and MMSE, showed a similar trend but failed to reach statistical significance. Discussion: Weight loss, a marker of successful diuresis in symptomatic CHF patients, was associated with improvement on a test of executive function. These preliminary results suggest that some of the cognitive dysfunction observed in CHF patients may be transient, and may be a target for future therapeutics in CHF patients. Study supported by: Dana Foundation/ McKhann Scholar Fund. T2316. Loss of Brain Substance in AD Is Steady and Predictable: In Vivo Imaging with Validation at Autopsy Charles D. Smith, Erin Abner, Gregory Jicha, Linda Van Eldik, Frederick Schmitt, Steven Scheff, Clinton V. Wellnitz and Peter T. Nelson. Lexington, KY and Phoenix, AZ Imaging studies have shown declines in brain volume over time in unconfirmed Alzheimer’s disease (AD) at an annualized rate of 1.5%. We imaged two groups of subjects in life: 30 undergoing clinical MRI scans for evaluation of cognitive symptoms and 47 cognitively normal persons who underwent a research MRI protocol. There were 26 in the clinical group and 14 in the research group who were later diagnosed with definite (AD) at autopsy. Despite differences in imaging protocols and cognitive status at scan, in both groups two variables best predicted fresh brain weight in definite AD: total cerebral volume at scan, and years from scan to autopsy. Age at scan, education and gender were not salient. A least squares regression model incorporating these two variables plus group status had a robust adjusted Rsquare of 0.85, and predicts a linear loss of 22.8 grams/ year in the clinical group (t 5 6.8, p < 0.0001), and a similar 24.8 grams/year in the research group (t 5 3.1, p 5 0.004). The surprising observation is the constant loss of cerebral substance in AD over a wide range of clinical, cognitive and imaging starting points. Study supported by: NIH/NIA 5 P30 AG028383. T2317. Benefits of Extended-Release Memantine in Moderate-to-Severe Alzheimer’s Disease as a Function of Disease Severity: Post Hoc Analysis from a Randomized Trial Michael Tocco, Suzanne Hendrix, Michael L. Miller, Vojislav Pejovio and Stephen M. Graham. Jersey City, NJ; Salt Lake City, UT and Chicago, IL It is currently unknown whether memantine provides consistent benefits across the entire moderate-to-severe spectrum (MMSE scores < 20) of Alzheimer’s disease (AD). In this post hoc analysis of a 24-week randomized trial in patients with moderate-to-severe AD who were receiving stable cholinesterase inhibitor therapy, we evaluated the effects of a new, 28-mg, once-daily extended-release (ER) memantine formulation as a linear or quadratic function of patients’ Baseline MMSE scores, using measures of cognition (SIB), function (ADCS-ADL19), behavior (NPI), verbal fluency (VFT), and global clinical status (CIBIC-Plus). Baseline-to-Endpoint changes were assessed using mixed effects models with repeated measures; between-group treatment differences were determined for each Baseline MMSE score. At Endpoint, the
memantine ER group significantly outperformed the placebo group (P < 0.05) on the measures of cognition (across the Baseline MMSE range of 6–13), behavior (7–14), global status (5–13), function (4–9) and verbal fluency (10–14), suggesting that 6 months of memantine ER treatment in patients with moderate-to-severe AD provides benefits in cognition, behavior, and global status across a wide range of severity, and benefits in function and verbal fluency over narrower ranges. Study supported by: Forest Laboratories, Inc. Dr. Michael Tocco is employed by and receives a salary from Forest Research Institute. T2318. RNA Helicases Ameliorate ALS- and FTDRelated Neurotoxicity Sami Barmada, Shulin Ju, Arpana Arjun, Anthony Batarse, Haiyan Qu, Eric Huang, Lynne Maquat, Greg Petsko and Steve Finkbeiner. San Francisco, CA; Waltham, MA and Rochester, NY Over 30% of patients with amyotrophic lateral sclerosis (ALS) exhibit motor neuron disease as well as cognitive deficits indicative of frontotemporal dementia (FTD), suggesting a common pathogenesis. Consistent with this hypothesis, neuronal and glial inclusions rich in TDP43, an essential RNA-binding protein, are found in the majority of both ALS and FTD, and mutations in TDP43 and a related RNAbinding protein, FUS, cause familial disease. TDP43 and FUS affect the splicing of thousands of transcripts, in some cases triggering nonsense mediated mRNA decay (NMD), a highly-conserved RNA degradation pathway. We previously demonstrated that hUPF1, an endogenous RNA helicase and master regulator of NMD, mitigates FUS-mediated toxicity in yeast. Here, we took advantage of a faithful primary neuron model of ALS and FTD to investigate the role of hUPF1 and NMD in these disorders. We show that hUPF1 significantly protected mammalian neurons from both TDP43- and FUSrelated toxicity. Other NMD components also improved survival, while NMD inhibition exacerbated toxicity and prevented rescue by hUPF1, suggesting that hUPF1 acts through NMD. These studies emphasize the importance of RNA processing in ALS and FTD, and identify a novel and potentially effective therapeutic strategy for these disorders. Study supported by: This work was supported by National Institutes of Health (NIH) grants 1K08NS072233-01A1 (to S.B.) 2R01 NS039074 and U24 NS078370 (to S.F.) from the National Institutes of Neurological Disorders and Stroke and 2P01 AG022074 (to S.F.) from the National Institutes of Aging, the Taube-Koret Center for Neurodegenerative Disease (S.F.), and the Hellman Family Foundation Alzheimer’s Disease Research Program (S.F.). T2319. Nrf2 Lowers Risk for Neurodegenerative Diseases Caused by Oxidative Stresses Induced by Diesel Exhaust Masao Sugamata, Tomomi Ihara, Miho Sugamata, Ying Ji Li, Masayuki Yamamoto and Ken Takeda. Tochigi, Japan; Tokyo, Japan; Sendai, Japan and Chiba, Japan Diesel exhaust (DE) is a major air pollutant and we have already reported that DE particles (DEPs) exposure to animals exert severe influences on brains. Some reports show
that exposure to DEPs generates reactive oxygen species, and Nrf2 is a transcription factor for regulating expression of antioxidant enzymes. We examined the influences of Nrf2 on risk of neurodegenerative diseases of DEPs exposure using wild type (WT) and Nrf2 knockout (KO) mice exposed to DEPs or clean air by light and electron microscopy, compared between with and without DEPs, or between WT and KO. All mice with DEPs exposure showed swelling of astrocytes’ endfoot, endothelial cell apoptosis, and diffuse obstruction of capillaries. Especially, in DEPs group, KO had early reaction and severe damages than WT. These findings suggest that DEPs exposure might carry atrophy in brain, and Nrf2-KO made damages by DEPs severe. Nrf2 may be an important protective factor against oxidative stresses, and have a possibility to lower the risk for some neurodegenerative diseases (vascular dementia, etc.), induced by DEPs in brain. Study supported by: Health and Labour Scinces Research Grants, Research on Risk of Chemical Substances, from the Ministry of Health, Labour and Welfare (in Japan). T2320. Reproductive Cycle Stage Differentially Alters Normal and Alzheimer-Related Cognitive and Network Function in Female Mice Lauren Broestl, Kurtresha Worden, Laure Verret, Jorge J. Palop and Dena B. Dubal. San Francisco, CA Endogenous gonadal steroids exert profound effects on neural functions that fluctuate with the reproductive cycle. Network function, a critical substrate of cognition, is destabilized in Alzheimer’s disease (AD). Since AD begins decades before diagnosis, when women still undergo reproductive cycling, we wondered whether cycle stage influences AD–related deficits. We probed this question using female mice that model AD and express hAPP. We assessed cycles daily in nontransgenic (NTG) and hAPP females and compared mice in proestrous/ estrous (high estrogen/progesterone) to mice in diestrous/ metestrous (high progesterone/estrogen) and to gonadectomized (Gnx) mice with depleted hormones. We measured cognitive and network functions. Estrogen-dominant stages improved memory in NTG mice but dramatically worsened memory in hAPP mice. Furthermore, estrogen-dominant stages increased network dysfunction as measured by electroencephalography. These data show that ovarian-linked fluctuations in gonadal hormones exert profound, and opposing, effects on neural function in the normal compared to the diseased brain. Understanding effects of the reproductive cycle on the pathogenesis of AD could provide insight into early preclinical markers of the shift from normal to abnormal network function in women at risk for AD. Study supported by: NIA, AFAR, Weeks-Coulter Foundation. Neuromuscular Disease T2401. Treatment of Sporadic Inclusion Body Myositis with an Anti-Activin Receptor IIB Antibody Anthony A. Amato, Kumaraswamy Sivakumar, Namita Goyal, William David, Richard J. Barohn, Mohammad Salajegheh,
Abstracts, American Neurological Association
Didier Laurent, Jens Praestgaard, Estelle Trifilieff, Anne-Ulrike Trendelenburg, David J. Glass, Ronenn Roubenoff, Brian S. Tseng and Steven A. Greenberg. Boston, MA; Phoenix, AZ; Kansas City, KS and Cambridge, MA Background: We found TGFb superfamily signaling through the activin type IIB receptor (ActRIIB) to be elevated in muscle of patients with inclusion body myositis (sIBM) through assay of SMAD2/3 phosphorylation. We therefore conducted a randomized, placebo-controlled clinical trial of BYM338, a monoclonal antibody that blocks ActRIIB, in sIBM. Methods: A single dose of BYM338 or placebo was administered to 14 randomized patients with sIBM. The primary outcome was the change in thigh muscle volume (TMV) by MRI at 8 weeks. Lean body mass (LBM), strength, and function were secondary outcomes. Twelve of the patients participated in a subsequent 16-week observation phase. Results: Eight weeks after dosing, the BYM338-treated patients increased TMV (right leg 1 6.5%, P 5 0.024; left leg 17.6%, P 5 0.009) and LBM (15.7%, P 5 0.014). BYM338-treated patients had improved 6 minute walking distance, which peaked at 16 weeks (1 14.6%, P 5 0.008). There were no serious adverse events. Conclusions: TGFb superfamily signaling, at least partially through ActRIIB, is implicated in the pathophysiology of sIBM. Inhibition of ActRIIB increased muscle mass and function in this pilot trial, offering a potential novel treatment of sIBM. Study supported by: Novartis Institutes for Biomedical Research; DL, JP, ET, AU, DG, RR and BT are employees of Novartis. T2402. Cytosolic 5’-Nucleotidase 1A Autoimmunity in Sporadic Inclusion Body Myositis H. Benjamin Larman, Mohammad Salajegheh, Remedios Nazareno, Theresa Lam, John Sauld, Hanno Steen, Sek Won Kong, Jack L. Pinkus, Anthony A. Amato, Stephen J. Elledge and Steven A. Greenberg. Boston, MA Objective: We previously identified a circulating autoantibody against a 43 kDa muscle autoantigen (anti-IBM43) in sporadic inclusion body myositis (IBM) and demonstrated feasibility of an IBM diagnostic blood test. Here we sought to identify the molecular target of anti-IBM43, link IBM autoimmunity and myodegeneration, and describe a highaccuracy IBM blood test. Methods: IBM blood samples were screened using mass spectrometry and a synthetic human peptidome. Plasma and serum samples (N 5 200 patients) underwent immunoblotting assays. Muscle biopsy samples (N 5 30) were examined by immunohistochemistry and immunoblotting. Exome or whole genome sequencing was performed on DNA from 19 patients. Results: We identified cytosolic 5’-nucleotidase 1A (cN1A; NT5C1A) as the previously identified 43 kDa IBM autoantigen. Detection of anti-cN1A autoantibodies was 70% sensitive and 92% specific for the diagnosis of IBM. One to three major cN1A immunodominant epitopes were
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identified. cN1A accumulated in perinuclear regions and rimmed vacuoles in IBM muscle, localizing to areas of myonuclear degeneration. Interpretation. Autoantibodies against cN1A are common in and highly specific to IBM among muscle diseases. They provide a link between IBM’s dual processes of autoimmunity and myodegeneration. Blood diagnostic testing is feasible and should improve early and reliable IBM diagnosis. Study supported by: Inclusion Body Myositis Foundation and Muscular Dystrophy Association. T2403. Motor Neuron Pathology in Human SMA David Valdivia, Lingling Kong, Melissa Crowder, James Van Meerbeke, Michelle Polley, Kathryn Swoboda, Thomas Crawford and Charlotte Sumner. Baltimore and Salt Lake City As promising therapeutics transition from preclinical studies in SMA mice to clinical trials in patients, it becomes urgent to better understand the pathological characteristics of the human disease. We collected spinal cord and nerve roots from Type I SMA and age-matched control autopsies. Choline acetyltransferase and neurofilament antibodies were used to visualize neurons in the ventral horn. The total number of neurons was reduced in SMA patients by 52% at cervical, 48% at thoracic, 47%, at upper lumbar, and 36% at lower lumbar levels, but the loss of ChAT1 motor neurons was more dramatic: cervical 5 80%, thoracic 5 80%, upper lumbar 5 76%, lower lumbar 5 65%. Examination of roots confirmed a severe loss of large, myelinated axons in the ventral roots, but a surprisingly modest degree of active axonal degeneration (3%). Ultrastructural analysis unexpectedly showed an abundance of small, unmyelinated axons ensheathed within processes of single Schwann cells suggesting developmentally-arrested axons. Unlike SMA mice, motor neuron loss is severe at all spinal levels in type I SMA patients at death indicating that early delivery of SMNinducing drugs will be critical to their sucess. Impaired axonal development may a key contributor to SMA pathogenesis in severe SMA patients. Study supported by: SMA Foundation and the National Institutes of Health, NINDS R01NS062869 (Charlotte J. Sumner) and NICHD R01-HD054599 (Kathryn J. Swoboda). T2404. Calpains Mediate Axonal Cytoskeleton Disintegration during Wallerian Degeneration Marek Ma, Ferguson Toby, Kathleen Schoch, Jian Li, Yaping Qian, Frances Shofer, Kathryn Saatman and Robert Neumar. Philadelphia, PA; Lexington, KY and Ann Arbor, MI In both the CNS and PNS, transected axons undergo Wallerian degeneration. Though initially described after axon transection, the molecular mechanisms of degeneration may be shared, at least in part, by many human diseases. Early pathology includes failure of synaptic transmission and granular disintegration of the axonal cytoskeleton (GDC). The Ca21-dependent proteases calpains have been implicated in GDC but causality has not been established. To test the hypothesis that calpains play a causal role in axonal and synaptic degeneration in vivo, we studied transgenic mice that express human calpastatin (hCAST), the endogenous calpain
inhibitor, in optic and sciatic nerve axons. Five days after optic nerve transection and 48 hours after sciatic nerve transection, robust neurofilament proteolysis observed in wild-type controls was reduced in hCAST transgenic mice. Protection of the axonal cytoskeleton in sciatic nerves of hCAST mice was nearly complete 48 hours post-transection. In addition, hCAST expression preserved the morphological integrity of neuromuscular junctions. However, compound muscle action potential amplitudes after nerve transection were similar in wild-type and hCAST mice. These results, in total, provide evidence that calpains are responsible for the morphological degeneration of the axon and synapse during Wallerian degeneration. Study supported by: This work was supported by National Institutes of Health grants K08NS055880 (MM), K08NS065157 (TAF), P30AR050950 (TAF, S. Scherer, Penn Center for Musculoskeletal Disorders), F31NS071804 (KMS), and P01NS058484 (KES), Shriners Pediatric Research Center Seed funding (TAF), and Kentucky Spinal Cord and Head Injury Research Trust (KSCHIRT) 6–12 (KES). T2405. Phase II Trial of NP001 in ALS Robert G. Miller, Gil Block, Vidhya Gopalakrishnam, Michael McGrath and NP001 Phase II Study Group. San Francisco, CA and Palo Alto, CA Background: Inflammatory macrophages (InM) are implicated in ALS progression. NP001, a novel immune regulator, lowers ALS markers of InM. Objectives: Assess safety and preliminary efficacy of NP001 in a phase II trial. Methods: Entry criteria were: FVC 70%, and onset of weakness < 3 years. Patients were randomized 1:1:1 to receive 6 monthly iv cycles of NP001 1mg/kg, 2 mg/kg or placebo with a 3-month follow-up. The ALSFRS-R slope and change from baseline were efficacy measures. A posthoc assessment of non-progressors over the 6-month treatment period was conducted. Blood wrCRP was monitored. Results: 136 patients were randomized. NP001 was safe and well-tolerated. NP001 2 mg/kg slowed progression by 13–21%. Patients with wrCRP > baseline had the greatest slowing. Importantly, NP001 2 mg/kg halted disease progression in 27% of patients. At 6 months, wr CRP in responders was decreased in 67% of patients vs. increases in 89% of non-responders. The majority of responders remained stable during follow-up. Discussion: NP001 reduced ALSFRS-R slope and stopped progression in a significant subset of patients, confirming drug activity and inflammation as a component of ALS pathogenesis. These data support development of NP001. Study supported by: Neuraltus Pharmaceuticals. Dr. McGrath is a co-founder. Dr. Block is a Chief Medical Officer for Neuraltus. Dr. Miller is the PI and has no financial conflicts. T2406. Nicotinamide Adenine Nucleotide (NAD1) Regulation of Sirtuin 1 (SIRT1) in the Treatment of Diabetic Neuropathy Krish Chandrasekaran, Joungil Choi, Helen Chen and James W. Russell. Baltimore, MD
NAD1 activates expression of molecular pathways that protect against diabetes. Nicotinamide mononucleotide (NMN) is a direct substrate for generation of NAD1. Sirtuins are regulated by NAD1 and some SIRT1 mutations increase the risk of diabetes mellitus. We determined the effect of NMN and the SIRT1/PGC1alpha axis on experimental diabetic neuropathy. In adult streptozotocin-treated diabetic rats, NMN was administered subcutaneously for 2 months. Sensory thresholds and sciatic conduction velocities were normalized and loss of skin Intraepidermal nerve fibers (IENFD) was prevented with 100 mg/kg NMN. There was a significant decrease in NAD1 and in SIRT1 activity in diabetic dorsal root ganglion neurons (DRG) but NMN normalized both. Using cultured adult mouse DRG from a neuron specific, inducible, CamK2alpha-SIRT1 overexpressing (OE) mouse and control (5.5 mM total) and high (25 mM total) glucose, we show that SIRT1OE reduces glucose-induced generation of reactive oxygen species (ROS) and increases neurite growth. These changes are coupled with an increase in neuronal SIRT1 deacetylase activity and mitochondrial SIRT1. The findings support a therapeutic and mechanistic role for NAD1 substrates in the treatment of diabetic neuropathy. Study supported by: Office of Research Development (Biomemedical and Laboratory Research Service), Department of Veterans Affairs, NIH RR024888.
T2407. Arimocolomol in Inclusion Body Myositis: A Two-Center Phase 2a Study Mazen Dimachkie, Pedro Machado, Jianghua He, Yunxia Wang, April L. McVey, Mamatha Pasnoor, Philip Gallagher, Laura Herbelin, Jeffrey Statland, Adrian Miller, Linda Greensmith, Janice Holton, Michael Hanna and Richard J. Barohn. Kansas City, KS; London, United Kingdom and Lawrence, KS Sporadic inclusion body myositis (IBM) is the most common inflammatory myopathy in patients older than 50. Arimoclomol interferes with protein misfolding and aggregation, and may slow IBM functional decline. We performed a randomized placebo-controlled safety study of arimoclomol100 mg PO TID administered for 4 months, with 8 month follow up. Twenty-four IBM subjects received arimoclomol or placebo with a 2/1 ratio. We obtained monthly safety data, strength and functional measures at 2 participating sites. We enrolled 17 men and 7 women with a mean age of 69 years (53–81) and diagnosis of definite (10) or probable (14) IBM. There were 8 treatment-related adverse events in the placebo group and 14 with arimoclomol, the most common being gastrointestinal. At 8 months, we detected in the arimoclomol group a trend of slower decline in the IBMFRS (20.68 6 1.58 vs 22.50 6 3.31, p 5 0.06), average MMT (20.12 6 0.22 vs 20.26 6 0.27, p 5 0.15) and MVICT of right hand grip (1.26 6 2.63 vs 20.54 6 1.86, p 5 0.06). We observed no differences in the other MVICT scores, DEXA fat free mass and muscle HSP70 levels.
