Opinion
EDITORIAL
Cerebrospinal Fluid Total Prion Protein A Potential In Vivo Marker of Cerebral Prion Pathology Henrik Zetterberg, MD, PhD
Several human degenerative diseases appear as a result of the misfolding and aggregation of proteins.1 The prototype central nervous system proteinopathy is Creutzfeldt-Jakob disease (CJD), in which neuronal prion protein (PrP) with high α-helical content switches into a stable structure rich in Related article page 267 β-pleated sheets in a selfcatalyzing process that eventually, after a prolonged build-up phase, turns neurotoxic, causing a plethora of neurological and psychiatric symptoms.2 Although human prion diseases are rare, affecting around 1 to 2 people per million individuals each year,3 they are frequent differential diagnoses when patients present with clinical signs of rapidly progressive central nervous system disease. Reliable tools for diagnosis are needed because prion diseases are transmissible, which became clear in the 1930s when healthy sheep were inoculated with brain tissue from sheep affected by scrapie (a sheep prion disease) and fell ill following an incubation period of a few years.4 The transmissibility was further emphasized during the 1980s epidemic of bovine spongiform encephalopathy, a prion disease of cattle in the United Kingdom,5 which eventually also made it clear that bovine spongiform encephalopathy could be transmitted to humans in the form of variant CJD, typically affecting younger individuals showing prion aggregation in peripheral tissues as well as in the central nervous system.6-8 Clinical, epidemiological, and experimental research has demonstrated that prions are transmissible by multiple routes, may have long incubation periods, and are resistant to conditions that would inactivate most previously recognized pathogens, such as formalin treatment and heat denaturation. The first fluid biomarker for CJD was discovered using a classic proteomics approach in which cerebrospinal fluid (CSF) proteins were separated on 2-dimensional gels that were stained with silver, followed by mass spectrometric identification of proteins with differential expression in CJD vs control samples.9 Increased CSF levels of the neuronal 14-3-3 protein were established as a distinctive feature of CJD and developed into a diagnostic test that made it into clinical diagnostic criteria.10 Presently, the diagnosis of human prion diseases relies on identifying typical patterns of clinical features (dementia, cerebellar or visual dysfunction, pyramidal or extrapyramidal dysfunction, and akinetic mutism) combined with supportive investigation findings (elevated CSF levels of 14-3-3 protein, periodic sharp wave complexes on electroencephalogram, or typical patterns of signal change on magnetic resonance imaging of the brain) to reach a probable dijamaneurology.com
agnosis. However, large-scale studies have shown that this results in a diagnostic specificity of only 71% for sporadic CJD.10 A definite diagnosis of sporadic CJD can only be reached by confirming the presence of typical neuropathological changes (spongiosis, astrogliosis, and deposition of misfolded PrP in a characteristic pattern) in brain tissue obtained either at autopsy or biopsy. Another potential biomarker for CJD is CSF tau, an intraaxonal protein selectively expressed within the central nervous system. Cerebrospinal fluid levels of total tau (T-tau, measured using assays that do not discriminate between different tau isoforms) are believed to correlate with the rate of axonal degeneration across several neurological diseases, including CJD.11 In contrast, CSF levels of tau proteins phosphorylated at specific amino acid residues (P-tau) are increased in Alzheimer disease (AD) but generally not in other progressive neurological diseases. Predictive values of T-tau and the T-tau to P-tau ratio suggest that they are of value especially in conjunction with other diagnostic methods to differentiate CJD from AD.12-14 However, as is the case for the 14-3-3 protein, other conditions with severe neuronal injury may cause increase in T-tau. Thus, the T-tau to P-tau ratio lacks in diagnostic specificity against non-AD disorders. In recent years, a number of novel molecular techniques for the detection and/or amplification of disease-associated PrP species have been developed. These techniques have the potential to be specific for the basic pathogenic process in prion diseases. There are approaches based on the Protein Misfolding Cyclic Amplification technique where the templated misfolding of PrP