Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important?

Abstract

The relative importance of Lewy- and Alzheimer-type pathologies to dementia in Parkinson's disease remains unclear. We have examined the combined associations of α-synuclein, tau and amyloid-β accumulation in 56 pathologically confirmed Parkinson's disease cases, 29 of whom had developed dementia. Cortical and subcortical amyloid-β scores were obtained, while tau and α-synuclein pathologies were rated according to the respective Braak stages. Additionally, cortical Lewy body and Lewy neurite scores were determined and Lewy body densities were generated using morphometry. Non-parametric statistics, together with regression models, receiver-operating characteristic curves and survival analyses were applied. Cortical and striatal amyloid-β scores, Braak tau stages, cortical Lewy body, Lewy neurite scores and Lewy body densities, but not Braak α-synuclein stages, were all significantly greater in the Parkinson's disease-dementia group (P<0.05), with all the pathologies showing a significant positive correlation to each other (P<0.05). A combination of pathologies [area under the receiver-operating characteristic curve=0.95 (0.88-1.00); P<0.0001] was a better predictor of dementia than the severity of any single pathology. Additionally, cortical amyloid-β scores (r=-0.62; P=0.043) and Braak tau stages (r=-0.52; P=0.028), but not Lewy body scores (r=-0.25; P=0.41) or Braak α-synuclein stages (r=-0.44; P=0.13), significantly correlated with mini-mental state examination scores in the subset of cases with this information available within the last year of life (n=15). High cortical amyloid-β score (P=0.017) along with an older age at onset (P=0.001) were associated with a shorter time-to-dementia period. A combination of Lewy- and Alzheimer-type pathologies is a robust pathological correlate of dementia in Parkinson's disease, with quantitative and semi-quantitative assessment of Lewy pathology being more informative than Braak α-synuclein stages. Cortical amyloid-β and age at disease onset seem to determine the rate to dementia.

Figure 1

Distribution of cases with each of the Braak Alzheimer’s disease (AD) tau stages (A) and Braak Parkinson’s disease (PD) stages (B) as represented by empty (PDND) and striped bars (PDD). Asterisk denotes significant differences. αS = α-synuclein.

Figure 2

(A) Bar diagrams of regional and total semi-quantitative Lewy body (LB) scores with dashed and dotted lines, respectively, delineating cut-off values of 10 and 5 (score >10: 88% PDD; score >5: 79% PDD). (B) Bar diagrams of regional and total Lewy body (LB) densities with dashed and dotted lines, respectively, delineating cut-off values of 5 and 2 (scores >5: 91% PDD; scores >2: 83% PDD). (C) Bar diagrams of the regional and total semi-quantitative Lewy neurite scores with dashed and dotted lines, respectively, delineating cut-off values of 5 and 2 (scores >5: 86% PDD; scores >2: 74% PDD). *P < 0.005; **P < 0.05.

Figure 3

(A) Bar diagrams of regional and total amyloid-β diffuse plaque scores with dashed and dotted lines, respectively, delineating 10 and 5 cut-offs (score >10: 79% PDD; score >5: 71% PDD). (B) Bar diagrams of regional and total amyloid-β mature plaque scores with dashed and dotted lines, respectively, delineating 10 and 5 cut-offs (score >10: 100% PDD; score >5: 93% PDD). (C) Regional and total amyloid-β diffuse + mature plaque scores with dashed and dotted lines, respectively, delineating 18 and 12 (score >18: 100% PDD; score >12: 76% PDD). (D) amyloid-β diffuse plaque scores in the caudate and the putamen separately and together (striatum) with a dashed line delineating cut-off value of 3 for the total striatal score (73% PDD), as well as in the claustrum, with a dotted line delineating cut-off value of 2 (90% PDD). *P < 0.005; **P < 0.05.

Figure 4

Receiver operating characteristic (ROC) curves for ability of pathology to classify cases as demented or non-demented created using the probabilities obtained in the binary regression models. (A) Cortical Lewy body (LB) scores alone (area under the curve = 0.83, 95% CI = 0.70–0.97, P = 0.001); (B) tau stages alone (area under the curve = 0.82, 95% CI = 0.70–0.93, P = 0.0001); (C) cortical amyloid-β (A-β) scores alone (area under the curve = 0.83, 95% CI = 0.69–0.97, P = 0.001); and (D) all three pathologies in combination (area under the curve = 0.95, 95% CI = 0.88–1.00, P = 0.000003). AD = Alzheimer’s disease.

Figure 5

Survival analysis of time to dementia by means of Kaplan–Meier curves. (A) Effect on time to dementia of cortical amyloid-β (A-β) score; (B) effect on time to dementia of Braak Alzheimer’s disease (AD) tau stage; and (C) effect on time to dementia of cortical Lewy body (LB) load.