Abstracts, American Neurological Association
Arimoclomol is safe and well-tolerated in IBM. Further investigation of arimoclomol in a larger IBM patient population is warranted. Study supported by: This investigator-initiated trial was funded by University of Kansas Neurology Ziegler Grant and Kansas University General Clinical Research Centre CReFF Grant and Arthritis Research UK. T2408. Lowered Glucose and Weight Loss Improve Cutaneous Re-Innervation in Non-Neuropathic Subjects with Diabetes or Prediabetes J. Robinson Singleton, Robin Marcus and A. Gordon Smith. Salt Lake City, UT Obesity and dyslipidemia are risk factors for neuropathy in diabetes, independent of glucose control and may inhibit nerve regenerative capacity. Topical capsaicin results in denervation into the dermis. Serial skin biopsies for intraepidermal fiber density (IENFD) measure nerve regeneration rate. We compared 30 day cutaneous regeneration rate between cohorts of normal controls, subjects with metabolic syndrome, and subjects with type 2 diabetes, all without symptoms or exam signs of neuropathy. Subjects then participated in 6 months of nutritional counseling and twice weekly supervised exercise, and the re-innervation protocol was repeated. A similar baseline reinnervation rate was observed for subjects with metabolic syndrome (0.066 1/0.045 fibers/mm/day, N 5 29) and diabetes (0.0581/0.037, N 5 37), reduced compared to controls (0.096 f/ mm/day). Following 3 months of diet and exercise, there was a significant improvement in 30-day reinnervation rate for all subjects (0.057 1/- 0.31 before versus 0.71 1/0.027 post, p 5 0.04 by paired t-test). There was significant improvement in re-innervation rate in subjects who reduced fasting glucose (p < 0.04) or weight (p 5 0.03) during the lifestyle intervention compared to those who did not. These results suggest metabolic syndrome features suppress cutaneous re-innervation even before diabetes is present, and their control improves re-innervation rate. Study supported by: The American Diabetes Association. T2409. Desert Hedgehog Deficiency Accentuates Peripheral Nerve Demyelination James Jung, Derek Frump, Ranjan Gupta and Tahseen Mozaffar. Irvine, CA and Irvine Hypothesis: Defining the molecular mechanisms underlying chronic compressive neuropathies (CNC) is crucial for identifying novel treatment methods. Desert hedgehog (dhh) is a Schwann cell produced protein responsible for formation of nerve perineurium. We hypothesize that it is a potential therapeutic target, given its interaction with extracellular matrix and connective tissue. Methods: CNC injury was created with 3mm tube placed around sciatic nerve of six-week old dhh-/- mice. Electrophysiology was performed bi-weekly. IHC was performed for select connective tissue proteins. Results: Nerve conduction velocities (NCV) showed a marked rapid decline in dhh-/- compared to wildtype mice. NCV declined from 52.15 6 0.5 m/s at baseline to 15.06 6 0.578 m/s at 2 weeks, and slight improvement at
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4 and 6 weeks to 25.63 6 1.514 m/s and 26.13 6 1.21 m/ s, respectively. Wildtype animals show the slowest NCV at 6 weeks and never reach equivalent slowing seen in dhh-/-. Immunohistochemical stains for collagen IV, laminin-a2, and fibronectin showed abnormally profuse scarring in dhh-/- at 2 weeks, compared to wildtypes. Summary: Desert hedgehog deficiency appears to accentuate peripheral nerve demyelination in chronic compression neuropathies, signifying a vital role for dhh in the propagation of nerve impulses. Study supported by: PHS Grant (NIH 5 R01 NS049203 09). T2410. Dermal Nodes and Internodes in Diabetes Mellitus Iliza Myers, Jun Li, Kay Artibee and Amanda C. Peltier. Nashville, TN We investigated dermal myelinated nerves obtained from the digital skin of patients with diabetic polyneuropathy (DPN). We evaluated glabrous skin biopsies of 17 DPN patients (Type I n 5 7; Type II n 5 10), and 10 agematched healthy controls. Diabetic patients of both types had similar reductions in intraepidermal nerve fiber density and abnormal nerve conduction studies (NCS). Immunostaining for PGP 9.5, myelin basic protein, and pan-sodium channel antibodies revealed an average of 69 internodes per healthy control, 71 per Type II patient, and 49 per Type I. A significant reduction in the density of myelinated fibers was identifiable in all DPN patients but was more severe in Type I patients. Indicative of a length dependent neuropathy, DPN patients had 9% fewer internodes in the superficial papillary layer than controls. The average internodal length was longer in Type I patients (100 mm) compared to controls and Type II patients (89 and 91 mm, respectively). A higher percentage of abnormal nodes were also seen in Type I patients (13% vs. 6% in Type II and controls). These data indicate glabrous skin biopsy is a suitable method for investigating myelinated fiber morphology in patients with DPN. Study supported by: Supported by NINDS K23 NS056009 (Peltier), R01NS066927; (Li), and Vanderbilt CTSA grant NCRR UL1 RR024975. Confocal imaging was performed through the use of the VUMC Cell Imaging Shared Resource (supported by NIH grants CA68485, DK20593, DK58404, HD15052, DK59637 and Ey008126). T2412. Clinical Neuropathy Scales in Early Diabetic Neuropathy Lindsay A. Zilliox, Sandra K. Ruby, Sujal Singh and James W. Russell. Baltimore, MD There is disagreement on outcome measures in trials of diabetic neuropathy and there is no agreed clinical scale. Prospective data on patients was obtained in symptomatic early neuropathy and controls for six neuropathy scales: Lower Limb (NIS-LL), Michigan Diabetic Neuropathy Score (MNDS), Toronto Clinical Neuropathy Scale (TCNS), Total Neuropathy Score (Clinical) (TNSc), The Utah Early Neuropathy Scale (UENS), and the Early Neuropathy Score
(ENS). These were compared to the intraepidermal nerve fiber density (IENFD) and the sural nerve conduction velocity (SCV). The TCNS followed by the TNSc achieved the greatest sensitivity and specificity using ROC curves. The MDNS and UENS showed the strongest association with an abnormal IENFD. In conclusion, all the examined scales can be used to distinguish patients with an early neuropathy and the scales perform well with regard to sensitivity and specificity. For the purpose of screening potential patients for a clinical trial, the TCNS followed by the TNSc would be most helpful to select patients with symptomatic neuropathy; the MDNS and the UENS would identify patients with small fiber involvement; and the NIS-LL would identify patients with large fiber involvement. Study supported by: In part by NIH. T2413. Exome Sequencing: A Diagnostic Tool in Diverse Neuropathies Christopher J. Klein, Sumit Midha, Xiaohui Duan, Yanhong Wu, William J. Litchy, Weihong Gu, James B. Dyck, Ralitza Gavrilova, David I. Smith, Jean Pierre Kocher and Peter J. Dyck. Rochester, MN and Beijing, China Inherited and acquired neuropathies have overlapping signs, symptoms, course, and test abnormalities. There is interest in the development of efficient and reliable methods to identify different molecular causal abnormalities. We studied 24 undiagnosed neuropathy cases from 15 families by whole exome sequencing. Acquired diagnosis was made in 1/3rd prior to kindred evaluations. Pathogenic mutations were found in 5, including two that were initially diagnosed with acquired process, 1) BSCL2 p.90Ser>Leu; 2) LITAF p.112Gly>Ser; 3) MFN2 p.94Arg>Glu; 4) GARS p.334Ile>Phe; 5) Atlastin p.253Val>Ile. Three cases were found to have novel variants in known neuropathy genes (SOD1, SPTLC1, DCTN) in conserved amino acids and absent in 8000 controls. Among the remaining 7 kindreds, rare non-synonymous base alterations (13–101, MAF < 0.0001) were identified. Atypical clinical presentations, uncertainty of inheritance, cost and limited understanding of genotype-phenotype correlation all hindered earlier pathogenic gene identification. Focused analysis of the 24 exomes in 74 genes responsible for HMSN, dHMN, HSAN, complicated-HSP, and common hereditary metabolic neuropathies and their 4468 reported pathogenic mutations were assessed efficiently and accurately. WES diagnoses many genetic neuropathies previously undiagnosed including some initially thought to have acquired cause and will revolutionize both neuropathy diagnosis and discovery. Study supported by: Center for Individualized Medicine, Mayo Clinic Foundation and National Institutes of Health grant (NS065007, C.J.K.). Mayo Clinic CTSA through grant number UL1 RR024150 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). T2414. The Disease Burden of Polyneuropathy - A Population-Based Assessment E. Matthew Hoffman, Nathan P. Staff, Jared M. Robb, Brian F. Kabat, Jennifer St. Sauver and Christopher J. Klein. Rochester
Population-based studies on polyneuropathy including epidemiology and disability are lacking and important in estimating the disease burden. The Rochester Epidemiology Project (REP) database was queried for polyneuropathy cases identified by ICD-9 codes from 2006–2010 and compared to age- and gender-matched controls for markers of disability and other medical comorbidities. Polyneuropathy is common, with 2,897 cases identified in the study period and a prevalence peak at 9.4% for those in their 70’s (2.1% for all ages). The cohort was well described with 58% having neurologic evaluation including comprehensive neurologic examinations and 43% having electrodiagnostic testing. Markers of disability, such as difficulty walking, difficulty climbing stairs, use of assistive devices, fall tendency, and other factors relating to independence were more commonly abnormal in polyneuropathy than in controls (n 5 14,435). Also, polyneuropathy cases were more likely to have medical interventions including pain medications, amputations, and surgery. When the associations between disease categories and disability markers were tested with logistic regression modeling, polyneuropathy had the most significant contribution to disability independent of other comorbidities. Public attention and resources are needed to address the large burden of polyneuropathy. Study supported by: K08 NS065007 (C.J.K.), K08 CA169443 (N.P.S.), 9R01-AG034676-45 (REP), Mayo Foundation (E.M.H.). T2415. MRI Abnormalities of Peripheral Nerve and Muscle in Amyotrophic Lateral Sclerosis (ALS) Are Common and Share Features with Multifocal Motor Neuropathy (MMN) Zheyan Chen, Benjamin M. Howe, Kimberly K. Amrami and Nathan P. Staff. Rochester, MN Background: MRI of peripheral nerves may be performed to consider alternative diagnoses for ALS like MMN; however, detailed studies of MRI abnormalities within nerves and muscles of patients with ALS are lacking. Methods: We conducted a retrospective review of patients with clinically-definite ALS and MMN seen at Mayo Clinic Rochester from 01/01/2002 to 12/31/2011 who underwent MRI of brachial plexus. The MR exams were evaluated by a musculoskeletal radiologist who was blinded to diagnoses and clinical histories. Results: 36 patients with ALS (at diagnosis 56.6 6 13.2 years, 55% male) and 8 patients with MMN (at diagnosis 58.2 6 12.1 years, 75% male) were identified. In ALS, nerve T2 hyperintensity (69%) and enlargement (17%) were frequently present, with one study exhibiting gadolinium enhancement. Muscle T2 hyperintensity (56%) and atrophy (33%) were seen. In the MMN cohort, there was nerve T2 hyperintensity (63%) and enlargement (25%), with muscle T2 hyperintensity (25%) but no atrophy. Conclusions: MRI of peripheral nerve and muscle is commonly abnormal in patients with ALS. The MRI features in ALS are similar to those seen in MMN. Study supported by: Mayo Foundation; NIH (K08 CA169443).
Abstracts, American Neurological Association
T2416. Mutant CUG RNA Induces Skeletal Muscle Degeneration via Stimulating NADPH Oxidase Activity in Myotonic Dystrophy Type 1 (DM1) Xiang Fang, Rui Gao, Yongping Liu, Zilong Liu, Glenn R. Smith and Parthar S. Srakar. Galveston, TX Expanded CUG sequences in mutant DMPK transcripts contribute to the pathogenesis in DM1. Despite significant progress, the mechanism by which CUG sequences elicit degenerative skeletal muscle defects in DM1 remains unclear. Here we show that expanded CUG RNA increase oxidative stress by stimulating NADPH oxidase (NOX) activity in DM1, and that oxidative stress activates the double-stranded RNA-activated protein kinase (PKR) pathway in DM1. Activated PKR in turn phosphorylates translation initiation factor 2a, and stimulates expression of CHOP, a key proapoptotic factor in DM1. Mut-CUG RNA-mediated activation of the PKR!CHOP pathway antagonizes expression of antiapoptotic factor Bcl2 and stimulates expression of proapoptotic factors PUMA, NOXA, BAX and BIM, facilitating apoptosis of DM1 cells. These data suggest that NOX-mediated chronic activation of PKR plays a pivotal role in facilitating apoptotic demise of muscle cells in DM1. Buffering oxidative stress dramatically reduced cell toxicity and protected the mutant DM1 cells from stress-induced toxicity. Discovery of this novel mechanism by which CUG RNA stimulates pro-death pathways to facilitate degeneration of muscle cells may open new avenues for the development of therapies for DM1. Study supported by: UTMB Junior Faculty Start-up Fund. T2417. Chemotherapy-Induced Peripheral Neuropathy From Human Genetics to Drosophila Models Jewel L. Podratz, Andreas S. Beutler and Anthony J. Windebank. Rochester, MN Chemotherapy-induced peripheral neuropathy (CIPN) is the major, dose-limiting, adverse event for patients undergoing chemotherapy. The annual burden is estimated to be between 2.39 and 2.73 billion dollars in the US. We have used whole exome sequencing to analyze 20,794 genes at nucleotide resolution in 73 CIPN cases and 46 controls. The primary endpoint was the association of hereditary neuropathy genes with CIPN. Bioinformatic analysis determined SNV and other variations across 6.2 3 10(7) nucleotides. A previously identified minor allele (C>T) at rs7349683 in the gene EPHA5 was confirmed. In addition, two novel genes associated with hereditary neuropathy were highly associated with CIPN. To test genetic hypotheses for the mechanism of CIPN we have developed an automated, semi-high throughput system for measuring climbing behavior in Drosophila. Modulating expression of genes associated with hereditary neuropathy identified two candidates (HSP22 and HSP27) that significantly altered the Drosophila behavioral response to cisplatin treatment. The convergence of bioinformatic approaches to analysis of genome sequencing with genetic model systems will allow both mechanistic and therapeutic advances in CIPN. Patient specific genomic profiles associated with risk of developing CIPN may also be identified.
