Patterns of α-synuclein pathology in incidental cases and clinical subtypes of Parkinson's disease

Parkinson's disease (PD) is characterized by a gradual accumulation of neuropathology that may begin many years before a clinical diagnosis can be made using currently accepted criteria. Here, we first review the prevalence of α-synuclein neuropathology in elderly and discuss its clinical relevance in Parkinson patients. Subsequently, the results of a retrospective study focussing on the distribution of neuropathology in Parkinson patients with a tremor-dominant (TD), non-tremordominant (NTD) or rapid disease progression (RDP) subtype are presented. The study population recruited by the Netherlands Brain bank consisted of 149 non-neurological donors, 26 donors with incidental Lewy body disease (iLBD) and 111 Parkinson patients. In total, 89% of these cases could be classified in accordance with the Braak staging when taking into account the severity of α-synuclein pathology and adding an amygdala-predominant category of synucleinopathy. The pathological progression seemed to be non-linear. Interestingly, a strong correlation between neuronal loss and α-synuclein pathology was observed in the substantia nigra in Braak stages 3-6 (P < 0.01). However, there was no correlation between Hoehn & Yahr and Braak stages. Neuropathological progression may, however, vary between subtypes as cortical Lewy body load and Braak stages were higher in patients with NTD compared to TD and Alzheimer pathology was more prevalent in RDP patients. Recognition of clinical subtypes in neuropathological studies is essential to identify selective vulnerability to protein accumulation that may determine the clinical phenotype in PD.     

The synaptic pathology of α-synuclein aggregation in dementia with Lewy bodies, Parkinson’s disease and Parkinson’s disease dementia

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are usually associated with loss of dopaminergic neurons. Loss of substantia nigra neurons and presence of Lewy body inclusions in some of the remaining neurons are the hallmark pathology seen in the final stages of the disease. Attempts to correlate Lewy body pathology to either cell death or severity of clinical symptoms, however, have not been successful. While the pathophysiology of the neurodegenerative process can hardly be explained by Lewy bodies, the clinical symptoms do indicate a degenerative process located at the presynapse resulting in a neurotransmitter deficiency. Recently it was shown that 90% or even more of α-synuclein aggregates in DLB cases were located at the presynapses in the form of very small deposits. In parallel, dendritic spines are retracted, whereas the presynapses are relatively preserved, suggesting a neurotransmitter deprivation. The same α-synuclein pathology can be demonstrated for PD. These findings give rise to the notion that not cell death but rather α-synuclein aggregate-related synaptic dysfunction causes the neurodegeneration. This opens new perspectives for understanding PD and DLB. If presynaptic α-synuclein aggregation, not neuronal loss, is the key issue of the neurodegenerative process, then PD and DLB may eventually be treatable in the future. The disease may progress via trans-synaptical spread, suggesting that stem cell transplants are of limited use. Future therapies may focus on the regeneration of synapses.     

Tau and α-synuclein brainstem pathology in Alzheimer disease: relation with extrapyramidal signs

Extrapyramidal symptoms (EPS) in Alzheimer disease (AD) often increase with disease severity. Their neuropathological substrate is a matter of discussion. We investigated tau and alpha-synuclein (AS) pathologies in brainstem in AD patients with and without EPS. Among 160 elderly subjects with autopsy-proven AD (110 female, 50 male, aged 61-102, mean 84.1 +/- 8.3 SD years), 151 (94.4%) being demented, 35 (21.9%) had clinically reported EPS (rigidity, bradykinesia, gait impairment). Neuropathological examination included standardized classification of AD according to current criteria, and semiquantitative assessment of neuronal loss in substantia nigra (SN), locus coeruleus (LC), and of tau and AS lesions in brainstem, and, in addition, of cerebrovascular lesions. The prevalence of EPS was only slightly more frequent in higher Braak stages. Tau pathology in brainstem significantly increased with increasing Braak stages, while AS lesions did not. EPS correlated best with SN cell loss (P < 0.001) and much less with AS pathology in several brain areas (P < 0.05), except in medulla oblongata (P < 0.001). Although both pathologies in substantia nigra correlated with neuron loss (P < 0.001), nigral tau lesions, present in 88.5% of EPS positive cases (without AS lesions in 55.6%), did not correlate with EPS. Additional cerebrovascular changes apparently did not influence the development of EPS symptoms in fully developed AD. With other recent data, these results suggest that neuronal loss in SN, partly related to tau lesions, is a major pathological substrate of EPS in AD, but some cases with and without EPS may show no or only minimal nigral changes. However, often associated with nigral tau lesions and higher Braak stages, EPS in elderly patients may be a surrogate marker for severe neuritic AD pathology.     

