Cognitive and Pathological Influences of Tau Pathology in Lewy Body Disorders

Abstract

Objective: To use digital histology in a large autopsy cohort of Lewy body disorder (LBD) patients with dementia to test the hypotheses that co-occurring Alzheimer disease (AD) pathology impacts the anatomic distribution of α-synuclein (SYN) pathology and that co-occurring neocortical tau pathology in LBDs associates with worse cognitive performance and occurs in a pattern differing from AD.

Methods: Fifty-five autopsy-confirmed LBD (Parkinson disease with dementia, n = 36; dementia with Lewy bodies, n = 19) patients and 25 AD patients were studied. LBD patients were categorized as having moderate/severe AD copathology (SYN + AD = 20) or little/no AD copathology (SYN-AD = 35). Digital measures of tau, β-amyloid (Aβ), and SYN histopathology in neocortical and subcortical/limbic regions were compared between groups and related to antemortem cognitive testing.

Results: SYN burden was higher in SYN + AD than SYN-AD in each neocortical region (F_{1, 54} = 5.6-6.0, p < 0.02) but was equivalent in entorhinal cortex and putamen (F_{1, 43-49} = 0.7-1.7, p > 0.2). SYN + AD performed worse than SYN-AD on a temporal lobe-mediated naming task (t₂₇ = 2.1, p = 0.04). Antemortem cognitive test scores inversely correlated with tau burden (r = -0.39 to -0.68, p < 0.05). AD had higher tau than SYN + AD in all regions (F_{1, 43} = 12.8-97.2, p < 0.001); however, SYN + AD had a greater proportion of tau in the temporal neocortex than AD (t₄₁ = 2.0, p < 0.05), whereas AD had a greater proportion of tau in the frontal neocortex than SYN + AD (t₄₁ = 3.3, p < 0.002). SYN + AD had similar severity and distribution of neocortical Aβ compared to AD (F_{1, 40-43} = 1.6-2.0, p > 0.1).

Interpretation: LBD patients with AD copathology harbor greater neocortical SYN pathology. Regional tau pathology relates to cognitive performance in LBD dementia, and its distribution may diverge from pure AD. Tau copathology contributes uniquely to the heterogeneity of cognitive impairment in LBD. Ann Neurol 2018; 1-13 ANN NEUROL 2019;85:259-271.

Figure 1:. Microscopic Pathology of LBD and AD.

Representative photomicrographs from STC in A) SYN-AD, B) SYN+AD, and C) AD cases stained for tau (AT8,left), Aβ (NAB228,middle), and SYN (SYN303,right). Top row for each group shows raw images and lower row for each group depicts digital detection of pathology (%AO- red overlay). SYN+AD has higher burden of Tau, Aβ and SYN pathology compared to SYN-AD, while pure AD has much higher cortical Tau %AO and similar Aβ compared to SYN+AD. Images taken at 32x; scale bar is 100 micrometers.

Figure 2:. Higher pathology stages are associated with higher Neocortical %Area Occupied.

Box-plots depict the median, interquartile range, and range of A) Aβ %AO in each Thal Phase: F(49,3)=50.4, p<.001, B) Aβ plaque %AO in each CERAD stage: F(50,2)=58.9 p<.001, , C) tau pathology %AO in each Braak tau stage: F(52,2)=19.4, p<.001D) SYN %AO in each LBD stage: F(53,1)=8.3 p=.006 and E) Neocortical average SYN %AO for each AD level: F(51,3)=5.7, p=.002. Increasing stages of pathology are associated with higher measures of neocortical pathology, including increasing SYN pathology for each stage of coexisting AD NPC. Bars with single asterisk denote p<0.05 and bars with double asterisks denote p<0.01 between groups

Figure 3:. Regional pathology in LBD with SYN+AD compared to SYN-AD.

Box-plots depict median, interquartile range and range of %AO of SYN pathology (A), Tau pathology (B), Aβ pathology (C) in each region and in the average of the three neocortical regions. SYN-AD (brown) and SYN+AD (purple). Bars with single asterisk denote p<0.05 and bars with double asterisks denote p<0.01 in univariate analysis.

Figure 4:. Regional Tau and Aβ pathology in LBD with SYN+AD compared to AD without neocortical SYN.

Box plots depict median, interquartile range and range %AO of A) Tau pathology and B) Aβ pathology in each region and average of the three neocortical regions. Bars with single asterisk denote p<0.05 and bars with double asterisks denote p<0.01 in univariate analysis. Of note, all multivariate models were non-significant for Aβ %AO burden in SYN+AD compared to AD while all models and pathology factor variables tor Tau %AO burden were significant. Box-plots depict the proportion of total pathology in each region (e.g. MFC/neocortical average) for C) Tau D) and Aβ. SYN+AD (purple) and AD (green). Bars with single asterisk denote p<0.05 and bars with double asterisks denote p<0.01.