Clinical Review & Education
Review
Parkinson Disease Subtypes Mary Ann Thenganatt, MD; Joseph Jankovic, MD
IMPORTANCE It is increasingly evident that Parkinson disease (PD) is not a single entity but
rather a heterogeneous neurodegenerative disorder. OBJECTIVE To evaluate available evidence, based on findings from clinical, imaging, genetic and pathologic studies, supporting the differentiation of PD into subtypes. EVIDENCE REVIEW We performed a systematic review of articles cited in PubMed between 1980 and 2013 using the following search terms: Parkinson disease, parkinsonism, tremor, postural instability and gait difficulty, and Parkinson disease subtypes. The final reference list was generated on the basis of originality and relevance to the broad scope of this review. FINDINGS Several subtypes, such as tremor-dominant PD and postural instability gait difficulty form of PD, have been found to cluster together. Other subtypes also have been identified, but validation by subtype-specific biomarkers is still lacking. CONCLUSIONS AND RELEVANCE Several PD subtypes have been identified, but the pathogenic mechanisms underlying the observed clinicopathologic heterogeneity in PD are still not well understood. Further research into subtype-specific diagnostic and prognostic biomarkers may provide insights into mechanisms of neurodegeneration and improve epidemiologic and therapeutic clinical trial designs. JAMA Neurol. 2014;71(4):499-504. doi:10.1001/jamaneurol.2013.6233 Published online February 10, 2014.
P
arkinson disease (PD) is a complex neurodegenerative disease with a broad spectrum of motor and nonmotor features. It is increasingly evident that PD is a heterogeneous disorder with variable clinicopathologic phenotypes and natural history. Subtypes of PD have emerged, with patients classified according to distinct clinical features (Figure). In-depth knowledge about these subtypes may lead to further insights into mechanisms of disease and pathogenesis-targeted and symptomatic treatments. We performed a systematic review of articles cited in PubMed between 1980 and 2013 using the following search terms: Parkinson disease, parkinsonism, tremor, postural instability and gait difficulty, and Parkinson disease subtypes. In this review article, we discuss the most commonly identified PD subtypes and their distinguishing features. Parkinson disease can be defined clinically, pathologically, and genetically.1,2 According to the United Kingdom Parkinson Disease Society Brain Bank, the clinical criteria for probable PD require the presence of bradykinesia and at least 1 of the following features: rigidity, rest tremor of 4 to 6 Hz, or postural instability. In addition, 3 supportive features are required.3 With the emergence of new genetic, imaging, and pathologic findings, coupled with the clinical variability, there is a growing consensus that PD should be considered a syndrome rather than a single entity and that its diagnostic criteria should be reexamined. A multiple-tier approach may be required, including the core clinical criteria based on United Kingdom Parkinson Disease Society Brain Bank, jamaneurology.com
Author Affiliations: Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas. Corresponding Author: Joseph Jankovic, MD, Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, 6550 Fannin St, Ste 1801, Houston, TX 77030 ([email protected]). Section Editor: David E. Pleasure, MD.
pathologic criteria, supported by typical Lewy body (LB) pathology and genetic criteria (genetic mutations confirmed to cause PD phenotype).1
Methods of Classification Traditionally, PD subtypes have been identified empirically based on clinical observations and analyses of cohort studies, focusing on data sets that identify clinical features clustered together.4 One of the earliest classifications categorized PD into two subtypes: (1) tremordominant PD and (2) postural instability and gait difficulty (PIGD).4 The DATATOP database, which includes information on more than 800 patients with early, untreated PD, was analyzed to explore the clinical heterogeneity of PD.4 Using the Unified Parkinson’s Disease Rating Scale, an average global tremor score and a mean score for the complex of PIGD were determined, and patients were assigned to a tremor group and a PIGD group based on the ratio of these scores.4 This finding was validated with the new Movement Disorder Society Unified Parkinson’s Disease Rating Scale in 877 patients with PD, a scale for which cutoff scores reliably differentiate the two subtypes with optimal sensitivity and specificity.5 A data-driven approach using a process called cluster analysis has been used to identify PD subtypes.6 This process, based on the relationship between selected variables without an a priori hypothesis, is still dependent on certain choices, such as variables seJAMA Neurology April 2014 Volume 71, Number 4
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lected for analysis, the clustering technique, and the number of clusters. A recent systematic review6 evaluated the data obtained with cluster analysis and identified the following common subtypes: (1) old age at onset and rapid disease progression, (2) young-onset PD (YOPD) and slow progression, (3) tremor-dominant phenotype (which may overlap with benign tremulous PD), and (4) PIGD phenotype (also dominated by bradykinesia and rigidity).
Clinical Features Age at Onset Although age is the most important risk factor for the development of PD, disease onset may start at a young age. When we compared 88 patients with YOPD (aged 20-40 years) and 110 with late-onset PD (LOPD; aged >60 years) evaluated in the Movement Disorders Clinic at Baylor College of Medicine, we found that patients with YOPD initially presented more often with rigidity and dystonia and had a higher frequency of levodopa-related motor complications than those with LOPD, who presented more often with the PIGD pattern (Figure). Nearly one-third of patients with YOPD represent PARK2-associated PD, caused by parkin gene (PRKN) mutation, often manifested by early levodopa-induced dyskinesias, hallucinations, dystonic gait, cervical dystonia, dopa-responsive dystonia, leg tremor at rest and on standing, marked sleep benefit, hyperreflexia, ataxia, peripheral neuropathy, and dysautonomia.7,8 Although parkinsonian symptoms are readily discernible in young individuals, they may be less obvious at onset in the elderly and are often initially attributed to age-related frailty. Mild parkinsonism may be seen in older patients without a diagnosis of PD and have been associated with PD susceptibility loci.9 Patients with LOPD are often characterized by the PIGD subtype.10 Although it is well recog-
Figure. Parkinson Disease (PD) Subtypes
PIGD PD • Poor prognosis with rapid progression • Bradykinesia and rigidity • Dementia • Depression • Anosmia Mixed PD • Levodopa • Degeneration in ventrolateral SN • DAT SPECT • “Egg-shaped” configuration on DAT SPECT
Tremor-dominant PD • Good prognosis with slow progression • Essential tremor • Benign tremulous parkinsonism • Good response to levodopa • Wearing off • Increased fMRI activity in CTC circuitry • Degeneration in medial SN, ventral GPi, thalamic serotonin, and midbrain (A8) • “Eagle wing” configuration on DAT SPECT YOPD
LOPD
Onset between ages 20 and 40 y Genetic Dystonia
Onset after age 60 y Sporadic
Subtypes include postural instability and gait difficulty (PIGD) and tremor-dominant PD. CTC indicates cerebellothalamocortical; DAT, dopamine transporter; fMRI, functional magnetic resonance imaging; GPi, globus pallidus interna; LOPD, late-onset PD; SN, substantia nigra; SPECT, single-photon emission computed tomography; YOPD, young-onset PD.