is seeded by a test sample containing misfolded PrP and the accumulated misfolded protein is then detected having shown promise.15 Quaking-Induced Conversion, a modified form of Protein Misfolding Cyclic Amplification combined with an immunoprecipitation step, has been shown to detect extremely small amounts of brain-derived diseaseassociated PrP when CJD brain homogenate is diluted into human plasma, according to work published by Orrú et al.16 As high as 1014-fold dilutions (estimated to contain only a few attograms of abnormal PrP per mL) can be differentiated from dilutions of nonprion disease brain homogenate16 and the assay can be used to detect CJD-causing misfolded PrP in CSF samples with high analytical sensitivity and specificity and good diagnostic accuracy.17 However, these techniques are difficult to standardize and are currently being performed only in a few specialized laboratories around the world. In an attempt to develop a screening test for variant CJD, a solidstate binding matrix to capture and concentrate disease(Reprinted) JAMA Neurology March 2015 Volume 72, Number 3
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Georgia User on 05/27/2015
261
Opinion Editorial
associated prion proteins coupled to direct immunodetection of surface-bound PrP has been developed into a blood-based test.18 This test does not work for sporadic CJD owing to the low amount of misfolded PrP in blood and other peripheral tissues in this disorder and has an unknown performance in CSF. In the current issue of JAMA Neurology, Dorey et al19 evaluated the diagnostic performance of a commercial BetaPrion Human Enzyme Immumoassay Test Kit to measure total prion protein (t-PrP) levels in CSF from patients with CJD and patients with AD, as well as from control individuals. An important feature of their study was that a substantial proportion of patients with AD and patients with CJD were autopsy confirmed. Furthermore, patients with AD with atypical clinical presentation including focal symptoms unrelated to AD-type temporal lobe dysfunction were included, making the study clinically relevant in a differential diagnostic context. Patients with CJD had the lowest CSF t-PrP levels compared with all types of patients with AD, with control individuals expressing intermediate levels. The selective lowering of CSF t-PrP in CJD may reflect sequestration of the protein in PrP aggregates in the brain with lower amounts being able to diffuse via the brain interstitial fluid to reach the lumbar CSF where it can be sampled and measured. At present, this is only a hypothesis, but if verified, the phenomenon would be very similar to the AD-associated change in the CSF levels of the 42 amino acid
ARTICLE INFORMATION Author Affiliations: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology, Queen Square, London, England.
3. Head MW. Human prion diseases: molecular, cellular and population biology. Neuropathology. 2013;33(3):221-236.
in cerebrospinal fluid discriminates Creutzfeldt-Jakob disease from other dementias. Mol Psychiatry. 2003;8(3):343-347.
4. Schneider K, Fangerau H, Michaelsen B, Raab WH. The early history of the transmissible spongiform encephalopathies exemplified by scrapie. Brain Res Bull. 2008;77(6):343-355.
13. Blennow K, Johansson A, Zetterberg H. Diagnostic value of 14-3-3β immunoblot and T-tau/P-tau ratio in clinically suspected Creutzfeldt-Jakob disease. Int J Mol Med. 2005;16 (6):1147-1149.
Corresponding Author: Henrik Zetterberg, MD, PhD, The Sahlgrenska Academy at University of Gothenburg, Institute of Neuroscience & Physiology, Department of Psychiatry & Neurochemistry, Sahlgrenska University Hospital, S-431 80 Mölndal, Sweden (henrik.zetterberg @clinchem.gu.se).
5. Anderson RM, Donnelly CA, Ferguson NM, et al. Transmission dynamics and epidemiology of BSE in British cattle. Nature. 1996;382(6594):779-788.
Published Online: January 5, 2015. doi:10.1001/jamaneurol.2014.4078.
7. Will RG, Ironside JW, Zeidler M, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet. 1996;347(9006):921-925.
Conflict of Interest Disclosures: None reported. Funding/Support: Work in Dr Zetterberg’s laboratory is supported by grants from the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Alzheimer’s Association, Swedish State Support for Clinical Research, and the Wolfson Foundation. Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. REFERENCES 1. Pepys MB. Amyloidosis. Annu Rev Med. 2006;57: 223-241. 2. Wadsworth JD, Collinge J. Molecular pathology of human prion disease. Acta Neuropathol. 2011;121 (1):69-77.
