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.