Applicability of current staging/categorization of α-synuclein pathology and their clinical relevance

In Parkinson's disease (PD) and dementia with Lewy bodies (DLB) alpha-synuclein (alpha S) pathology is seen that displays a predictable topographic distribution. There are two staging/categorization systems, i.e. Braak's and McKeith's, currently in use for the assessment of alpha S pathology. The aim of these diagnostic strategies in pathology is, in addition to assess the stage/severity of pathology, to assess the probabilities of the related clinical symptomatology i.e. dementia and extrapyramidal symptoms (EPS). Herein, we assessed the applicability of these two staging/categorization systems and the frequency of dementia and EPS in a cohort of 226 alpha S-positive-subjects. These subject were selected from a large autopsy sample (n = 1,720), irrespective of the clinical presentation, based on the detection of alpha S-immunoreactivity (IR) in one of the most vulnerable nuclei; in the dorsal motor nucleus of vagus, substantia nigra and basal forebrain. The frequency of alpha S-IR lesions in this large cohort was 14% (248 out of 1,720). If applicable, each of the 226 subjects with all required material available was assigned a neuropathological stage/category of PD/DLB and finally the neuropathological data was analyzed in relation to dementia and EPS. 83% of subjects showed a distribution pattern of alpha S-IR that was compatible with the current staging/categorization systems. Around 55% of subjects with widespread alpha S pathology (Braak's PD stages 5-6) lacked clinical signs of dementia or EPS. Similarly, in respect to those subjects that fulfilled the McKeith criteria for diffuse neocortical category and displaying only mild concomitant Alzheimer's disease-related pathology, only 48% were demented and 54% displayed EPS. It is noteworthy that some subjects (17%) deviated from the suggested caudo-rostral propagation suggesting alternative routes of progression, perhaps due to concomitant diseases and genetic predisposition. In conclusion, our results do indeed confirm that current staging/categorization systems can readily be applied to most of the subjects with alpha S pathology. However, finding that around half of the subjects with abundant alpha S pathology remain neurologically intact is intriguing and raises the question whether we do assess the actual disease process.