262
aggregation–prone form of β-amyloid 42. Autopsy, biopsy, and β-amyloid positron emission tomography imaging studies collectively show that there is an inverse correlation of CSF β-amyloid 42 with β-amyloid build-up in the brain,20-22 demonstrating that CSF β-amyloid 42 is a direct marker of senile plaque pathology (one of the neuropathological hallmarks of AD) in living individuals. If CSF t-PrP indeed is a direct measure of PrP pathology in the brain, this would be a welcome complement to the more technically challenging methods that detect PrP seeding activity or misfolding in CSF or blood. Dorey et al19 showed elevated CSF t-PrP levels in patients with AD, suggesting that neuronal injury may result in increased release of PrP from neurons into the CSF. Neuronal death in CJD should also lead to increased release of PrP into the brain interstitial fluid; the lower levels in CJD could then be explained by aggregation of the protein in the brain parenchyma. All this bodes well for the differential diagnostics capacity of CSF t-PrP. Neuronal injury in the absence of PrP pathology should result in increased CSF levels, whereas neuronal injury in the presence of PrP pathology should result in reduced levels. Combining CSF t-PrP with tau proteins into a socalled Creutzfeldt-Jakob factor (T-tau/(P-tau × t-PrP) differentiated CJD and atypical AD with 100% sensitivity and 95.7% specificity.19 This is a very promising result that should now be validated in independent replication studies.
6. Bateman D, Hilton D, Love S, Zeidler M, Beck J, Collinge J. Sporadic Creutzfeldt-Jakob disease in a 18-year-old in the UK. Lancet. 1995;346(8983): 1155-1156.
8. Britton TC, al-Sarraj S, Shaw C, Campbell T, Collinge J. Sporadic Creutzfeldt-Jakob disease in a 16-year-old in the UK. Lancet. 1995;346(8983):1155. 9. Hsich G, Kenney K, Gibbs CJ, Lee KH, Harrington MG. The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. N Engl J Med. 1996;335(13):924930. 10. Zerr I, Kallenberg K, Summers DM, et al. Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Brain. 2009;132(Pt 10): 2659-2668. 11. Skillbäck T, Rosén C, Asztely F, Mattsson N, Blennow K, Zetterberg H. Diagnostic performance of cerebrospinal fluid total tau and phosphorylated tau in Creutzfeldt-Jakob disease: results from the Swedish Mortality Registry. JAMA Neurol. 2014;71 (4):476-483. 12. Riemenschneider M, Wagenpfeil S, Vanderstichele H, et al. Phospho-tau/total tau ratio
14. Baldeiras IE, Ribeiro MH, Pacheco P, et al. Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients. J Neurol. 2009;256(9):1540-1550. 15. Gonzalez-Montalban N, Makarava N, Ostapchenko VG, et al. Highly efficient protein misfolding cyclic amplification. PLoS Pathog. 2011;7 (2):e1001277. 16. Orrú CD, Wilham JM, Raymond LD, et al. Prion disease blood test using immunoprecipitation and improved quaking-induced conversion. MBio. 2011; 2(3):e00078-e11. 17. McGuire LI, Peden AH, Orrú CD, et al. Real time quaking-induced conversion analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease. Ann Neurol. 2012;72(2):278-285. 18. Edgeworth JA, Farmer M, Sicilia A, et al. Detection of prion infection in variant Creutzfeldt-Jakob disease: a blood-based assay. Lancet. 2011;377(9764):487-493. 19. Dorey A, Tholance Y, Vighetto A, et al. Association of cerebrospinal fluid prion protein levels and the distinction between Alzheimer disease and Creutzfeldt-Jakob disease [published online January 5, 2014]. JAMA Neurol. doi:10.1001 /jamaneurol.2014.4068. 20. Palmqvist S, Zetterberg H, Blennow K, et al. Accuracy of brain amyloid detection in clinical practice using cerebrospinal fluid β-amyloid 42:
JAMA Neurology March 2015 Volume 72, Number 3 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Georgia User on 05/27/2015
jamaneurology.com
Editorial Opinion
a cross-validation study against amyloid positron emission tomography. JAMA Neurol. 2014;71(10): 1282-1289. 21. Seppälä TT, Nerg O, Koivisto AM, et al. CSF biomarkers for Alzheimer disease correlate with
cortical brain biopsy findings. Neurology. 2012;78 (20):1568-1575.
neuropathology in a population-based autopsy study. Neurology. 2003;60(4):652-656.