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Study supported by: National Institutes of Health; Mayo Foundation. T2418. WITHDRAWN T2419. Effects of Denervation on Experimental Skeletal Muscle Regeneration Analyzed by Virtual Northern Blots Takahiro Jimi, Yoshihiro Wakayama and Hiroo Ichikawa. Yokohama, Japan Nerve supply is important for regeneration of skeletal muscle. Some trophic factors may work in the regeneration of skeletal muscle under innervation. To find putative trophic factors, we carried out a comparison of expressed genes between innervated and denervated experimental regenerating rat muscle by subtraction analysis. We isolated 312 cDNA clones (ANA2003). To confirm that these clones were expressed differentially in the innervated regenerating muscle, “Virtual Northern Blot” analysis was conducted. Both cDNAs from innervated and denervated regenerating muscle were electrophoresed and were transferred to a membrane. The insert of each subtracted clone was amplified as a probe. Each probe was hybridized with both cDNAs from the innervated and the denervated regenerating muscle. Differences of signal intensity between the innervated and the denervated regenerating muscle were analyzed. We found 17 clones which were highly expressed in the innervated regenerating muscle as compared with the denervated one. Among these clones, there were some potentially trophic factors, as well as some noteworthy genes such as insulinlike growth factor and 20kDa heat shock protein. These genes might play some roles in the regenerating process of skeletal muscle under innervation. Study supported by: none. T2420. The Incidence of Subtypes of Guillain-Barre Syndrome; Japanese Multi-Center Prospective Study Susumu Kusunoki, Yoshiyuki Mitsui, Kimiyoshi Arimura, Ryuji Kaji, Takashi Kanda, Satoshi Kuwabara, Masahiro Sonoo and Kazuo Takada. Osaka-Sayama, Osaka, Japan; Kagoshima, Japan; Tokushima, Japan; Ube, Yamaguchi, Japan; Chiba, Japan and Tokyo, Japan Acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN) and Fisher syndrome (FS) are major subtypes of Guillain-Barre Syndrome (GBS). The incidence of each subtype is different geographically. We aimed to clarify the incidence of the subtypes of GBS in Japan. During three years (2007–2010), 222 patients with GBS were treated at 23 hospitals in the Japan GBS study group. Clinical and electrophysiological findings could be obtained from188 patients. The criteria of Ho et al (1995) and that of Hadden et al (1998) were used to discriminate between demyelination and axonal damage. The incidence of FS also was surveyed. By Ho’s criteria, 78 patients (42%) were classified as AIDP, 34 (18%) as AMAN, and 76 (40%) were unclassified. By Hadden’s criteria, 86 patients (53%) were classified as demyelination, 19 (10%) as axonal, none as inexcitable, 14 (6%) as normal, and 69 (26%) as equivocal. During the same period, 79 patients with FS were identified and the percentage of FS
cases among all cases (GBS and FS) was 26%. The incidence of AMAN and that of FS are significantly higher in Japan than those in Western countries. Study supported by: the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Ministry of Health, Labor and Welfare of Japan. T2421. The Impact of Glycemic Variability on CAN in Patients with Type 1 Diabetes Mamta Jaiswal, Cynthia Plunkett, James Henderson, Nicholas Comment, Patrick Nelson, Rodica Pop-Busui and Eva L. Feldman. Ann Arbor, MI Hemoglobin A1c (HbA1c) is considered the gold standard measure for glycemic control; however, it fails to capture short- and long-term glycemic excursions suggested to contribute to the risk of chronic diabetic complications. We explored the impact of glycemic variability on indices of cardiac autonomic neuropathy (CAN) in 41 adults with type 1 diabetes (T1DM). Continuous blood glucose recordings for 5 days were used to derive the low (LBGI) and high BG index (HBGI), time spent in hypoglycemia ( < 60 mg/dl), time spent in hyperglycemia (>180 mg/dl), and mean amplitude of glucose excursion (MAGE). CAN measures included cardiovascular reflex testing and heart rate variability (HRV). Multiple linear regression analysis was used to examine the association between measures of glycemic variability and CAN. Higher LBGI and time spent in hypoglycemia were significantly associated with HRV, independent of age, sex, and HbA1c. Measures of glycemic variability reflective of hypoglycemic stress were also associated with reduced HRV, suggesting sympathetic/parasympathetic dysfunction. Longitudinal studies are ongoing to assess the impact of glycemic variability on the progression of CAN and other complications in adults with T1DM. Study supported by: NIH RO1- HL-102334-03. T2422. Disease-Specific Care (DSC) Certification in Amyotrophic Lateral Sclerosis (ALS) through the Joint Commission (TJC) Audit Protocol - Adding New Performance Measures (PMs) To Improve Patient Outcomes Benjamin R. Brooks, Nicole M. Lucas, Elena K. Bravver, John S. Story, Nicole P. Smith, Mindy S. Nichols, Sharon L. Belcher, Kathryn A. Wright, Amber L. Ward, Velma L. Langford, Scott E. Holsten, Scott S. Lindblom, Thomas J. Paccico, William L. Bockenek, Mohammed S. Sanjak, Kristy L. Walgren, Lucille H. Frumkin, Michael P. Fischer, Quincy D. Corey and Heather L. Oplinger. Charlotte, NC Background: The Carolinas Neuromuscular/ALS-MDA Center of the Carolinas Healthcare System was the first ALS Clinic in the nation to achieve ALS-DSC-TJCcertification in 2012 by implementing best practices derived from American Academy of Neurology(AAN)ALS evidencebased(EB)practice-parameter to show improved ALS management. Objective: Initiate patient outcome-based PMs per EBguidelines according to ALS-DSC-TJC practice-based audit. Methods: Standardized PMs: 1)cognition-screening, 2)depression-screening, 3)communication to primary care physician and 4)respiratory management were measured
according to AAN-ALS-EB-guidelines via monthly and quarterly audits across 6501188(SD)annual ALS encounters from 2009–2012. Results: Cognition, depression, communication to primary care physician and respiratory management PMs achieved benchmark practice standards. ALS-DSC-TJC protocol requires advancing implementation of new PMs in each two-year cycle to improve patient outcomes based on audit results. Improving riluzole monitoring to prevent liver damage, assessing vital capacity monitoring to improve safe gastrostomy tube placement, and increasing pneumococcal immunization rate to decrease community-associated pneumonias were implemented in the succeeding two-year cycle. Preliminary monthly and quarterly assessments show improvement in these PMs compared to the previous audit cycle. Conclusion: ALS-DSC-TJC protocol is a clinic-based process for implementing PMs to improve ALS patient outcomes. Study supported by: Carolinas ALS Research Fund, Pinstripes Fund, Carolinas Healthcare Foundation. T2423. Which Is the Best Primary Outcome in Trials for IgM Anti-Myelin-Associated Glycoprotein Antibody Demyelinating Neuropathy? Lessons from the RIMAG Study Jean-Marc Leger, Karine Viala, Guillaume Nicolas, Alain Creange, Jean-Michel Vallat, Jean Pouget, Pierre Clavelou, Christophe Vial, Andreas Steck, Lucile Musset and Benoit Marin. Paris, France; Angers, France; Creteil, France; Limoges, France; Marseille, France; Clermont-Ferrand, France; Lyon, France and Basel, Switzerland There is no recognized primary outcome to be used in patients with IgM anti-myelin-associated-glycoprotein antibody demyelinating neuropathy (IgM anti-MAG demyelinating neuropathy) for inclusion in clinical trials. A trial (Dalakas et al. Ann Neurol 2009) showed significant changes in inflammatory neuropathy cause and treatment (INCAT) score for the lower limbs only at 8 months. The RIMAG study included 54 patients with IgM anti-MAG demyelinating neuropathy. The primary outcome was mean change in INCAT sensory score (ISS) at 12 months. Twenty six patients were randomized to a group receiving 4 weekly infusions of 375 mg/m2 rituximab, and 28 patients to placebo. Intention-to-treat analysis, with imputation of missing ISS values by the last observation carried forward method, showed a lack of mean change in ISS at 12 months. However, changes were observed, in per protocol analysis, for the number of patients with an improvement of at least 2 points in the INCAT disability scale (p 5 0.027), the selfevaluation scale (p 5 0.016), and 2 subscores of the SF-36 questionnaire. A disability scale focusing on sensory changes could be the best primary outcome for future trials. Study supported by: Direction de la Recherche Clinique. Assistance Publique-Hopitaux de Paris (PHRC 04049). T2424. Corneal Confocal Microscopy as a Surrogate Measure of Diabetic Neuropathy A. Gordon Smith, Gene Kim, Margaret Lessar, Renee Gerardi and J. Robinson Singleton. Salt Lake City, UT
Abstracts, American Neurological Association
CCM quantitatively assesses corneal nerve fiber length (NFL), density (NFD) and complexity (branch density NBD). 17 Control and 44 diabetic subjects including 10 with neuropathy underwent CCM. Each diabetic subject had nerve conduction studies and distal skin biopsy for intraepidermal nerve fiber density (IENFD) measurement. Age was 58 1/- 6.9 years old for diabetic versus 51 1/- 18 for control subjects. NFL and NFD declined from controls to diabetic to neuropathy groups: NFL: 27.8 1/- 5.7, 23.0 1/- 7.5, 21.4 1/- 7.1 and NFD 79.8 1/- 17, 66.2 1/- 19, 61.6 1/- 25 (p < 0.03). NFL correlated with age (cc 20.287, p < 0.04) and weight (cc 20.296, p < 0.02). NFL and NFD correlated with sural amplitude (cc 0.376, p < 0.02, cc 0.319, p < 0.04). There was a trend towards inverse correlation between NFL and NFD and neuropathy severity based on UENS (cc 20.247, 20.343). While the relationship between IENFD and NFL was not significant in this small sample, the two appeared to co-vary. These findings suggest NFL and NFD decline early in neuropathy, similar to IENFD, and that they correlate with other measures of neuropathy severity. Study supported by: NIHR01DK064814, ADA08-CR52, ADA 70110AEC-23, University of Utah Vice President for Research (AGS, ML, RG, JRS), and The Research to Prevent Blindness Foundation (GK). T2425. INF2-Related CMT: 6 Nerve Biopsies Jean-Michel Vallat, Stephane Mathis, Laurent Magy and Benoit Funalot. Limoges, France and Poitiers, France Charcot-Marie-Tooth (CMT) disease is mostly linked to PMP22, MPZ (P0) or GJB1 gene mutations. Some other gene mutations can be associated with specific accompanying features, as for INF2 with focal segmental glomerulosclerosis (FSGS). INF2-related CMT is an autosomal dominant hereditary neuropathy with classical clinical CMT features and proteinuria (and then renal failure in the course of the disease). Motor median nerve conduction velocity is in the range of the intermediate sub-type CMT. Pathological lesions are consistent with a chronic demyelinating and remyelinating process, associated to a progressive axonal loss, which may be very severe. We also observed unusual whorl-like proliferations of flattened Schwann cell cytoplasms and unusual anomalies of the unmyelinated Schwann cell cytoplasms, with supernumerary elongated extensions. We hypothezise that these lesions are due to a disorganization of the actin network within Schwann cells. At the present time, rapid screening of about 40 causative genes is not really feasible for a single patient. So, such lesions confirm that detailed microscopic analysis can orientate the search for mutations in specific genes. Study supported by: NA. T2426. Small Fiber Involvement in Alcohol Related Peripheral Neuropathy Michelle L. Mellion, Elizabeth Silbermann, James M. Gilchrist, Lorenzo Leggio and Suzanne De La Monte. Providence, RI; Springfield, IL and Bethesda, MD
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Alcohol related peripheral neuropathy (ALN) is traditionally believed to be an axonal large-fiber polyneuropathy caused by chronic ethanol ingestion and nutritional deficiency. We hypothesized that ALN is associated with a small fiber polyneuropathy that can be diagnosed with skin biopsy in chronic alcoholic, nutritionally replete, individuals. Eighteen patients, 9 alcoholic, and 9 healthy controls, were assessed for adequacy of nutritional and thiamine status. Other causes for neuropathy were excluded with serologic studies. Patients underwent physical examination, Utah Early Neuropathy Scale, nerve conduction studies (NCS) and skin biopsy. There was no difference between the two groups in clinical assessment for neuropathy or in nutritional or thiamine status. End nerve fiber densities in alcoholic patients were significantly less than controls (p 5 < .005). NCS in both groups were normal; however, sural sensory amplitudes and velocities were significantly decreased in the chronic alcoholic subjects compared with controls. This study demonstrates that ALN is associated with a small fiber neuropathy that can be diagnosed by skin biopsy in chronic alcoholic, nutritionally replete individuals. Skin biopsy may be a more sensitive tool for earlier detection of ALN and a useful biomarker in understanding pathogenesis. Study supported by: ABMRF/The Foundation for Alcohol Research and a Special Research Fund from Rhode Island Hospital.
T2427. The Role of the Wnt/Beta-Catenin Signaling Pathway at the Motor Endplate Following Traumatic Nerve Injury James Jung, Derek Frump, Marian Waterman, Ranjan Gupta and Tahseen Mozaffar. Irvine, CA and Irvine Hypothesis: We recently showed that preservation of the motor endplate after traumatic nerve injury improves functional recovery after surgical repair. Developmentally the Wnt signaling proteins, particularly the canonical Wnt/betacatenin pathway, plays an important role in maintenance of motor endplates. Therefore, we explored the role of Wnt/ beta-catenin after traumatic nerve injury. Methods: Gastrocnemius, soleus and plantaris muscles were harvested at 1-month and 2-months after nerve injury for Wnt3a and beta-catenin western and IHC, respectively. Results: Wnt3a protein levels were elevated at 1-month (0.633 6 0.0540 vs 0.937 6 0.128) and 2-months postinjury (0.488 6 0.0170 vs. 0.970 6 0.232; p < 0.002) compared to control. Moreover, activated beta-catenin showed a similar increase (0.532 6 0.0250 vs. 1.050 6 0.204; p < 0.026). In contrast to uninjured muscles, Wnt3a staining remained localized at the motor endplate after denervation where it was upregulated near degrading AChRs. Summary: Our data implicates Wnt/beta-catenin pathway as a potential source of motor endplate instability after injury. Our data presents a potential novel target to optimize functional outcomes following surgical management of traumatic nerve injuries. Study supported by: Departmental Funds.
T2428. Musculoskeletal Pain in ALS Charles D. Clarke, Peter D. Donofrio and Amanda C. Peltier. Nashville, TN Objectives: Pain is often an undervalued sensory symptom in amyotrophic lateral sclerosis (ALS). The purpose of this study was to determine the prevalence, timing, and types of pain associated with increased morbidity in ALS. Methods: A representative cohort for age, race, and functional status of fifty consecutive Vanderbilt ALS clinic patients were surveyed using a modified Brief Pain Inventory. Results: 76% reported pain and in this subgroup 87% reported worsened pain with progression of their disease. The most common locations of pain were muscle (50%) and joints (18%). Nearly 40% of those with pain reported a significant reduction in quality of life related to their pain. Conclusions: Currently treatment of ALS focuses on symptom control to improve quality of life. Our results show that pain is prevalent in the ALS population, worsens with disease progression, and is disproportionately musculoskeletal. These results show a higher prevalence of pain compared to previous studies. Poorly controlled pain is associated with decreased quality of life, highlighting the importance of recognizing and adequately treating musculoskeletal pain in the ALS population. Future studies to elucidate the cause of pain and best treatment are needed to improve quality of life in ALS patients. Study supported by: Vanderbilt CTSA grant NCRR UL1 RR024975. T2429. Initial Evaluation of Neuropathy: Etiology and Management Brian C. Callaghan, Kevin A. Kerber, Ruth Longoria, Ann Rodgers, Lewis B. Morgenstern, Lynda D. Lisabeth and Eva L. Feldman. Ann Arbor, MI Background: Little is known about the management of patients with distal symmetric polyneuropathy (DSP) after their initial evaluation. Design/Methods: We utilized a validated case-capture method (ICD-9 screening technique with subsequent medical chart abstraction) to identify patients with DSP seen by community neurologists in Corpus Christi, Texas. Using a structured data abstraction process, diagnostic testing, diagnoses rendered (before and after testing), and subsequent management were recorded. Results: We identified 458 DSP patients between 1/1/ 2010-3/31/2011. After diagnostic testing, 38 patients were diagnosed with pre-diabetes/diabetes, 20 B12 deficiency, 8 thyroid disease, 1 immune-mediated neuropathy, and 121 idiopathic. Prescribing B12 (7.2%), advising diet and exercise (7.2%), adjusting thyroid medications (2.2%), removing toxic exposures (0.9%), and prescribing prednisone (0.4%, both with atypical presentation) were the only disease modifying management changes. Conclusions: One fifth of DSP patients evaluated by neurologists in this community have a new etiology discovered after diagnostic testing. Testing for diabetes, B12 deficiency, and thyroid disease leads to important management
changes, but only 2 other patients received disease modifying therapy both of which had warning signs of atypical neuropathy. This data supports limited routine testing in patients with DSP. Study supported by: ADA Junior Faculty Award. T2430. Brain Perfusion Correlates of Cognitive Deficits in Patients with Macrophagic Myofasciitis Emmanuel Itti, Mehdi Aoun Sebaiti, Eva Evangelista, Romain K. Gherardi, Nilusha Thangarajah and Francois-Jerome Authier. Creteil, France Macrophagic myofasciitis (MMF) is an emerging condition characterized by abnormal biopersistence of aluminum hydroxide at site of previous immunizations. MMF patients complain of arthromyalgias, chronic fatigue and marked cognitive deficits, not related to pain, fatigue or depression. Methods: Brain perfusion 99mTc-ECD SPECT was performed in 76 consecutive patients (aged 49 6 10 y). All patients also underwent a comprehensive battery of neuropsychological tests, within 1.3 6 5.5 mo from SPECT. Statistical parametric maps (SPM2) were obtained for each test using a correlation design between performance scores and perfusion, and using an ANCOVA group analysis after dividing the population in good vs. bad performers according to the cognitive scores. Results: Correlation analysis revealed diffuse hypoperfusion in the periventricular areas, posterior associative areas, cerebellum and limbic system (including amygdalo-hippocampic complexes and anterior cingulate). These abnormalities were confirmed by ANCOVA group analysis, and contribute to highlight a specific pattern of hypoperfusion in MMF patients. Conclusion: Brain perfusion SPECT showed a pattern of diffuse cortical and subcortical abnormalities, in accordance with the MMF-associated cognitive disorder previously described. These results provide a neurobiological substrate for brain dysfunction in aluminum hydroxide-induced MMF patients. Study supported by: French patients association “Entraide des Malades de la Myofasciite a Macrophages” (E3M); In 2012, E3M funded 20% of M Aoun-Sebaiti salary. T2431. Electrical Impedance Myography and Quantitative Ultrasound for Assessment of Duchenne Muscular Dystrophy Rebecca Parad, Sarah Wilder, Amy Pasternak, Elizabeth Shriber, Nicole Visyak, Thomas Geisbush, Jim Wu, Craig Zaidman, Basil Darras and Seward Rutkove. Boston, MA and Saint Louis, MO Objective: To preliminarily evaluate electrical impedance myography (EIM) and quantitative ultrasound (QU) as biomarkers in Duchenne muscular dystrophy (DMD). Design/Methods: EIM and QU were performed unilaterally on six muscle groups in 18 boys with DMD and 20 healthy controls (all aged 2–12 years). For EIM, the 50:300 kHz phase ratio was used for analysis. For QU, mean gray scale levels (GSL) of muscle were obtained using an imageprocessing program. The Northstar Ambulatory Assessment (NSAA) was also performed in 9 DMD boys.
Abstracts, American Neurological Association
Results: Compared to healthy boys, in DMD the average EIM phase ratio was lower (mean 6 SD: 0.064 6 0.072 vs. 0.78 6 0.096) and the GSL was higher (49.2 6 8.4 vs. 26.1 6 4.2) (both p < 0.001). NSAA correlated nonsignificantly with both EIM (R 5 0.62, p 5 0.07) and GSL (R 5 20.53, p 5 0.146). In DMD boys, EIM and GSL had a coefficient of determination (R2) of 0.32, p 5 0.01. Conclusions: Individually, EIM and QU distinguish DMD from healthy muscle and trend toward a correlation with function. Since EIM and QU are only moderately correlated to one another, these techniques could be used in combination to improve the quantitative assessment of muscle in DMD. Study supported by: NIAMS/National Institutes of Health; Dr. Rutkove holds equity interest and receives consulting fees from Convergence Medical Devices, Inc, a company whose main focus is the development of devices for the measurement of muscle impedance. No equipment from this company was used in this research, however. T2432. Hip Flexion Weakness Is Associated with Loss of Independent Ambulation in Oculopharyngeal Muscular Dystrophy Sarah Youssof, Gulmohor Roy, David Bear and Leslie Morrison. Albuquerque, NM Objectives: To determine whether limb weakness in oculopharyngeal muscular dystrophy (OPMD) is associated with loss of independent ambulation. Methods: We performed a retrospective chart review of 47 OPMD cases at one center. We used multiple linear regression to identify predictors of limb weakness, KaplanMeier methods to estimate time to loss of independent ambulation, and a Cox proportional hazard model to assess risk of loss of independent ambulation in subgroups. Results: 77% of cases had proximal leg weakness. Hip flexors were the weakest muscle group. Disease duration was a significant predictor of hip flexion strength (R2 5 0.19, p 5 0.002), while age was not. There was a 25% probability of losing independent ambulation by 65 yrs. Moderate (or worse) hip flexion weakness ( grade 31) was associated with a greater risk of losing independent ambulation (logrank test: chi2 5 8.7, p 5 0.003). The hazard ratio was 8.5 (95% CI: 1.6,47; p 5 0.014) for loss of independent ambulation if hip flexors were at least moderately weak. Conclusions: Hip flexion weakness is common in OPMD, worsens with disease progression, and is associated with loss of independent ambulation. Study supported by: University of New Mexico’s Clinical and Translational Science Center (DHHS/NIH/NCRR #1UL1RR031977-01). T2433. West Nile Virus Infection Presenting as AIDP (MADSAM) Shri Mishra, Edward Chang, Sharon Yegiaian and Bhavesh Trikamji. Los Angeles, CA; Sylmar, CA and North Hills, CA We report the case of a 61 y/o male who presented with an acute, rapidly progressive painful ascending quadriparesis associated with sensory deficits. He deteriorated clinically and required intubation within 24 hours of admission. CSF
Annals of Neurology Vol 74 (suppl 17) 2013
studies were remarkable for a leukocytosis (lymphocyte predominance but presence of neutrophil and monocytes as well) and imaging of his spine showed enhancement of the conus and cauda equina. Initial electrodiagnostics were remarkable for mildly decreased CMAP and SNAP amplitudes and absent F waves. Because of religious beliefs, he refused treatment with plasmapheresis or IVIg, and treatment was supportive. Respiratory function improved enough to allow extubation spontaneously within three days, but he had persistent quadriparesis and sensory deficit. Laboratory workup was negative for autoantibodies to GM1, GQ1b, or MAG but was positive for WNV while negative for other infectious etiologies. Repeat electrodiagnostics four weeks later showed sensorimotor polyneuropathy with axonal and demyelinating features as well as persistent loss of F waves consistent with multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). This case demonstrates an unusual presentation of WNV infection while also demonstrating the natural course of this presentation given the lack of directed treatment. Study supported by: N/A.
