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

Abstract

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.

Keywords: Aging; Brain pathology; Cognitive decline; Parkinsonism.

Figure 1.

Combinations of common brain pathologies independently associated with progressive parkinsonism. This figure shows the burden of mixed-pathologies independently associated with progressive parkinsonism in the aging brain. The bar chart in the lower left corner shows the frequencies of individual brain pathologies indices collected in this study. Connected black dots on the x-axis indicate the specific combination of brain pathology in 5 or more individuals. Histograms in the main panel show the frequencies of the brain pathology indices for persons with and without parkinsonism proximate to death (parkinsonism present [blue] versus parkinsonism absent [black]), ordered by their frequency. The height of each bar corresponds to the number of persons with each combination. PD = PD pathology; CAA = cerebral amyloid angiopathy. As illustrated in the figure, brain pathology indices frequently co-occur. Cerebrovascular disease pathologies alone or in combination were the most common pathologies related to progressive parkinsonism. It was uncommon for PD pathology to occur alone, and it was most commonly found together with one or more cerebrovascular disease pathologies.

Figure 2.

Person-specific proportions of progressive parkinsonism associated with specific brain pathologies. Histogram showing the frequency (x-axis) and person-specific proportion of progressive parkinsonism (x-axis) accounted for by each of the 5 pathologies related to progressive parkinsonism. PD = PD pathology; CAA = cerebral amyloid angiopathy.