22. Strozyk D, Blennow K, White LR, Launer LJ. CSF Abeta 42 levels correlate with amyloid-
Carotid Stenting—Why Treating an Artery May Not Treat the Patient Mark J. Alberts, MD
In this issue of JAMA Neurology, Jalbert and colleagues1 present the results of a detailed analysis of Centers for Medicare & Medicaid Services (CMS) administrative data on patients with carotid artery stenosis treated with carotid artery stenting. Their well-written manuscript and timely study included more than 22 000 patients treated and followed up between Author Audio Interview at 2000 and 2009. They anajamaneurology.com lyzed periprocedural complications (defined as stroke, Related article page 276 transient ischemic attack [TIA], myocardial infarction [MI], and death within 30 days), as well as long-term stroke and mortality. Important variables that were analyzed included the degree of carotid stenosis, symptom status, urgency of the procedure, experience of the interventionalist, some medical comorbidities, and hospital characteristics. Several aspects of the study population and operators are important to note. Approximately half of all patients were asymptomatic even if they were at high risk for cerebrovascular events. Patients who were symptomatic (approximately 47% of the total) and had greater degrees of carotid stenosis had higher periprocedural complication rates, which is consistent with findings in prior studies.2,3 On the other hand, results from the landmark Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)4 showed that patients with symptomatic carotid stenosis had better outcomes overall in terms of stroke and death with carotid endarterectomy than with carotid artery stenting, with event rates approximately 1.5% lower with carotid endarterectomy compared with carotid artery stenting. Overall, the periprocedural complication rates in the study by Jalbert and colleagues1 were approximately 7.5%, with stroke or TIA being more common than MI (3.3% vs 2.5%). These results are generally consistent with those reported from the CREST4 but are approximately 3% higher than those in the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial.5 Beyond the periprocedural period, the rate of stroke or TIA was 9.1%. Only 15.5% of facilities and 9.3% of operators met the SAPPHIRE criteria for proficiency in performing carotid stenting.5 This is highly relevant for this procedure. A 2011 study6 found higher mortality rates for operators with low volumes vs high volumes. Higher-volume operators had 30-day mortality rates of 1.4% compared with 2.5% for low-volume operators. jamaneurology.com
The somewhat surprising, if not alarming, result was the mean 2-year mortality of 32.0% in the study group overall (approximately 37% in the symptomatic group and 28% in the asymptomatic group). This 2-year mortality rate is approximately 4 times greater than the periprocedural complication rate. Patients who were symptomatic and at least 80 years old fared much worse than younger groups, with an overall mortality of 46.0%.1 Patients admitted emergently (presumably owing to recent symptoms) had a mortality of 40.4%. These outcomes are much worse than the mortality of almost any type of ischemic stroke. This would obviously negate most, if not all, of the benefits of carotid stenting in at least one-third of treated patients. While the above data and outcomes are important, it is unlikely that the symptom status of the vessel, or the skills of the interventionalist, can alone explain the high mortality because most of the deaths occurred well after the periprocedural period. Either this cohort of patients was inherently sicker with more comorbidities or their care was in some way different (and perhaps suboptimal). Although the authors tend to focus on issues such as hospital characteristics and the experience of the interventionalists, it is unlikely that any of these factors account for the high 2-year mortality rate. What other factors might explain these troublesome outcomes? The overall patient cohort had significant comorbidities, as noted by the authors. These included hypertension in 95.7% and ischemic heart disease in 83.8%. What was not reported was how these various diseases were treated in terms of medications, control of cardiovascular disease (CVD) risk factors, lifestyle modification, and medical follow-up. This is one of the common limitations of using administrative databases to assess outcomes: treatment of comorbidities, compliance, and medical follow-up cannot be well evaluated. Furthermore, we have no information about the type and use of antiplatelet therapy in this patient group. Age is clearly a powerful risk factor for stroke and death. By using a CMS database that focused on Medicare beneficiaries, the study population was clearly focused on this older population with a mean age older than 76 years. This population was older than the stented groups of the CREST (mean age, 69 years) and the SAPPHIRE trial (mean age, 72.5 years). An examination of long-term outcomes in the CREST showed a mortality of 11.3% after a median follow-up of 2.5 years4; the SAPPHIRE trial reported a 20% mortality after 3 years.5 Both of these studies clearly have a much lower mortality rate than (Reprinted) JAMA Neurology March 2015 Volume 72, Number 3
