Relative Contributions of Mixed Pathologies to Cognitive and Functional Symptoms in Brain Donors Exposed to Repetitive Head Impacts

Abstract

ObjectiveExposure to repetitive head impacts (RHI) is associated with later‐life cognitive symptoms and neuropathologies including chronic traumatic encephalopathy (CTE). Cognitive decline in community cohorts is often due to multiple pathologies; however, the frequency and contributions of these pathologies to cognitive impairment in people exposed to RHI is unknown. Here, we examined the relative contributions of 13 neuropathologies to cognitive symptoms and dementia in RHI‐exposed brain donors.MethodsNeuropathologists examined brain tissue from 571 RHI‐exposed donors and assessed for the presence of 13 neuropathologies, including CTE, Alzheimer disease (AD), Lewy body disease (LBD), and TDP‐43 inclusions. Cognitive status was assessed by presence of dementia, Functional Activities Questionnaire (FAQ), and Cognitive Difficulties Scale (CDS). Spearman's rho was calculated to assess intercorrelation of pathologies. Additionally, frequencies of pathological co‐occurrence were compared to a simulated distribution assuming no intercorrelation. Logistic and linear regressions tested associations between neuropathologies and dementia status and cognitive scale scores.ResultsThe sample age range was 18–97 (median: 65.0 [IQR 46.0–76.0]). 77.2% of donors had at least one moderate–severe neurodegenerative or cerebrovascular pathology. Stage III‐IV CTE was the most common neurodegenerative disease (43.1%), followed by TDP‐43 pathology, AD, and hippocampal sclerosis. Neuropathologies were intercorrelated and there were fewer unique combinations than expected if pathologies were independent (p < 0.001). The greatest contributors to dementia were AD, neocortical LBD, hippocampal sclerosis, CAA, and CTE.InterpretationIn this sample of RHI‐exposed brain donors with wide‐ranging ages, multiple neuropathologies were common and correlated. Mixed neuropathologies, including CTE, underlie cognitive impairment in contact sport athletes.This article is protected by copyright. All rights reserved.

Disentangling and quantifying the relative cognitive impact of concurrent mixed neurodegenerative pathologies

“…These cases may represent subjects with underlying pathologies that were unassessed due to previous versions of the NACC NP dataset, subjects with very low levels of multiple different pathologies adding up to produce a cognitive effect (i.e., low level ADNC in combination with LATE-NC stage 1, LBD stage 1, and/or relatively mild cerebrovascular changes), pathologic findings that do not fit into one or more of the designated NACC categories, or subjects with unspecified/undocumented genetic alterations [ 22 ]. Similar to previous studies [ 10 , 66 ], between 42.2% and 58.4% of the variance in cognitive impairment was accounted for by the most common neuropathological findings (ADNC, LATE-NC, LBD, and CVD) (Supplemental Fig. 2 ).…”

“…Correlations with total number of pathologies were modeled using linear regression and Pearson correlation coefficient. Percent contributions of each pathology to cognitive impairment was determined using multiple regression analysis where the calculated β coefficient for each pathology was divided by the sum of all β values, as previously described in detail [ 10 , 66 ]. Statistical significance was set at α = 0.05.…”