Large French-Canadian family with Lewy body parkinsonism: exclusion of known loci.

The identification of rare, large families with Parkinson's disease (PD) has provided important clues that have contributed to our understanding of this complex disorder. We have identified a large French-Canadian kindred that spans five generations consisting of more than 90 individuals. A total of 65 individuals now have been examined, had venous blood drawn, and DNA extracted. Two-point and multipoint linkage analysis was performed to assess linkage to known PD genes or loci. Within the third and fourth generations of this family there are 10 living, plus 3 deceased members with well-documented levodopa responsive parkinsonism. Autopsy results on 1 member demonstrated the loss of pigmented neurons in the substantia nigra and the presence of alpha-synuclein positive Lewy bodies. Four of the PD patients have prominent postural and kinetic tremors that preceded their parkinsonism by up to 10 years. Two other individuals within the family have prominent isolated postural and kinetic tremors without parkinsonism. The alpha-synuclein(4q21.3-23), Parkin(6q25.2-27), PARK3 (2p13), PARK4, and ubiquitin carboxy terminal hydrolase-L1 (4p14-16.3) and PARK6 and PARK7 (1p35-36) loci were excluded in this kindred using closely linked markers. The clinical and pathological features of this family are consistent with the diagnosis of PD. This family further demonstrates the known genetic heterogeneity in PD and is large enough that a genome-wide screen has been undertaken in an effort to identify a novel PD gene.     

Immunoreactivity of myelin‐associated oligodendrocytic basic protein in Lewy bodies

Myelin‐associated oligodendrocytic basic protein (MOBP) plays a role in structural maintenance of the myelin sheath in the central nervous system. Recent genome analyses have revealed that mutation in MOBP is a risk factor for various neurodegenerative diseases, including Alzheimer's disease (AD), tauopathies and transactivation response DNA‐binding protein 43 kDa proteinopathies. Proteomics analysis has shown that MOBP is a component of cortical Lewy bodies (LBs). However, the immunohistochemical localization of MOBP in the human brain is not known. Using immunohistochemistry, we examined the brain, spinal cord and peripheral ganglia from patients with various neurodegenerative diseases and control subjects. In normal controls, MOBP immunoreactivity was evident in the myelin in the central and peripheral nervous systems (PNS), and neuronal cytoplasm in both the central and PNS. In Parkinson's disease and dementia with LBs, MOBP immunoreactivity was found in the core of LBs in the brainstem, cingulate cortex and sympathetic ganglia. No MOBP immunoreactivity was found in a variety of other neuronal or glial inclusions in other disorders, including multiple system atrophy, AD, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Considering that up‐regulation of MOBP has been reported in neurotoxic conditions, accumulation of MOBP in LBs may imply a cytoprotective mechanism in LB disease.     

Non‐uniformity in the regional pattern of Lewy pathology in brains of dementia with Lewy bodies

We examined the regional pattern of Lewy pathology in brains of dementia with Lewy bodies (DLB) to clarify whether Lewy pathology uniformly progresses or not. Thirty‐five autopsied DLB cases were examined using α‐synuclein‐immunohistochemistry, and the regional degree of Lewy pathology in the brainstem, diencephalon and cerebral cortex was quantitatively evaluated. Consequently, we found that the regional pattern of Lewy pathology differed according to the pathological subtype, and was divided into three types: type 1 showed a brainstem‐predominant pattern, type 2 was almost equal for the brainstem and cerebral cortex, and type 3 showed a cerebral cortex‐predominant pattern. The limbic type/pure and common forms were mainly composed of type 1, whereas the neocortical type/common and Alzheimer's disease (AD) forms were mainly composed of type 3. These findings suggest the possibility that Lewy pathology of the limbic type/pure and common forms mainly progresses from the brainstem to the cerebrum, whereas that of the neocortical type/common and AD forms mainly progresses from the cerebrum to the brainstem. Cases with type 1 Lewy pathology mainly developed parkinsonism, whereas those with type 3 Lewy pathology mainly developed dementia. This corresponded to most of the limbic type/pure and common forms which developed parkinsonism, whereas most of the neocortical type/common and AD forms developed dementia. Type 1 cases may thus be clinically diagnosed as having Parkinson's disease (PD) with dementia. These findings suggest that PD has clinico‐pathological continuity with DLB, and that the regional pattern of Lewy pathology is not uniform.     