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263
EDITORIAL
Cerebrospinal Fluid Total Prion Protein A Potential In Vivo Marker of Cerebral Prion Pathology Henrik Zetterberg, MD, PhD
Several human degenerative diseases appear as a result of the misfolding and aggregation of proteins.1 The prototype central nervous system proteinopathy is Creutzfeldt-Jakob disease (CJD), in which neuronal prion protein (PrP) with high α-helical content switches into a stable structure rich in Related article page 267 β-pleated sheets in a selfcatalyzing process that eventually, after a prolonged build-up phase, turns neurotoxic, causing a plethora of neurological and psychiatric symptoms.2 Although human prion diseases are rare, affecting around 1 to 2 people per million individuals each year,3 they are frequent differential diagnoses when patients present with clinical signs of rapidly progressive central nervous system disease. Reliable tools for diagnosis are needed because prion diseases are transmissible, which became clear in the 1930s when healthy sheep were inoculated with brain tissue from sheep affected by scrapie (a sheep prion disease) and fell ill following an incubation period of a few years.4 The transmissibility was further emphasized during the 1980s epidemic of bovine spongiform encephalopathy, a prion disease of cattle in the United Kingdom,5 which eventually also made it clear that bovine spongiform encephalopathy could be transmitted to humans in the form of variant CJD, typically affecting younger individuals showing prion aggregation in peripheral tissues as well as in the central nervous system.6-8 Clinical, epidemiological, and experimental research has demonstrated that prions are transmissible by multiple routes, may have long incubation periods, and are resistant to conditions that would inactivate most previously recognized pathogens, such as formalin treatment and heat denaturation. The first fluid biomarker for CJD was discovered using a classic proteomics approach in which cerebrospinal fluid (CSF) proteins were separated on 2-dimensional gels that were stained with silver, followed by mass spectrometric identification of proteins with differential expression in CJD vs control samples.9 Increased CSF levels of the neuronal 14-3-3 protein were established as a distinctive feature of CJD and developed into a diagnostic test that made it into clinical diagnostic criteria.10 Presently, the diagnosis of human prion diseases relies on identifying typical patterns of clinical features (dementia, cerebellar or visual dysfunction, pyramidal or extrapyramidal dysfunction, and akinetic mutism) combined with supportive investigation findings (elevated CSF levels of 14-3-3 protein, periodic sharp wave complexes on electroencephalogram, or typical patterns of signal change on magnetic resonance imaging of the brain) to reach a probable dijamaneurology.com
agnosis. However, large-scale studies have shown that this results in a diagnostic specificity of only 71% for sporadic CJD.10 A definite diagnosis of sporadic CJD can only be reached by confirming the presence of typical neuropathological changes (spongiosis, astrogliosis, and deposition of misfolded PrP in a characteristic pattern) in brain tissue obtained either at autopsy or biopsy. Another potential biomarker for CJD is CSF tau, an intraaxonal protein selectively expressed within the central nervous system. Cerebrospinal fluid levels of total tau (T-tau, measured using assays that do not discriminate between different tau isoforms) are believed to correlate with the rate of axonal degeneration across several neurological diseases, including CJD.11 In contrast, CSF levels of tau proteins phosphorylated at specific amino acid residues (P-tau) are increased in Alzheimer disease (AD) but generally not in other progressive neurological diseases. Predictive values of T-tau and the T-tau to P-tau ratio suggest that they are of value especially in conjunction with other diagnostic methods to differentiate CJD from AD.12-14 However, as is the case for the 14-3-3 protein, other conditions with severe neuronal injury may cause increase in T-tau. Thus, the T-tau to P-tau ratio lacks in diagnostic specificity against non-AD disorders. In recent years, a number of novel molecular techniques for the detection and/or amplification of disease-associated