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nized that patients with YOPD have an excellent response to levodopa, it is also clear that they have a greater tendency for early development of dyskinesias and motor fluctuations. Several studies have shown that patients with YOPD have a slower progression of disease than those with LOPD.4,11 The Sydney Multi-Center Study group11 assessed the course of disease in 125 patients with de novo PD and concluded that age at onset was a major determinant of the course of disease. Although the course may be more protracted in patients with YOPD, the terminal stage, manifested by more rapid physical and cognitive decline, may be similar across groups irrespective of age at onset.12 Compared with patients with LOPD, the disease in those with YOPD affects quality of life more adversely in terms of loss of employment, disruption of family life, perceived stigma, and depression.13
Motor Phenotype Several studies have confirmed that patients presenting with tremor at onset have a slower progression of disease than those with a PIGD subtype4,14 The tremor-dominant form of PD is often initially misdiagnosed as essential tremor, particularly if the patients have had a long-standing history of tremor. The overlap between clinical features of PD and essential tremor and the possible pathogenic link between the two disorders has been a subject of several recent reviews.15,16 An entity named benign tremulous parkinsonism has been described in patients with predominant rest tremor, mild nontremor signs, absence of gait disorder, and mild progression of parkinsonism other than tremor despite many years of disease.17 A case series of 16 such patients were found to have a lower mean age at onset (58.5 years) than most PD series and a poor response to levodopa.18 An autopsy evaluation of 21 such cases found less severe neuronal loss in the substantia nigra than in pathologically proven PD controls, indicating a slower progression of neuronal degeneration.18 Others have argued against the term benign tremulous parkinsonism and proposed the term monosymptomatic tremor at rest19 because patients with advanced cases have troublesome symptoms along with imaging evidence of dopaminergic deficit; hence, the condition is not “benign.” Nonmotor symptoms, such as cognitive impairment, also vary according to motor subtype. The PIGD form of PD is associated with a faster rate of cognitive decline and a higher incidence of dementia.20 One study demonstrated that patients with tremordominant PD may start to show signs of dementia only after PIGD symptoms develop.20 In addition to cognitive decline, depression and apathy are often associated with the nontremor-dominant PD subtype.21,22 Olfaction among PD subtypes has been the focus of few studies, demonstrating more impaired olfaction in the akineticrigid subtype than in the tremor-dominant group.23
Imaging Findings Various imaging modalities, including positron emission tomography (PET), single-photon emission computed tomography (SPECT), and functional magnetic resonance imaging, are increasingly used to identify the neural circuits and connectivity involved in specific PD signs. Fluorodopa PET scans have been shown to correlate well with certain PD signs and symptoms, particularly bradykinesia, and with postmortem nigral cell count.24 In terms of age at onset, a study using
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3 presynaptic dopamine markers, (6) dihydrotetrabenazine labeled with carbon 11 (11C), [11C]d-threo-methylphenidate, and 6-fluoro-L-dopa labeled with fluorine 18 (18F) found that younger patients have a greater decrease of dihydrotetrabenazine putaminal binding at onset than older patients; however, the rate of dihydrotetrabenazine binding loss progressed more slowly in patients with YOPD.25 Scanning with SPECT can be used to evaluate the presynaptic dopaminergic system by measuring the density of striatal dopamine transporter. Several dopamine transporter SPECT studies have found a significant correlation between striatal iodine 123 (123I) fluoropropyl (FP) carbomethoxy-3 β-(4-iodophenyltropane) (CIT) uptake and the severity of akinetic-rigid symptoms but not with tremor.26,27 One FP-CIT SPECT study comparing 24 patients with tremor-dominant PD and 28 with akinetic-rigid PD found that uptake in the contralateral putamen was significantly lower in the akinetic-rigid phenotype than in the tremor-dominant phenotype.26 Another study comparing FP-CIT SPECT findings in 122 patients with PD found different patterns of dopamine uptake based on visual analysis.27 The tremor-dominant patients had an “eagle wing” striatal configuration, corresponding to dopamine loss in the caudate and lateral putamen. In contrast, the patients with akinetic-rigid PD had an egg-shaped configuration, corresponding to dopaminergic loss in the dorsal putamen.27 These findings, however, require validation by other studies using larger samples and different imaging techniques, such as PET tracer [18F]9-fluoropropyl-(+)-dihydrotetrabenazine ([18F]AV-133), targeting vesicular monoamine transporter 2.28 Several imaging studies have demonstrated that loss of neurotransmitters other than dopamine contribute to the pathophysiologic mechanism of parkinsonian tremor and other parkinsonian motor and nonmotor features. For example, loss of thalamic serotonin has been implicated in the generation of rest tremor.29,30 One PET study involving 23 patients with PD found a 27% reduction in raphe 5-HT1A receptor binding compared with controls; this reduction correlated with Unified Parkinson’s Disease Rating Scale tremor scores but not with rigidity or bradykinesia.29 With [ 11 C]dihydrotetrabenazine dopaminergic and [ 11 C]methyl-4piperidinyl propionate acetylcholinesterase PET imaging, cortical cholinergic denervation was found to correlate more with slowing of gait in PD than with nigrostriatal denervation.31 Thus, the various cardinal signs of PD may be related to different neurotransmitter deficiencies: whereas dopaminergic deficiency correlates well with bradykinesia and rigidity, serotonin seems to play a role in tremor, and cholinergic deficit seems to contribute to gait disorder associated with PD. One study used functional magnetic resonance imaging to compare the activation of striatothalamocortical and cerebellothalamocortical circuits in 17 patients with PD (9 with tremordominant and 8 with akinetic-rigid PD) and 14 controls and found that patients with tremor-dominant PD had significantly more activity in contralateral cerebellothalamocortical circuits, supporting the differential involvement of the two circuits in PD subtypes.32 Another study, including 44 patients with PD (21 with tremor-dominant and 23 with nontremor-dominant PD) and 36 controls, used functional magnetic resonance imaging and [123I]FP-CIT to investigate the interplay between the basal ganglia and the cerebellothalamic circuitry in generating rest tremor and jamaneurology.com
found that pallidal dopamine depletion was correlated with tremor severity.33 These findings suggest that rest tremor involves cerebellothalamocortical circuitry, which is driven largely by the dopamine-depleted basal ganglia. In a study using functional magnetic resonance imaging and voxel-based morphometry to examine functional and structural differences between 20 patients with tremor-dominant or nontremor-dominant PD and healthy controls, both voxel-based and region-of-interest analyses showed that patients with nontremor-dominant PD had reduced brain activity in the prefrontal cortex and globus pallidus compared with both patients with tremor-dominant PD and controls. 34 Another study found decreased gray matter volume in the cerebellum of patients with PD and rest tremor compared with patients with PD without rest tremor. 35 These and other studies provide evidence for the involvement of the cerebellothalamocortical circuitry in parkinsonian tremor. In contrast, voxel-based morphometry showed smaller gray matter and presupplementary motor volume in the PIGD subgroup, particularly in areas involving motor, cognitive, limbic, and associative functions.36 This pattern suggests that degeneration of cortical areas involved in motor planning may contribute to the PIGD phenotype.