Isopentenyl diphosphate isomerase,a cholesterol synthesizing enzyme,is localized in Lewy bodies

Isopentenyl diphosphate isomerase (IDI) is a cytoplasmic enzyme involved in the biosynthesis of isoprenoids including cholesterols. IDI has two isoforms in humans: IDI1 and IDI2. Since lipids are known to be a component of Lewy bodies (LBs), we investigated the immunohistochemical localization of IDI1 and IDI2 in the brain of patients with LB disease and multiple system atrophy (MSA) and normal control subjects. In normal controls, the cytoplasm of neurons was weakly immunostained with anti‐IDI1 and anti‐IDI2 antibodies throughout the nervous system. In LB disease, brainstem‐type LBs were strongly positive for IDI1 and IDI2, and cortical LBs were unstained or barely immunolabeled. Double immunofluorescence staining revealed co‐localization of phosphorylated α‐synuclein with IDI1 or IDI2. Glial cytoplasmic inclusions in MSA were unstained. Previous studies have shown that levels of cholesterol metabolites are increased in the cerebral cortex of patients with LB disease, and that these metabolites accelerate α‐synuclein aggregation. The present findings suggest that IDI1 and IDI2 may be associated with the production of cholesterol metabolites in neurons, leading to α‐synuclein aggregation during the process of LB formation.     

Stage‐dependent nigral neuronal loss in incidental Lewy body and Parkinson's disease

To gain a better understanding of the significance of α‐synuclein pathological conditions during disease progression in Parkinson's disease, we investigated whether 1) nigral neuronal loss in incidental Lewy body disease and Parkinson's disease donors is associated with the local burden α‐synuclein pathological conditions during progression of pathological conditions; 2) the burden and distribution of α‐synuclein pathological conditions are related to clinical measures of disease progression. Post‐mortem tissue and medical records of 24 Parkinson's disease patients, 20 incidental Lewy body disease donors, and 12 age‐matched controls were obtained from the Netherlands Brain Bank for morphometric analysis. We observed a 20% decrease in nigral neuronal cell density in incidental Lewy body disease compared with controls. Nigral neuronal loss (12%) was already observed before the appearance α‐synuclein aggregates. The progression from Braak α‐synuclein stage 3 to 4 was associated with a significant decline in neuronal cell density (46%). Nigral neuronal loss increased with later Braak α‐synuclein stages but did not vary across consecutive Braak α‐synuclein stages. We observed a negative correlation between neuronal density and local α‐synuclein burden in the substantia nigra of Parkinson's disease patients (ρ = ?0.54), but no relationship with Hoehn & Yahr stage or disease duration. In conclusion, our findings cast doubt on the pathogenic role of α‐synuclein aggregates in elderly, but do suggest that the severity of neurodegeneration and local burden of α‐synuclein pathological conditions are closely coupled during disease progression in Parkinson's disease. © 2014 International Parkinson and Movement Disorder Society     

Microglial phagocytosis is enhanced by monomeric alpha-synuclein, not aggregated alpha-synuclein: implications for Parkinson's disease

Gathering evidence has associated activation of microglia with the pathogenesis of numerous neurodegenerative diseases of the central nervous system (CNS) such as Alzheimer's disease and Parkinson's disease. Microglia are the resident macrophages of the CNS whose functions include chemotaxis, phagocytosis, and secretion of a variety of cytokines and proteases. In this study, we examined the possibility that alpha-synuclein (alpha-syn), which is associated with the pathogenesis of Parkinson's disease, may affect the phagocytic function of microglia. We found that extracellular monomeric alpha-syn enhanced microglial phagocytosis in both a dose- and time-dependent manner, but beta- and gamma- syn did not. We also found that the N-terminal and NAC region of alpha-syn, especially the NAC region, might be responsible for the effect of alpha-syn on microglial phagocytosis. In contrast to monomeric alpha-syn, aggregated alpha-syn actually inhibited microglial phagocytosis. The different effects of monomeric and aggregated alpha-syn on phagocytosis might be related to their localization in cells. This study indicates that alpha-syn can modulate the function of microglia and influence inflammatory changes such as those seen in neurodegenerative disorders.     