PrP species have been developed. These techniques have the potential to be specific for the basic pathogenic process in prion diseases. There are approaches based on the Protein Misfolding Cyclic Amplification technique where the templated misfolding of PrP is seeded by a test sample containing misfolded PrP and the accumulated misfolded protein is then detected having shown promise.15 Quaking-Induced Conversion, a modified form of Protein Misfolding Cyclic Amplification combined with an immunoprecipitation step, has been shown to detect extremely small amounts of brain-derived diseaseassociated PrP when CJD brain homogenate is diluted into human plasma, according to work published by Orrú et al.16 As high as 1014-fold dilutions (estimated to contain only a few attograms of abnormal PrP per mL) can be differentiated from dilutions of nonprion disease brain homogenate16 and the assay can be used to detect CJD-causing misfolded PrP in CSF samples with high analytical sensitivity and specificity and good diagnostic accuracy.17 However, these techniques are difficult to standardize and are currently being performed only in a few specialized laboratories around the world. In an attempt to develop a screening test for variant CJD, a solidstate binding matrix to capture and concentrate disease(Reprinted) JAMA Neurology March 2015 Volume 72, Number 3
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Georgia User on 05/27/2015
261
Opinion Editorial
associated prion proteins coupled to direct immunodetection of surface-bound PrP has been developed into a blood-based test.18 This test does not work for sporadic CJD owing to the low amount of misfolded PrP in blood and other peripheral tissues in this disorder and has an unknown performance in CSF. In the current issue of JAMA Neurology, Dorey et al19 evaluated the diagnostic performance of a commercial BetaPrion Human Enzyme Immumoassay Test Kit to measure total prion protein (t-PrP) levels in CSF from patients with CJD and patients with AD, as well as from control individuals. An important feature of their study was that a substantial proportion of patients with AD and patients with CJD were autopsy confirmed. Furthermore, patients with AD with atypical clinical presentation including focal symptoms unrelated to AD-type temporal lobe dysfunction were included, making the study clinically relevant in a differential diagnostic context. Patients with CJD had the lowest CSF t-PrP levels compared with all types of patients with AD, with control individuals expressing intermediate levels. The selective lowering of CSF t-PrP in CJD may reflect sequestration of the protein in PrP aggregates in the brain with lower amounts being able to diffuse via the brain interstitial fluid to reach the lumbar CSF where it can be sampled and measured. At present, this is only a hypothesis, but if verified, the phenomenon would be very similar to the AD-associated change in the CSF levels of the 42 amino acid
ARTICLE INFORMATION Author Affiliations: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology, Queen Square, London, England.
3. Head MW. Human prion diseases: molecular, cellular and population biology. Neuropathology. 2013;33(3):221-236.
in cerebrospinal fluid discriminates Creutzfeldt-Jakob disease from other dementias. Mol Psychiatry. 2003;8(3):343-347.
4. Schneider K, Fangerau H, Michaelsen B, Raab WH. The early history of the transmissible spongiform encephalopathies exemplified by scrapie. Brain Res Bull. 2008;77(6):343-355.
13. Blennow K, Johansson A, Zetterberg H. Diagnostic value of 14-3-3β immunoblot and T-tau/P-tau ratio in clinically suspected Creutzfeldt-Jakob disease. Int J Mol Med. 2005;16 (6):1147-1149.
Corresponding Author: Henrik Zetterberg, MD, PhD, The Sahlgrenska Academy at University of Gothenburg, Institute of Neuroscience & Physiology, Department of Psychiatry & Neurochemistry, Sahlgrenska University Hospital, S-431 80 Mölndal, Sweden (henrik.zetterberg @clinchem.gu.se).
5. Anderson RM, Donnelly CA, Ferguson NM, et al. Transmission dynamics and epidemiology of BSE in British cattle. Nature. 1996;382(6594):779-788.
Published Online: January 5, 2015. doi:10.1001/jamaneurol.2014.4078.
7. Will RG, Ironside JW, Zeidler M, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet. 1996;347(9006):921-925.
Conflict of Interest Disclosures: None reported. Funding/Support: Work in Dr Zetterberg’s laboratory is supported by grants from the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Alzheimer’s Association, Swedish State Support for Clinical Research, and the Wolfson Foundation. Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. REFERENCES 1. Pepys MB. Amyloidosis. Annu Rev Med. 2006;57: 223-241. 2. Wadsworth JD, Collinge J. Molecular pathology of human prion disease. Acta Neuropathol. 2011;121 (1):69-77.
