Progressive parkinsonism in older adults is related to the burden of mixed brain pathologies

Abstract

Objective: To examine whether indices of Parkinson disease (PD) pathology and other brain pathologies are associated with the progression of parkinsonism in older adults.

Methods: We used data from decedents who had undergone annual clinical testing prior to death and structured brain autopsy. Parkinsonism was based on assessment with a modified Unified Parkinson's Disease Rating Scale and a clinical diagnosis of PD was based on medical history. We used a series of mixed-effects models controlling for age and sex to investigate the association of PD pathology (nigral neuronal loss and Lewy bodies) and indices of 8 other brain pathologies with the progression of parkinsonism prior to death.

Results: During an average of 8.5 years' follow-up, more than half (771/1,430, 53.9%) developed parkinsonism proximate to death. On average, parkinsonism was progressive (estimate 0.130, SE 0.005, p < 0.001) in all older adults, but more rapid in adults with a clinical diagnosis of PD (n = 52; 3.6%) (estimate 0.066, SE 0.021, p < 0.001). Progression of parkinsonism was more rapid in adults with PD pathology (estimate 0.087, SE 0.013, p < 0.001). Alzheimer disease and several cerebrovascular pathologies were all independently associated with more rapid progression (all p values <0.05). The association between a higher person-specific weighted pathology score and more rapidly progressive parkinsonism did not differ between individuals with and without a clinical diagnosis of PD (estimate 0.003, SE 0.047, p = 0.957).

Conclusion: The rate of progressive parkinsonism in older adults with and without a clinical diagnosis of PD is related to the burden of mixed brain pathologies.

Figure 1. PD pathology in older adults with and without clinical parkinsonism

The number of individuals with clinical parkinsonism (red) and without clinical parkinsonism (blue) at the last visit proximate to death for each of the 3 Parkinson disease (PD) pathology groups (LB [Lewy bodies present], NNL [nigral neuronal loss], PD pathology [presence of both LB and NNL]) and a fourth reference group of individuals without either of the elements of PD pathology. The majority of older adults who developed parkinsonism proximate to death (red) did not show evidence of either of the elements of PD pathology.

Figure 2. Proportions of individuals with each of 9 brain pathologies in older adults with parkinsonism before death

The majority of older individuals with clinical evidence of parkinsonism prior to death, with and without a clinical diagnosis of PD, showed mixed brain pathologies. AD = Alzheimer disease; CAA = cerebral amyloid angiopathy; CVDA = atherosclerosis; HS = hippocampal sclerosis; LIPO = arteriolosclerosis; MACRO = macroinfarcts; MICRO = microinfarcts; PD = Parkinson disease; TDP = TAR DNA-binding protein.

Figure 3. A higher burden of brain pathologies is related to more rapid progression of parkinsonism

Model-derived trajectories of progressive parkinsonism for 5 average participants, an 89-year-old woman, with increasing weighted pathology scores derived from the associations between different postmortem indices and the rate of progressive parkinsonism. Since a higher global parkinsonism score (y-axis) represents more severe parkinsonism, the slope for more rapid progression is positive and larger. Slope values increase with a higher burden of pathology as illustrated by showing increasing weighted pathology scores and slope values: black line (no pathology, rate: 0.051/y); red line (25th percentile, weighted pathology score 0.316; rate: 0.101/y); green line (50th percentile weighted pathology score 0.483; rate: 0.130/y); blue line (75th percentile, weighted pathology score 0.678; rate: 0.159/y); and gray line (90th percentile weighted pathology score 0.868; rate: 0.189/y).