T2434. Amyotrophic Lateral Sclerosis (ALS) ClinicBased Analysis of Burden of Center for Disease Control (CDC) Agency for Toxic Substances and Disease Registry (ATSDR) ALS Registry Participation for Incident and Prevalent Urban and Rural ALS Patients Benjamin R. Brooks, Nicole M. Lucas, Elena K. Bravver, John S. Story, Nicole P. Smith, Mindy S. Nichols, Sharon L. Belcher, Kathryn A. Wright, Amber L. Ward, Scott E. Holsten, Scott S. Lindblom, Thomas J. Paccico, William L. Bockenek, Mohammed S. Sanjak, Kristy L. Walgren, Lucille H. Frumkin, Michael P. Fischer, Quincy D. Corey, Heather L. Oplinger, Cynthia Lary, Joanne Nemeth, Carissa C. Ingram, Rita M. Rouse and Priscilla C. Russo. Charlotte, NC Background: The CDC-ATSDR-National ALS Registry was launched with a cost estimated as $0.21 per USA citizen annually. Patient recruitment at the Carolinas Medical Center was brisk initially but decreased over time. Among entered ALS patients, not all have completed all modules in the Registry. Multiple ALS patient blogs have questioned the benefit of participating in the Registry and whether the goals of the Registry will be met without more wide-spread patient participation. Objective: To identify barriers to patient entry and complete participation in CDC-ATSDR-National ALS Registry. Methods: At each quarterly follow-up clinic, ALS patient registration in the CDC-ATSDR-National ALS Registry was ascertained. Results: Non-registrants(25.4%)were further along in mean disease duration from onset[42 months vs 33 months] and had lower ALSFRS-R[25 vs 36]than ALS Registry registrants. Age, sex, site of ALS onset, or riluzole treatment were not discriminating factors. Education and rural vs urban dwelling were factors. Conclusion: Participation in the CDC-ATSDR-National ALS Registry involves attention at the clinic level to mitigate
the barriers that might prevent entry and participation in the CDC-ATSDR-National ALS Registry. Study supported by: Carolinas ALS Research Fund, Pinstripes Fund, Carolinas Healthcare Foundation. T2435. Hypocalcemia Disguising as Myasthenia Gravis Sayyed A. Sohrab, James Selwa and Agnes Jani-Acsadi. Ann Arbor, MI; Detroit, MI and Farmington, CT Background: Neuromuscular complications of hypocalcemia are well described and include clinical and electrophysiological evidence of muscle and nerve irritability such as muscle spasms, weakness and paresthesia among others. Hypocalcemic myopathy and laryngospasm have been reported as rare but important complications of hypoparathyroidism, and hypocalcemia has been also considered in the differential diagnosis of irritable myopathies. Case Report: We report a case of a 52-year-old man with a 6 months history of intermittent hoarseness and double vision, worsening of proximal muscle weakness and fatigue on confrontational strength testing. His work up included normal laryngoscopy. Electromyography and nerve conduction studies with repetitive stimulation and single fiber EMG revealed evidence of neuromuscular transmission defect similar to changes seen in myasthenia gravis. Weeks after responding to low dose pyridostigmine, he was diagnosed with idiopathic hypoparathyroidism and his symptoms improved after correction of serum calcium. Pyridostigmine was stopped. Conclusion: Hyoparathyroidism and related hypocalcemia may mimic myasthenia gravis and should be included in the differential diagnosis of myasthenia gravis. Study unfunded. Study supported by: unfunded. T2436. Acute Onset of Weakness and Numbness in the Proximal Left Upper Extremity in a Swimmer Divpreet Kaur, Alexandra Soriano and Aiesha Ahmed. Hershey, PA Introduction: Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant disease characterized by recurrent mononeuropathies precipitated by minor trauma or compression. Case Report: 17-year-old male swimmer presented with 2 week history of weakness and numbness in proximal left arm. Exam findings included decreased strength in the left spinati and biceps,decreased pinprick in the left C5/ C6 dermatomes,absent left biceps reflex. Electrodiagnostic testing showed chronic bilateral ulnar neuropathies at the elbow,left suprascapular and musculocutaneous neuropathies with active denervation in the left biceps muscle.Genetic testing was positive for PMP 22 deletion. Discussion: HNPP usually presents in 2nd-3rd decade of life.Clinical spectrum ranges from asymptomatic patients to a typical presentation of mononeuropathy pressure palsy. Electrodiagnostic studies typically show generalized motor and sensory slowing commonly involving a single superficial nerve being more prone to pressure/trauma. Sural nerve biopsy demonstrates tomaculi or “sausage”shape structures due to patchy myelination.Genetic testing shows PMP 22 deletion.
Conclusion: HNPP should be considered as a diagnosis in young patients presenting clinically as brachial plexopathy.Clinical suspicion and early diagnosis with electrodiagnostic testing confirmed by genetic testing is important in order to prevent recurrent palsies. Study supported by: Not Applicable as it is a case report. T2437. Construction of Drug Screening System and Allele-Specific Silencing Against Pathogenic ALK2 Mutants in Pluripotent Stem Cell (iPSC) of Fibrodysplasia Ossificans Progressive (FOP) Hirokazu Furuya, Masaki Takahashi, Hirohiko Hohjoh and Takumi Era. Omuta, Fukuoka, Japan; Tokyo, Japan and Kumamoto, Japan Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant congenital disorder characterized by postnatal progressive heterotopic ossification especially in skeletal muscle. FOP is caused by mutations in activin receptor-like kinase 2 (ALK2/ACVR1) that cause its constitutive activation and result in dysregulation of bone morphogenetic proteins signaling and which induce heterotopic bone formation and initiate to convert myoblasts into osteoblastic cells. Chemical inhibitors such as dorsomorphin to the pathogenic ALK2 receptors are considered possible medical agents. Here we describe another treatment strategy for FOP using allele-specific RNA interference, and generation of iPSCs from FOP-derived skin fibroblasts repressed of iPSC maintenance due to incomplete reprogramming. This repression was mostly overcome by specific suppression of mutated ALK2 expression and treatment with an ALK2 inhibitor. Using this iPSC, we identified an ALK2 inhibitor as a potential candidate for future drug development. This study highlights the potential of the inhibited production and maintenance of iPSCs seen in diseases as a useful phenotype not only for studying the molecular mechanisms but also for identifying drug candidates. (Hamasaki M, et al. Stem Cells 2012; 30: 2437–2449). Study supported by: A Research Grant for the Muscular Dystrophy and Clinical Research Network of the National Hospital Organization (NHO) from the Ministry of Health, Labor and Welfare of Japan. T2438. Pain in Charcot-Marie-Tooth Disease - Predictive Factors and Functional Impact Sindhu Ramchandren, Richard Finkel, Eva Feldman and Michael Shy. Ann Arbor, MI; Philadelphia, PA and Iowa City, IA Health-related quality of life (QOL) is significantly reduced in children with Charcot-Marie-Tooth disease (CMT). The specific contributors of reduced QOL, however, remain to be identified. Studies have shown that a significant portion of adults with CMT have painful distal extremities, however, it is unclear whether the pain is due to the neuropathy or the structural, disabling changes that may occur in the disease. Assessing pain in children with CMT, who may be less disabled, can thus offer insight not only into the physiology of the pain but also to the contributors of reduced QOL in children with CMT. We are collecting prospective data on children with CMT through the multicenter Inherited Neuropathy Consortium. Included in these assessments are standardized assessments of pain as well as
Abstracts, American Neurological Association
functional outcomes. We have collected data in 137 children aged 8–18 (self-report) and 40 children aged 7 and under (parent-proxy report). Correlations with the Charcot Marie Tooth Neuropathy Score to assess functional disability, and the Child Health questionnaire (CHQ) to assess quality of life, will be presented at the meeting. Study supported by: NIH: K23-NS072279 (SR); U54NS065712 (MES). T2439. Unilateral Femoral Neuropathy in the Setting of Drug Overdose and Anoxic Injury: Two Cases with Radiographic Findings Suggestive of Rhabdomyolysis, Compressive Neuropathy and Myonecrosis Alexandra LaMela, Juan Small, Michal Vytopil, James A. Russell, Jayashri Srinivasan and Doreen T. Ho. Biddeford, ME and Burlington, MA Unilateral femoral neuropathy related to anoxic injury and drug use has been described, but the mechanism remains unknown. Previous reports have posited both compressive and ischemic mechanisms. Magnetic resonance imaging (MRI) of the nerve and adjacent musculature, not described in this setting previously, can help us further elucidate the underlying mechanism. We describe two cases of unilateral femoral neuropathy associated with anoxic injury and myonecrosis. In Case 1, MRI revealed necrosis of the right quadriceps, iliacus, obturator externus, and gluteus medius. The patient was diagnosed with rhabdomyolysis. In Case 2, there was necrosis of the right quadriceps, iliopsoas, quadratus femoris, sartorius, and gluteus medius. Neither pattern of muscle injury is consistent with a single nerve or artery lesion, thus excluding denervation and arterial ischemia as possible mechanisms. Abscess, endocarditis, and emboli were ruled out. Positioning also may have contributed to the pathology. The first patient was positioned on his back, the second on his right side. We postulate that diffuse or focal rhabdomyolysis, along with positioning, caused a compressive femoral neuropathy and associated myonecrosis. Study supported by: N/A. T2440. Acute Intermittent Porphyria: Nervous System Manifestations David S. Younger. New York, NY Acute intermittent porphyria (AIP) results from mutation in the HMBS gene encoding hydroxmethylbilane synthase (HMBS). A teenager had recurrent fainting spells. After prolonged antibiotics for incidental infection and psychotropic medication for depression, he developed clinically manifest AIP characterized by bouts of palpitation, sweating, impaired voiding, abdominal pain, and hyponatremia prompting neurological evaluation. Tilt table showed symptomatic orthostatic intolerance (OI) with minimal SBP of 79 mmHg and maximal HR of 138 bpm. Nerve conduction studies (NCS) and electromyography (EMG), and teased sural nerve fibers indicated segmental demyelination and remyelination. Epidermal nerve fiber (ENF) analysis showed reduced ENF density in the leg with qualitative histological alterations. Brain neuroimaging was normal. Cerebrospinal fluid was acellular with protein
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content of 101 mg/dL. Fractionated urinary porphyrins were consistent with AIP with urinary porophobilinogen of 295.4 umol/L (normal 0–8.8). Genetic assay of HMBS is forthcoming. Discontinuation of provocating medications lessened attacks and the neuropsychiatric sequela. Beta-blocker and fludocortisone medication corrected symptomatic OI. A short course of intravenous immune globulin (IVIg) improved demyelinating peripheral neuropathy. Prompt recognition of the central (CNS), peripheral (PNS), and autonomic nervous system (ANS) manifestations of AIP is essential in instituting effective management and forestalling progression. Study supported by: None. T2441. Self-Reported Measures Predict Survival in ALS Nimish J. Thakore and Erik P. Pioro. Cleveland, OH Objective: To explore the effect of rate of decline of selfreported ALSFRS-R (SR-DFS) and other self-reported measures on survival in ALS Methods: ALSFRS-R and other self-reported measures were prospectively captured on tablet devices in waiting rooms at Cleveland Clinic using software developed inhouse (Knowledge Program). Cox proportional hazard models identified predictors of survival. Results: Of 805 patients with ALS seen over a 6-year period, 229 died with a median survival of 681 days (1.87 years). SR-DFS was calculated from two ALSFRS-R measures at least 45 days apart in 252 patients. Median SR-DFS was 0.59 points/month. Hazard ratio (HR) for each point increase in SR-DFS was 2 (CI 1.64-2.44, p < 10211). Other significant predictors were age (HR 1.04 per year of increasing age, p < 1029), initial ALSFRS-R (HR 1.025 per point decrease, p < .05), PHQ9 (HR 1.08 per point increase, p < 1029), EQ-5D (HR 1.17 per 0.1 point decrease, p < 1026), and bulbar/respiratory onset (HR 1.55, p < .05). Only SR-DFS, PHQ9 and age emerged as significant independent predictors of survival on stepwise regression. Conclusion: Self-reported measures have utility in predicting outcomes and for stratification of ALS patients to clinical trials. Models with additional discrete clinical covariates will be examined next. Study supported by: This study did not receive financial support from any external or internal source. T2442. Seropositive Inclusion Body Myositis: The Clinical Spectrum Farzin B. Pedouim, Sameen Enam, Namita Goyal and Tahseen Mozaffar. Orange, CA Inclusion body myositis (IBM) is an inflammatory myopathy characterized by asymmetric progressive weakness and wasting of both proximal and distal muscles usually starting after 40 years of age. Whereas the “amyloid” theory has predominated to explain disease pathogenesis, there has been substantial recent work that has reignited the debate about the role of autoinflammation in this disease. A novel antibody to a 44 KD protein NT5C1A, involved in RNA processing, was recently described. We performed a retrospective analysis of the clinical, pathological and treatment responses in our cohort of inclusion body myositis who have had this antibody tested in their blood.
Seven of the nine tested so far were seropositive; the seropositive patients appear to be younger (mean age 62 6 years in seropositive vs. 73 6 years in seronegative patients), and have less bulbar dysfunction 5/7 vs. 2/2 patients in seronegative group. Seropositive patients may also respond more to immunosuppressive; 3/7 vs. 0/2 in the seronegative group. We plan to prospective analyze this cohort and additional patients to analyze any differences in clinical phenotype, myopathologic changes, disease course and response to treatment. Study supported by: No conflict of interest. Nothing to disclose. T2443. Electrical Impedance Myography for the In Vivo Assessment of the Muscular Dystrophy (mdx) Mouse Jia Li, Tom R. Geisbush, Ravi Kumar, Aaron Mulivor and Seward B. Rutkove. Boston, MA and Cambridge, MA Background: Sensitive, non-invasive techniques that can measure disease status and the effects of therapy in Duchenne muscular dystrophy (DMD) are needed to speed therapeutic testing in both animal research and human clinical trials. Objective: To determine whether electrical impedance myography (EIM) has the potential to serve as a sensitive biomarker in the mdx mouse. Methods: We studied 2-month-old and 18-month-old mdx and wild-type (WT) animals (10 animals in each of four groups). EIM was performed via a simple 4-electrode surface technique on the unilateral gastrocnemius muscle of each animal. Results: Marked differences were observed in the EIM values between the mdx and WT animals, with those differences being more pronounced between the older age groups (e.g., reactance of 92.6 6 4.3 ohms for mdx animals vs. 130 6 4.1 ohms for the WT animals, p < 0.001). In addition, in vivo EIM reactance correlated with a marker of connective tissue deposition (hydroxyproline content) with r 5 0.65, p < 0.001. Discussion: These findings support that EIM can serve as an important non-invasive method for evaluating DMD, assisting with therapeutic testing in animal research and potentially serving as a biomarker in human clinical trials. Study supported by: NIH Grant R01 NS055099. T2444. The Influence of Age and Height on Latency and Amplitude of Contact Heat Evoked Potentials (CHEPS) Benn Smith, Yelena Granovsky, Osvaldo Nascimento, Josep Valls-Sole, Aya Nakae, David Yarnitsky, Les Huson and Praveen Anand. Scottsdale, AZ; Haifa, Israel; Rio de Janeiro, Brazil; Barcelona, Spain; Osaka, Japan and London, United Kingdom Background: CHEPS assess A delta fiber conduction in the PNS and CNS, unlike nerve conduction studies which test large diameter fibers. Rigorous normative CHEPS data, which are required for clinical diagnostic use, are not available. Methods: Sixty-one neurologically normal adults (20–80 years) were recruited to five centers (in Brazil, Israel, Japan, Spain and USA) with full IRB approval; data were analyzed
in the UK. These individuals underwent CHEPS testing at 8 sites (forearm, leg and face on both sides, and over the C7 and L1 spine), using 51 degree C stimuli and 10–14 stimuli per site, recording scalp potentials at Cz-TE (tied ears), Fz-TE and T3/4-TE. Results: Peak N2 and P2 latencies were related positively to age (p < 0.0001) and leg length (p < 0.0004), whereas N2-P2 amplitude was related negatively to age (p < 0.0001) and positively to leg length (p < 0.0001). Conclusions: 1) Age- and height-related changes in CHEPS amplitude and latency should be considered for the assessment of nociceptive (A delta) pathway abnormalities, and 2) loss of fibers and impaired synchronization of conduction times may account for the observed decreases in CHEPS amplitude and prolongation in CHEPS latency with aging. Study supported by: Medoc Ltd. and Nihon Koden. T2445. Peripheral Nerve Amyloidosis: Phenotype, Natural History, and Autonomic Dysfunction in Inherited Versus Acquired Subtypes Adam J. Loavenbruck, Wolfgang Singer, Paola Sandroni, Michelle L. Mauermann, P.J.B. Dyck, Christopher J. Klein and Phillip A. Low. Rochester, MN Objective: To compare laboratory and clinical phenotypes of primary (AL) amyloid neuropathy (AN) versus V30M and other TTR mutations. Background: AN is a devastating condition predominantly involving autonomic and somatic C fibers. Differences between acquired and inherited subtypes have been recognized, but detailed studies are lacking. Methods: We reviewed clinical features and disease course in patients with AN seen at Mayo Clinic Rochester between 1993 and 2013 who underwent standardized autonomic testing. Results: 63 AL and 47 TTR cases (V30M, n 5 20; nonV30M, n 5 20; unknown, n 5 7) were identified. There was longer survival and longer time to diagnosis in TTR compared to AL. Neuropathy in TTR was paradoxically more severe (higher CASS score, more frequent somatic fiber involvement and occurrence of weakness); longer survival was related to later cardiac and gastrointestinal involvement. Compared to other TTR mutations, V30M cases more often reported distal paresthesias at onset and had lower distal QSART volumes. IgM cases had longer time to diagnosis, less sudomotor, and less cardiac involvement compared to other AL cases. Conclusions: Our results delineate differences in clinical phenotype, natural history, and autonomic involvement between amyloid subtypes in AN. Study supported by: NS 44233 Pathogenesis and Diagnosis of Multiple System Atrophy; U54 NS065736 Autonomic Rare Disease Clinical Consortium. T2446WIP. Virtual Demyelination in PMP22 Deficiency Audra Hamilton, Jiasong Guo, Yang Zhang, Leiming Wang, Jiawen Wu, Sezgi Arpag, Bo Hu, Beat A. Imhof, Bruce D. Carter, Ueli Suter and Jun Li. Nashville; Geneva, Swaziland and Zurich, Switzerland
Abstracts, American Neurological Association
The peripheral myelin protein-22 (PMP22) gene is associated with the most common types of inherited neuropathies, including hereditary neuropathy with liability to pressure palsies (HNPP) caused by PMP22 deficiency. However, the function of PMP22 has yet to be defined. Utilizing Pmp221/- mice as a model of HNPP, we show disruption of multiple types of cell junction complexes in peripheral myelin, resulting in increased permeability of myelin and impaired action potential propagation. We further demonstrate that PMP22 interacts with immunoglobulin (Ig) domain-containing proteins known to regulate tight/adherens junctions and/or transmembrane adhesions, including junctional adhesion molecule-C (JAM-C) and myelinassociated glycoprotein (MAG). Deletion of Jam-c or Mag in mice recapitulates pathology in HNPP. Taken together, our study reveals a novel mechanism by which PMP22 deficiency affects nerve conduction through changes of myelin junction permeability, not removal of myelin, a mechanism that we call “virtual demyelination”. Study supported by: NINDS.
