Structural and Molecular Imaging for Clinically Uncertain Parkinsonism

Sanskriti Sasikumar; Antonio P. Strafella

doi:10.1055/s-0043-1764228

Seminars in Neurology, Table of Contents

Semin Neurol 2023; 43(01): 095-105
DOI: 10.1055/s-0043-1764228

Review Article

Structural and Molecular Imaging for Clinically Uncertain Parkinsonism

Authors

Sanskriti Sasikumar

¹Morton and Gloria Shulman Movement Disorder Unit and Edmond J. Safra Parkinson Disease Program, Neurology Division, Department of Medicine, University of Toronto, Toronto Western Hospital, UHN, Ontario, Canada
Antonio P. Strafella

¹Morton and Gloria Shulman Movement Disorder Unit and Edmond J. Safra Parkinson Disease Program, Neurology Division, Department of Medicine, University of Toronto, Toronto Western Hospital, UHN, Ontario, Canada

²Krembil Brain Institute, University Health Network and Brain Health Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada

Abstract

Neuroimaging is an important adjunct to the clinical assessment of Parkinson disease (PD). Parkinsonism can be challenging to differentiate, especially in early disease stages, when it mimics other movement disorders or when there is a poor response to dopaminergic therapies. There is also a discrepancy between the phenotypic presentation of degenerative parkinsonism and the pathological outcome. The emergence of more sophisticated and accessible neuroimaging can identify molecular mechanisms of PD, the variation between clinical phenotypes, and the compensatory mechanisms that occur with disease progression. Ultra-high-field imaging techniques have improved spatial resolution and contrast that can detect microstructural changes, disruptions in neural pathways, and metabolic and blood flow alterations. We highlight the imaging modalities that can be accessed in clinical practice and recommend an approach to the diagnosis of clinically uncertain parkinsonism.

Keywords

Parkinson disease - atypical parkinsonism - molecular imaging - MRI - diagnostic imaging

