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1292 September-October 2014
radiographics.rsna.org
Invited Commentary on “Structural and Functional Imaging in Parkinsonian Syndromes” From: Nicolaas I. Bohnen, MD, PhD Departments of Radiology and Neurology, University of Michigan VA Ann Arbor Healthcare System Ann Arbor, Michigan Kirk A. Frey, MD, PhD Departments of Radiology and Neurology, University of Michigan Ann Arbor, Michigan Parkinson disease is a neurodegenerative disorder consisting of various combinations of motor symptoms that include tremor, rigidity, postural imbalance, and bradykinesia. These parkinsonian motor impairments may also be encountered in neurologic disorders other than idiopathic Parkinson disease. For example, a clinical-postmortem correlation study by Hughes et al (1) found idiopathic Parkinson disease in about 75% of patients with clinical parkinsonism. The remaining 25% of patients were found to have APS, including disorders such as PSP, MSA, and CBD (1). Accurate diagnosis is needed, not only to guide treatment, but also to provide prognostic information and, ultimately, to discover effective therapies for APS. Unlike the diagnosis of idiopathic Parkinson disease, that of APS can be challenging for the clinician.
Recent advances in anatomic and functional neuroimaging may provide the clinician with useful adjunct information for the diagnostic workup of patients with APS. Broski et al (2) discuss MR and nuclear imaging approaches for tackling the complex topic of the differential diagnosis for APS, which defies simple imaging algorithms and requires not only imaging expertise but also clinical knowledge of these neurologic disorders. The topic has become more complex because of recent studies showing significant pathologic and genetic heterogeneity underlying clinically distinct neurologic syndromes (3). A prime example is CBD, which can be associated with either a frontotemporal dementia or Alzheimer-type neurodegeneration (4,5). Thus, emerging new information about etiologic heterogeneity makes an accurate differential diagnosis for APS a bit
RG • Volume 34 Number 5
of a “moving target,” not only for neurologists, but also for radiologists and nuclear medicine physicians. Broski et al (2) emphasize an important point: The diagnosis of typical idiopathic Parkinson disease does not require neuroimaging. This is because strict clinical criteria allow a highly accurate diagnosis of idiopathic Parkinson disease to be made solely on the basis of motor symptoms and response to dopaminergic therapy (1). If a patient with clinical features of idiopathic Parkinson disease demonstrates an excellent response to dopaminergic therapy, no further diagnostic testing or imaging is indicated. However, Broski et al (2) provide good rationale for the use of adjunct neuroimaging in patients with parkinsonism who fail to meet the clinical diagnostic criteria for idiopathic Parkinson disease, or who do not demonstrate a significant response to therapy. The authors emphasize that baseline anatomic imaging is critical for identifying patients with cerebrovascular disease, normal-pressure hydrocephalus, or focal lesions who may present with secondary causes of parkinsonism. They also describe useful MR imaging findings that may indicate the presence of APS, such as (a) the hummingbird sign in PSP due to midbrain atrophy, or (b) the hot cross bun sign, a slitlike putaminal rim, and hyperintense areas in the middle cerebellar peduncles, findings that can be seen in MSA. Broski et al (2) also discuss the recent FDA approval of novel neuroimaging radiotracers, including 123I ioflupane SPECT and florbetapir PET. Ioflupane SPECT is indicated for the visualization of striatal dopamine transporters to assist in the evaluation of adult patients with suspected parkinsonian syndromes. However, as the authors correctly point out, this technique cannot help distinguish between Parkinson disease, DLB, PSP, CBD, and MSA, since loss of striatal dopamine transporters is seen in all of these conditions. Therefore, there is no role for ioflupane SPECT in distinguishing between Parkinson disease and APS or among APS. It should be noted, however, that dopamine transporter imaging findings may be normal in a small subset of patients with CBD (6). Florbetapir PET has been approved for the assessment of moderate to high levels of fibrillary amyloid plaque deposition, which in the presence of cognitive impairment can be seen with Alzheimer disease. Although Broski et al (2) try to present a more clear-cut picture of how imaging findings may differ among the various APS, recent insights into the pathologic heterogeneity of these syndromes make the situation more complex due to partially overlapping neuropathologic
Broski et al 1293