262
aggregation–prone form of β-amyloid 42. Autopsy, biopsy, and β-amyloid positron emission tomography imaging studies collectively show that there is an inverse correlation of CSF β-amyloid 42 with β-amyloid build-up in the brain,20-22 demonstrating that CSF β-amyloid 42 is a direct marker of senile plaque pathology (one of the neuropathological hallmarks of AD) in living individuals. If CSF t-PrP indeed is a direct measure of PrP pathology in the brain, this would be a welcome complement to the more technically challenging methods that detect PrP seeding activity or misfolding in CSF or blood. Dorey et al19 showed elevated CSF t-PrP levels in patients with AD, suggesting that neuronal injury may result in increased release of PrP from neurons into the CSF. Neuronal death in CJD should also lead to increased release of PrP into the brain interstitial fluid; the lower levels in CJD could then be explained by aggregation of the protein in the brain parenchyma. All this bodes well for the differential diagnostics capacity of CSF t-PrP. Neuronal injury in the absence of PrP pathology should result in increased CSF levels, whereas neuronal injury in the presence of PrP pathology should result in reduced levels. Combining CSF t-PrP with tau proteins into a socalled Creutzfeldt-Jakob factor (T-tau/(P-tau × t-PrP) differentiated CJD and atypical AD with 100% sensitivity and 95.7% specificity.19 This is a very promising result that should now be validated in independent replication studies.
6. Bateman D, Hilton D, Love S, Zeidler M, Beck J, Collinge J. Sporadic Creutzfeldt-Jakob disease in a 18-year-old in the UK. Lancet. 1995;346(8983): 1155-1156.
8. Britton TC, al-Sarraj S, Shaw C, Campbell T, Collinge J. Sporadic Creutzfeldt-Jakob disease in a 16-year-old in the UK. Lancet. 1995;346(8983):1155. 9. Hsich G, Kenney K, Gibbs CJ, Lee KH, Harrington MG. The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. N Engl J Med. 1996;335(13):924930. 10. Zerr I, Kallenberg K, Summers DM, et al. Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Brain. 2009;132(Pt 10): 2659-2668. 11. Skillbäck T, Rosén C, Asztely F, Mattsson N, Blennow K, Zetterberg H. Diagnostic performance of cerebrospinal fluid total tau and phosphorylated tau in Creutzfeldt-Jakob disease: results from the Swedish Mortality Registry. JAMA Neurol. 2014;71 (4):476-483. 12. Riemenschneider M, Wagenpfeil S, Vanderstichele H, et al. Phospho-tau/total tau ratio
14. Baldeiras IE, Ribeiro MH, Pacheco P, et al. Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients. J Neurol. 2009;256(9):1540-1550. 15. Gonzalez-Montalban N, Makarava N, Ostapchenko VG, et al. Highly efficient protein misfolding cyclic amplification. PLoS Pathog. 2011;7 (2):e1001277. 16. Orrú CD, Wilham JM, Raymond LD, et al. Prion disease blood test using immunoprecipitation and improved quaking-induced conversion. MBio. 2011; 2(3):e00078-e11. 17. McGuire LI, Peden AH, Orrú CD, et al. Real time quaking-induced conversion analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease. Ann Neurol. 2012;72(2):278-285. 18. Edgeworth JA, Farmer M, Sicilia A, et al. Detection of prion infection in variant Creutzfeldt-Jakob disease: a blood-based assay. Lancet. 2011;377(9764):487-493. 19. Dorey A, Tholance Y, Vighetto A, et al. Association of cerebrospinal fluid prion protein levels and the distinction between Alzheimer disease and Creutzfeldt-Jakob disease [published online January 5, 2014]. JAMA Neurol. doi:10.1001 /jamaneurol.2014.4068. 20. Palmqvist S, Zetterberg H, Blennow K, et al. Accuracy of brain amyloid detection in clinical practice using cerebrospinal fluid β-amyloid 42:
JAMA Neurology March 2015 Volume 72, Number 3 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Georgia User on 05/27/2015
jamaneurology.com
Editorial Opinion
a cross-validation study against amyloid positron emission tomography. JAMA Neurol. 2014;71(10): 1282-1289. 21. Seppälä TT, Nerg O, Koivisto AM, et al. CSF biomarkers for Alzheimer disease correlate with
cortical brain biopsy findings. Neurology. 2012;78 (20):1568-1575.
neuropathology in a population-based autopsy study. Neurology. 2003;60(4):652-656.