Full Text

References

References
1 Tolosa E, Garrido A, Scholz SW, Poewe W. Challenges in the diagnosis of Parkinson's disease. Lancet Neurol 2021; 20 (05) 385-397
2 Politis M. Neuroimaging in Parkinson disease: from research setting to clinical practice. Nat Rev Neurol 2014; 10 (12) 708-722
3 Fearnley JM, Lees AJ. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 1991; 114 (Pt 5): 2283-2301
4 Delenclos M, Jones DR, McLean PJ, Uitti RJ. Biomarkers in Parkinson's disease: advances and strategies. Parkinsonism Relat Disord 2016; 22 (Suppl 1, Suppl 1): S106-S110
5 Peralta C, Strafella AP, van Eimeren T. et al; International Parkinson Movement Disorders Society-Neuroimaging Study Group. Pragmatic approach on neuroimaging techniques for the differential diagnosis of parkinsonisms. Mov Disord Clin Pract (Hoboken) 2021; 9 (01) 6-19
6 Jellinger KA. Neuropathology of sporadic Parkinson's disease: evaluation and changes of concepts. Mov Disord 2012; 27 (01) 8-30
7 Lehéricy S, Bardinet E, Poupon C, Vidailhet M, François C. 7 Tesla magnetic resonance imaging: a closer look at substantia nigra anatomy in Parkinson's disease. Mov Disord 2014; 29 (13) 1574-1581
8 Gibb WR. Melanin, tyrosine hydroxylase, calbindin and substance P in the human midbrain and substantia nigra in relation to nigrostriatal projections and differential neuronal susceptibility in Parkinson's disease. Brain Res 1992; 581 (02) 283-291
9 Pavese N, Tai YF. Nigrosome imaging and neuromelanin sensitive MRI in diagnostic evaluation of parkinsonism. Mov Disord Clin Pract (Hoboken) 2018; 5 (02) 131-140
10 Blazejewska AI, Schwarz ST, Pitiot A. et al. Visualization of nigrosome 1 and its loss in PD: pathoanatomical correlation and in vivo 7 T MRI. Neurology 2013; 81 (06) 534-540
11 Schwarz ST, Afzal M, Morgan PS, Bajaj N, Gowland PA, Auer DP. The ‘swallow tail’ appearance of the healthy nigrosome - a new accurate test of Parkinson's disease: a case-control and retrospective cross-sectional MRI study at 3T. PLoS One 2014; 9 (04) e93814
12 Lehericy S, Vaillancourt DE, Seppi K. et al; International Parkinson and Movement Disorder Society (IPMDS)-Neuroimaging Study Group. The role of high-field magnetic resonance imaging in parkinsonian disorders: pushing the boundaries forward. Mov Disord 2017; 32 (04) 510-525
13 Brooks DJ. Imaging approaches to Parkinson disease. J Nucl Med 2010; 51 (04) 596-609
14 Mahlknecht P, Krismer F, Poewe W, Seppi K. Meta-analysis of dorsolateral nigral hyperintensity on magnetic resonance imaging as a marker for Parkinson's disease. Mov Disord 2017; 32 (04) 619-623
15 De Marzi R, Seppi K, Högl B. et al. Loss of dorsolateral nigral hyperintensity on 3.0 tesla susceptibility-weighted imaging in idiopathic rapid eye movement sleep behavior disorder. Ann Neurol 2016; 79 (06) 1026-1030
16 Ceravolo R, Antonini A, Frosini D. et al. Nigral anatomy and striatal denervation in genetic Parkinsonism: a family report. Mov Disord 2015; 30 (08) 1148-1149
17 Kim EY, Sung YH, Lee J. Nigrosome 1 imaging: technical considerations and clinical applications. Br J Radiol 2019; 92 (1101): 20180842
18 Weber WA, Czernin J, Anderson CJ. et al. The future of nuclear medicine, molecular imaging, and theranostics. J Nucl Med 2020; 61 (Suppl 2): 263S-272S
19 Lee CS, Samii A, Sossi V. et al. In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson's disease. Ann Neurol 2000; 47 (04) 493-503
20 Strafella AP, Bohnen NI, Pavese N. et al; IPMDS-Neuroimaging Study Group. Imaging markers of progression in Parkinson's disease. Mov Disord Clin Pract (Hoboken) 2018; 5 (06) 586-596
21 Saari L, Kivinen K, Gardberg M, Joutsa J, Noponen T, Kaasinen V. Dopamine transporter imaging does not predict the number of nigral neurons in Parkinson disease. Neurology 2017; 88 (15) 1461-1467
