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

Abstract

Objective: Exposure 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 are unknown. Here, we examined the relative contributions of 13 neuropathologies to cognitive symptoms and dementia in RHI-exposed brain donors.

Methods: Neuropathologists 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 transactive response DNA-binding protein 43 (TDP-43) inclusions. Cognitive status was assessed by presence of dementia, Functional Activities Questionnaire, and Cognitive Difficulties Scale. Spearman 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.

Results: The sample age range was 18-97 years (median = 65.0, interquartile range = 46.0-76.0). Of the donors, 77.2% 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, cerebral amyloid angiopathy, and CTE.

Interpretation: In 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. ANN NEUROL 2024;95:314-324.

Figure 1:

Actual and expected unique number of combinations of neuropathologies. The distribution of numbers of unique combinations of pathologies assuming each is independent is shown from a simulation of 10,000 datasets that are representative of our brain donors in sample size and frequencies of individual pathologies. The dashed lines represent the observed and predicted numbers of unique pathologies observed in our sample.

Figure 2:

The relative percent contribution of each neuropathology to variance in dementia status or cognitive scale scores. The percent contribution of each pathology relative to the total effect of all the pathologies on the variance in dementia status and cognitive scale scores is shown. FAQ = functional activities questionnaire; CDS = cognitive difficulties scale; AD = Alzheimer’s disease; LBD = neocortical Lewy body disease; HS = hippocampal sclerosis; CAA = cerebral amyloid angiopathy; CTE = chronic traumatic encephalopathy stages III-IV; FTLD = frontotemporal lobar degeneration; TDP-43 = transactive response DNA-binding protein 43; WMR = white matter rarefaction.