Polymorphisms of the α-synuclein promoter: expression analyses and association studies in Parkinson's disease

Summary. Mutations of the α-synuclein gene have shown to be relevant in some rare families with autosomal dominant Parkinson's disease (PD). Furthermore, α-synuclein protein is a major component of the Lewy bodies also in sporadic PD patients. Increased levels of wildtype α-synuclein in the cell leads to increased intracellular hydrogen peroxide levels and causes death of dopaminergic neurons in rat primary culture. Subsequently, oxidative stress has been directly linked with α-synuclein aggregation in vitro. This raises the question whether increased α-synuclein expression might be linked to higher susceptibility to PD and whether α-synuclein promoter polymorphisms are associated with PD. Here, two polymorphisms (−116C>G and −668T>C) of the α-synuclein promoter defining four haplotypes have been characterized in 315 German PD patients. The influence of the four haplotypes on gene expression was studied by CAT reporter gene assays in neuronal SK-N-AS cells. The −668C/−116G haplotype revealed significant higher CAT expression than the −668T/−116G or the −668T/−116C haplotype, respectively. Although the −668C/−116G haplotype was more common in PD patients, this difference was not significant. Received January 8, 2002; accepted June 10, 2002 Published online August 22, 2002 Authors' address: O. Riess, M.D., Department of Medical Genetics, University of Tübingen, Calwerstrasse 7, D-72076 Tübingen, Federal Republic of Germany, e-mail: olaf.riess@med.uni-tuebingen.de     

Co-Existence of tau and α-synuclein pathology in fetal graft tissue at autopsy: A case report

IntroductionTransplant of fetal ventral mesencephalic tissue into the striatum of Parkinson's disease (PD) patients has been performed to increase dopamine production and stimulate neuronal regeneration. Analysis of fetal graft tissue at autopsy has demonstrated 6 cases of α-synuclein pathology in PD patients, one case with both α-synuclein and tau pathology in a PD patient, and two cases of tau pathology within a Huntington's Disease patient.MethodsA 49 year old man with PD underwent bilateral fetal ventral mesencephalic cell transplants into the striatum. Autopsy at age 70 included immunohistochemical staining of host and graft tissue with antibodies to phosphorylated α-synuclein and phosphorylated tau protein.ResultsAutopsy confirmed the diagnosis of PD. Immunohistochemical staining of graft tissue demonstrated frequent neuronal perikaryal inclusions of phosphorylated α -synuclein and tau in the left graft only.ConclusionSpeculations on the formation of pathology include: 1) α-synuclein and tau pathology spread from host to the graft in a neuron-neuron manner. 2) The nature of the fetal cells themselves, or transplantation process, may render fetal tissue more susceptible to the spontaneous generation of pathology. 3) Factors within host environment caused native tau and α-synuclein in fetal tissue graft to become phosphorylated.     

Does α-synuclein have a dual and opposing effect in preclinical vs. clinical Parkinson's disease?

α-Synuclein gene (SNCA) multiplications cause familial parkinsonism and allele-length polymorphisms within the SNCA dinucleotide repeat REP1 increase the risk for developing Parkinson's disease (PD). Since SNCA multiplications increase SNCA expression, and REP1 genotypes that increase the risk of developing PD show increased SNCA expression in cell-culture systems, animal models, and human blood and brain, PD therapies seek to reduce SNCA expression. We conducted an observational study of 1098 PD cases to test the hypothesis that REP1 genotypes correlated with reduced SNCA expression are associated with better motor and cognitive outcomes. We evaluated the association of REP1 genotypes with survival free of Hoehn and Yahr stages 4 or 5 (motor outcome) and of Modified Telephone Interview for Cognitive Status score ≤27 or Alzheimer's Disease Dementia Screening Interview score ≥2 (cognitive outcome). Median disease duration at baseline was 3.3 years and median lag time from baseline to follow-up was 7.8 years. Paradoxically, REP1 genotypes associated with increased risk of developing PD and increased SNCA expression were associated with better motor (HR = 0.87, p = 0.046, covariate-adjusted age-scale analysis; HR = 0.85, p = 0.020, covariate-adjusted time-scale analysis) and cognitive outcomes (HR = 0.90, p = 0.12, covariate-adjusted age-scale analysis; HR = 0.85, p = 0.023, covariate-adjusted time-scale analysis). Our findings raise the possibility that SNCA has a dual, opposing, and time-dependent role. This may have implications for the development of therapies that target SNCA expression.     