22 Honkanen EA, Saari L, Orte K. et al. No link between striatal dopaminergic axons and dopamine transporter imaging in Parkinson's disease. Mov Disord 2019; 34 (10) 1562-1566
23 Lee JW, Song YS, Kim H, Ku BD, Lee WW. Alteration of tremor dominant and postural instability gait difficulty subtypes during the progression of Parkinson's disease: analysis of the PPMI cohort. Front Neurol 2019; 10: 471
24 Kaasinen V, Kinos M, Joutsa J, Seppänen M, Noponen T. Differences in striatal dopamine transporter density between tremor dominant and non-tremor Parkinson's disease. Eur J Nucl Med Mol Imaging 2014; 41 (10) 1931-1937
25 Eggers C, Pedrosa DJ, Kahraman D. et al. Parkinson subtypes progress differently in clinical course and imaging pattern. PLoS One 2012; 7 (10) e46813
26 Ramani L, Malek N, Patterson J, Nissen T, Newman EJ. Relationship between [¹²³ I]-FP-CIT SPECT and clinical progression in Parkinson's disease. Acta Neurol Scand 2017; 135 (04) 400-406
27 Hellwig S, Amtage F, Kreft A. et al. [¹⁸F]FDG-PET is superior to [¹²³I]IBZM-SPECT for the differential diagnosis of parkinsonism. Neurology 2012; 79 (13) 1314-1322
28 Zhang L, Li TN, Yuan YS. et al. The neural basis of postural instability gait disorder subtype of Parkinson's disease: a PET and fMRI study. CNS Neurosci Ther 2016; 22 (05) 360-367
29 Visser E, Keuken MC, Forstmann BU, Jenkinson M. Automated segmentation of the substantia nigra, subthalamic nucleus and red nucleus in 7T data at young and old age. Neuroimage 2016; 139: 324-336
30 Lenglet C, Abosch A, Yacoub E, De Martino F, Sapiro G, Harel N. Comprehensive in vivo mapping of the human basal ganglia and thalamic connectome in individuals using 7T MRI. PLoS One 2012; 7 (01) e29153
31 Helmich RC, Vaillancourt DE, Brooks DJ. The future of brain imaging in Parkinson's disease. J Parkinsons Dis 2018; 8 (s1): S47-S51
32 Tinaz S, Courtney MG, Stern CE. Focal cortical and subcortical atrophy in early Parkinson's disease. Mov Disord 2011; 26 (03) 436-441
33 Atkinson-Clement C, Pinto S, Eusebio A, Coulon O. Diffusion tensor imaging in Parkinson's disease: review and meta-analysis. Neuroimage Clin 2017; 16: 98-110
34 Prodoehl J, Li H, Planetta PJ. et al. Diffusion tensor imaging of Parkinson's disease, atypical parkinsonism, and essential tremor. Mov Disord 2013; 28 (13) 1816-1822
35 Schwarz ST, Abaei M, Gontu V, Morgan PS, Bajaj N, Auer DP. Diffusion tensor imaging of nigral degeneration in Parkinson's disease: a region-of-interest and voxel-based study at 3 T and systematic review with meta-analysis. Neuroimage Clin 2013; 3: 481-488
36 Vaillancourt DE, Spraker MB, Prodoehl J. et al. High-resolution diffusion tensor imaging in the substantia nigra of de novo Parkinson disease. Neurology 2009; 72 (16) 1378-1384
37 Ofori E, Pasternak O, Planetta PJ. et al. Longitudinal changes in free-water within the substantia nigra of Parkinson's disease. Brain 2015; 138 (Pt 8): 2322-2331
38 Burciu RG, Ofori E, Archer DB. et al. Progression marker of Parkinson's disease: a 4-year multi-site imaging study. Brain 2017; 140 (08) 2183-2192
39 Planetta PJ, Ofori E, Pasternak O. et al. Free-water imaging in Parkinson's disease and atypical parkinsonism. Brain 2016; 139 (Pt 2): 495-508
40 Al-Bachari S, Vidyasagar R, Emsley HC, Parkes LM. Structural and physiological neurovascular changes in idiopathic Parkinson's disease and its clinical phenotypes. J Cereb Blood Flow Metab 2017; 37 (10) 3409-3421
41 Chiu WT, Chan L, Wu D, Ko TH, Chen DY, Hong CT. Cerebral microbleeds are associated with postural instability and gait disturbance subtype in people with Parkinson's disease. Eur Neurol 2018; 80 (5-6): 335-340
42 Fang E, Ann CN, Maréchal B. et al. Differentiating Parkinson's disease motor subtypes using automated volume-based morphometry incorporating white matter and deep gray nuclear lesion load. J Magn Reson Imaging 2020; 51 (03) 748-756