Advanced glycation end products induce in vitro cross-linking of alpha-synuclein and accelerate the process of intracellular inclusion body formation

Cross-linking of alpha-synuclein and Lewy body formation have been implicated in the dopaminergic neuronal cell death observed in Parkinson's disease (PD); the mechanisms responsible, however, are not clear. Reactive oxygen species and advanced glycation end products (AGEs) have been found in the intracellular, alpha-synuclein-positive Lewy bodies in the brains of both PD as well as incidental Lewy body disease patients, suggesting a role for AGEs in alpha-synuclein cross-linking and Lewy body formation. The aims of the present study were to determine 1) whether AGEs can induce cross-linking of alpha-synuclein peptides, 2) the progressive and time-dependent intracellular accumulation of AGEs and inclusion body formation, and 3) the effects of extracellular or exogenous AGEs on intracellular inclusion formation. We first investigated the time-dependent cross-linking of recombinant human alpha-synuclein in the presence of AGEs in vitro, then used a cell culture model based on chronic rotenone treatment of human dopaminergic neuroblastoma cells (SH-SY5Y) over a period of 1-4 weeks, in the presence of different doses of AGEs. Cells (grown on coverslips) and cell lysates, collected at the end of every week, were analyzed for the presence of intracellular reactive oxygen species, AGEs, alpha-synuclein proteins, and intracellular alpha-synuclein- and AGE-positive inclusion bodies by using immunocytochemical, biochemical, and Western blot techniques. Our results show that AGEs promote in vitro cross-linking of alpha-synuclein, that intracellular accumulation of AGEs precedes alpha-synuclein-positive inclusion body formation, and that extracellular AGEs accelerate the process of intracellular alpha-synuclein-positive inclusion body formation.     

Genetics of parkinsonism.

Parkinson's disease (PD) was noted to have a familial component as early as 1880 (Leroux, 1880). More recently, the discovery of several genetic factors influencing parkinsonism has emphasized the importance of heredity in PD. The clinical spectrum of familial parkinsonism is wide; it includes not only PD, but also dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), essential tremor, and other disorders. In the general population, it is likely that PD results from combined genetic and environmental factors, most of which are not yet known. The discovery of causal mutations in the gene for alpha-synuclein, parkin, and of genetic linkages to chromosomes 2p4, 4p5, and three loci on 1q6-8 have revolutionized PD research. This review focuses on recent progress in the Mendelian genetics of PD and those diseases in which parkinsonism is a prominent feature, and considers how these discoveries modify our beliefs regarding the etiology and pathogenesis of these disorders.     

1-Benzyl-1,2,3,4-tetrahydroisoquinoline, a Parkinsonism-inducing endogenous toxin, increases alpha-synuclein expression and causes nuclear damage in human dopaminergic cells

1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), an endogenous neurotoxin, is known to cause parkinsonism in rodents and nonhuman primates. The levels of 1BnTIQ in cerebrospinal fluid of patients with Parkinson's disease (PD) were reported to be three times higher than those in control subjects. In the present study, we have evaluated the effects of 1BnTIQ on alpha-synuclein (alpha-syn) expression together with biochemical and morphological changes in human dopaminergic SH-SY5Y cells in culture. 1BnTIQ at lower concentrations (1-50 microM) increased alpha-syn protein expression in a time- and dose-dependent manner in these cells. There was also up-regulation of alpha-syn mRNA by 1BnTIQ. Inhibition of complex I by rotenone and depletion of glutathione by L-buthionine sulfoxamine also correlated with an increase in alpha-syn expression, suggesting that oxidative stress may cause an increase in alpha-syn levels in dopaminergic cells. Furthermore, 1BnTIQ significantly depleted glutathione levels. 1BnTIQ at higher concentrations (500 microM) increased reactive oxygen species levels, decreased ATP levels, and caused nuclear damage in the cells. The 1BnTIQ-induced alpha-syn up-regulation was inhibited by cotreatment with the antioxidants selegiline, coenzyme Q(10), and N-acetylcystein and the caspase inhibitor DEVD-CHO. Taken together, these results suggest that alpha-syn up-regulation and oxidative stress are contributing factors in 1BnTIQ-induced neurotoxicity in dopaminergic neurons in PD.     