conditions. For example, amyloid plaque disease can demonstrate a variable presence among patients with a-synuclein proteinopathy (eg, DLB, Parkinson disease, and even MSA) (7,8). Furthermore, levels of cortical amyloid plaque deposition that are lower than those typically seen in Alzheimer disease (ie, below the authors’ suggested cut-off point of 1.3–1.6 for the standardized uptake value ratio) can commonly occur in Parkinson disease and can demonstrate significant correlation with cognitive function (9). This observation departs from the prevailing theory about Alzheimer disease, according to which amyloid plaque accumulation has typically reached a high plateau level at the time that symptoms begin to manifest (10). Unlike the variable presence of amyloid plaques at PET in patients with DLB, Parkinson disease, or MSA, amyloid PET findings will be normal in most frontotemporal dementia disorders (11), with the partial exception of CBD (4). Cerebral glucose hypometabolism as identified with FDG PET is a characteristic feature of many neurodegenerative disorders, and is an effective and useful adjunct to other diagnostic information in the assessment of patients with symptoms of dementia (12). FDG PET is clinically used in the United States to distinguish between Alzheimer disease and frontotemporal dementia. The interpreting radiologist or nuclear medicine physician may encounter images obtained in patients with frontotemporal dementia who may have additional features of parkinsonism (eg, patients with PSP). In this context, knowledge of specific metabolic patterns may be useful for more accurate scan interpretation. Although not approved by the FDA for this particular indication, FDG PET has shown good diagnostic accuracy in distinguishing among parkinsonian subtypes, as shown in a recent prospective cohort research study (13). Previous research studies have shown that the diagnostic accuracy of FDG PET can be significantly improved by making use of voxelbased statistical analysis maps (14), as suggested by Broski et al (2). This technology is highly recommended for neuroimagers interpreting cerebral FDG PET studies. Another statistical analysis approach, based on network-level assessment of resting-state FDG PET findings with principal component analysis, may allow user-independent diagnostic classification of APS subtypes (15); at present, however, this approach remains investigational. For the time being, the article by Broski et al (2) represents a systematic atlas-style presentation of clinical, MR imaging, and molecular imaging findings that may be encountered in each of the major
1294 September-October 2014
APS. We highly recommend the article to radiologists and nuclear medicine physicians who interpret brain scans performed in patients with atypical parkinsonian symptoms.
References 1. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55(3):181–184. 2. Broski SM, Hunt CH, Johnson GB, Morreale RF, Lowe VJ, Peller PJ. Structural and functional imaging in parkinsonian syndromes. RadioGraphics 2014;34(5):1273–1292. 3. Espay AJ, Litvan I. Parkinsonism and frontotemporal dementia: the clinical overlap. J Mol Neurosci 2011;45(3):343–349. 4. Alladi S, Xuereb J, Bak T, et al. Focal cortical presentations of Alzheimer’s disease. Brain 2007;130 (pt 10):2636–2645. 5. Sakurai Y, Ishii K, Sonoo M, et al. Progressive apraxic agraphia with micrographia presenting as corticobasal syndrome showing extensive Pittsburgh compound B uptake. J Neurol 2013;260(8): 1982–1991. 6. Cilia R, Rossi C, Frosini D, et al. Dopamine transporter SPECT imaging in corticobasal syndrome. PLoS ONE 2011;6(5):e18301. 7. Foster ER, Campbell MC, Burack MA, et al. Amyloid imaging of Lewy body-associated disorders. Mov Disord 2010;25(15):2516–2523.
radiographics.rsna.org 8. Kim HJ, Jeon BS, Kim YE, et al. Clinical and imaging characteristics of dementia in multiple system atrophy. Parkinsonism Relat Disord 2013;19(6):617–621. 9. Petrou M, Bohnen NI, Müller ML, Koeppe RA, Albin RL, Frey KA. Ab-amyloid deposition in patients with Parkinson disease at risk for development of dementia. Neurology 2012;79(11):1161–1167. 10. Trojanowski JQ, Vandeerstichele H, Korecka M, et al. Update on the biomarker core of the Alzheimer’s Disease Neuroimaging Initiative subjects. Alzheimers Dement 2010;6(3):230–238. 11. Burke JF, Albin RL, Koeppe RA, et al. Assessment of mild dementia with amyloid and dopamine terminal positron emission tomography. Brain 2011;134 (pt 6):1647–1657. 12. Bohnen NI, Djang DS, Herholz K, Anzai Y, Minoshima S. Effectiveness and safety of 18F-FDG PET in the evaluation of dementia: a review of the recent literature. J Nucl Med 2012;53(1):59–71. 13. Hellwig S, Amtage F, Kreft A, et al. [18F]FDGPET is superior to [¹²³I]IBZM-SPECT for the differential diagnosis of parkinsonism. Neurology 2012;79(13):1314–1322. 14. Burdette JH, Minoshima S, Vander Borght T, Tran DD, Kuhl DE. Alzheimer disease: improved visual interpretation of PET images by using three-dimensional stereotaxic surface projections. Radiology 1996;198(3):837–843. 15. Tang CC, Poston KL, Eckert T, et al. Differential diagnosis of parkinsonism: a metabolic imaging study using pattern analysis. Lancet Neurol 2010;9(2): 149–158.