without effective treatment. Many different diagnostic criteria have been proposed for IBM, however, the sensitivity and specificity have not been compared. Objectives: Determine optimal IBM diagnostic criteria for clinical trials. Methods: We retrospectively reviewed records of 200 IBM patients diagnosed as having sporadic IBM (s-IBM) and 150 patients diagnosed with other muscle diseases, including those that mimic s-IBM such as hereditary IBM, vacuolar myopathies, muscular dystrophies, and other myositides. Results: We were able to apply 9 different sets of IBM diagnostic criteria comprising 24 different categories to our patients. We find that while the proposed criteria all have very high specificity, they differ markedly in their sensitivity. Conclusions: Several proposed IBM diagnostic criteria exclude a majority of IBM patients and are not optimal for clinical trials. Study supported by: NIH/NINDS
T2447WIP. Molecular Mechanism of Segmental Demyelination in Fig4 Deficiency Bo Hu, Qing Yan, Sezgi Arpag and Jun Li. Nashville
T2449WIP. Ubiquitin-E3 Pathway Defect by DCAF8 Mutation Causes HMSN2 Christopher J. Klein, P. Vogel, Hans H. Goebel, Xiaohui Duan, Maria-Victoria Botuyan, Georges Mer, Yanhong Wu and Peter J. Dyck. Rochester, MN; Berlin, Germany and Rochester
Deletion of c-Jun and Notch-1 genes prevents Schwann cells from demyelination after nerve transection. Thus, the two dedifferentiation molecules are considered to promote demyelination by dedifferentiating the mature myelinating Schwann cells to their immature state. Charcot-Marie-Tooth type-4J (CMT4J) with Fig4 deficiency cause segmental demyelination that resembles acquired demyelinating neuropathies. Thus, CMT4J and its mouse model with inactivation of Fig4 gene (Fig4-/-) may serve as genetic models for investigating demyelination. We have observed an increase of c-Jun and Notch-1 that were tightly correlated with demyelinating internodes and a robust increase of intracellular calcium level of the myelinating Schwann cells in Fig4-/mouse sciatic nerves. We further demonstrate that the increase of intracellular calcium in Fig4-/- Schwann cells suppresses the proteasome degradation of c-Jun. In contrast, Notch-1 increase is related to a dysfunction of lysosomal degradation in Fig4-/- Schwann cells. Taken together, this study suggests that segmental demyelination in Fig4 deficiency is likely caused by suppression of dedifferentiation molecule degradation through two distinct mechanisms. Study supported by: NINDS R21 and VA RR&D. T2448WIP. Evaluation of Diagnostic Criteria for Inclusion Body Myositis Thomas E. Lloyd, Andrew L. Mammen and Steven A. Greenberg. Baltimore, MD and Boston, MA Introduction: Inclusion Body Myositis (IBM) is an adultonset, slowly progressive muscle disease of unknown cause
Annals of Neurology Vol 74 (suppl 17) 2013
We identified a novel DCAF8 p.R317C mutation in our previously published large hereditary motor and sensory neuropathy kindred (HMSN2). (Vogel et al. Annals of Neurology 1985) Nerve biopsies of affected persons show giant axons consistent with protein degradation accumulation deposition. DCAF8 is a substrate-recruiting module of the DDB1–CUL4 ubiquitin-ligase E3 complex important in regulating DNA repair, DNA replication and transcription. The discovered novel mutation tracked with affected status in this large kinship and is absent in dBSNP137, 1000Genome and ESP 6500Exome database. We also confirmed its absence using our in-house clinically examined 1500 controls. The mutation is predicted damaging and at a highly conserved site. The gene has high fidelity without common missense coding variants. Additionally, this mutation resides in one of its 7 WD repeats (WD3). DCAF8 directly binds to DDB1 protein. Mutagenesis analysis showed that mutant DCAF8 with p.R314H and p.R362H drastically reduces its affinity to DDB1. HEK293 cotransfection results are ongoing to determine if p. R317C reduces DCAF8 binding to DDB1. This study indicates that DCAF8 is a novel causal gene for HMSN2 and exerts its pathogenesis for axonal health through the ubiquitin E3 mediated pathway. Study supported by: National Institutes of Health grant (NS065007, C.J.K.)
ABSTRACT AUTHOR INDEX Aasly, Jan O. M1227 Abcede, Hermelinda T2108 Abel, G. M1235 Abend, Nicholas S. T2002 Abhishek, Hulegar M2227 Abner, Erin T2316 Abramihina, Tatiana M1238 Absoud, Michael S503 Acebo, Christine M1009 Aceves, Jose M2217 Achhal El Kadmiri, Mohammed Amine T1807 Adamski, Mateusz G. S438 Adeoye, Opeulu S429 Agarwal, Nitin S206 Agostinelli, Lindsay J. M1002 Agricola, Karen T2103 Aguirre, Geoffrey K. T1701 Ahlskog, Eric J. M1411 Ahmed, Aiesha T2436 Ajlen, Aaron C. S406 Akpinar, Zehra S521 Aksamit, Allen J. S709 Aksan, Nazan S612, S614 Ala, Thomas S703 Albright, Karen C. S421, S422, S423, S426, S427, S431, S432, S433, S434 Alexia, Potet S613 Algon, Avi M1226 Allen, Mariet T1903 Allen, Simon S517 Allison, Kirk C. M2218 Almeida, Leonardo M1215 Alonso, Alvaro S408 Alonso, Maria E. M2205 Alt, Jesse S608 Alwell, Kathleen S429 Amara, Amy W. M1228 Amato, Anthony A. T2401, T2402 Ambady, Prakash T2107 Amirbekian, Bagrat T2301 Amorim, Edilberto M1301 Amrami, Kimberly K. T2415 Amy, Quek M.L. S502 ANA Public Policy Committee S207 Anand, Praveen T2444 Anderson, Steven S612, S614 Andrade, Edgard T2003 Anton Rodriguez, Jose T2307 Antonini, Angelo M1213
Aoun Sebaiti, Mehdi T2430 Apeltsin, Leonard S517 Arain, Amir M. M2210 Arcot, Karthikeyan M. M1310 Ardelt, Agnieszka T1801 Arimura, Kimiyoshi T2420 Arjun, Arpana T2318 Armangue, Thais S527WIP Arnason, Barry G.W. S518 Arpag, Sezgi T2446WIP, T2447WIP Arthur, Adam M1309 Artibee, Kay T2410 Astor, Brad C. T2310 Atanga, Pascal A. S509 Attix, Deborah S413 Authier, Francois-Jerome T2430 Axtell, Robert C. S425 Ayman, Tourbah S613 Azimi, Vahid S603 Aziz-Sultan, Mohammad A. M1312 Babiak, Miranda T2301 Baca, Christine B. S204 Backus, Carey M1422 Bagla, Shruti M2202 Bahouth, Mona T2315 Bahrainwala, Zainab T2315 Bai, Dongsheng M2205 Bailey, Julia N. M2205 Baird, Alison E. S438 Balabanov, Roumen S522 Baldassarre, Antonello S610 Baldwin, Roger A. M2209 Baloyannis, Ioannis S. S437 Baloyannis, Stavros J. S437 Bankoti, Jaishree S517 Barker, Peter B. S608 Barmada, Sami T2318 Barohn, Richard S520 Barohn, Richard J. T2401, T2407 Barraza, Leticia M1304 Barrett, Kevin M. S304 Barron, Daniel S. M2204 Barron, Loretta T2109 Barry, Elizabeth M2222 Bartusis, Laimonas T1504 Batarse, Anthony T2318 Batchu, Vera V.K. M1424 Battey, Thomas W. S410 Baughn, Michael W. M1402 Baxter, Joshua R. M1208
Bazan, Nicolas G. S444 Beal, Flint M1223 Beall, Erik S101 Bear, David T2432 Beasley, T. Mark S421, S422, S426, S427, S431, S433, S434 Bebin, Martina T2102 Becker, Daniel M905 Bedoin, Nathalie M2206 Bekersky, Ihor M2213, M2216 Bekker, Simon S703 Belayev, Ludmila S444 Belcher, Sharon L. T2422, T2434 Belousova, Elena T2102 Beltagy, Abdelrahman M1314 Benarroch, Eduardo E. M1411 Benbadis, Selim R. M2221 Bender, Diane E. M1428, M1432 Benesh, Janet M1210, M1213 Bennett, Frank M1402, M1414 Benninger, David M1203 Berg, Anne T. S204 Berg, Robert A. T2002 Berka, Vladimir S404 Berkowitz, Noah T2102, T2103 Bernardo, Danilo T1602 Berry-Kravis, Elizabeth T1908WIP Bershad, Eric M1316 Beutler, Andreas S. T2417 Bhargava, Pavan S703, M2223 Bhat, Sushanth S708, M802, M1229 Bhole, Rohini S430 Bhuva, Parita M1304, M1306 Biaggioni, Italio M1412 Bick, Diane L. M1417 Biglan, Kevin M. M1223 Billioux, Jeanne M2226 Binney, Richard T2301 Bisceglio, Gina T1903 Black, Jed M1003, M1004, M1006, M1007 Blair, Aaron M1232 Blakeley, Jaishri T2107 Blasco, Maria R. S516 Bliwise, Donald L. M1207, M1221 Block, Gil T2405 Block, Nik T2301 Bloom, Julianne T2109 Bockenek, William L. T2422, T2434 Bodis-Wollner, Ivan M1240 Boehme, Amelia K. S421, S422,
Abstracts, American Neurological Association
S426, S427, S431, S432, S433, S434 Bonakdarpour, Borna S617 Bonner-Jackson, Aaron S611 Boscolo, Francesca S. M1238 Bose, Arani M1304 Bosley, Thomas S712 Botha, Hugo M1222 Bothwell, Mark T1905 Botuyan, Maria-Victoria T2449WIP Bower, James H. M1411 Boyd, James T. M1210, M1213 Brag, Katherine S433 Bragg, Katie S422 Branas, Charles C. S432 Brandstatt, Kelly L. T1802 Brandt, Jason S608 Brannas, Charles S423 Braun, Tricia L. M2212 Bravata, Dawn M. S402 Bravver, Elena K. T2422, T2434 Breen, Elizabeth M1224 Bricker, Paul T2105 Brickman, Adam M. M902 Brickshawana, Adipong S506 Britton, Jeffery M2214 Britton, Jeffrey W. S205, S502 Brockington, John C. T2311 Broestl, Lauren T2320 Brooks, Benjamin R. T2422, T2434 Brott, Thomas G. S405 Brown, Candice S413 Brown, Cheryl L. S430 Brown, Daniel M1231 Brown, Devin L. S201 Brown, Robert H. M1243WIP Browner, Carole H. T1904 Bruce, Joycelyn S519 Brunetto, Giovanna M2226 Bryan, David S711 Bryant, Joseph S505 Buchhalter, Jeffrey M2220 Buckwalter, Marion S. S425 Buddhala, Chandana M1204 Buell, Hope M1304 Bukshpun, Polina S601 Burke, James F. S201, S202, T1702 Burke, Kenneth J. M1201 Burkholder, David B. S205 Burnett, Melinda S. M1411 Bush, Matthew M1306 Bushnell, Cheryl S413 Cadavid, Diego M1319WIP Caffall, Zachary M1244WIP S108
Calabresi, Peter A. S608 Calakos, Nicole M1244WIP Calderon-Garciduenas, Ana L. M1234 Callaghan, Brian C. S202, M1419, M1428, T1702, T2429 Cambon, Alex C. M1209 Cameron, Debra M1243WIP Campbell, Meghan C. M1204 Caplan, Rochelle S204 Care, Marguerite T2103 Carey, Robert F. S516 Carlson, Lauren A. M1302, M1304, M1305, M1306, M1307, M1311, M1313 Carr, Brendan G. S423, S432 Carrasquillo, Minerva T1903 Carraway III, Kermit L. T2112WIP Carrazana, Enrique S619 Carrithers, Michael D. S507 Carter, Alex R. S610 Carter, Bruce D. T2446WIP Carter, Lawrence P. M1009 Cascino, Gregory D. M2214 Case, Amanda T1905 Case, Michael T2304 Castanedo, Juan P. M1413 Castellani, Rudolph J. M1424 Castillo, Richard M2217 Cataldo, Michael D. M1428 Cauwel, Helene T2102 Caverzasi, Eduardo T2301 Cechetto, David T2303 Cervantes-Arslanian, Anna M. S414 Chai, High Seng T1903 Chambers, Patrick T2313 Chandra, Satish M1236 Chandrasekaran, Krish T2406 Chang, Edward T2433 Channer, Dwight D. S436 Charbonnier-Beaupel, Fanny M1206 Charles, David S207, M1214, M1241 Chatamra, Krai M1210, M1213 Chau, Nelson M1407 Chaudhry, Burhan Z. S512 Chauhan, Prashant S. S716 Chelimsky, Thomas M1412 Chen, C. M1242 Chen, Edward S515 Chen, Helen T2406 Chen, Honglei M1232
Annals of Neurology Vol 74 (suppl 17) 2013
Chen, Sherman H. M1302, M1304, M1306, M1313 Chen, Xiaodong T2314 Chen, Yun M1319WIP Chen, Zheyan T2415 Cheng, Hsinlin T. M1432, T1703 Chen-Plotkin, Alice T1901 Cheung, Raymond M1304 Chian, RuJu M1243WIP Chibnik, Lori T1601 Chii, Erika M1234, M1413 Chisulo, Brian S424 Chitnis, Tanuja T1601 Cho, Jeong Hee S618 Choi, Joungil M1424, T2406 Choi, Sun-Ah S618 Chokroverty, Sudhansu M1229 Chomskis, Romanas T1504 Chung, Amy T2109 Chung, Kathryn T1901 Ciarlini, Pedro D.S.C. S707 Ciumas, Carolina M2206 Clark, Annie M. M2212 Clark, David G. T2311 Clarke, Charles D. T2428 Clavelou, Pierre T2423 Cleveland, Don M1402 Cloonan, Lisa S413 Cloyd, James C. M2212 Coffman, Stewart M1306 Coffman, Stewart R. M1302 Coker, Laura H. S408 Cole, John W. T1906 Coleman, Todd P. T1501 Collier, Timothy J. M1408 Comment, Nicholas T2421 Concato, John S402 Conrad, Katherine T2001 Cook, Jared F. T1503 Coon, Elizabeth A. S205 Copeland, Brian J. M1218 Corbett, James J. S512 Corbetta, Maurizio S610 Cordonnier, Charlotte S403 Coresh, Josef T2310 Corey, Quincy D. T2422, T2434 Corey-Bloom, Jody M1224, M1231 Cormier-Dequaire, Florence M1206 Corvol, Jean-Chirstophe M1206 Cory-Slechta, Deborah T2001 Couch, James R. M903 Coulson, Jeff M1305, M1307, M1311
Cowles, V.E. M1242 Cox, Garett S703 Crain, Andrew M1238 Crainiceanu, Ciprian M. S407 Crainiceau, Ciprian M. S608 Craw, John S. M1238 Crawford, Thomas T2403 Creange, Alain T2423 Cristopher, Klein J. S502 Crook, Julia T1903 Crowder, Melissa T2403 Cucchiara, Brett L. S435, T1701 Cunningham, Chris R. M1209 Cunningham, David A. S101 Currie, Amanda D. M1214, M1241 Cusumano, Joseph P. M1208 Cutler, David J. T1907 Cutter, Gary M1228 Dabir, Aman M1318 Dachet, Fabien M2202 Dagar, Anjali S206 Dahodwala, Nabila M1216 Dai, Minxian S704, S705 Daley, Elizabeth M1414 Dalmau, Josep S525WIP, S527WIP, S528WIP Dalmau, Josep O. S510 Dammer, Eric T2306 Dandapat, Sudeepta M2223 Darras, Basil T2431 Datta, Rito T1701 Daubaris, Gediminas T1504 Dauch, Jacqueline R. M1422, M1423, M1432, T1703 Dauvilliers, Yves M1004 Davenport, Janine S505 David, Schuster M2227 David, William T2401 Davis, Harry S505 Davis, Marie T1901 Dawson, Jeffery S612 Dawson, Jeffrey S614 Day, Gregory S. S524 de Bellescize, Julitta M2206 De Girolami, Umberto S707 De Jager, Philip T1601 de Jong, Pieter J. M1243WIP De La Monte, Suzanne T2426 Dean, Robert T2304 Dearborn, Jennifer L. S408 Deburghraeve, Cory T1908WIP Deel, M. Elizabeth M2229WIP Dekermenjian, Rony M1229 Delbrune, Jean M1310 Delgado, Silvia R. S519