Association of alpha-synuclein Rep1 polymorphism and Parkinson's disease: influence of Rep1 on age at onset.

The alpha-synuclein Rep1 polymorphism was studied in patients and controls in an ethnic Greek population. There was an association of allele 2 with risk of Parkinson's disease (PD; adjusted odd ratio = 3.25; 95% CI = 1.80-5.87). Survival analyses (Cox proportional hazards models) were employed to explore the influence of genotypes on age at onset of PD. Age at onset of carriers of at least one Rep1 allele 2 was earlier (3.6 years) compared to noncarriers (adjusted hazard ratio = 2.21; 95% CI = 1.58-3.10). Kaplan-Meier analysis also supported a dosage effect of Rep1 allele 2 on age at onset. For Rep1 allele 1, there was neither association with risk of PD nor influence on age at onset. This is the first study showing an influence of Rep1 polymorphism on age at onset of PD.     

Characterization of kinases involved in the phosphorylation of aggregated α-synuclein

α-Synuclein (α-syn) is the major component of pathological inclusions characteristic of several neurodegenerative disorders, such as Parkinson's disease. The major posttranslational modification of α-syn is phosphorylation at S129, and previous studies estimate that approximately 90% of α-syn in proteinaceous, pathological inclusions is phosphorylated at this site. α-Syn can be phosphorylated by polo-like kinases (PLKs) 1-3 and casein kinases (CK) 1 and 2; however, the kinases associated with the hyperphosphorylation of aggregated α-syn are still under debate. Using a high-efficiency cellular model of α-syn aggregate formation, we found that selective inhibitors for CK2 and PLKs each partially inhibited S129 phosphorylation of soluble (nonaggregated) α-syn, but only PLK inhibitors modestly attenuated the phosphorylation of aggregated α-syn. In addition, none of the kinase inhibitors used had a substantial effect on the propensity of α-syn to aggregate. Overexpression of all PLKs promoted robust phosphorylation of soluble α-syn, but none altered the propensity of α-syn to aggregate. Overexpression of only PLK2 increased phosphorylation of aggregated α-syn at S129, which likely is due to increased phosphorylation of soluble α-syn, which then was incorporated into aggregates. Overexpression of PLK1 and treatment with BI2536 resulted in a significant reduction of phosphorylated, aggregated α-syn protein, beyond that of BI2536 treatment alone. These studies suggest that phosphorylation of α-syn is independent of α-syn aggregate formation, that PLK1 is involved in the phosphorylation of aggregated α-syn at S129 in this system, and that mechanisms resulting in hyperphosphorylation of aggregated α-syn appear to be independent of those responsible for the phosphorylation of soluble α-syn.     

The Lewy body in Parkinson's disease: Molecules implicated in the formation and degradation of α‐synuclein aggregates

The histological hallmark of Parkinson's disease (PD) is the presence of fibrillar aggregates called Lewy bodies (LBs). LB formation has been considered to be a marker for neuronal degeneration, because neuronal loss is found in the predilection sites for LBs. To date, more than 70 molecules have been identified in LBs, in which α‐synuclein is a major constituent of LB fibrils. α‐synuclein immunohistochemistry reveals that diffuse cytoplasmic staining develops into pale bodies via compaction, and that LBs arise from the peripheral portion of pale bodies. This α‐synuclein abnormality is found in 10% of pigmented neurons in the substantia nigra and more than 50% of those in the locus ceruleus in PD. Recent studies have suggested that oligomers and protofibrils of α‐synuclein are cytotoxic, and that LBs may represent a cytoprotective mechanism in PD.     

TorsinA accumulation in Lewy bodies in sporadic Parkinson's disease

Parkinson's disease (PD) is a neurodegnerative disorder that is pathologically characterized by the presence of Lewy bodies in the brain. We show that Lewy bodies in PD are strongly immunoreactive for torsinA, the protein product of the DYT1 gene, which is associated with primary generalized dystonia. In the substantia nigra, torsinA immunoreactivity is localized to the periphery of Lewy bodies, whereas, in cortical Lewy bodies it is uniformly distributed. The significance of this finding is unknown, but may implicate torsinA in neuronal dysfunction that occurs in PD as well as in primary dystonia.     