1292 September-October 2014
radiographics.rsna.org
Invited Commentary on “Structural and Functional Imaging in Parkinsonian Syndromes” From: Nicolaas I. Bohnen, MD, PhD Departments of Radiology and Neurology, University of Michigan VA Ann Arbor Healthcare System Ann Arbor, Michigan Kirk A. Frey, MD, PhD Departments of Radiology and Neurology, University of Michigan Ann Arbor, Michigan Parkinson disease is a neurodegenerative disorder consisting of various combinations of motor symptoms that include tremor, rigidity, postural imbalance, and bradykinesia. These parkinsonian motor impairments may also be encountered in neurologic disorders other than idiopathic Parkinson disease. For example, a clinical-postmortem correlation study by Hughes et al (1) found idiopathic Parkinson disease in about 75% of patients with clinical parkinsonism. The remaining 25% of patients were found to have APS, including disorders such as PSP, MSA, and CBD (1). Accurate diagnosis is needed, not only to guide treatment, but also to provide prognostic information and, ultimately, to discover effective therapies for APS. Unlike the diagnosis of idiopathic Parkinson disease, that of APS can be challenging for the clinician.
Recent advances in anatomic and functional neuroimaging may provide the clinician with useful adjunct information for the diagnostic workup of patients with APS. Broski et al (2) discuss MR and nuclear imaging approaches for tackling the complex topic of the differential diagnosis for APS, which defies simple imaging algorithms and requires not only imaging expertise but also clinical knowledge of these neurologic disorders. The topic has become more complex because of recent studies showing significant pathologic and genetic heterogeneity underlying clinically distinct neurologic syndromes (3). A prime example is CBD, which can be associated with either a frontotemporal dementia or Alzheimer-type neurodegeneration (4,5). Thus, emerging new information about etiologic heterogeneity makes an accurate differential diagnosis for APS a bit
RG • Volume 34 Number 5
of a “moving target,” not only for neurologists, but also for radiologists and nuclear medicine physicians. Broski et al (2) emphasize an important point: The diagnosis of typical idiopathic Parkinson disease does not require neuroimaging. This is because strict clinical criteria allow a highly accurate diagnosis of idiopathic Parkinson disease to be made solely on the basis of motor symptoms and response to dopaminergic therapy (1). If a patient with clinical features of idiopathic Parkinson disease demonstrates an excellent response to dopaminergic therapy, no further diagnostic testing or imaging is indicated. However, Broski et al (2) provide good rationale for the use of adjunct neuroimaging in patients with parkinsonism who fail to meet the clinical diagnostic criteria for idiopathic Parkinson disease, or who do not demonstrate a significant response to therapy. The authors emphasize that baseline anatomic imaging is critical for identifying patients with cerebrovascular disease, normal-pressure hydrocephalus, or focal lesions who may present with secondary causes of parkinsonism. They also describe useful MR imaging findings that may indicate the presence of APS, such as (a) the hummingbird sign in PSP due to midbrain atrophy, or (b) the hot cross bun sign, a slitlike putaminal rim, and hyperintense areas in the middle cerebellar peduncles, findings that can be seen in MSA. Broski et al (2) also discuss the recent FDA approval of novel neuroimaging radiotracers, including 123I ioflupane SPECT and florbetapir PET. Ioflupane SPECT is indicated for the visualization of striatal dopamine transporters to assist in the evaluation of adult patients with suspected parkinsonian syndromes. However, as the authors correctly point out, this technique cannot help distinguish between Parkinson disease, DLB, PSP, CBD, and MSA, since loss of striatal dopamine transporters is seen in all of these conditions. Therefore, there is no role for ioflupane SPECT in distinguishing between Parkinson disease and APS or among APS. It should be noted, however, that dopamine transporter imaging findings may be normal in a small subset of patients with CBD (6). Florbetapir PET has been approved for the assessment of moderate to high levels of fibrillary amyloid plaque deposition, which in the presence of cognitive impairment can be seen with Alzheimer disease. Although Broski et al (2) try to present a more clear-cut picture of how imaging findings may differ among the various APS, recent insights into the pathologic heterogeneity of these syndromes make the situation more complex due to partially overlapping neuropathologic
Broski et al 1293
