Quantifying associations of four major proteinopathies with grey matter atrophy: an imaging‐pathology study

Abstract

AbstractBackgroundGross atrophy observed on MRI provides a clinically useful marker of possible neurodegenerative disease. However, autopsy studies of polypathology suggest atrophy is likely driven not by a single proteinopathy but also co‐pathologies. We hypothesized that in a clinically heterogeneous autopsy sample, amyloid‐β, tau, α‐synuclein, and TDP‐43, would co‐occur within regions, and that co‐pathologies would have independent associations with grey matter atrophy.MethodT1‐weighted antemortem MRI was available in 121 patients with postmortem ordinal pathology ratings (0 = none; 1 = mild; 2 = intermediate; 3 = severe). Primary neuropathologic diagnoses included Alzheimer’s disease (AD; n = 52), amyotrophic lateral sclerosis (n = 2), frontotemporal lobar degeneration due to tau (n = 29) and TDP‐43 (n = 22), and Lewy body disease (16). Regional volumes were expressed as W‐scores adjusting for age, sex, and intracranial volume for 10 regions spanning the limbic system, neocortex, and subcortex. We used mixed effects models with a random intercept per patient to regress W‐scores on ordinal pathology ratings.ResultAmyloid‐β and tau co‐occurred in all regions, reflecting the prevalence of AD neuropathologic change (Fig. 2, top). Alpha‐synuclein and TDP‐43 pathology were highest in amygdala, anterior cingulate, entorhinal cortex, and hippocampus, where they frequently co‐occurred with amyloid‐β and tau. Neocortical regions including middle frontal, angular, and superior/middle temporal cortex had intermediate rates of co‐pathology, while thalamus, striatum, and globus pallidus had the lowest polypathologic burden (Fig. 2, bottom). Ordinal measures of tau [F(3,1073) = 24.1, p<0.001], TDP‐43 [F(3,1073) = 13.7, p<0.001], and ‐synuclein [F(3,1073) = 4.3, p<0.005] burden were inversely associated with regional volumes, but amyloid‐ [F(3,1073) = 1.8, p>0.15] was not. An increase in ordinal tau scoring by one unit was associated with a mean reduction of ‐0.29 in regional W‐score; for TDP‐43, a decrease of ‐0.51; and for α‐synuclein, a decrease of ‐0.16.ConclusionMixed proteinopathies were common at the regional level in limbic and neocortical structures. Using blinded ordinal pathology scoring, TDP‐43 was associated with greater atrophy than tau; α‐synuclein had a smaller but significant association. Amyloid‐β was not associated with atrophy when adjusting for tau. Results suggest co‐pathologies have a measurable effect on observed brain atrophy.