Delgado-Escueta, Antonio V. M2205 Demaerschalk, Bart M. S436 Dequatre-Ponchelle, Nelly S403 Derakhshan, Iraj S615, M906 DeRosa, Janet T. S605 Desmond, John E. S603 DeSousa, Keith G. M1317 Desruisseaux, Mahalia S. S704, S705 Detre, John A. S435, T1701 Deutsch, Reena S715 Devos, David M1206 Dharmadhikari, Sushrut S. M1312 Dickoff, David J. M1220 Dickson, Dennis T1903 Dickson, Dennis W. M1226 Dillmann, U. M1205 Dimachkie, Mazen T2407 DiMario, Francis J. T2004 Ding, Li M2229WIP Dissin, Jonathan S714 Dlugos, Dennis J. T2002 Dong, Chuanhui S605 Donnelly, Christopher J. M1414 Donofrio, Peter D. T2428 Dontje, Stephanie M. M1220 Dorsey, E. Ray S301 Dosado, Lea M1434 Doss, Vinodh T. M1309 Doyle, Kristian P. S425 Drazkowski, Joseph F. M2215 Duan, Xiaohui T2413, T2449WIP Dubal, Dena B. T2320 Duffy, Joseph R. S607, S609 duMaine, Xavier M1407 Dunn, C. M1235 Dunn, Tiffany M1429 Dupont, William M1412 Duquette, Pierre S516 Duron, Rayna M2205 Dustin, Irene M. M2226 Dyck, James B. T2413 Dyck, P.J.B. T2445 Dyck, Peter J. T2413, T2449WIP Dynin, Efim M1004 Eady, Tiffany N. S444 Eberlein, Sharon M1313 Edwards, Karen T1901 Elaine, Wirrell C. S502 Elfahal, M. M1235 El-Ghanem, Mohammad H. S206, S443 Elhammady, Mohamed
Samy A. M1312 Elijovich, Lucas M1309 Elkind, Mitchell S.V. S414, S605 Elledge, Stephen J. T2402 Ellenbogen, Aaron M1205 Ellis, Ronald J. S715 Ellison, Brian M1211 Elllenbogen, Aaron M1219 Ellmore, Timothy M. M1218, M1433 Elm, Jordan J. S410 Elson, So S502 Elzinga, Grace T2109 Emir, Birol M1308 Enam, Sameen T2442 Endo, Hitoshi T2110 ENGENE Study Group M1209 Era, Takumi T2437 Eremita, Matthew J. T2004 Ertekin-Taner, Nilufer T1903 Eskey, Clifford T2104 Espay, Alberto J. M1210 Evangelista, Eva T2430 Eze, Chigolum M2226 Fabris, Rachel R. S205 Factor, Stewart T1901 Factor, Stewart A. M1207, M1221 Fadul, Camilo T2104 Fagerlin, Angela T1803 Fahn, Stanley M1219 Fanale, Chris M1306 Fang, Xiang M1429, T2416 Faridar, Alireza S601 Farkas, Jeffrey M1310 Farlow, Martin R. T2312 Faulkner, Monica L. S603 Fava, Maurizio M1415, M1426 Fazeli, Pariya Lynne S715 Fealey, Robert D. M1411 Feil, Julian M1420 Feil, Katharina M1420 Fekete, Robert S442, T1806 Feldman, Eva T2438 Feldman, Eva L. M1418, M1419, M1421, M1422, M1423, M1428, M1431, M1432, T1703, T2421, T2429 Fendrick, A. Mark S201 Fenoy, Albert M1218 Fenoy, Albert J. M1433 Ferioli, Simona S429 Fernandez, Hubert H. M1210 Ferrara, Joseph M. S428 Ferreira-Guilhoto, Laura M. M2205
Abstracts, American Neurological Association
Ferris, Steven T2312 Ferrucci, Luigi T2308 Figueroa-Romero, Claudia M1428, M1431 Fine, Eugene J. S705 Finelli, Pasquale F. S305 Finkbeiner, Steve T2318 Finkel, Richard T2438 Fiol, Miguel E. M2218 Fischer, Michael P. T2422, T2434 Fishcer, Kimberlee M1407 Fishel Ben Kenan, Rotem M1425 Fitts, Whitney M1216 Flaherty, Matthew L. S429 Flamini, Robert T2102 Fogel, Brent L. T1904 Fogelman, Alan M. S412 Fonkem, Ekokobe T2105 Ford, Kristin J. M1228 Forrester, Kelly S701 Fox, Peter T. M2204 Frank, Jefferey T1801 Frank, Summer S620 Frankenberg, Emily S606 Franklin, Donald S715 Franz, David N. T2102, T2103 Fredieu, Andre M1313 Freedman, Mark S. M1319WIP Freeman, Alan M1207, M1221 Freeman, Brandi D. S704, S705 Freeman, Roy M1412 Freeman, William D. S405 Fregeau, Brieana S601 Friedman, Andrzej M1416 Friedman, Mark S203 Frost, Michael T2102 Frumkin, Lucille H. T2422, T2434 Frump, Derek T2409, T2427 Fryer, James P. S506 Fugate, Jennifer E. M2214 Fuhrel-Forbis, Andrea T1803 Fujioka, Shinsuke M1226 Fuller, Patrick M. M1001 Funalot, Benoit T2425 Fung, Victor S.C. M1213 Funk, Susan M1003, M1007 Furie, Karen L. S410 Furuya, Hirokazu T2437 Gadallah, Nancy M1229 Galazka-Friedman, Jolanta M1416 Gallagher, Martin J. M2229WIP Gallagher, Philip T2407 Gallea, Cecile M1203 Galpern, Wendy M1412 Galpern, Wendy R. M1223 S110
Galt, James M2227 Gamber, Mark M1302 Gamez, Jeffrey D. S509 Gao, Rui M1429, T2416 Gao, Shan M1223 Garden, Gwenn T1905 Garitaonandia, Ibon M1238 Garza, Philip M1303 Gavrilova, Ralitza T2413 Gearing, Marla T2306 Gebhart, Nichole S405 Geffin, Rebeca S706 Gehrking, Jade A. M1411 Gehrking, Tonette L. M1411 Geisbush, Thomas T2431 Geisbush, Tom R. T2443 Geldmacher, David S. T2311 George, Alex J. S421, S422, S426, S427, S431, S433, S434 George, Benjamin P. S301 Georgiou, Michael M1239 Gerardi, Renee T2424 Gerhard, Alex T2307 Ghazi, Rabia M1314 Gherardi, Romain K. T2430 Ghias, Ahson S715 Ghuznavi, Nasreen T1806 Gianatasio, Ryan M. M1302, M1304, M1306, M1307, M1311 Giannini, Alessandra M1303 Gilbert, Paul M1224, M1231 Gilchrist, James M. T2426 Gill, Chandler E. M1214 Gilman, Sid M1412 Giraldo, Elias A. S430 Glaser, Carol S527WIP Glass, David J. T2401 Glazer, Hilary P. S605 Glazman, Sofya M1240 Gluhm, Shea M1224, M1231 Gobinathan, Devathasan M1434 Goebel, Hans H. T2449WIP Goetzl, Edward J. T2308 Gokhale, Sankalp T1804 Goldenberg, James S619 Goldman Gross, Rachel T1901 Goldman, Myla D. M1319WIP Goldsmith, Jeff S407 Goldstein, Felicia C. M1207, M1221 Goldstein, Jody M1224, M1231 Goldstein, Larry B. S413 Gomeni, Roberto M1415, M1426 Gonzalez, Christopher L. M1225 Gonzalez, Rodolfo M1238
Annals of Neurology Vol 74 (suppl 17) 2013
Goodman, Clay S710 Gopalakrishnam, Vidhya T2405 Gordon, Barry T2313 Gorin, Fredric T2112WIP Gorno-Tempini, Maria Luisa T2301 Gossett, James M902 Gottesman, Rebecca F. S408, S416, T2310, T2315 Gourraud, Pierre Antoine S516 Gouse, Brittany M. S422, S433 Goyal, Namita T2401, T2442 Graff-Radford, Jonathan S205, S609, T1704 Graff-Radford, Neill T1903 Graham, Stephen M. T2302, T2317 Grandhi, Ramesh M1301 Granovsky, Yelena T2444 Grant, Igor S715 Graus, Francesc S525WIP, S528WIP Green, Ari S508 Green, Ari J. S526WIP Green, Kari B. T1902 Greenberg, Steven A. T2401, T2402, T2448WIP Greensmith, Linda T2407 Greer, Michelle S520 Gregory, Cascino D. S502 Gregory, Jeremy K. S709 Gregory, Worrell A. S502 Gresa-Arribas, Nuria S525WIP Grishkan, Inna S608 Gross, Rachel G. M1216 Grotta, James C. S423, S432 Grouse, Carrie Katherine S522 Grunwald, Iris M1304 Gu, Weihong T2413 Guilleminault, Christian M1003, M1007 Guinta, Diane M1004 Gumus, Haluk S521 Gunathilagan, Gunaratnam S441 Guo, Jiasong T2446WIP Guo, Ming S505 Guo, Yong S522 Gupta, Ranjan T2409, T2427 Gupta, Suneel M1205, M1219 Guthmann, Anita M1304, M1305, M1306, M1311 Guthrie, Barton M1215 Guthrie, Barton L. M1225 Habs, Maximilian M1420 Hachinski, Vladimir T2303 Hacker, Carl S610
Hacohen, Yael S503 Haith, Adrian S407 Hake, Ann T2304 Hales, Chadwick M. T2306 Hall, Coleen M1213 Hall, Deborah A. T1908WIP Hall, Taryn T1901 Hallett, Mark M1203 Halvorsen, Mark B. M2212 Hamid, Hussein S. M1421 Hamilton, Audra T2446WIP Hammer, Robert E. T1902 Hampton, Thomas T2104 Han, Eugene M1425 Han, Jullet S425 Han, Li-Xin S102 Hanley, Daniel F. S415 Hanna, Michael T2407 Hanna, Phillip A. M1229 Hannoun, Salem M2206 Hansen, Paul A. M1304, M1306, M1307 Hara, Hideo S514 Harbert, Mary J. T1501 Hardison, Rachael T1902 Hardwick, J. Marie M2208 Harmeet, Moti T1902 Harrell, Lindy T2311 Harriott, Andrea M. T1906 Hartman, Adam L. M2208 Hartman, W. Tim M1302 Hartung, Hans-Peter M1319WIP Hassanzadeh, Bahareh S708, M802, M1229 Hauser, Robert M1219, M1412 Hauser, Stephen L. S517 Haussen, Diogo C. M1312, M1317 Havrdova, Eva M1319WIP Hayes, John M. M1418, M1421, M1422, M1423, T1703 He, Fang M1401 He, Jianghua T2407 He, Ming S708, M802 Heaton, Robert K. S715 Heiss, Wolf-Dieter S411, T2303 Helekar, Santosh A. S604 Henderson, James T2421 Hendrix, Suzanne T2302, T2317 Henney III, Herbert R. S619 Henon, Hilde S403 Henry, Maya L. T2301 Henry, Roland G. T2301 Herbelin, Laura T2407 Herbillon, Vania M2206 Herholz, Karl T2307
Herman, Melissa P. S421, S426, S427, S431, S434 Hernandez, Heather M1304 Hernandez, Julia T2313 Herndon, Robert M. S512 Hershey, Linda A. S620 Hessler, Amanda S423 Hillard, Virany H. S442 Hillen, Machteld E. S206, S443 Hillis, Argye E. S416 Himeno, Tatsuhito M1422 Hinder, Lucy M. M1422, M1431 Hinson, Shannon R. S506 Hinz, Rainer T2307 Hirano, Makito S514, M1230, M1404 Ho, Doreen S711 Ho, Doreen T. T2439 Hoche, Franziska S606 Hochstetler, Helen T2304 Hochstetler, Helen M. M1430 Hocker, Sara M2214 Hoerth, Matthew T. M2215 Hoffman, E. Matthew T2414 Hoftberger, Romana S528WIP Hohjoh, Hirohiko T2437 Holland-Bouley, Katherine T2103 Hollenbeck, Albert M1232 Holsten, Scott E. T2422, T2434 Holton, Janice T2407 Hong, Suzi S715 Hong, Yu M1423, M1432 Hoover, Benjamin M1414 Horovitz, H. Robert M1243WIP Hough, Greg S412 Howe, Benjamin M. T2415 Hsieh, Wilson M1432 Hsieh, Yu-Hsiang S415 Hsu, Ann M1205, M1219 Hu, Bo T2446WIP, T2447WIP Huang, Eric T2318 Huang, He M1215, M1225 Huang, Juebin S512 Huang, Peng S405 Huang, Xuemei M1208, M1232 Hur, Junguk M1419, M1422, M1423, M1428 Hurley, Rob S. S617 Hurtig, Howard M1216, T1901 Huson, Les T2444 Ichihara, Gaku S303 Ichikawa, Hiroo T2419 Ihara, Tomomi T2319 Iizuka, Takahiro S528WIP Ilieva, Jorjetta S515 Ilski, Faustine M2206
Imhof, Beat A. T2446WIP Inati, Sara M2226 Ingram, Carissa C. T2434 Isojarvi, Jouko M2203, M2211, M2219, M2220, M2221, M2224 Isono, Chiharu M1230, M1404 Issac, Biju S706 Itti, Emmanuel T2430 Iudicello, Jennifer E. S715 Iwuchukwu, Ifeanyi T1801 Jack, Clifford R. S408, S607 Jackson, Leila W. M1209 Jacobson, Steven M2226 Jadhav, Ashutosh M1301 Jaiswal, Mamta T2421 Janardhan, Vallabh M1302, M1304, M1305, M1306, M1307, M1311, M1313 Jani-Acsadi, Agnes T2435 Janjua, Sophia M1317 Jankovic, Joseph M1219 Jankowitz, Brian M1301 Jara-Prado, Aurelio M2205 Jasmin, Fnu S704 Jayadev, Suman T1905 Jayatillake, Rasika T2313 Jeevan, Dhruve S. S442 Jeffery, Douglas M1319WIP Jeffery, Oliver M2214 Jelicks, Linda A. S705 Jen, Jin T1903 Jensen, Mark A. S518 Jiang, Wenlei M2222 Jicha, Gregory T2316 Jimenez-Capdeville, Maria E. M1234, M1413 Jimi, Takahiro T2419 Jin, Chengshi S508, S526WIP Johansen, Krisztina K. M1227 John, Blessy S. S604 Johnson, Aaron J. S509 Johnson-Greene, Doug M904 Johnston, Anna M1228 Joishi, Suchitra M2201 Jonassaint, Charles T2310 Jones, David T. S609 Jones, Lyell K. S205 Jones, Stephen S101 Joo, Eunyeon M1008 Josephs, Keith A. S607, S609, M1222 Jovin, Tudor M1301 Jozwiak, Sergiusz T2102 Ju, Shulin T2318 Juan, Axel M2216
Abstracts, American Neurological Association
Julian, Laura S508 Julian, Laura J. S526WIP Julian-Baros, Elaine M1223 Jung, Christine J. M1243WIP Jung, James T2409, T2427 Jung, Youngsin S607 Kabat, Brian F. T2414 Kachadoorian, Michaela T1903 Kaji, Ryuji T2420 Kakar, Ristya M. S439 Kalita, Jayantee S716, M1236 Kamal, Haris M1314, M1318 Kanda, Takashi T2420 Kang, Joseph M1008 Kao, Yu-Ting S715 Kaplin, Adam M905 Kaplin, Adam I. S608 Kapogiannis, Dimitrios T2308 Kapoor, Raj M1319WIP Kapoor, Seema S713 Kapur, Jaideep M2201 Kapur, Puneet T2311 Karanjia, Navaz P. T1501 Kasner, Scott E. S435, T1701 Kataria, Natasha T1705 Katherine, Nickels C. S502 Katou, Mari S514 Kattah, Jorge C. S415 Katz, Jonathan S520 Katzin, Lara S520 Kaufmann, Horacio M1412 Kaur, Divpreet T2436 Kayse, Regina S418 Keirsey, Jeremy T1902 Kell, Sherron M1205, M1219 Kelly, Zachary A. M1432 Kemp, Chris J. M1408 Kenmuir, Cynthia M1301 Kennedy, Vanessa E. M2210 Kent, Thomas A. S404, S419 Kerber, Kevin A. S201, S415, T1702, T2429 Kessler, Jill T2313 Khalid, Shahram M1315 Khan, Fawad M2228 Khan, Hiba S439 Khanna, Rahul T1705 Khanna, Sarita M1205 Khatri, Ismail A. S439 Khatri, Pooja S429 Khattak, Jamal F. S439 Khoury, Jane S429 Khoutorova, Larissa S444 Kieslich, Matthias S606 Kijsirichareanchai, Kunut T2005 Killoran, Annie M1223 S112
Kim, Ann Y. M1009 Kim, Gene T2424 Kim, Gyu Sik S618 Kim, Jong Hun S618 Kim, Minjee M1002 Kimberly, W. Taylor S410 Kinkel, Revere P. S516 Kirlin, Kristin A. M2215 Kirmani, Batool F. M2217 Kisanuki, Yaz Y. T1902 Kissela, Brett S429 Kissoon, Narayan R. T1704 Kitago, Tomoko S407 Klaas, James P. S205 Klein, Christopher J. T2413, T2414, T2445, T2449WIP Kleindorfer, Dawn S429 Klepitskaya, Olga M1233 Klopstock, Thomas M1420 Knopman, David S. S408 Koba, Wade R. S705 Kobylecki, Christopher T2307 Kocher, Jean Pierre T2413 Kohane, Issac T1601 Kohrman, Michael T2102 Kolbert, Christopher T1903 Konen, John R. M1408 Kong, Lingling T2403 Kong, Sek Won T2402 Korb, Pearce J. M2227 Korf, Bruce T2102 Kosteva, Adam R. T1802 Kotzbauer, Paul T. M1204 Koval, Erica D. M1407 Kozlowski, Piotr B. M1240 Krakauer, John W. S407 Krans, Amy M1401 Kreitzer, Anatol M1202 Krishnan, Siddharth T1903 Krueger, Darcy T2103 Krumholz, Allan M2222 Kryzer, Thomas J. S511 Kumar, Ravi T2443 Kumar, Surinder S713 Kumar, Vijay M1236 Kung, Nathan S208WIP Kuo, Sophia S. M1304 Kuperman, Rachel T2102 Kuroiwa, Kenji T2110 Kurukumbi, Mohankumar T1807 Kushner, David S. M904 Kusunoki, Susumu S303, S514, M1230, M1404, T2420 Kuwabara, Satoshi T2420 Kuwahara, Motoi S514 Kwong, Winghan J. S203