conditions. For example, amyloid plaque disease can demonstrate a variable presence among patients with a-synuclein proteinopathy (eg, DLB, Parkinson disease, and even MSA) (7,8). Furthermore, levels of cortical amyloid plaque deposition that are lower than those typically seen in Alzheimer disease (ie, below the authors’ suggested cut-off point of 1.3–1.6 for the standardized uptake value ratio) can commonly occur in Parkinson disease and can demonstrate significant correlation with cognitive function (9). This observation departs from the prevailing theory about Alzheimer disease, according to which amyloid plaque accumulation has typically reached a high plateau level at the time that symptoms begin to manifest (10). Unlike the variable presence of amyloid plaques at PET in patients with DLB, Parkinson disease, or MSA, amyloid PET findings will be normal in most frontotemporal dementia disorders (11), with the partial exception of CBD (4). Cerebral glucose hypometabolism as identified with FDG PET is a characteristic feature of many neurodegenerative disorders, and is an effective and useful adjunct to other diagnostic information in the assessment of patients with symptoms of dementia (12). FDG PET is clinically used in the United States to distinguish between Alzheimer disease and frontotemporal dementia. The interpreting radiologist or nuclear medicine physician may encounter images obtained in patients with frontotemporal dementia who may have additional features of parkinsonism (eg, patients with PSP). In this context, knowledge of specific metabolic patterns may be useful for more accurate scan interpretation. Although not approved by the FDA for this particular indication, FDG PET has shown good diagnostic accuracy in distinguishing among parkinsonian subtypes, as shown in a recent prospective cohort research study (13). Previous research studies have shown that the diagnostic accuracy of FDG PET can be significantly improved by making use of voxelbased statistical analysis maps (14), as suggested by Broski et al (2). This technology is highly recommended for neuroimagers interpreting cerebral FDG PET studies. Another statistical analysis approach, based on network-level assessment of resting-state FDG PET findings with principal component analysis, may allow user-independent diagnostic classification of APS subtypes (15); at present, however, this approach remains investigational. For the time being, the article by Broski et al (2) represents a systematic atlas-style presentation of clinical, MR imaging, and molecular imaging findings that may be encountered in each of the major
1294 September-October 2014
APS. We highly recommend the article to radiologists and nuclear medicine physicians who interpret brain scans performed in patients with atypical parkinsonian symptoms.
References 1. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55(3):181–184. 2. Broski SM, Hunt CH, Johnson GB, Morreale RF, Lowe VJ, Peller PJ. Structural and functional imaging in parkinsonian syndromes. RadioGraphics 2014;34(5):1273–1292. 3. Espay AJ, Litvan I. Parkinsonism and frontotemporal dementia: the clinical overlap. J Mol Neurosci 2011;45(3):343–349. 4. Alladi S, Xuereb J, Bak T, et al. Focal cortical presentations of Alzheimer’s disease. Brain 2007;130 (pt 10):2636–2645. 5. Sakurai Y, Ishii K, Sonoo M, et al. Progressive apraxic agraphia with micrographia presenting as corticobasal syndrome showing extensive Pittsburgh compound B uptake. J Neurol 2013;260(8): 1982–1991. 6. Cilia R, Rossi C, Frosini D, et al. Dopamine transporter SPECT imaging in corticobasal syndrome. PLoS ONE 2011;6(5):e18301. 7. Foster ER, Campbell MC, Burack MA, et al. Amyloid imaging of Lewy body-associated disorders. Mov Disord 2010;25(15):2516–2523.
radiographics.rsna.org 8. Kim HJ, Jeon BS, Kim YE, et al. Clinical and imaging characteristics of dementia in multiple system atrophy. Parkinsonism Relat Disord 2013;19(6):617–621. 9. Petrou M, Bohnen NI, Müller ML, Koeppe RA, Albin RL, Frey KA. Ab-amyloid deposition in patients with Parkinson disease at risk for development of dementia. Neurology 2012;79(11):1161–1167. 10. Trojanowski JQ, Vandeerstichele H, Korecka M, et al. Update on the biomarker core of the Alzheimer’s Disease Neuroimaging Initiative subjects. Alzheimers Dement 2010;6(3):230–238. 11. Burke JF, Albin RL, Koeppe RA, et al. Assessment of mild dementia with amyloid and dopamine terminal positron emission tomography. Brain 2011;134 (pt 6):1647–1657. 12. Bohnen NI, Djang DS, Herholz K, Anzai Y, Minoshima S. Effectiveness and safety of 18F-FDG PET in the evaluation of dementia: a review of the recent literature. J Nucl Med 2012;53(1):59–71. 13. Hellwig S, Amtage F, Kreft A, et al. [18F]FDGPET is superior to [¹²³I]IBZM-SPECT for the differential diagnosis of parkinsonism. Neurology 2012;79(13):1314–1322. 14. Burdette JH, Minoshima S, Vander Borght T, Tran DD, Kuhl DE. Alzheimer disease: improved visual interpretation of PET images by using three-dimensional stereotaxic surface projections. Radiology 1996;198(3):837–843. 15. Tang CC, Poston KL, Eckert T, et al. Differential diagnosis of parkinsonism: a metabolic imaging study using pattern analysis. Lancet Neurol 2010;9(2): 149–158.
