Person-Specific Contributions of Brain Pathologies to Progressive Parkinsonism in Older Adults

Background: Mixed-brain pathologies are the most common cause of progressive parkinsonism in older adults. We tested the hypothesis that the impact of individual pathologies associated with progressive parkinsonism differs among older adults. Methods: Data were from 1089 decedents who had undergone annual clinical testing and autopsy. Parkinsonism was based on a modified United Parkinson's Disease Rating Scale. Linear mixed-effects models were employed, to investigate the combinations of 9 pathologies related to progressive parkinsonism. Then we estimated the person-specific contributions of each pathology for progressive parkinsonism. Results: The average participant showed 3 pathologies. Parkinson's disease (PD) and 4 cerebrovascular pathologies (macroinfarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy [CAA]), but not Alzheimer's disease, TDP-43, hippocampal sclerosis, and microinfarcts, were independently associated with progressive parkinsonism. These pathologies accounted for 13% of additional variance of progressive parkinsonism. Thirty-one different combinations of these 5 pathologies were observed to be associated with progressive parkinsonism observed. On average, PD and CAA accounted, respectively, for 66% and 65% of person-specific progression of parkinsonism, while macroinfarcts, atherosclerosis, and arteriolosclerosis accounted for 41%-48%. Conclusion: There is much greater heterogeneity in the comorbidity and relative impact of individual brain pathologies affecting progressive parkinsonism than previously recognized and this may account in part for its phenotypic heterogeneity in older adults.