43 Ohtsuka C, Sasaki M, Konno K. et al. Changes in substantia nigra and locus coeruleus in patients with early-stage Parkinson's disease using neuromelanin-sensitive MR imaging. Neurosci Lett 2013; 541: 93-98
44 Xiang Y, Gong T, Wu J. et al. Subtypes evaluation of motor dysfunction in Parkinson's disease using neuromelanin-sensitive magnetic resonance imaging. Neurosci Lett 2017; 638: 145-150
45 Ohtsuka C, Sasaki M, Konno K. et al. Differentiation of early-stage parkinsonisms using neuromelanin-sensitive magnetic resonance imaging. Parkinsonism Relat Disord 2014; 20 (07) 755-760
46 Isaias IU, Trujillo P, Summers P. et al. Neuromelanin imaging and dopaminergic loss in Parkinson's disease. Front Aging Neurosci 2016; 8: 196
47 Rispoli V, Schreglmann SR, Bhatia KP. Neuroimaging advances in Parkinson's disease. Curr Opin Neurol 2018; 31 (04) 415-424
48 Langkammer C, Pirpamer L, Seiler S. et al. Quantitative susceptibility mapping in Parkinson's disease. PLoS One 2016; 11 (09) e0162460
49 Jin L, Wang J, Jin H. et al. Nigral iron deposition occurs across motor phenotypes of Parkinson's disease. Eur J Neurol 2012; 19 (07) 969-976
50 He N, Huang P, Ling H. et al. Dentate nucleus iron deposition is a potential biomarker for tremor-dominant Parkinson's disease. NMR Biomed 2017; 30 (04) e3554
51 Loane C, Wu K, Bain P, Brooks DJ, Piccini P, Politis M. Serotonergic loss in motor circuitries correlates with severity of action-postural tremor in PD. Neurology 2013; 80 (20) 1850-1855
52 Maillet A, Krack P, Lhommée E. et al. The prominent role of serotonergic degeneration in apathy, anxiety and depression in de novo Parkinson's disease. Brain 2016; 139 (Pt 9): 2486-2502
53 Shimada H, Hirano S, Shinotoh H. et al. Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET. Neurology 2009; 73 (04) 273-278
54 Luo CY, Guo XY, Song W. et al. Functional connectome assessed using graph theory in drug-naive Parkinson's disease. J Neurol 2015; 262 (06) 1557-1567
55 Kanel P, Bedard MA, Aghourian M. et al. Molecular imaging of the cholinergic system in alzheimer and lewy body dementias: expanding views. Curr Neurol Neurosci Rep 2021; 21 (10) 52
56 Mazère J, Lamare F, Allard M, Fernandez P, Mayo W. 123I-Iodobenzovesamicol SPECT imaging of cholinergic systems in dementia with Lewy bodies. J Nucl Med 2017; 58 (01) 123-128
57 Gersel Stokholm M, Iranzo A, Østergaard K. et al. Cholinergic denervation in patients with idiopathic rapid eye movement sleep behaviour disorder. Eur J Neurol 2020; 27 (04) 644-652
58 Mahlknecht P, Hotter A, Hussl A, Esterhammer R, Schocke M, Seppi K. Significance of MRI in diagnosis and differential diagnosis of Parkinson's disease. Neurodegener Dis 2010; 7 (05) 300-318
59 Bae YJ, Kim JM, Sohn CH. et al. Imaging the substantia nigra in Parkinson disease and other Parkinsonian syndromes. Radiology 2021; 300 (02) 260-278
60 Lee W. Conventional magnetic resonance imaging in the diagnosis of Parkinsonian disorders: a meta-analysis. Mov Disord Clin Pract (Hoboken) 2020; 8 (02) 217-223
61 Nigro S, Antonini A, Vaillancourt DE. et al. Automated MRI classification in progressive supranuclear palsy: a large international cohort study. Mov Disord 2020; 35 (06) 976-983
62 Morelli M, Arabia G, Novellino F. et al. MRI measurements predict PSP in unclassifiable parkinsonisms: a cohort study. Neurology 2011; 77 (11) 1042-1047
63 Quattrone A, Morelli M, Williams DR. et al. MR parkinsonism index predicts vertical supranuclear gaze palsy in patients with PSP-parkinsonism. Neurology 2016; 87 (12) 1266-1273
64 Quattrone A, Antonini A, Vaillancourt DE. et al. A new MRI measure to early differentiate progressive supranuclear palsy from de novo Parkinson's disease in clinical practice: an international study. Mov Disord 2021; 36 (03) 681-689
65 Gilman S, Low P, Quinn N. et al; American Autonomic Society and American Academy of Neurology. Consensus statement on the diagnosis of multiple system atrophy. Clin Auton Res 1998; 8 (06) 359-362
