Cognitive, functional, and neuropsychiatric correlates of regional tau pathology in autopsy-confirmed chronic traumatic encephalopathy

Abstract

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by hyperphosphorylated tau (p-tau) accumulation. The clinical features associated with CTE pathology are unclear. In brain donors with autopsy-confirmed CTE, we investigated the association of CTE p-tau pathology density and location with cognitive, functional, and neuropsychiatric symptoms.

Methods: In 364 brain donors with autopsy confirmed CTE, semi-quantitative p-tau severity (range: 0-3) was assessed in 10 cortical and subcortical regions. We summed ratings across regions to form a p-tau severity global composite (range: 0-30). Informants completed standardized scales of cognition (Cognitive Difficulties Scale, CDS; BRIEF-A Metacognition Index, MI), activities of daily living (Functional Activities Questionnaire), neurobehavioral dysregulation (BRIEF-A Behavioral Regulation Index, BRI; Barratt Impulsiveness Scale, BIS-11), aggression (Brown-Goodwin Aggression Scale), depression (Geriatric Depression Scale-15, GDS-15), and apathy (Apathy Evaluation Scale, AES). Ordinary least squares regression models examined associations between global and regional p-tau severity (separate models for each region) with each clinical scale, adjusting for age at death, racial identity, education level, and history of hypertension, obstructive sleep apnea, and substance use treatment. Ridge regression models that incorporated p-tau severity across all regions in the same model assessed which regions showed independent effects.

Results: The sample was predominantly American football players (333; 91.2%); 140 (38.5%) had low CTE and 224 (61.5%) had high CTE. Global p-tau severity was associated with higher (i.e., worse) scores on the cognitive and functional scales: MI ([Formula: see text] _standardized = 0.02, 95%CI = 0.01-0.04), CDS ([Formula: see text] _standardized = 0.02, 95%CI = 0.01-0.04), and FAQ ([Formula: see text] _standardized = 0.03, 95%CI = 0.01-0.04). After false-discovery rate correction, p-tau severity in the frontal, inferior parietal, and superior temporal cortex, and the amygdala was associated with higher CDS ([Formula: see text] s_standardized = 0.17-0.29, ps < 0.01) and FAQ ([Formula: see text] s_standardized = 0.21-0.26, ps < 0.01); frontal and inferior parietal cortex was associated with higher MI ([Formula: see text] s_standardized = 0.21-0.29, ps < 0.05); frontal cortex was associated with higher BRI ([Formula: see text] _standardized = 0.21, p < 0.01). Regions with effects independent of other regions included frontal cortex (CDS, MI, FAQ, BRI), inferior parietal cortex (CDS) and amygdala (FAQ). P-tau explained 13-49% of variance in cognitive and functional scales and 6-14% of variance in neuropsychiatric scales.

Conclusion: Accumulation of p-tau aggregates, especially in the frontal cortex, are associated with cognitive, functional, and certain neurobehavioral symptoms in CTE.

Keywords: Activities of daily living; Amygdala; Behavioral dysregulation; Chronic traumatic encephalopathy; Clinicopathological correlation; Cognition; Frontal cortex; Tau; Temporal cortex; Traumatic brain injury.

Fig. 1

Regional Hyperphosphorylated Tau Pathology in CTE. Photomicrographs of AT8 immunostained cortical neurofibrillary tangles (NFTs), neurites, and astrocytic inclusions around small central vessels within the depths of sulci in a 71- year-old former professional American football player with stage IV CTE in the dorsolateral frontal cortex (a), inferior frontal cortex (b), inferior parietal cortex (c), superior temporal cortex (d), globose NFTs and neurities in the locus coeruleus (e), NFTs in the CA1 (f), CA2 (g) CA4 (h) hippocampal subfields, NFTs and neurites in the entorhinal cortex (i) layer 4 and basal nucleus of the amygdala (j). Scale bar = 100μm

Fig. 2

Forest Plot of The Estimated Effects of Regional P-tau Pathology on Standardized Cognitive Scales. Legend: Standardized estimates and associated 95% confidence intervals are from the multivariable OLS regression models (Table 4). The whiskers represent the 95% confidence intervals. Regional p-tau severity was rated on a 0–3 scale with 0 being none and 3 being severe. Frontal is a summary composite of the dorsolateral frontal cortex and the inferior frontal cortex. CA1, CA2, and CA4 were summed to create the hippocampus composite. For all clinical scales, higher scores are worse. Abbreviations: OLS Ordinary least squares, CDS Cognitive Difficulties Scale, BRIEF-A Behavior Rating Inventory of Executive Function for Adults, MI Metacognition Index, FAQ Functional Activities Questionnaire

Fig. 3

Forest Plot of The Estimated Effects of Regional P-tau Pathology on Standardized Scales of Neurobehavioral Dysregulation, Depression, and Apathy. Legend: Standardized estimates and associated 95% confidence intervals are from the multivariable OLS regression models (Table 4). The whiskers represent the 95% confidence intervals. Regional p-tau severity was rated on a 0–3 scale with 0 being none and 3 being severe. Frontal is a summary composite of the dorsolateral frontal cortex and the inferior frontal cortex. CA1, CA2, and CA4 were summed to create the hippocampus composite. For all clinical scales, higher scores are worse. Abbreviations: OLS Ordinary least squares, BRIEF-A Behavior Rating Inventory of Executive Function for Adults, BRI Behavioral Regulation Index, BIS-11 Barratt Impulsiveness Scale, GDS Geriatric Depression Scale, 15-item version, AES Apathy Evaluation Scale