Biomarkers Refinements in genomics, proteomics, lipidomics, and metabolics applied to blood, cerebrospinal fluid, and other tissues may lead to early identification of PD and aid in differentiating the various subtypes.37 There are emerging data on blood and cerebrospinal fluid markers that correlate with motor or nonmotor symptoms associated with PD. For example, low plasma levels of epidermal growth factor have been found to correlate with baseline cognitive impairment in patients with PD.38 Furthermore, lower cerebrospinal fluid Aβ1-42 and P-tau181 concentrations were associated with PIGD PD but not with the tremor-dominant form.39
Genetics In the past decade, there has been an explosion of knowledge about the genetics of PD, and 18 PD-related gene loci have been identified40 (Table). Both autosomal dominant and autosomal recessive genetic forms of PD have been identified, with distinct and overlapping phenotypes. The first gene associated with PD was identified in 1997 as a missense mutation in the α-synuclein (SNCA) gene with an autosomal dominant mode of inheritance.41 Later, duplications or triplications of the SNCA gene were found in patients with PD phenotypes.42 Seven SNCA mutations have since been identified and found to be associated with early-onset parkinsonism, moderate response to levodopa, rapid progression, pyramidal signs, frequent psychiatric symptoms, and prominent cognitive dysfunction.41-43 The most common autosomal dominant form of parkinsonism involves missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene.44 The G2019S LRRK2 mutation is highly prevalent in the Ashkenazi Jewish and North African populations.44 The phenotype associated with LRRK2 mutation is highly variable but is quite similar to sporadic PD, particularly asymmetric parkinsonism with tremor, but with a decreased risk of cognitive and olfactory impairment, although atypical features such as orthostatic hypotension, dementia, hallucinations, and sleep disturbance have been deJAMA Neurology April 2014 Volume 71, Number 4
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Table. Genetically Determined Parkinsonism Locus
Inheritance
Gene
Protein
PARK1
AD
SNCA
α-Synuclein
PARK2
AR
PARK2
Ubiquitin ligase
PARK3
AD
?
?
PARK4
AD
SNCA
α-Synuclein
PARK5
AD
UCHL1
Ubiquitin cyclohydrolase A
PARK6
AR
PINK1
PTEN-induced kinase 1
PARK7
AR
DJ-1
DJ-1
PARK8
AD
LRRK2
LRRK2 (dardarin)
PARK9
AR
ATP13A2
Lysosomal type 5 P-type ATPase
PARK10
AD
?
?
PARK11
AD
GIGYF2
GRB10-interacting GYF protein 2
PARK12
X-linked
?
?
PARK13
AD
HTRA2
Serine protease
PARK14
AR
PLA2G6
Phospholipase A2
PARK15
AR
FBXO7
F-box protein 7
PARK16
?
?
?
PARK17
AD
VPS35
VPS35
PARK18
AD
EIF4G1
EIF4G1
scribed in LRRK2 cases. In contrast, based on a study of patients with YOPD, G2019S mutation carriers were more likely to have a PIGD phenotype and less tremor.45 The pathologic changes in the brains of patients with LRRK2-associated PD are quite variable and may include pure nigral degeneration without LBs, typical α-synuclein LB disease, and even neurofibrillary tangle disease with TDP-43 (transactive response DNA-binding protein 43 kDa) inclusions and β-amyloid deposits in anterior horn cells. Mutations in two new genes causing autosomal dominant PD have been recently identified: vacuolar protein sorting 35 homologue gene (VPS35)46 and eukaryotic translation initiation factor 4G1.47 The autosomal recessive forms of parkinsonism include mutations in the parkin gene (PARK2),48 the phosphatase and tensin homologue–induced putative kinase 1 gene (PINK1),49 and the DJ1 gene.50 These mutations are generally associated with YOPD and manifested by a good response to levodopa and early development of dyskinesias.40 Although early cognitive impairment is uncommon, psychiatric comorbid conditions have been reported to be present in PINK1-associated and DJ1-associated PD. Both PARK2 and PINK1 genes have been reported to play a role in mitochondrial function, suggesting that mitochondrial dysfunction plays a role in PD pathogenesis. Furthermore, mutations in the glucocerebrosidase gene have been found to be a risk factor for PD in the Ashkenazi Jewish population. Patients with these mutations have been shown to have an earlier onset of disease and more prominent cognitive dysfunction.51 The loss of function mutations in glucocerebrosidase suggests a role for lysosomal dysfunction in the pathogenesis of PD.52
Pathologic Findings A definite diagnosis of PD requires autopsy confirmation of pathologic findings typical for PD. The core pathologic findings underlying PD are degeneration of melanin and dopamine-containing neurons, especially in the zona compacta of the substantia nigra, and the presence of LBs, eosinophilic cytoplasmic inclusions, and 502
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; ATPase, adenosine triphosphatase; EIF4G1, eukaryotic translation initiation factor 4G1; LRRK2, leucine-rich repeat kinase 2; PTEN, phosphatase and tensin homologue; VPS35, vacuolar protein sorting 35; ?, unknown.
