Cognitive, functional, and neuropsychiatric correlates of regional tau pathology in autopsy-confirmed chronic traumatic encephalopathy
Authors: Alosco Michael L. , White Micaela , Bell Carter , Faheem Farwa , Tripodis Yorghos , Yhang Eukyung , Baucom Zachary , Martin Brett , Palmisano Joseph , Dams-O’Connor Kristen , Crary John F. , Goldstein Lee E. , Katz Douglas I. , Dwyer Brigid , Daneshvar Daniel H. , Nowinski Christopher , Cantu Robert C. , Kowall Neil W. , Stern Robert A. , Alvarez Victor E. , Huber Bertrand Russell , Stein Thor D. , McKee Ann C. , Mez Jesse 
Published: February 2024

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 ($$\beta$$
β
standardized = 0.02, 95%CI = 0.01–0.04), CDS ($$\beta$$
β
standardized = 0.02, 95%CI = 0.01–0.04), and FAQ ($$\beta$$
β
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 ($$\beta$$
β
sstandardized = 0.17–0.29, ps < 0.01) and FAQ ($$\beta$$
β
sstandardized = 0.21–0.26, ps < 0.01); frontal and inferior parietal cortex was associated with higher MI ($$\beta$$
β
sstandardized = 0.21–0.29, ps < 0.05); frontal cortex was associated with higher BRI ($$\beta$$
β
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.