66 Nicoletti G, Fera F, Condino F. et al. MR imaging of middle cerebellar peduncle width: differentiation of multiple system atrophy from Parkinson disease. Radiology 2006; 239 (03) 825-830
67 Heim B, Krismer F, Seppi K. Structural imaging in atypical parkinsonism. Int Rev Neurobiol 2018; 142: 67-148
68 Zhu S, Li H, Deng B. et al. Various diseases and clinical heterogeneity are associated with “Hot Cross Bun”. Front Aging Neurosci 2020; 12: 592212
69 Way C, Pettersson D, Hiller A. The ‘hot cross bun'sign is not always multiple system atrophy: etiologies of 11 cases. J Mov Disord 2019; 12 (01) 27-30
70 Lee WH, Lee CC, Shyu WC, Chong PN, Lin SZ. Hyperintense putaminal rim sign is not a hallmark of multiple system atrophy at 3T. AJNR Am J Neuroradiol 2005; 26 (09) 2238-2242
71 Mestre TA, Gupta A, Lang AE. MRI signs of multiple system atrophy preceding the clinical diagnosis: the case for an imaging-supported probable MSA diagnostic category. J Neurol Neurosurg Psychiatry 2016; 87 (04) 443-444
72 Kouri N, Whitwell JL, Josephs KA, Rademakers R, Dickson DW. Corticobasal degeneration: a pathologically distinct 4R tauopathy. Nat Rev Neurol 2011; 7 (05) 263-272
73 Alexander SK, Rittman T, Xuereb JH, Bak TH, Hodges JR, Rowe JB. Validation of the new consensus criteria for the diagnosis of corticobasal degeneration. J Neurol Neurosurg Psychiatry 2014; 85 (08) 925-929
74 Boxer AL, Geschwind MD, Belfor N. et al. Patterns of brain atrophy that differentiate corticobasal degeneration syndrome from progressive supranuclear palsy. Arch Neurol 2006; 63 (01) 81-86
75 Südmeyer M, Pieperhoff P, Ferrea S. et al. Longitudinal deformation-based morphometry reveals spatio-temporal dynamics of brain volume changes in patients with corticobasal syndrome. PLoS One 2012; 7 (07) e41873
76 Bajaj S, Krismer F, Palma JA. et al. Diffusion-weighted MRI distinguishes Parkinson disease from the parkinsonian variant of multiple system atrophy: a systematic review and meta-analysis. PLoS One 2017; 12 (12) e0189897
77 Mangesius S, Hussl A, Krismer F. et al. MR planimetry in neurodegenerative parkinsonism yields high diagnostic accuracy for PSP. Parkinsonism Relat Disord 2018; 46: 47-55
78 Nicoletti G, Tonon C, Lodi R. et al. Apparent diffusion coefficient of the superior cerebellar peduncle differentiates progressive supranuclear palsy from Parkinson's disease. Mov Disord 2008; 23 (16) 2370-2376
79 Pyatigorskaya N, Sanz-Morère CB, Gaurav R. et al. Iron imaging as a diagnostic tool for Parkinson's disease: a systematic review and meta-analysis. Front Neurol 2020; 11: 366
80 Lee JH, Han YH, Kang BM, Mun CW, Lee SJ, Baik SK. Quantitative assessment of subcortical atrophy and iron content in progressive supranuclear palsy and parkinsonian variant of multiple system atrophy. J Neurol 2013; 260 (08) 2094-2101
81 Han YH, Lee JH, Kang BM. et al. Topographical differences of brain iron deposition between progressive supranuclear palsy and parkinsonian variant multiple system atrophy. J Neurol Sci 2013; 325 (1-2): 29-35
82 Oh M, Kim JS, Kim JY. et al. Subregional patterns of preferential striatal dopamine transporter loss differ in Parkinson disease, progressive supranuclear palsy, and multiple-system atrophy. J Nucl Med 2012; 53 (03) 399-406
83 Cilia R, Rossi C, Frosini D. et al. Dopamine transporter SPECT imaging in corticobasal syndrome. PLoS One 2011; 6 (05) e18301
84 Juh R, Pae CU, Lee CU. et al. Voxel based comparison of glucose metabolism in the differential diagnosis of the multiple system atrophy using statistical parametric mapping. Neurosci Res 2005; 52 (03) 211-219
85 Teune LK, Bartels AL, de Jong BM. et al. Typical cerebral metabolic patterns in neurodegenerative brain diseases. Mov Disord 2010; 25 (14) 2395-2404
86 Holtbernd F, Ma Y, Peng S. et al. Dopaminergic correlates of metabolic network activity in Parkinson's disease. Hum Brain Mapp 2015; 36 (09) 3575-3585