dystrophic Lewy neurites.1,53,54 There is growing appreciation for pathologic involvement in PD not only of brain dopaminergic systems but also of nondopaminergic systems in the brain as well as peripheral and autonomic systems. Several studies have drawn attention to the involvement of cardiac, gastrointestinal, submandibular gland, cutaneous, and other body regions, all of which have been found to have LB disease with deposition of abnormal α-synuclein.55-57 There is also growing evidence that the initial site of disease in PD may not necessarily be in the substantia nigra but may be in the nuclei of the caudal brainstem or even in the peripheral nervous system and peripheral organs.54 The hypothesis that progression of neurodegenerative disease is mediated via seeding of misfolded proteins, also known as “templating,” with intracerebral and transynaptic propagation of fibrils has extended to a broad range of proteins, including α-synuclein, tau, huntingtin, superoxide dismutase 1, and TDP-43.58 Furthermore, in the central nervous system there is evidence for striatonigral rather than nigrostriatal progression, with the initial disease site in the striatum and “dying-back” axonopathy resulting in retrograde degeneration and neuronal loss in the substantia nigra.59 Postmortem studies have examined differences between PD subtypes, particularly tremor-dominant vs akinetic-rigid phenotypes.60-63 In a clinicopathologic study involving 166 cases collected over 39 years, 26% of pathologically confirmed PD cases were classified as akinetic-rigid, 8% as tremor dominant, and 66% as mixed. 64 Another clinicopathologic study of 72 autopsyconfirmed cases at a tertiary care center found that 16% of patients had PIGD at onset and 49% had tremor at onset.65 In a neuropathologic study of 27 patients with akinetic-rigid PD and 18 with tremor-dominant PD, those in the former group had greater neuronal loss in the substantia nigra pars compacta, especially the lateral portion, and the locus coeruleus.60 Another clinicopathologic study found degeneration of a subgroup of midbrain (A8) neurons in patients with tremor-dominant PD, but this region was
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spared in patients with PD without tremor.61 This is consistent with the finding of greater loss of neurons in the retrorubral A8 field, which contains predominantly calretinin-staining cells but few tyrosine hydroxylase and dopamine transporter immunoreactive neurons.62 Patterns of striatal and pallidal dopamine loss seem to vary among the different PD motor subtypes. 63 For example, in contrast to severe loss of dopamine in the ventral globus pallidus internus, near-normal dopamine levels were found in the basal ganglia of patients with tremor-dominant PD. Studies have also demonstrated more severe cortical LB disease in patients with nontremor-dominant PD than in those with tremordominant PD.66,67 ARTICLE INFORMATION Accepted for Publication: December 13, 2013. Published Online: February 10, 2014. doi:10.1001/jamaneurol.2013.6233. Author Contributions: Drs Thenganatt and Jankovic had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Both authors. Acquisition of data: Both authors. Analysis and interpretation of data: Both authors. Drafting of the manuscript: Thenganatt. Critical revision of the manuscript for important intellectual content: Both authors. Administrative, technical, or material support: Both authors. Conflict of Interest Disclosures: None reported. REFERENCES
Conclusions As we learn more about PD, it is becoming abundantly clear that PD is a heterogeneous disorder with variable clinical characteristics and imaging findings, as well as different genetic and other underlying neuropathologic mechanisms. Identifying subtype-specific biomarkers will enhance our ability to categorize various PD phenotypes into subtypes, which will lead to a better understanding of pathogenesis, clinical progression, and prognosis. The existence of the various PD subtypes should be considered in the design and interpretation of epidemiologic studies and clinical trials.
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37. Wu Y, Le W, Jankovic J. Preclinical biomarkers of Parkinson disease. Arch Neurol. 2011;68(1):22-30.
48. Lohmann E, Thobois S, Lesage S, et al; French Parkinson’s Disease Genetics Study Group. A multidisciplinary study of patients with early-onset PD with and without parkin mutations. Neurology. 2009;72(2):110-116.
34. Prodoehl J, Planetta PJ, Kurani AS, Comella CL, Corcos DM, Vaillancourt DE. Differences in brain activation between tremor- and nontremordominant Parkinson disease. JAMA Neurol. 2013;70(1):100-106.
38. Chen-Plotkin AS, Hu WT, Siderowf A, et al. Plasma epidermal growth factor levels predict cognitive decline in Parkinson disease. Ann Neurol. 2011;69(4):655-663. 39. Kang JH, Irwin DJ, Chen-Plotkin AS, et al; the Parkinson’s Progression Markers Initiative. Association of cerebrospinal fluid β-amyloid 1-42, T-tau, P-tau181, and α-synuclein levels with clinical features of drug-naive patients with early Parkinson disease. JAMA Neurol. 2013;70(10):1277-1287. 40. Crosiers D, Theuns J, Cras P, Van Broeckhoven C. Parkinson disease: insights in clinical, genetic and pathological features of monogenic disease subtypes. J Chem Neuroanat. 2011;42(2):131-141. 41. Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276(5321):2045-2047. 42. Ibáñez P, Lesage S, Janin S, et al; French Parkinson’s Disease Genetics Study Group. α-Synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms. Arch Neurol. 2009;66(1):102-108. 43. Lesage S, Anheim M, Letournel F, et al; French Parkinson’s Disease Genetics (PDG) Study Group. G51D α-synuclein mutation causes a novel parkinsonian-pyramidal syndrome [published online March 22, 2013]. Ann Neurol. 2013. doi:10.1002/ana.23894. 44. Healy DG, Falchi M, O’Sullivan SS, et al; International LRRK2 Consortium. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease:
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49. Valente EM, Abou-Sleiman PM, Caputo V, et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science. 2004;304(5674): 1158-1160.
59. Chu Y, Morfini GA, Langhamer LB, He Y, Brady ST, Kordower JH. Alterations in axonal transport motor proteins in sporadic and experimental Parkinson’s disease. Brain. 2012;135(pt 7): 2058-2073. 60. Paulus W, Jellinger K. The neuropathologic basis of different clinical subgroups of Parkinson’s disease. J Neuropathol Exp Neurol. 1991;50(6):743-755. 61. Hirsch EC, Mouatt A, Faucheux B, et al. Dopamine, tremor, and Parkinson’s disease. Lancet. 1992;340(8811):125-126.
50. Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2003;299(5604):256-259.
62. Jellinger KA. Post mortem studies in Parkinson’s disease—is it possible to detect brain areas for specific symptoms? J Neural Transm Suppl. 1999;56:1-29.
51. McNeill A, Duran R, Hughes DA, Mehta A, Schapira AH. A clinical and family history study of Parkinson’s disease in heterozygous glucocerebrosidase mutation carriers. J Neurol Neurosurg Psychiatry. 2012;83(8):853-854.
63. Rajput AH, Sitte HH, Rajput A, Fenton ME, Pifl C, Hornykiewicz O. Globus pallidus dopamine and Parkinson motor subtypes: clinical and brain biochemical correlation. Neurology. 2008;70 (16, pt 2):1403-1410.
52. Pan T, Kondo S, Le W, Jankovic J. The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson’s disease. Brain. 2008;131 (pt 8):1969-1978.
64. Rajput AH, Voll A, Rajput ML, Robinson CA, Rajput A. Course in Parkinson disease subtypes: a 39-year clinicopathologic study. Neurology. 2009;73(3):206-212.
53. Jellinger KA. Neuropathology of sporadic Parkinson’s disease: evaluation and changes of concepts. Mov Disord. 2012;27(1):8-30.
65. Rajput AH, Pahwa R, Pahwa P, Rajput A. Prognostic significance of the onset mode in parkinsonism. Neurology. 1993;43(4):829-830.
54. Goedert M, Spillantini MG, Del Tredici K, Braak H. 100 Years of Lewy pathology. Nat Rev Neurol. 2013;9(1):13-24.
66. Selikhova M, Williams DR, Kempster PA, Holton JL, Revesz T, Lees AJ. A clinico-pathological study of subtypes in Parkinson’s disease. Brain. 2009;132 (pt 11):2947-2957.
55. Pan T, Zhu J, Hwu WJ, Jankovic J. The role of alpha-synuclein in melanin synthesis in melanoma and dopaminergic neuronal cells. PLoS One. 2012;7(9):e45183. 56. Shannon KM, Keshavarzian A, Mutlu E, et al. Alpha-synuclein in colonic submucosa in early
67. van de Berg WD, Hepp DH, Dijkstra AA, Rozemuller JA, Berendse HW, Foncke E. Patterns of α-synuclein pathology in incidental cases and clinical subtypes of Parkinson’s disease. Parkinsonism Relat Disord. 2012;18(suppl 1):S28-S30.
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Review
Parkinson Disease Subtypes Mary Ann Thenganatt, MD; Joseph Jankovic, MD
IMPORTANCE It is increasingly evident that Parkinson disease (PD) is not a single entity but
rather a heterogeneous neurodegenerative disorder. OBJECTIVE To evaluate available evidence, based on findings from clinical, imaging, genetic and pathologic studies, supporting the differentiation of PD into subtypes. EVIDENCE REVIEW We performed a systematic review of articles cited in PubMed between 1980 and 2013 using the following search terms: Parkinson disease, parkinsonism, tremor, postural instability and gait difficulty, and Parkinson disease subtypes. The final reference list was generated on the basis of originality and relevance to the broad scope of this review. FINDINGS Several subtypes, such as tremor-dominant PD and postural instability gait difficulty form of PD, have been found to cluster together. Other subtypes also have been identified, but validation by subtype-specific biomarkers is still lacking. CONCLUSIONS AND RELEVANCE Several PD subtypes have been identified, but the pathogenic mechanisms underlying the observed clinicopathologic heterogeneity in PD are still not well understood. Further research into subtype-specific diagnostic and prognostic biomarkers may provide insights into mechanisms of neurodegeneration and improve epidemiologic and therapeutic clinical trial designs. JAMA Neurol. 2014;71(4):499-504. doi:10.1001/jamaneurol.2013.6233 Published online February 10, 2014.
P
arkinson disease (PD) is a complex neurodegenerative disease with a broad spectrum of motor and nonmotor features. It is increasingly evident that PD is a heterogeneous disorder with variable clinicopathologic phenotypes and natural history. Subtypes of PD have emerged, with patients classified according to distinct clinical features (Figure). In-depth knowledge about these subtypes may lead to further insights into mechanisms of disease and pathogenesis-targeted and symptomatic treatments. We performed a systematic review of articles cited in PubMed between 1980 and 2013 using the following search terms: Parkinson disease, parkinsonism, tremor, postural instability and gait difficulty, and Parkinson disease subtypes. In this review article, we discuss the most commonly identified PD subtypes and their distinguishing features. Parkinson disease can be defined clinically, pathologically, and genetically.1,2 According to the United Kingdom Parkinson Disease Society Brain Bank, the clinical criteria for probable PD require the presence of bradykinesia and at least 1 of the following features: rigidity, rest tremor of 4 to 6 Hz, or postural instability. In addition, 3 supportive features are required.3 With the emergence of new genetic, imaging, and pathologic findings, coupled with the clinical variability, there is a growing consensus that PD should be considered a syndrome rather than a single entity and that its diagnostic criteria should be reexamined. A multiple-tier approach may be required, including the core clinical criteria based on United Kingdom Parkinson Disease Society Brain Bank, jamaneurology.com
Author Affiliations: Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas. Corresponding Author: Joseph Jankovic, MD, Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, 6550 Fannin St, Ste 1801, Houston, TX 77030 ([email protected]). Section Editor: David E. Pleasure, MD.
pathologic criteria, supported by typical Lewy body (LB) pathology and genetic criteria (genetic mutations confirmed to cause PD phenotype).1
Methods of Classification Traditionally, PD subtypes have been identified empirically based on clinical observations and analyses of cohort studies, focusing on data sets that identify clinical features clustered together.4 One of the earliest classifications categorized PD into two subtypes: (1) tremordominant PD and (2) postural instability and gait difficulty (PIGD).4 The DATATOP database, which includes information on more than 800 patients with early, untreated PD, was analyzed to explore the clinical heterogeneity of PD.4 Using the Unified Parkinson’s Disease Rating Scale, an average global tremor score and a mean score for the complex of PIGD were determined, and patients were assigned to a tremor group and a PIGD group based on the ratio of these scores.4 This finding was validated with the new Movement Disorder Society Unified Parkinson’s Disease Rating Scale in 877 patients with PD, a scale for which cutoff scores reliably differentiate the two subtypes with optimal sensitivity and specificity.5 A data-driven approach using a process called cluster analysis has been used to identify PD subtypes.6 This process, based on the relationship between selected variables without an a priori hypothesis, is still dependent on certain choices, such as variables seJAMA Neurology April 2014 Volume 71, Number 4
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lected for analysis, the clustering technique, and the number of clusters. A recent systematic review6 evaluated the data obtained with cluster analysis and identified the following common subtypes: (1) old age at onset and rapid disease progression, (2) young-onset PD (YOPD) and slow progression, (3) tremor-dominant phenotype (which may overlap with benign tremulous PD), and (4) PIGD phenotype (also dominated by bradykinesia and rigidity).