Lysosomal pathology associated with alpha-synuclein accumulation in transgenic models using an eGFP fusion protein

Disorders with Lewy body (LB) formation, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB), are characterized by alpha-synuclein accumulation in the neuronal cell body. Recent studies have suggested that in addition to LBs, alpha-synuclein might accumulate more widely throughout the neurons and their processes, leading to neurodegeneration and functional impairment. The precise patterns of alpha-synuclein accumulation in vivo, however, and its relationship with subcellular neuronal alterations such as lysosomal pathology are not completely clear. To this end, we developed transgenic (tg) in vivo and in vitro models expressing a stable enhanced green fluorescent protein (eGFP) tagged in the C-terminal site of a human (h)alpha-synuclein construct under the regulatory control of the platelet-derived growth factor-beta (PDGFbeta) promoter and carried out confocal, ultrastructural, and biochemical studies. In tg mice, confocal studies demonstrated a wide distribution of halpha-synuclein-eGFP in the neuronal cell bodies, axons, and presynaptic terminals. In several neuronal cell bodies and their neurites, halpha-synuclein-eGFP was found not only as inclusions but also as discrete granular structures that in double-labeling studies colocalized with antibodies against halpha-synuclein and the lysosomal marker cathepsin D. Consistent with these findings, ultrastructural analysis showed that halpha-synuclein-eGFP overexpression resulted in the accumulation of electrodense inclusions and laminated bodies suggestive of lysosomal pathology, and that the halpha-synuclein-eGFP protein was more abundant in the lysosomal fractions of the tg animals. Taken together, these findings support the notion that enhanced visualization of alpha-synuclein utilizing a hybrid eGFP molecule reveals a more widespread accumulation of this molecule in several neuronal compartments, promoting lysosomal dysfunction. Furthermore, the PDGFbeta-halpha-synuclein-eGFP tg model might be a valuable tool in testing new treatments for LBD in a fast and reliable manner.     

Accumulation of histone deacetylase 6, an aggresome‐related protein,is specific to Lewy bodies and glial cytoplasmic inclusions

Histone deacetylase 6 (HDAC6) plays a crucial role in aggresome formation, resulting in the clearance of misfolded proteins. Previous studies have shown that HDAC6 is concentrated in Lewy bodies (LBs) in Parkinson's disease (PD) and dementia with LBs (DLB) (Cell 115: 727–738, 2003). We performed immunohistochemical and ultrastructural investigations on the brains of patients with various neurodegenerative disorders. Anti‐HDAC6 antibody faintly immunostained the cytoplasm of neuronal and glial cells in control subjects. In PD and DLB, almost all of the cortical, brainstem‐type and peripheral LBs were intensely immunolabeled with anti‐HDAC6. In multiple system atrophy (MSA), the vast majority of glial cytoplasmic inclusions (GCIs) were also positive for HDAC6. Immunoelectron microscopy revealed that the reaction product was localized to the filamentous structures in LBs and GCIs. Various neuronal and glial inclusions in neurodegenerative disorders other than LB disease and MSA were HDAC6‐negative. These findings suggest that accumulation of HDAC6 is specific to α‐synucleinopathy and that both LBs and GCIs may represent cytoprotective responses to sequester toxic proteins.     

Multiple organ involvement by alpha‐synuclein pathology in Lewy body disorders

Lewy body (LB) diseases are characterized by alpha‐synuclein (AS) aggregates in the central nervous system (CNS). Involvement of the peripheral autonomic nervous system (pANS) is increasingly recognized, although less studied. The aim of this study was to systematically analyze the distribution and severity of AS pathology in the CNS and pANS. Detailed postmortem histopathological study of brain and peripheral tissues from 28 brain bank donors (10 with Parkinson's disease [PD], 5 with dementia with LB [DLB], and 13 with non‐LB diseases including atypical parkinsonism and non‐LB dementia). AS aggregates were found in the pANS of all 15 LB disease cases (PD, DLB) in stellate and sympathetic ganglia (100%), vagus nerve (86.7%), gastrointestinal tract (86.7%), adrenal gland and/or surrounding fat (53.3%), heart (100%), and genitourinary tract (13.3%), as well as in 1 case of incidental Lewy body disease (iLBD). A craniocaudal gradient of AS burden in sympathetic chain and gastrointestinal tract was observed. DLB cases showed higher amounts of CNS AS aggregates than PD cases, but this was not the case in the pANS. No pANS AS aggregates were detected in Alzheimer's disease (AD) cases with or without CNS AS aggregates. All pathologically confirmed LB disease cases including 1 case of iLBD had AS aggregates in the pANS with a craniocaudal gradient of pathology burden in sympathetic chain and gastrointestinal tract. AS was not detected in the pANS of any AD case. These findings may help in the search of peripheral AS aggregates in vivo for the early diagnosis of PD. © 2014 International Parkinson and Movement Disorder Society     