Annals of Neurology Vol 74 (suppl 17) 2013
Ladner, Travis R. M2210 Laengvejkal, Pavis T2005 LaFrance, Stephanie J. S509 Lafuente-Hidalgo, Miguel S527WIP Lagier-Tourenne, Clotilde M1402 Lah, James T2306 Laiq, Simin S524 Lam, Sandi T1801 Lam, Theresa T2402 Lamb, Jessica S446WIP LaMela, Alexandra T2439 Lancaster, Eric S510 Lancaster, Jack L. M2204 Land, Julia M1207, M1221 Langford, Velma L. T2422 Langheinrich, Tobias C. T2307 Larman, H. Benjamin T2402 Lary, Cynthia T2434 Lassmann, Hans S522 Latorre, Julius G. S440 Latorre, Julius Gene T1805 Laughlin, Ruple S. T1704 Laurent, Agathe M2206 Laurent, Didier T2401 Laurent, Louise C. M1238 Lawrence, Erin S416 Lee, Deborah M2203, M2211, M2219, M2220, M2221, M2224 Lee, Eugene S518 Lee, John S614 Lee, Jun Hong S618 Lee, Lauren S203 Lee, Raven M1207, M1221 Lee, Sophia M1319WIP Lee, Sung W. T1502, T1503 Leehey, Maureen M1233 Lees, Peter S.J. M1209 Leger, Jean-Marc T2423 Leggio, Lorenzo T2426 Leibovitch, Emily M2226 Leigh, Richard S401, T2107 Leite, M. Isabel S503 Lejeune, Stephanie M1206 Lemay, Lori M1305 Lennon, Vanda A. S506, S511, S522 Lentz, Stephen I. M1418, M1421 Leon, Leonardo T2112WIP Lessar, Margaret T2424 Lessig, Stephanie M1412 Leung, Thomas M1304 Leverenz, James T1901 Levey, Allan I. T2306 Levine, Todd S520
Levine, William Lewis, Danielle K. Lewis, Mechelle M. Leypoldt, Frank
M902 S406 M1208 S525WIP, S527WIP Leys, Didier S403 Li, Jia T2443 Li, Jian T2404 Li, Jun T2410, T2446WIP, T2447WIP Li, Ping M1314 Li, Sui M1235 Li, Xiaojin M1217 Li, Yan S438 Li, Ying Ji T2319 Li, Yin-Kai S102 Li, Yuanyuan T2314 Liang, Grace M1205 Liao, Diana A. S603 Liberski, Pawel P. M1405, M1405 Lieber, Eli T1904 Lim, Ming S503 Lin, Iris S203 Linares, Guillermo M1301 Lincoln, Sarah T1903 Lindblad, Chelsea N. M1418 Lindblom, Scott S. T2422, T2434 Lindsell, Christopher S429 Lippa, Carol S602 Lippoldt, Jennifer S620 Lisabeth, Lynda D. S201, T2429 Litchy, William J. T2413 Litvan, Irene M1209 Liu, Anna M1244WIP Liu, Guodong M1208 Liu, Rui M1232 Liu, Shuang S508, S526WIP Liu, Weiqiang S501 Liu, Yan S102, T2314 Liu, Yongping M1429, T2416 Liu, Yu S406 Liu, Zhao T2003 Liu, Zilong M1429, T2416 Liu, Zuolu S602 Lizarraga, Karlo J. S702 Llinas, Rafael H. S416 Lloyd, Thomas E. T2448WIP Loavenbruck, Adam J. M1411, T2445 Locke, Dona E. M2215 Loeb, Jeffrey A. M2202 Longo, Frank M. S425 Longoria, Ruth T2429 Lotta, Jr., Louis T. T2001
Low, Phillip M1412 Low, Phillip A. M1411, T2445 Lowder, Lindsey S701 Lowe, Mark J. S101 Lowe, Val S607 Luca, Corneliu M1239 Lucas, Nicole M. T2422, T2434 Lucchinetti, Claudia F. S506, S522 Luke, Sothear M. S304 Lulu, Sabeen T. S516 Lunn, J. Simon M1422 Lyden, Patrick S446WIP Lyerly, Michael J. S423, S432 Lyons, Jennifer L. S414 Ma, Li T1903 Ma, Marek T2404 Maas, Matthew B. T1802 Macaya, Alfons S527WIP Machado, Andre S101 Machado, Pedro T2407 Machulda, Mary M. S607 Maghzi, Amir-Hadi S508, S526WIP Magy, Laurent T2425 Mahboob, Nadia S439 Mahler, Andreas M1205 Mahoney, Joseph M. M1208 Malaga, Ignacio S527WIP Malenka, Robert C. S425 Malhotra, Konark S513 Malik, Sabeena I. S439 Malikova, Irina S516 Malkani, Roneil T2309 Malphrus, Kimberly T1903 Mammen, Andrew L. T2448WIP Mandava, Pitchaiah S419 Mandelli, Maria Luisa T2301 Mandrekar, Jay M1411, M1412 Mann, David D. T2307 Mantokoudis, Georgios S415 Maquat, Lynne T2318 Marcano, Daniela C. S404 Marcus, Robin T2408 Marie-Pierre, Chaunu S613 Marin, Benoit T2423 Marks, Stephen J. S442 Marquine, Maria J. S715 Marsh, Elisabeth B. S416 Marson, Daniel C. T2311 Martenyi, Ferenc T2305 Marti, Itxaso S527WIP Martinez, Ricardo S706 Martinez-Juarez, Iris M2205 Martino Casado, Maria E. T2307
Martin-Schild, Sheryl S421, S422, S426, S427, S431, S433, S434 Marvel, Cherie L. S603 Mateen, Farrah J. S414 Mathis, Stephane T2425 Matijosaitis, Vaidas T1504 Matson, Wayne M1223 Matsumoto, Joseph Y. M1411 Mauermann, Michelle L. T2445 Mavroudis, Ioannis S437 Maygers, Joyce S416 Mazzoni, Pietro S407 McCabe, Andrew L. S305 McCarthy, Micheline S706 McCulloch, Charles S508 McCulloch, Charles E. S526WIP McCutchan, J. Allen S715 McDermott, Michael P. M1223 McDonagh, David T1804 McDonald, Anthony S614 McDonald, Jaime S516 McDonald, Kim R. S512 McDonald, William M1221 McGaughey, Karen M1003, M1007 McGee Koch, Lori L. T2309 McGrath, Michael T2405 McGuire, Mary F. M1417 McHenry, Monica M1433 McKee, Elizabeth M1217 Mckeon, Andrew S502, S506, S511 McLean, Lisa L. M1422 McManus, Andrea M1313 Mcmurtray, Aaron M1314, M1318 McVey, April L. T2407 Medina, Marco T. M2205 Medina-Mier, Veronica M1413 Meek, Brandon M1306 Mehta, Bijal M1318 Mehta, Bijal K. M1314 Mellion, Michelle L. T2426 Mendoza, Michael S440 Meng, Xiangyi T2312 Menon, Uma M2228 Menzin, Joseph S203 Mer, Georges T2449WIP Mervak, Colin M. M1421 Mesa, Diego T1501 Meschia, James F. S304, S405, T1906 Messier, Jessica S423 Mesulam, Marsel S617 Metcalf, Nick V. S610 Meterville, Jake M1243WIP
Abstracts, American Neurological Association
Meurer, William J. S201 Midha, Sumit T2413 Mikol, Daniel M1319WIP Miller, Aaron M1319WIP Miller, Adrian T2407 Miller, Bruce L. T2301 Miller, Michael L. T2302, T2317 Miller, Robert G. T2405 Miller, Timothy M. M1407 Milone, Margherita S522 Minagar, Alireza S519 Mishra, Shri T2433 Mishra, Shri K. T2108 Misra, Usha K. S716, M1236 Mitsui, Yoshiyuki S303, T2420 Mobley, William M1425 Mobley, William C. M1403 Mogan, Sathis S441 Molinari, Anna L. M1214, M1241 Moller, David S515 Monlezun, Dominique J. S421, S422, S426, S427, S431, S433, S434 Montine, Thomas T1901 Moomaw, Charles S429 Moore, Ryan M1203 Moore, Samuel A. S205 Morgan, Clinton D. M2210 Morgenstern, Lewis B. S201, T1803, T2429 Morita, Mitsuya T2110 Morparia, Neha P. S205 Morrison, Leslie T2432 Mosley, Thomas H. S408, T2310 Mourany, Lyla S611 Mowry, Ellen S526WIP Mowry, Ellen M. S504, S516 Mozaffar, Tahseen S520, T2409, T2427, T2442 Mudambi, Lakshmi T1806 Mukerji, Shibani S. S707 Mulivor, Aaron T2443 Mullen, Michael T. S432 Multami, Sumeet S714 Munch, Alexandra E. M1421 Mungall, Diana M2217 Munoz, David G. S524 Munsell, Michael S203 Munshi, Nehal S421, S426, S427, S434 Murphy, Michael S438 Murray, Joseph A. S511 Murray, Mark M. M1304, M1306 Murray, Melissa E. M1226 S114
Murthy, Santosh B. Musset, Lucile Mustafa, Ghulam
M1316 T2423 M1314, M1318 Myers, Iliza T2410 Myers, John M1306 Myers, John H. M1302 Myers, Laura J. S402 Nagae, Lidia M. S435 Nahab, Fatta B. M1239 Naidech, Andrew M. T1802 Nakae, Aya T2444 Nakamura, Yusaku S514, M1230, M1404 Nascimento, Osvaldo T2444 Nathalie, Ehrle S613 Navab, Anahita Dona S420 Navab, Mohammad S412, S420 Navas-Reyes, Sandra S505 Nayyar, Sonia S440 Nazareno, Remedios T2402 Nazir, Rashid S439 Neary, David T2307 Nelson, Alexandra B. M1202 Nelson, Patrick T2421 Nelson, Peter T. T2316 Nemeth, Joanne T2434 Nespeca, Mark T1501 Neumar, Robert T2404 Neuwelt, Alexander M1233 Neuwelt, Edward A. T2111 Newman-Toker, David E. S415 Nguyen, Tam M1233 Nguyen, Thuy T1903 Nguyen, Thuy-Vi S425 Nichols, Mindy S. T2422, T2434 Nicholson, Andrew S409 Nichter, Charles S527WIP Nicolas, Guillaume T2423 Nicoll, Diane M1224 Niquet, Jerome M2209 Noble, James M. M902 Nochlin, David S708 Noe, Katherine H. M2215 Nogueira, Raul G. M1317 Nowacek, Dustin G. S202 NP001 Phase II Study Group T2405 Nugent, Kenneth T2005 Nye, Jonathon M2227 Obenaus, Andre S444 Oberg, Traci M1306 O’Brien, Phillipe D. M1422, M1423 Ochoa, Adriana M2205 O’Conell, Martin M1219
Annals of Neurology Vol 74 (suppl 17) 2013
O’Connor, Kevin S503 Oh, SangSu M1422, M1423, T1703 Oh, Seok Yoon M1401 Ohayon, Maurice M1003, M1007 Ohayon, Maurice M. M1005, M1006 Oka, Nobuyuki S303 Olsen, Abby L. S510 Omron, Rodney S415 Ooi, Winnie S711 Oplinger, Heather L. T2422, T2434 Ostrowska, Alina M1238 Ostrowsky-Coste, Karine M2206 Paccico, Thomas J. T2422, T2434 Pace, Rob T1702 Pacut, Crystal M1422, M1431 Pahwa, Rajesh M1219 Pajeswki, Nicholas M. T1502 Palace, Jacqueline S503 Palop, Jorge J. T2320 Panagiotakaki, Eleni M2206 Pankratz, V. Shane T1903 Paolicchi, Juliann M2219 Papa, Stella M. M1201 Parad, Rebecca T2431 Pardo, Carlos A. S515 Parent, Jack M. S406 Park, Yikyung M1232 Parker, Collete C. S512 Parres, Christopher S711 Parsons, Bruce M1308 Pasinetti, Giulio M. M1409, M1410, M1427 Pasnoor, Mamatha T2407 Pasternak, Amy T2431 Pasupuleti, Nagarekha T2112WIP Patel, Shnehal M1239 Paulson, Henry L. M1401 Pearson, James M1244WIP Pedersen, Nigel P. M1001 Pedouim, Farzin B. T2442 Pejovio, Vojislav T2302, T2317 Pelletier, Daniel S504, S508, S526WIP Pelletier, Jean S516 Peltier, Amanda C. T2410, T2428 Pennathur, Subramaniam M1431 Pereira Bruno, Fernando S704, S705 Perez, Roberto S706 Periera, Benedict S446WIP Perlman, Susan M1412
Perlmutter, Joel S.
S208WIP, M1204 Peters, Owen M. M1243WIP Petersen, Ronald T1903 Petkus, Vytautas T1504 Petrikonis, Kestutis T1504 Petsko, Greg T2318 Pettigrew, Luther C. S417 Peyard, Severine T2103 Pham, Ly S410 Piazza, Stephen J. M1208 Pillai, Jagan S611 Pinkus, Jack L. T2402 Pioro, Erik P. T2441 Pirko, Istvan S509 Pittock, Sean J. S506, S511, S522 Pletnikov, Mikhail V. S608 Plow, Ela B. S101 Plunkett, Cynthia T2421 Pluta, Tim T1602 Podratz, Jewel L. T2417 Pojman, Nicholas S601 Polderman, Kees M1301 Polley, Michelle T2403 Polli, James M2222 Pomerantz, Daniel J. M2210 Pomper, Martin G. S608 Pool, Angela S701 Pop-Busui, Rodica M1419, T2421 Porto, Luciana S606 Pouget, Jean T2423 Pourcher, Emmanuelle M1219 Poustovoitov, Maxim M1238 Praestgaard, Jens T2401 Prasad, Sashank S707 Pritchett, Yili M1210 Probasco, John C. S301 Psaroulis, Demetrios S437 Pula, John H. S415 Pulido, Angel S302 Punia, Vineet S206, S443 Qian, Yaping T2404 Qu, Haiyan T2318 Qu, Wang S424 Quach, Lisa N. S425 Quicksall, Zachary T1903 Quinn, Joseph T1901 Rabinowicz, Adrian L. S619 Rabinstein, Alejandro A. M2214 Racette, Brad A. S208WIP Ragauskas, Arminas T1504 Rahgozar, Kusha S507 Rahn, Kristen M905 Rahn, Kristen A. S608 Rai, Shesh N. M1209
Rais, Rana S608 Rajagopalan, Venkateswaran S101 Rajasekaran, Karthik M2201 Rajput, Padmesh S446WIP Ramakrishnan, Aravind T1905 Ramanathan, Ramanth Santosh S513 Ramanathan, Shruthikaa S441 Rambow, Jennifer S606 Ramchandren, Sindhu T2438 Ramos-Estebanez, Ciro S702 Ramsay, Eugene M2228 Ramsey, Lenny S610 Raspall-Chaure, Miquel S527WIP Rastenyte, Daiva T1504 Rathore, Bhawana M2227 Ravichandran, Vina M2227 Ravits, John M1402 Rawal, Pawan V. M1215 Reaven, Nancy M1003, M1007 Reding, Michael J. S619 Redmond, D. Eugene M1238 Reid, Kathryn J. M1008, T2309 Reindl, Markus S503 Renan-Perez, Jose M1234 Renfroe, J. Ben M2224 Rengachary, Jennifer S610 Resnick, Susan M. T2308 Revirajan, Nisha S508, S526WIP Reyes-Mantilla, Maria I. S515 Richardson, Anna M. T2307 Rick, Jacqueline M1216 Riehm, Alison M905 Riggs, Patricia K. S715 Rigo, Frank M1402, M1414 Rilee, Jessica J. S603 Ritt, Elissa S520 Rizzo, Matthew S612, S614 Robb, Jared M. T2414 Robell, Nicholas J. M1421 Robell, Nick J. M1423 Robert, Gross E. M2227 Robertson, David M1412 Robins, Scott M1306, M1307, M1311, M1313 Robinson, Catrina M1422 Robinson, Maisha T. S304 Roby, David S714 Rodgers, Ann T2429 Rodriguez-Leyva, Ildefonso M1234, M1413 Rodriguez-Porcelli, Federico S418 Roger, Elaine S516 Rojas, Camilo S608 Rolland, Alex M1307 Ronan, Lara J. T2104
Roney, Meghan E. T1803 Roper, Debbie M1305, M1306, M1307, M1311, M1313 Rosenberg, Neil F. T1802 Rosenberg, Sheila S. T1501 Rosenfeld, Myrna R. S525WIP, S528WIP Rosenfeld, William M2211 Rosenfield, David B. S604 Ross, Christopher A. M1223 Ross, Owen A. T1906 Rossi, Costanza S403 Rost, Natalia S413 Roth, Thomas M1004 Rothstein, Jeffrey D. M1414, M1414 Rouaix, Nathalie M1206 Roubenoff, Ronenn T2401 Rouleau, Guy A. M1010 Rouse, Rita M. T2434 Roy, Gulmohor T2432 Royal III, Walter S505 Rubens, Robert M1205 Rubin, Mark N. S436, M2214 Ruby, Sandra K. T2412 Rumbaugh, Jeffrey A. S701 Ruoff, Chad M1003, M1007 Russell, James A. T2439 Russell, James W. M1424, T2406, T2412 Russo, Priscilla C. T2434 Rutkove, Seward T2431 Rutkove, Seward B. T2443 Ryvlin, Philippe M2206 Saad, John M1306 Saatman, Kathryn T2404 Saber Tehrani, Ali S. S415 Sacco, Ralph L. S605 Saigal, Sanjeev R. S713 Saignavongs, Mani M2206 Saigoh, Kazumasa M1404 Saiz, Albert S528WIP Sakaie, Ken S101 Sakamoto, Hikaru S514, M1230, M1404 Salajegheh, Mohammad T2401, T2402 Sales, Eleanor M2216 Salim, Sumaiya Z. M1229 Samardzic, Tamara M1211 Samsa, Gregory S413 Samuel, Errol L.G. S404 Samukawa, Makoto S303, S514 Sandhu, Gauravjot T1705 Sandroni, Paola M1411, T2445 Sandulescu, Mihai-Cosmin S714
Abstracts, American Neurological Association
Sanjak, Mohammed S.