Clinical Features Age at Onset Although age is the most important risk factor for the development of PD, disease onset may start at a young age. When we compared 88 patients with YOPD (aged 20-40 years) and 110 with late-onset PD (LOPD; aged >60 years) evaluated in the Movement Disorders Clinic at Baylor College of Medicine, we found that patients with YOPD initially presented more often with rigidity and dystonia and had a higher frequency of levodopa-related motor complications than those with LOPD, who presented more often with the PIGD pattern (Figure). Nearly one-third of patients with YOPD represent PARK2-associated PD, caused by parkin gene (PRKN) mutation, often manifested by early levodopa-induced dyskinesias, hallucinations, dystonic gait, cervical dystonia, dopa-responsive dystonia, leg tremor at rest and on standing, marked sleep benefit, hyperreflexia, ataxia, peripheral neuropathy, and dysautonomia.7,8 Although parkinsonian symptoms are readily discernible in young individuals, they may be less obvious at onset in the elderly and are often initially attributed to age-related frailty. Mild parkinsonism may be seen in older patients without a diagnosis of PD and have been associated with PD susceptibility loci.9 Patients with LOPD are often characterized by the PIGD subtype.10 Although it is well recog-
Figure. Parkinson Disease (PD) Subtypes
PIGD PD • Poor prognosis with rapid progression • Bradykinesia and rigidity • Dementia • Depression • Anosmia Mixed PD • Levodopa • Degeneration in ventrolateral SN • DAT SPECT • “Egg-shaped” configuration on DAT SPECT
Tremor-dominant PD • Good prognosis with slow progression • Essential tremor • Benign tremulous parkinsonism • Good response to levodopa • Wearing off • Increased fMRI activity in CTC circuitry • Degeneration in medial SN, ventral GPi, thalamic serotonin, and midbrain (A8) • “Eagle wing” configuration on DAT SPECT YOPD
LOPD
Onset between ages 20 and 40 y Genetic Dystonia
Onset after age 60 y Sporadic
Subtypes include postural instability and gait difficulty (PIGD) and tremor-dominant PD. CTC indicates cerebellothalamocortical; DAT, dopamine transporter; fMRI, functional magnetic resonance imaging; GPi, globus pallidus interna; LOPD, late-onset PD; SN, substantia nigra; SPECT, single-photon emission computed tomography; YOPD, young-onset PD.
500
nized that patients with YOPD have an excellent response to levodopa, it is also clear that they have a greater tendency for early development of dyskinesias and motor fluctuations. Several studies have shown that patients with YOPD have a slower progression of disease than those with LOPD.4,11 The Sydney Multi-Center Study group11 assessed the course of disease in 125 patients with de novo PD and concluded that age at onset was a major determinant of the course of disease. Although the course may be more protracted in patients with YOPD, the terminal stage, manifested by more rapid physical and cognitive decline, may be similar across groups irrespective of age at onset.12 Compared with patients with LOPD, the disease in those with YOPD affects quality of life more adversely in terms of loss of employment, disruption of family life, perceived stigma, and depression.13
Motor Phenotype Several studies have confirmed that patients presenting with tremor at onset have a slower progression of disease than those with a PIGD subtype4,14 The tremor-dominant form of PD is often initially misdiagnosed as essential tremor, particularly if the patients have had a long-standing history of tremor. The overlap between clinical features of PD and essential tremor and the possible pathogenic link between the two disorders has been a subject of several recent reviews.15,16 An entity named benign tremulous parkinsonism has been described in patients with predominant rest tremor, mild nontremor signs, absence of gait disorder, and mild progression of parkinsonism other than tremor despite many years of disease.17 A case series of 16 such patients were found to have a lower mean age at onset (58.5 years) than most PD series and a poor response to levodopa.18 An autopsy evaluation of 21 such cases found less severe neuronal loss in the substantia nigra than in pathologically proven PD controls, indicating a slower progression of neuronal degeneration.18 Others have argued against the term benign tremulous parkinsonism and proposed the term monosymptomatic tremor at rest19 because patients with advanced cases have troublesome symptoms along with imaging evidence of dopaminergic deficit; hence, the condition is not “benign.” Nonmotor symptoms, such as cognitive impairment, also vary according to motor subtype. The PIGD form of PD is associated with a faster rate of cognitive decline and a higher incidence of dementia.20 One study demonstrated that patients with tremordominant PD may start to show signs of dementia only after PIGD symptoms develop.20 In addition to cognitive decline, depression and apathy are often associated with the nontremor-dominant PD subtype.21,22 Olfaction among PD subtypes has been the focus of few studies, demonstrating more impaired olfaction in the akineticrigid subtype than in the tremor-dominant group.23
Imaging Findings Various imaging modalities, including positron emission tomography (PET), single-photon emission computed tomography (SPECT), and functional magnetic resonance imaging, are increasingly used to identify the neural circuits and connectivity involved in specific PD signs. Fluorodopa PET scans have been shown to correlate well with certain PD signs and symptoms, particularly bradykinesia, and with postmortem nigral cell count.24 In terms of age at onset, a study using