α‐Synuclein pathology in the cranial and spinal nerves in Lewy body disease

Accumulation of phosphorylated α‐synuclein in neurons and glial cells is a histological hallmark of Lewy body disease (LBD) and multiple system atrophy (MSA). Recently, filamentous aggregations of phosphorylated α‐synuclein have been reported in the cytoplasm of Schwann cells, but not in axons, in the peripheral nervous system in MSA, mainly in the cranial and spinal nerve roots. Here we conducted an immunohistochemical investigation of the cranial and spinal nerves and dorsal root ganglia of patients with LBD. Lewy axons were found in the oculomotor, trigeminal and glossopharyngeal‐vagus nerves, but not in the hypoglossal nerve. The glossopharyngeal‐vagus nerves were most frequently affected, with involvement in all of 20 subjects. In the spinal nerve roots, Lewy axons were found in all of the cases examined. Lewy axons in the anterior nerves were more frequent and numerous in the thoracic and sacral segments than in the cervical and lumbar segments. On the other hand, axonal lesions in the posterior spinal nerve roots appeared to increase along a cervical‐to‐sacral gradient. Although Schwann cell cytoplasmic inclusions were found in the spinal nerves, they were only minimal. In the dorsal root ganglia, axonal lesions were seldom evident. These findings indicate that α‐synuclein pathology in the peripheral nerves is axonal‐predominant in LBD, whereas it is restricted to glial cells in MSA.     

Widespread occurrence of argyrophilic glial inclusions in Parkinson's disease.

Argyrophilic glial inclusions, which are immunohistochemically positive for alpha-synuclein but negative for tau protein, were examined in the brain of Parkinson's disease (PD) patients. Autopsied brains of 10 individuals who died from PD, of two incidental Lewy body disease cases and of five age-matched individuals whose deaths were caused by non-neurological diseases were studied, histopathologically, by Gallyas-Braak staining and, immunohistochemically, with anti-alpha-synuclein antibody, anti-ubiquitin, and anti-tyrosine hydroxylase. All postmortem PD brains showed a significant number of argyrophilic glial inclusions, but no glial inclusions were found in control brains. The inclusions were found not only in the regions showing neuronal loss and gliosis, such as the substantia nigra, locus ceruleus and dorsal vagal nucleus, but also in regions without neuronal loss and gliosis, such as the cerebral cortex, cerebral white matter, striatum, globus pallidus, thalamus, cerebellum and spinal cord. The distribution and density of glial inclusions in PD brains varied from case to case but, in the cerebral cortex, the number of glial inclusions were fairly well correlated with the number of Lewy bodies. The distribution pattern of glial inclusions also showed a striking resemblance to that of catecholaminergic neurones and fibres. The abnormal accumulation of alpha-synuclein in glial cells was more widespread than neurone loss, and appears to be an important pathological feature of PD.     

Plasma α‐synuclein in patients with Parkinson's disease with and without treatment

Alpha‐synuclein (α‐syn) is an intracellular protein with a high tendency to aggregation. It is the major component of Lewy bodies and may play a key role in the pathogenesis of Parkinson's disease (PD). α‐Syn is also released by neurons and can be detected in biological fluids, such as plasma. The purpose of this study was to determine whether plasma α‐syn concentrations are elevated in newly diagnosed PD patients before treatment (nontreated PD group, ntPD; n = 53) and to compare them with concentrations in PD patients with at least 1 year of specific treatment (tPD; n = 42) and in healthy controls (n = 60). Plasma α‐syn concentrations in the ntPD and tPD groups were similar and significantly higher than in healthy controls. In conclusion, α‐syn was elevated early in the development of PD and specific PD treatment did not change plasma α‐syn levels. © 2010 Movement Disorder Society