The limbic and neocortical contribution of α-synuclein,tau, and amyloid β to disease duration in dementia with Lewy bodies

Introduction

We sought to assess the individual and combined contribution of limbic and neocortical α-synuclein, tau, and amyloid β (Aβ) to duration of illness in dementia with Lewy bodies (DLB).

Age-associated increases of α-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion: Is this the target for Parkinson's disease?

alpha-Synuclein is a synaptic protein that has been directly linked to both the etiology and pathogenesis of Parkinson's disease. We have previously shown that only nigral neurons in PD expressing alpha-synuclein inclusions display a loss dopaminergic phenotype. The present study tested the hypothesis that normal aging contributes to this effect. The relative abundance of alpha-synuclein protein within individual nigral neurons was quantified in eighteen normal humans between the age of 18 and 102 and twenty four rhesus monkeys between the age of 2 and 34. Optical densitometry revealed a robust age-related increase in alpha-synuclein protein within individual nigral neurons in both species. This effect was specific for nigral alpha-synuclein as no age-related changes were found in the ventral tegmental area nor were there changes in the nigra for non-pathogenic beta-synuclein. The age-related increases in nigral alpha-synuclein were non-aggregated and strongly associated with age-related decreases in tyrosine hydroxylase (TH), the rate limiting enzyme for dopamine production. In fact, only cells expressing alpha-synuclein displayed reductions in TH. We hypothesize that age-related increases in alpha-synuclein result in a subthreshold degeneration of nigrostriatal dopamine which, in PD, becomes symptomatic due to lysosomal failure resulting in protein misfolding and inclusion formation. We further hypothesize that preventing the age-related accumulation of non-aggregated alpha-synuclein might be a simple and potent therapeutic target for patients with PD.     

NACP/α-synuclein and tau constitute two distinctive subsets of filaments in the same neuronal inclusions in brains from a family of parkinsonism and dementia with Lewy bodies: double-immunolabeling fluorescence and electron microscopic studies

The co-localization of NACP/α-synuclein and tau epitopes was examined in the brain stem and hippocampal formation in two patients from a family of autosomal dominant parkinsonism and dementia with Lewy bodies (LBs) without two reported missense mutations in the NACP gene. Double-labeling immunofluorescence study revealed that some brain stem LBs, cortical LBs, pale bodies, Lewy-related neurites, and neurofibrillary tangles expressed both NACP epitopes and the PHF tau AT8 epitope. Double-immunolabeling electron microscopy demonstrated that the NACP antibody selectively labeled 9- to 13-nm-thick straight filaments (LB filaments), whereas AT8 recognized twisted tubules with 80- to 100-nm-interval constrictions in the same neuronal inclusions. We show that NACP and tau aggregate into different filamentous components even if both proteins are incorporated into the same inclusions. Received: 15 March 1999 / Revised, accepted: 25 October 1999     

Enduring involvement of tau, β-amyloid, α-synuclein,ubiquitin and TDP-43 pathology in the amyotrophic lateral sclerosis/parkinsonism–dementia complex of Guam (ALS/PDC)

Guam ALS/PDC is a severe tangle forming disorder endemic to Guam with features overlapping such neurodegenerative disorders as Alzheimer disease (AD), Parkinson disease (PD), progressive supranuclear palsy (PSP), ALS, corticobasal degeneration (CBD) and pallido-ponto-nigral degeneration (PPND). Since the prevalence is declining, we examined brain tissue from 35 clinically diagnosed Chamorro patients with ALS/PDC and two Chamorro controls autopsied between 1946 and 2006, to determine if distinct variations in the pathology could be identified up to this time. Although the age at autopsy increased by 4.5–5 years per decade, we identified no qualitative differences in pathological deposits with antibodies against tau, ubiquitin, Aβ, α-synuclein and TDP-43, indicating that these more recently identified proteins have been involved in the neuropathogenesis over the past 6 decades. Tau and TDP-43 positive neuronal, oligodendroglial and astrocytic inclusions involving multiple nerve fiber tracts occurred in both the ALS and PDC types, reinforcing the concept that these forms are part of the same disorder. The results obtained may help to define the commonality of the Guam disease with other tangle forming disorders and may help in monitoring the epidemiological changes that are taking place. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.