87 Meyer PT, Frings L, Rücker G, Hellwig S. 18F-FDG PET in parkinsonism: differential diagnosis and evaluation of cognitive impairment. J Nucl Med 2017; 58 (12) 1888-1898
88 Höglinger GU, Respondek G, Stamelou M. et al; Movement Disorder Society-endorsed PSP Study Group. Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria. Mov Disord 2017; 32 (06) 853-864
89 Pirker W, Djamshidian S, Asenbaum S. et al. Progression of dopaminergic degeneration in Parkinson's disease and atypical parkinsonism: a longitudinal β-CIT SPECT study. Mov Disord 2002; 17 (01) 45-53
90 Taniguchi D, Hatano T, Kamagata K. et al. Neuromelanin imaging and midbrain volumetry in progressive supranuclear palsy and Parkinson's disease. Mov Disord 2018; 33 (09) 1488-1492
91 Kashihara K, Shinya T, Higaki F. Neuromelanin magnetic resonance imaging of nigral volume loss in patients with Parkinson's disease. J Clin Neurosci 2011; 18 (08) 1093-1096
92 Matsuura K, Maeda M, Tabei KI. et al. A longitudinal study of neuromelanin-sensitive magnetic resonance imaging in Parkinson's disease. Neurosci Lett 2016; 633: 112-117
93 Hansen AK, Knudsen K, Lillethorup TP. et al. In vivo imaging of neuromelanin in Parkinson's disease using 18F-AV-1451 PET. Brain 2016; 139 (Pt 7): 2039-2049
94 Hammes J, Bischof GN, Giehl K. et al. Elevated in vivo [18F]-AV-1451 uptake in a patient with progressive supranuclear palsy. Mov Disord 2017; 32 (01) 170-171
95 Whitwell JL, Lowe VJ, Tosakulwong N. et al. [¹⁸ F]AV-1451 tau positron emission tomography in progressive supranuclear palsy. Mov Disord 2017; 32 (01) 124-133
96 Coakeley S, Cho SS, Koshimori Y. et al. [¹⁸F]AV-1451 binding to neuromelanin in the substantia nigra in PD and PSP. Brain Struct Funct 2018; 223 (02) 589-595
97 Kikuchi A, Okamura N, Hasegawa T. et al. In vivo visualization of tau deposits in corticobasal syndrome by 18F-THK5351 PET. Neurology 2016; 87 (22) 2309-2316
98 van Eimeren T, Bischof GN, Drzezga A. Is tau imaging more than just upside-down 18F-FDG imaging?. J Nucl Med 2017; 58 (09) 1357-1359
99 Song M, Beyer L, Kaiser L. et al. Binding characteristics of [¹⁸F]PI-2620 distinguish the clinically predicted tau isoform in different tauopathies by PET. J Cereb Blood Flow Metab 2021; 41 (11) 2957-2972
100 Tang CC, Eidelberg D. Abnormal metabolic brain networks in Parkinson's disease from blackboard to bedside. Prog Brain Res 2010; 184: 161-176
101 Tripathi M, Tang CC, Feigin A. et al. Automated differential diagnosis of early parkinsonism using metabolic brain networks: a validation study. J Nucl Med 2016; 57 (01) 60-66
102 Eckert T, Tang C, Ma Y. et al. Abnormal metabolic networks in atypical parkinsonism. Mov Disord 2008; 23 (05) 727-733
103 Niethammer M, Tang CC, Feigin A. et al. A disease-specific metabolic brain network associated with corticobasal degeneration. Brain 2014; 137 (Pt 11): 3036-3046
104 Garraux G, Phillips C, Schrouff J. et al. Multiclass classification of FDG PET scans for the distinction between Parkinson's disease and atypical parkinsonian syndromes. Neuroimage Clin 2013; 2: 883-893
105 Herz DM, Haagensen BN, Christensen MS. et al. The acute brain response to levodopa heralds dyskinesias in Parkinson disease. Ann Neurol 2014; 75 (06) 829-836
106 Schwingenschuh P, Ruge D, Edwards MJ. et al. Distinguishing SWEDDs patients with asymmetric resting tremor from Parkinson's disease: a clinical and electrophysiological study. Mov Disord 2010; 25 (05) 560-569
107 Erro R, Schneider SA, Stamelou M, Quinn NP, Bhatia KP. What do patients with scans without evidence of dopaminergic deficit (SWEDD) have? New evidence and continuing controversies. J Neurol Neurosurg Psychiatry 2016; 87 (03) 319-323
108 Postuma RB, Berg D, Stern M. et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord 2015; 30 (12) 1591-1601