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3 presynaptic dopamine markers, (6) dihydrotetrabenazine labeled with carbon 11 (11C), [11C]d-threo-methylphenidate, and 6-fluoro-L-dopa labeled with fluorine 18 (18F) found that younger patients have a greater decrease of dihydrotetrabenazine putaminal binding at onset than older patients; however, the rate of dihydrotetrabenazine binding loss progressed more slowly in patients with YOPD.25 Scanning with SPECT can be used to evaluate the presynaptic dopaminergic system by measuring the density of striatal dopamine transporter. Several dopamine transporter SPECT studies have found a significant correlation between striatal iodine 123 (123I) fluoropropyl (FP) carbomethoxy-3 β-(4-iodophenyltropane) (CIT) uptake and the severity of akinetic-rigid symptoms but not with tremor.26,27 One FP-CIT SPECT study comparing 24 patients with tremor-dominant PD and 28 with akinetic-rigid PD found that uptake in the contralateral putamen was significantly lower in the akinetic-rigid phenotype than in the tremor-dominant phenotype.26 Another study comparing FP-CIT SPECT findings in 122 patients with PD found different patterns of dopamine uptake based on visual analysis.27 The tremor-dominant patients had an “eagle wing” striatal configuration, corresponding to dopamine loss in the caudate and lateral putamen. In contrast, the patients with akinetic-rigid PD had an egg-shaped configuration, corresponding to dopaminergic loss in the dorsal putamen.27 These findings, however, require validation by other studies using larger samples and different imaging techniques, such as PET tracer [18F]9-fluoropropyl-(+)-dihydrotetrabenazine ([18F]AV-133), targeting vesicular monoamine transporter 2.28 Several imaging studies have demonstrated that loss of neurotransmitters other than dopamine contribute to the pathophysiologic mechanism of parkinsonian tremor and other parkinsonian motor and nonmotor features. For example, loss of thalamic serotonin has been implicated in the generation of rest tremor.29,30 One PET study involving 23 patients with PD found a 27% reduction in raphe 5-HT1A receptor binding compared with controls; this reduction correlated with Unified Parkinson’s Disease Rating Scale tremor scores but not with rigidity or bradykinesia.29 With [ 11 C]dihydrotetrabenazine dopaminergic and [ 11 C]methyl-4piperidinyl propionate acetylcholinesterase PET imaging, cortical cholinergic denervation was found to correlate more with slowing of gait in PD than with nigrostriatal denervation.31 Thus, the various cardinal signs of PD may be related to different neurotransmitter deficiencies: whereas dopaminergic deficiency correlates well with bradykinesia and rigidity, serotonin seems to play a role in tremor, and cholinergic deficit seems to contribute to gait disorder associated with PD. One study used functional magnetic resonance imaging to compare the activation of striatothalamocortical and cerebellothalamocortical circuits in 17 patients with PD (9 with tremordominant and 8 with akinetic-rigid PD) and 14 controls and found that patients with tremor-dominant PD had significantly more activity in contralateral cerebellothalamocortical circuits, supporting the differential involvement of the two circuits in PD subtypes.32 Another study, including 44 patients with PD (21 with tremor-dominant and 23 with nontremor-dominant PD) and 36 controls, used functional magnetic resonance imaging and [123I]FP-CIT to investigate the interplay between the basal ganglia and the cerebellothalamic circuitry in generating rest tremor and jamaneurology.com
found that pallidal dopamine depletion was correlated with tremor severity.33 These findings suggest that rest tremor involves cerebellothalamocortical circuitry, which is driven largely by the dopamine-depleted basal ganglia. In a study using functional magnetic resonance imaging and voxel-based morphometry to examine functional and structural differences between 20 patients with tremor-dominant or nontremor-dominant PD and healthy controls, both voxel-based and region-of-interest analyses showed that patients with nontremor-dominant PD had reduced brain activity in the prefrontal cortex and globus pallidus compared with both patients with tremor-dominant PD and controls. 34 Another study found decreased gray matter volume in the cerebellum of patients with PD and rest tremor compared with patients with PD without rest tremor. 35 These and other studies provide evidence for the involvement of the cerebellothalamocortical circuitry in parkinsonian tremor. In contrast, voxel-based morphometry showed smaller gray matter and presupplementary motor volume in the PIGD subgroup, particularly in areas involving motor, cognitive, limbic, and associative functions.36 This pattern suggests that degeneration of cortical areas involved in motor planning may contribute to the PIGD phenotype.
Biomarkers Refinements in genomics, proteomics, lipidomics, and metabolics applied to blood, cerebrospinal fluid, and other tissues may lead to early identification of PD and aid in differentiating the various subtypes.37 There are emerging data on blood and cerebrospinal fluid markers that correlate with motor or nonmotor symptoms associated with PD. For example, low plasma levels of epidermal growth factor have been found to correlate with baseline cognitive impairment in patients with PD.38 Furthermore, lower cerebrospinal fluid Aβ1-42 and P-tau181 concentrations were associated with PIGD PD but not with the tremor-dominant form.39
Genetics In the past decade, there has been an explosion of knowledge about the genetics of PD, and 18 PD-related gene loci have been identified40 (Table). Both autosomal dominant and autosomal recessive genetic forms of PD have been identified, with distinct and overlapping phenotypes. The first gene associated with PD was identified in 1997 as a missense mutation in the α-synuclein (SNCA) gene with an autosomal dominant mode of inheritance.41 Later, duplications or triplications of the SNCA gene were found in patients with PD phenotypes.42 Seven SNCA mutations have since been identified and found to be associated with early-onset parkinsonism, moderate response to levodopa, rapid progression, pyramidal signs, frequent psychiatric symptoms, and prominent cognitive dysfunction.41-43 The most common autosomal dominant form of parkinsonism involves missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene.44 The G2019S LRRK2 mutation is highly prevalent in the Ashkenazi Jewish and North African populations.44 The phenotype associated with LRRK2 mutation is highly variable but is quite similar to sporadic PD, particularly asymmetric parkinsonism with tremor, but with a decreased risk of cognitive and olfactory impairment, although atypical features such as orthostatic hypotension, dementia, hallucinations, and sleep disturbance have been deJAMA Neurology April 2014 Volume 71, Number 4
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Table. Genetically Determined Parkinsonism Locus
Inheritance
Gene
Protein
PARK1
AD
SNCA
α-Synuclein
PARK2
AR
PARK2
Ubiquitin ligase
PARK3
AD
?
?
PARK4
AD
SNCA
α-Synuclein
PARK5
AD
UCHL1
Ubiquitin cyclohydrolase A
PARK6
AR
PINK1
PTEN-induced kinase 1
PARK7
AR
DJ-1
DJ-1
PARK8
AD
LRRK2
LRRK2 (dardarin)
PARK9
AR
ATP13A2
Lysosomal type 5 P-type ATPase
PARK10
AD
?