22. Strozyk D, Blennow K, White LR, Launer LJ. CSF Abeta 42 levels correlate with amyloid-
Carotid Stenting—Why Treating an Artery May Not Treat the Patient Mark J. Alberts, MD
In this issue of JAMA Neurology, Jalbert and colleagues1 present the results of a detailed analysis of Centers for Medicare & Medicaid Services (CMS) administrative data on patients with carotid artery stenosis treated with carotid artery stenting. Their well-written manuscript and timely study included more than 22 000 patients treated and followed up between Author Audio Interview at 2000 and 2009. They anajamaneurology.com lyzed periprocedural complications (defined as stroke, Related article page 276 transient ischemic attack [TIA], myocardial infarction [MI], and death within 30 days), as well as long-term stroke and mortality. Important variables that were analyzed included the degree of carotid stenosis, symptom status, urgency of the procedure, experience of the interventionalist, some medical comorbidities, and hospital characteristics. Several aspects of the study population and operators are important to note. Approximately half of all patients were asymptomatic even if they were at high risk for cerebrovascular events. Patients who were symptomatic (approximately 47% of the total) and had greater degrees of carotid stenosis had higher periprocedural complication rates, which is consistent with findings in prior studies.2,3 On the other hand, results from the landmark Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)4 showed that patients with symptomatic carotid stenosis had better outcomes overall in terms of stroke and death with carotid endarterectomy than with carotid artery stenting, with event rates approximately 1.5% lower with carotid endarterectomy compared with carotid artery stenting. Overall, the periprocedural complication rates in the study by Jalbert and colleagues1 were approximately 7.5%, with stroke or TIA being more common than MI (3.3% vs 2.5%). These results are generally consistent with those reported from the CREST4 but are approximately 3% higher than those in the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial.5 Beyond the periprocedural period, the rate of stroke or TIA was 9.1%. Only 15.5% of facilities and 9.3% of operators met the SAPPHIRE criteria for proficiency in performing carotid stenting.5 This is highly relevant for this procedure. A 2011 study6 found higher mortality rates for operators with low volumes vs high volumes. Higher-volume operators had 30-day mortality rates of 1.4% compared with 2.5% for low-volume operators. jamaneurology.com
The somewhat surprising, if not alarming, result was the mean 2-year mortality of 32.0% in the study group overall (approximately 37% in the symptomatic group and 28% in the asymptomatic group). This 2-year mortality rate is approximately 4 times greater than the periprocedural complication rate. Patients who were symptomatic and at least 80 years old fared much worse than younger groups, with an overall mortality of 46.0%.1 Patients admitted emergently (presumably owing to recent symptoms) had a mortality of 40.4%. These outcomes are much worse than the mortality of almost any type of ischemic stroke. This would obviously negate most, if not all, of the benefits of carotid stenting in at least one-third of treated patients. While the above data and outcomes are important, it is unlikely that the symptom status of the vessel, or the skills of the interventionalist, can alone explain the high mortality because most of the deaths occurred well after the periprocedural period. Either this cohort of patients was inherently sicker with more comorbidities or their care was in some way different (and perhaps suboptimal). Although the authors tend to focus on issues such as hospital characteristics and the experience of the interventionalists, it is unlikely that any of these factors account for the high 2-year mortality rate. What other factors might explain these troublesome outcomes? The overall patient cohort had significant comorbidities, as noted by the authors. These included hypertension in 95.7% and ischemic heart disease in 83.8%. What was not reported was how these various diseases were treated in terms of medications, control of cardiovascular disease (CVD) risk factors, lifestyle modification, and medical follow-up. This is one of the common limitations of using administrative databases to assess outcomes: treatment of comorbidities, compliance, and medical follow-up cannot be well evaluated. Furthermore, we have no information about the type and use of antiplatelet therapy in this patient group. Age is clearly a powerful risk factor for stroke and death. By using a CMS database that focused on Medicare beneficiaries, the study population was clearly focused on this older population with a mean age older than 76 years. This population was older than the stented groups of the CREST (mean age, 69 years) and the SAPPHIRE trial (mean age, 72.5 years). An examination of long-term outcomes in the CREST showed a mortality of 11.3% after a median follow-up of 2.5 years4; the SAPPHIRE trial reported a 20% mortality after 3 years.5 Both of these studies clearly have a much lower mortality rate than (Reprinted) JAMA Neurology March 2015 Volume 72, Number 3
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