T2422, T2434 Santagata, Sandro S707 Santos, Cesar M1217 Santos, Polan M2208 Santoyo, Martha M1413 Santoyo, Martha E. M1234 Saper, Clifford B. M1001, M1211 Saperstein, David S520 Sapp, Peter M1243WIP Sappey Marinier, Dominique M2206 Sarkar, Parthar S. M1429 Sarma, Anand K. S419 Sattler, Rita M1414 Sauld, John T2402 Savitz, Sean I. S423, S432 Saykin, Andrew J. M1430 Scammell, Thomas E. M1002 Schall, Mark S614 Scheff, Steven T2316 Scherer, Steven S. S510 Schiess, Mya C. M1218, M1417, M1433 Schmelzer, James D. M1411 Schmidley, James W. S428 Schmidt, Cathleen T2307 Schmitt, Frederick T2316 Schneck, Michael J. S418 Schneider, Andrea L.C. S408, T2310 Schoch, Kathleen T2404 Schootman, Mario S208WIP Schor, Nina F. T2001 Schreiber, John M2226 Schretlen, David J. T2313 Schubert, Manfred M1424 Schwamm, Lee H. S414 Schwarz, Adam J. T2305 Schwebel, David C. M1228 Scott, Thomas S513 Scullen, Tyler S421, S426, S427, S434 Scullin, Michael K. M1207, M1221 Seales-Bailey, Chloe S438 Sean, Pittock J. S502 Selim, Magdy S203 Sellebjerg, Finn M1319WIP Selvin, Elizabeth S408, T2310 Selwa, James T2435 Semechkin, Ruslan A. M1238 Senjem, Matthew L. S607 Serge, Bakchine S613 Seth, Blackshaw M1414 Seyfried, Nicholas T. T2306 S116
Sfakianaki, Efrosyni M1239 Shacka, John M1212 Shah, Arpeet T. S425 Shah, Ruchir S712 Shah, Shreyansh S419, M1316 Shah, Syed O. T1806 Shah, Umang S712 Shaltout, Hossam A. T1502 Shams, Tanzid M902 Shaner, Carey M1407 Sharma, Sameer T1805 Sharrett, A. Richey S408, T2310 Sheikh, Kazim A. S501 Shenker, Joel I. S616 Sheremata, William A. S519 Sherr, Elliott S601 Sherwood, Karna S708 Sheth, Kevin N. S410 Shetty, Bhagya L.D. M1201 Shikani, Henry J. S704 Shin, Cheolsu N. S502 Shin, Hae-won T1602 Shinohara, Russell T. S414 Shofer, Frances T2404 Shriber, Elizabeth T2431 Shuaib, Umar A. S439 Shulman, Gordon L. S610 Shweta, Shweta S713 Shy, Michael T2438 Sico, Jason J. S402 Siddiqui, Mustafa S. M1217 Siegler, James E. S421, S422, S426, S427, S431, S433, S434 Siemers, Eric R. T2305 Sikorska, Beata M1405, M1405 Silbermann, Elizabeth T2426 Simons VIP Investigators S601 Simpson, David M. S619 Simpson, Jennifer R. S302 Sims, John R. T2305 Singer, Wolfgang M1411, M1412, T2445 Singh, Arun M1201 Singh, Niranjan T1705 Singh, Sujal T2412 Singhal, Aneesh B. S410 Singleton, J. Robinson M1421, T2408, T2424 Sinha, Mridu T1501 Sit, Siu Po M1304 Sivakumar, Kumaraswamy T2401 Skolarus, Lesli T1702 Sletten, David M. M1411 Slevin, John T. M1210, M1213 Slone, Sunny R. M1212 Slusher, Barbara S. S608
Annals of Neurology Vol 74 (suppl 17) 2013
Small, Juan Smelser, Luke Smith, A. Gordon
T2439 M1215 M1421, T2408, T2424 Smith, Andrea L. M1428 Smith, Benn T2444 Smith, Bryan R. S414 Smith, Charles D. T2316 Smith, David I. T2413 Smith, Glenn R. M1429, T2416 Smith, Keri C. M1417 Smith, Melinda A. S201 Smith, Nicole P. T2422, T2434 Snowden, Julie T2307 Snyder, Abraham Z. S610 Snyder, Evan Y. M1238 Sobesky, Jan S411 Sohrab, Sayyed A. T2435 Sole, Montse S425 Soler-Llavinia, Gilberto J. S425 Sollinger, Ann B. M1207, M1221 Somogyi, Monique T2312 Song, Julia J. S501 Sonoo, Masahiro T2420 Soper, Steven S438 Sopher, Bryce T1905 Soriano, Alexandra T2436 Sortwell, Caryl E. M1408 Spain, Rebecca S508, S526WIP Sparagana, Steven T2102 Spray, David C. S704 Srakar, Parthar S. T2416 Srinivasan, Jayashri S711, T2439 Sriram, Subramaniam S523 St. Sauver, Jennifer T2414 Staff, Nathan P. T2414, T2415 Standaert, David G. M1210, M1228 Stathis, Marigo S608 Statland, Jeffrey T2407 Steck, Andreas T2423 Steece-Collier, Kathy M1408 Steen, Hanno T2402 Stefoski, Dusan S522 Steinman, Lawrence S425 Sterling, Nicholas W. M1208 Stern, Barney J. S410 Stern, Yaakov S605 Stewart, Kenneth M903 Stiegelmeyer, Elizabeth M1430 Stocchi, Fabrizio M1205 Story, John S. T2422, T2434 Stover, N. M1242 Strand, Edythe S609 Strand, Edythe A. S607 Strupp, Michael M1420
Suarez, Gustavo A. S619 Suarez, Jose I. M1316 Sucharew, Heidi S429 Suchomelova, Lucie M2209 Sugamata, Masao T2319 Sugamata, Miho T2319 Sullivan, Jane T1905 Sullivan, Kelli A. M1419 Sumner, Charlotte T2403 Sun, Jia T2305 Sun, Johnny Chung-Huan M1317 Sun, Shuying M1402 Sung, Kijung M1403 Sussman, Matthew S203 Sutamtewagul, Grerk T2005 Suter, Ueli T2446WIP Suzuki, Seiko S514 Swanson, Kenneth D. T2109 Swartz, Jonathon S420 Sweeney, Elizabeth M. S414 Sweeney, M. M1242 Swoboda, Kathryn T2403 Tabata, Emi S514 Tahiri, Khadija M1206 Takada, Kazuo S514, T2420 Takahashi, Masaki T2437 Takeda, Ken T2319 Tanaka, Miyabi M2205 Tandon, Nitin M2204 Tang-Wai, David F. S524 Tanowitz, Herbert B. S704 Taub, Dennis T2308 Tay, Jia M1407 Tegeler, Catherine L. T1502 Tegeler, Charles H. T1502, T1503, T1503 Temesgen, Frehiwot T1807 Terrence, Lagerlund D. S502 Tetsuka, Syuichi T2110 Thakore, Nimish J. T2441 Thakur, Kiran T. S414 Thangarajah, Nilusha T2430 Theessen, Heike M1309 Theodore, William H. M2226 Thiel, Alexander T2303 Thieu, Tony S601 Thomas, Ajith J. M1312 Thomas, Christine S711 Thompson, David M. S620 Ticho, Barry M1319WIP Ting, Li S424 Ting, Tricia T. M2222 Tippin, Jon S612, S614 Titulaer, Maarten S525WIP Titulaer, Maarten J. S528WIP Toby, Ferguson T2404
Tocco, Michael T2302, T2317 Todd, Peter K. M1401 Todorova-Koteva, Kristina T1908WIP Tohidi, Vahid S708, M802, M1229 Tokgoz, Osman Serhat S521 Tolbert, Dwain M2213, M2216 Toledano, Michel S502 Tolod-Kemp, Emeline M1408 Tominaga, Kaoru T2110 Topel, Jordan S522 Topjian, Alexis A. T2002 Torres, Bertha M.B. M1413 Torress, Amanda M1303 Tour, James M. S404 Tran, Helene M1243WIP Traynor, Bryan M1414 Trendelenburg, Anne-Ulrike T2401 Trifilieff, Estelle T2401 Trikamji, Bhavesh T2108, T2433 Trojanowski, John T1901 Trzepacz, Paula M1430, T2304 Tsai, Ah-Lim S404 Tseng, Brian S. T2401 Tsuboi, Yoshio S514 Tsugawa, Jun S514 Tudor, Cindy T2103 Turchan, Maxim M1214, M1241 Ubel, Peter A. T1803 Ueda, Masami S303 Ueno, Shuichi M1230, M1404 Umbach, Daivd M1232 Unser, Cody M905 Uppal, Gulshan T1705 Valdivia, David T2403 Valenzuela, Anthony T2112WIP Vallat, Jean-Michel T2423, T2425 Valls-Sole, Josep T2444 Van Deerlin, Vivianna T1901 Van Eldik, Linda T2316 Van Liew, Charles M1231 Van Meerbeke, James T2403 van Steenburgh, J. Jason T2313 Vanda, Lennon A. S502 VanderHorst, Veronique M1211 Vannorsdall, Tracy D. T2313 Vardy, Emma R. T2307 Varvaris, Mark T2313 Vassar, Stefanie S204 Vaughan, Leslie S520 Vazirian, Samra S412, S420 Vedanarayanan, Vettaikorumakan V. S512 Venkatasubba Rao,
Chethan P. M1316 Venkatesan, Arun S301 Verhagen Metman, L. M1242 Vernino, Steven M1412 Verret, Laure T2320 Vial, Christophe T2423 Viala, Karine T2423 Vicente-Rasoamalala, Monica S527WIP Vickrey, Barbara G. S204, T1904 Vidailhet, Marie M1206 Vidensky, Svetlana M1414 Vijayappa, Madhu B. M1304, M1305 Villoslada, Pablo S516 Vincent, Angela S503 Vinuela, Fernando M1303 Visyak, Nicole T2431 Vivekanandan-Giri, Anuradha M1431 Vogel, P. T2449WIP von Budingen, H.-Christian S517 Voon, Valerie M1203 Voss, Joel L. T1802 Votaw, John S409 Vytopil, Michal M1235, T2439 Wagenman, Katie T2002 Wagner, Erin S438 Wakayama, Yoshihiro T2419 Walgren, Kristy L. T2422, T2434 Walker, Brett M1430 Walker, Esteban S611 Walker, Harrison M1215 Walker, Harrison C. M1225 Walker, Stephen J. M1217 Walsh, Maura T1908WIP Walton-Wetzel, Jenny T1904 Wambua, Gerald M1238 Wang, Arthur T1806 Wang, Charles M1217 Wang, Jun M1427 Wang, Leiming T2446WIP Wang, Shufang M1430, T2304 Wang, Xiao-Yu S208WIP Wang, Yunxia T2407 Ward, Amber L. T2422, T2434 Ward, Eric S423 Waro, Bjorg J. M1227 Wasterlain, Claude G. M2209 Watanabe, Fumihiro T1902 Waterman, Marian T2427 Waters, Patrick S503 Watkins, Crystal C. S608 Watson, Christa T2301
Abstracts, American Neurological Association
Waubant, Emmanuelle S504, S508, S516, S526WIP Webb, Tyler S620 Wechsler, Lawrence M1301 Weiner, Howard T1601 Weintraub, Daniel T1901 Weiss, Louis M. S704 Wellik, Kay E. S436 Wellnitz, Clinton V. T2316 Wenner, Andrea M2217 Whitehead, Shawn T2303 Whithear, Jessica S. M1201 Whitley, Mark M1305, M1306, M1311 Whitwell, Jennifer L. S607, M1222 Widnell, Katherine L. M1210, M1213 Wight, Jenny M2205 Wijdicks, Eelco F.M. M2214 Wijemanne, Subhashie M1235 Wilder, Sarah T2431 Willey, Josh Z. S414 Williams, Della C. S428 Williams, Linda S. S402 Willis, Allison W. S208WIP Windebank, Anthony J. T2417 Wingo, Thomas S. T1907 Winterfield, Jeffrey S418 Wisdom, Peggy M903 Witkowska, Ewa H. S517 Witte, Michael M1430 Witte, Michael M. T2304 Wolf, Ronald L. S435 Wolfe, Gil S520 Wolff, Catherine S423, S432 Wong, Eric T. T2105, T2109 Woo, Daniel S429 Woodhall, Mark S503
Wood-Siverio, Cathy M1207, M1221, T1901 Worden, Kurtresha T2320 Worley, Audrey M1211 Worrell, Gregory M2214 Wright, Clinton B. S605 Wright, Erik S507 Wright, Kathryn A. T2422, T2434 Wszolek, Zbigniew K. M1226 Wu, Chengbiao M1403, M1425 Wu, Fang S409 Wu, Greg M1407 Wu, Jiawen T2446WIP Wu, Jim T2431 Wu, Joyce Y. T2102 Wu, Ona S410 Wu, Ping M1429 Wu, Tzu-Ching S423, S432 Wu, Yanhong T2413, T2449WIP Wu, Yuhui S701 Xavier, Andrew M1315 Xia, Zongqi T1601 Xiao, Changrui M1244WIP Yacoubian, Talene A. M1212 Yacubian, Elza M. M2205 Yamada, Tatsuo S514 Yamamoto, Masayuki T2319 Yan, Qing T2447WIP Yanik, Brandon M. M1432 Yanowitch, Rachel S518 Yarnitsky, David T2444 Yavagal, Dileep R.
M1303, M1312, M1317 Yearout, Dora T1901 Yegiaian, Sharon T2433 Yepes, Manuel S409 Yi, Hong T2306 Yim, Soo Hwan S618 Yoo, Albert S410
Annals of Neurology Vol 74 (suppl 17) 2013
Yoritomo, Nadine M1223 Yoshinaga, Yuko M1243WIP Younger, David S. T2440 Younkin, Curtis T1903 Younkin, Steven T1903 Youssof, Sarah T2432 Yu, Hua S438 Yu, Peng T2304, T2305 Yung, Raymond M1428 Zabetian, Cyrus T1901 Zaghloul, Kareem M2226 Zahuranec, Darin B. S201, T1803 Zaidman, Craig T2431 Zaitlen, Noah T1907 Zakelis, Rolandas T1504 Zamvil, Scott S. S504 Zanders, Lavezza M1207, M1221 Zaro Weber, Olivier S411 Zee, David S. S415 Zee, Phyllis C. M1008, T2309 Zhang, Fangling S523 Zhang, Gang S501 Zhang, Helen S406 Zhang, Peter M1407 Zhang, Pingwu M1414 Zhang, Quan S435, T1701 Zhang, Wuyan M1210 Zhang, Yang T2446WIP Zhao, Lifu S446WIP Zhao, Ping S619 Zhao, Wei M1409 Zhao, Xiaobei M1425 Zhou, Chengwen M2229WIP Zilliox, Lindsay A. T2412 Zinn, Kristina L. S610 Zou, Fanggeng T1903 Zubair, Abba C. S405 Zweifler, Richard M. S619
ABSTRACT SUBJECT INDEX
A Acute Cerebral Ischemia S201, S424, S432, S433, S436, S440, S618, M1301, M1303, M1309, M1314, M1318 Acute Ischemic Stroke S401, S402, S409, S410, S411, S414, S415, S416, S419, S421, S422, S423, S426, S429, S430, S431, S434, S439, S440, S441, S443, S446WIP, S609, S615, S619, M1301, M1304, M1306, M1307, M1309, M1310, M1311, M1312, M1313, M1317, T1906 Acute Neuropathies T1801, T2414, T2420, T2433, T2436, T2439 Adenoviral Vectors M1002, M1211 Alpha Synuclein Toxicity M1408 Alzheimer’s Disease (AD) S437, S611, S620, M1403, M1409, M1413, M1427, M1430, T1903, T1907, T2302, T2304, T2305, T2306, T2307, T2308, T2311, T2312, T2316, T2317, T2320 Alzheimer’s Disease Mutants T1905, T1907 Amyotrophic Lateral Sclerosis (ALS) S202, M1243WIP, M1401, M1402, M1404, M1407, M1414, M1415, M1426, M1428, T2318, T2405, T2415, T2422, T2427, T2428, T2434, T2441 Antibodies S502, S506, S510, S511, S514, S520, S522, S525WIP, S527WIP, S528WIP, M1235, M2215, T2110, T2420, T2423, T2442 Apolipoprotein E (APOE) S420, S706 Apoptotic Cell Death S417, M1429, T2319, T2416 Astrocytes S506, M2226, T2319 Atherosclerosis S412, S420, S715 Autoimmune Demyelination S503, S504, S506, S514, S515, S518, S520, S521, S522, S526WIP, S528WIP, T1801, T2420, T2433, T2440, T2447WIP
M2215, T1602, T2105, T2309, T2310, T2312, T2313, T2315, T2320, T2430 Cognitive Outcomes S413, S602, S606, S610, S715, M903, M904, M906, M1430, T2308, T2309, T2311, T2313, T2314 Consciousness M906, M1001 Cortical Dysplasia (CD) M2226 Cytokines S413, S417, S505, S523, S701, S704, M1238, M1417, T2308 Cytotoxic T Cells M1417 Cytotoxicity S412, S420, M1429, T2112WIP
D Deep Brain Stimulation S208WIP, M1214, M1215, M1218, M1225, M1227, M1233, M1433 Delirium T2105 Dementia S605, S607, S611, S617, S620, S709, M1209, M1234, T1903, T1907, T2301, T2303, T2309, T2310, T2313, T2314 Demyelination S509, S521, S523, S526WIP, T1806, T2409, T2423, T2433, T2446WIP, T2447WIP Diabetic Neuropathy M1308, M1403, M1418, M1419, M1421, M1422, M1423, M1431, M1432, T1703, T2406, T2408, T2410, T2412, T2414, T2421, T2424, T2429, T2444 Drosophila M1401, T2448WIP Duchenne Muscular Dystrophy (DMD) T2431
Brain Imaging S101, S102, S408, S410, S411, S413, S435, S439, S509, S526WIP, S604, S610, S617, S704, S708, S712, M1203, M1239, M1301, M1303, M1309, M1310, M1318, M1433, M2204, M2217, M2227, T1806, T2005, T2104, T2107, T2108, T2109, T2111, T2301, T2304, T2305, T2316, T2430 Brain Ischemia S417, S424, S425, S428, S430, S440, S446WIP, S605, S615, M1312, M1318 Brain Mapping S101, S617, M2204 Brain Metabolism S705, M1010, M1424, M2208
S204, S206, S502, S620, M2201, M2202, M2204, M2205, M2206, M2209, M2210, M2212, M2213, M2214, M2215, M2216, M2218, M2219, M2220, M2221, M2222, M2224, M2227, M2228, T1602, T2003 Epilepsy Model M2208, M2222 Epileptic Seizures M2201, M2203, M2208, M2209, M2210, M2211, M2213, M2216, M2217, M2219, M2220, M2221, M2222, M2224, M2228, T1602, T1804, T2002, T2003, T2108 Epileptogenesis M2205, M2210, M2226, M2229WIP, T2003 Experimental Autoimmune Encephalomyelitis (EAE) S507
FDG PET fMRI
M1416, T2318, T2448WIP, T2449WIP Cerebrospinal Fluid (CSF) S515, S517, S701, S713, M1218, T1504, T2304, T2308 Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) S520, T2105, T2414, T2423, T2447WIP CJD S709 Cognitive and Neurobehavioral Status Examination (CNS) S602, S609, S613, S615, S618, T2309, T2311 Cognitive Dysfunction S208WIP, S403, S408, S424, S425, S511, S601, S602, S603, S605, S606, S607, S608, S611, S613, S615, S616, S620, S704, S705, S715, M902, M906, M1224, M1231, M1424,
Epilepsy M2203, M2211, M2217,
S705, M1222, M2227 S101, S102, S603, S604, S610, S617, M1203, M1218, T1701 Frontotemporal Dementia (FTD) S613, M1243WIP, M1401, M1402, T2307, T2318
G Gene Expression S438, S706, M1217, M1428, M2202, T1902, T1903, T2403, T2417, T2419, T2440, T2449WIP Gene Regulation M1428 Gene Therapy M1238, M1402, T2437
Abstracts, American Neurological Association
Genetic Mutations M1010, M1202, M1243WIP, M1402, M1403, M2205, M2229WIP, T1901, T1902, T1904, T1906, T1908WIP, T2102, T2103, T2318, T2413, T2425, T2436, T2438, T2445, T2446WIP, T2447WIP, T2449WIP Glioblastoma S519, T2107, T2109, T2111, T2112WIP Glioblastoma Multiforme T2104, T2107, T2112WIP Gliomas S519, T2102, T2103, T2108, T2111, T2112WIP
H Headache S418, M903, M1220, T1504, T1702, T1705 HIV S414, S701, S706, S715 Huntington’s Disease M1202, M1223, M1224, M1231, M1401, M1425 Hypoxic-Ischemic (HI) Injury M1301, T1805
N Neurodegenerative Diseases S437, S444, S506, S605, S606, M1207, M1209, M1210, M1213, M1218, M1221, M1230, M1234, M1236, M1239, M1242, M1405, M1411, M1412, M1413, M1414, M1416, M1417, M1418, M1425, M1434, M2217, T1902, T1903, T1904, T1905, T1907, T2303, T2307, T2316, T2319, T2403, T2407, T2413, T2422, T2434, T2440, T2442, T2445, T2448WIP, T2449WIP Neurogenesis S405, S406, S424, S706, T2406, T2446WIP Neuromyelitis Optica (NMO) S503, S512, S513, S522, S528WIP Neuronal Acetylcholine Receptor S425 Neuroprotection S405, S409, S420, S444, S446WIP, S507, S701, M905, M1238, M1314, M1408, M1410, M1412, M1427, T2404, T2406, T2417 Neurotrophin M1403, T2001, T2419 Non-Epileptic Seizures S619
I Interferon Treatments T2108 Intracerebral Haemorrhage (ICH) S403, S405, S414, S416, S442, M1307, T1802, T1803 Ischemia S404, S411, S430, S619, M1312, M1315
L L-Dopa Therapy
M1201, M1203, M1206, M1210, M1213, M1227, M1242 Levetiracetam S616, T1804 Levodopa M1201, M1205, M1210, M1213, M1219 Limbic Encephalitis S502, S510, S524, S525WIP, S527WIP, S712 Lyme Borreliosis T2440 Machado-Joseph Disease (MJD) M1230
M Magnetic Resonance Imaging (MRI) S401, S408, S444, S508, S509, S519, S609, S618, S707, S708, S712, M1222, M2204, T1705, T2104, T2107, T2111, T2301, T2316, T2415, T2439 Magnetic Resonance Spectroscopy (H-MRS) S608, T2104 Migraine S418, S435, M903, M1220, M2223, T1701, T1906 Morvan Syndrome S510 Motoneuron Disease M1243WIP, M1404, T2403, T2405, T2415, T2422, T2434 Multiple Sclerosis (MS) S503, S504, S505, S507, S508, S509, S516, S517, S518, S519, S521, S523, S526WIP, S608, S613, T1601 Muscular Dystrophies T2431, T2432, T2437, T2443 Myasthenia Gravis S520, T2427, T2435 Myelin S523, M905, T2319, T2410, T2436, T2446WIP Myelin Oligodendrocyte Glycoprotein (MOG) S503, S528WIP, S608 Myelopathy S511, M905, T1704, T2444 Myoclonus M1229 Myopathic Syndrome T2437, T2442, T2443 Myopathy S522, T2401, T2402, T2407, T2419, T2430, T2442, T2448WIP Myotonic Dystrophy Type 1 (DM1) T2416
Annals of Neurology Vol 74 (suppl 17) 2013
P Parkinson’s Disease (PD) S208WIP, M1201, M1202, M1203, M1204, M1205, M1206, M1207, M1208, M1209, M1210, M1212, M1213, M1214, M1215, M1216, M1217, M1219, M1221, M1225, M1227, M1228, M1232, M1233, M1234, M1238, M1239, M1408, M1410, M1417, M1433, M1434, T1901 PET S409, S411, S607, M2227, T2303, T2305,T2307 Pharmacokinetics M1205, M1206, M1219, M1242, M2212, M2213, M2216
R Reactive Oxygen Species (ROS)
S404, M1429, T2001, T2406, T2416 Single Photon Emission Computed Tomography M1239, T2430
S Sleep Disorders and Circadian Rhythm S612, S614, M1001, M1002, M1003, M1004, M1005, M1006, M1007, M1008, M1009, M1010, M1228 Stroke S101, S102, S201, S203, S206, S302, S401, S403, S405, S406, S407, S408, S413, S414, S415, S416, S418, S419, S423, S425, S427, S428, S429, S430, S436, S438, S439, S440, S441, S442, S443, S444, S446WIP, S610, S619, M906, M1241, M1302, M1303, M1304, M1305, M1306, M1309, M1313, M1314, M1315, M1317, M1318, T1803, T1906, T2105, T2303 Subarachnoid Hemorrhage S428, M1316, T1504 Subthalamic Nucleus (STN) Stimulation M1214, M1215, M1227, M1433
M1209, M1222, M1226, M1234, M1413, M1427, T2301, T2306 Temporal Lobe Epilepsy (TLE) S616, M2226
V Visual Cortex Visual Function
T1701 S508, S604, M802, M1228, T1701