?
PARK11
AD
GIGYF2
GRB10-interacting GYF protein 2
PARK12
X-linked
?
?
PARK13
AD
HTRA2
Serine protease
PARK14
AR
PLA2G6
Phospholipase A2
PARK15
AR
FBXO7
F-box protein 7
PARK16
?
?
?
PARK17
AD
VPS35
VPS35
PARK18
AD
EIF4G1
EIF4G1
scribed in LRRK2 cases. In contrast, based on a study of patients with YOPD, G2019S mutation carriers were more likely to have a PIGD phenotype and less tremor.45 The pathologic changes in the brains of patients with LRRK2-associated PD are quite variable and may include pure nigral degeneration without LBs, typical α-synuclein LB disease, and even neurofibrillary tangle disease with TDP-43 (transactive response DNA-binding protein 43 kDa) inclusions and β-amyloid deposits in anterior horn cells. Mutations in two new genes causing autosomal dominant PD have been recently identified: vacuolar protein sorting 35 homologue gene (VPS35)46 and eukaryotic translation initiation factor 4G1.47 The autosomal recessive forms of parkinsonism include mutations in the parkin gene (PARK2),48 the phosphatase and tensin homologue–induced putative kinase 1 gene (PINK1),49 and the DJ1 gene.50 These mutations are generally associated with YOPD and manifested by a good response to levodopa and early development of dyskinesias.40 Although early cognitive impairment is uncommon, psychiatric comorbid conditions have been reported to be present in PINK1-associated and DJ1-associated PD. Both PARK2 and PINK1 genes have been reported to play a role in mitochondrial function, suggesting that mitochondrial dysfunction plays a role in PD pathogenesis. Furthermore, mutations in the glucocerebrosidase gene have been found to be a risk factor for PD in the Ashkenazi Jewish population. Patients with these mutations have been shown to have an earlier onset of disease and more prominent cognitive dysfunction.51 The loss of function mutations in glucocerebrosidase suggests a role for lysosomal dysfunction in the pathogenesis of PD.52
Pathologic Findings A definite diagnosis of PD requires autopsy confirmation of pathologic findings typical for PD. The core pathologic findings underlying PD are degeneration of melanin and dopamine-containing neurons, especially in the zona compacta of the substantia nigra, and the presence of LBs, eosinophilic cytoplasmic inclusions, and 502
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; ATPase, adenosine triphosphatase; EIF4G1, eukaryotic translation initiation factor 4G1; LRRK2, leucine-rich repeat kinase 2; PTEN, phosphatase and tensin homologue; VPS35, vacuolar protein sorting 35; ?, unknown.
dystrophic Lewy neurites.1,53,54 There is growing appreciation for pathologic involvement in PD not only of brain dopaminergic systems but also of nondopaminergic systems in the brain as well as peripheral and autonomic systems. Several studies have drawn attention to the involvement of cardiac, gastrointestinal, submandibular gland, cutaneous, and other body regions, all of which have been found to have LB disease with deposition of abnormal α-synuclein.55-57 There is also growing evidence that the initial site of disease in PD may not necessarily be in the substantia nigra but may be in the nuclei of the caudal brainstem or even in the peripheral nervous system and peripheral organs.54 The hypothesis that progression of neurodegenerative disease is mediated via seeding of misfolded proteins, also known as “templating,” with intracerebral and transynaptic propagation of fibrils has extended to a broad range of proteins, including α-synuclein, tau, huntingtin, superoxide dismutase 1, and TDP-43.58 Furthermore, in the central nervous system there is evidence for striatonigral rather than nigrostriatal progression, with the initial disease site in the striatum and “dying-back” axonopathy resulting in retrograde degeneration and neuronal loss in the substantia nigra.59 Postmortem studies have examined differences between PD subtypes, particularly tremor-dominant vs akinetic-rigid phenotypes.60-63 In a clinicopathologic study involving 166 cases collected over 39 years, 26% of pathologically confirmed PD cases were classified as akinetic-rigid, 8% as tremor dominant, and 66% as mixed. 64 Another clinicopathologic study of 72 autopsyconfirmed cases at a tertiary care center found that 16% of patients had PIGD at onset and 49% had tremor at onset.65 In a neuropathologic study of 27 patients with akinetic-rigid PD and 18 with tremor-dominant PD, those in the former group had greater neuronal loss in the substantia nigra pars compacta, especially the lateral portion, and the locus coeruleus.60 Another clinicopathologic study found degeneration of a subgroup of midbrain (A8) neurons in patients with tremor-dominant PD, but this region was
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spared in patients with PD without tremor.61 This is consistent with the finding of greater loss of neurons in the retrorubral A8 field, which contains predominantly calretinin-staining cells but few tyrosine hydroxylase and dopamine transporter immunoreactive neurons.62 Patterns of striatal and pallidal dopamine loss seem to vary among the different PD motor subtypes. 63 For example, in contrast to severe loss of dopamine in the ventral globus pallidus internus, near-normal dopamine levels were found in the basal ganglia of patients with tremor-dominant PD. Studies have also demonstrated more severe cortical LB disease in patients with nontremor-dominant PD than in those with tremordominant PD.66,67 ARTICLE INFORMATION Accepted for Publication: December 13, 2013. Published Online: February 10, 2014. doi:10.1001/jamaneurol.2013.6233. Author Contributions: Drs Thenganatt and Jankovic had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Both authors. Acquisition of data: Both authors. Analysis and interpretation of data: Both authors. Drafting of the manuscript: Thenganatt. Critical revision of the manuscript for important intellectual content: Both authors. Administrative, technical, or material support: Both authors. Conflict of Interest Disclosures: None reported. REFERENCES
Conclusions As we learn more about PD, it is becoming abundantly clear that PD is a heterogeneous disorder with variable clinical characteristics and imaging findings, as well as different genetic and other underlying neuropathologic mechanisms. Identifying subtype-specific biomarkers will enhance our ability to categorize various PD phenotypes into subtypes, which will lead to a better understanding of pathogenesis, clinical progression, and prognosis. The existence of the various PD subtypes should be considered in the design and interpretation of epidemiologic studies and clinical trials.
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