Clinical and Neuropathological Correlates of Substance Use Disorders in Brain Donors Exposed to Repetitive Head Impacts

Abstract

BackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impacts (RHI) like those from American football. Causes of cognitive and neuropsychiatric symptoms (e.g., neurobehavioral dysregulation) in CTE are unclear. Substance use disorders (SUDs) are common among individuals with autopsy‐confirmed CTE, but their association with CTE and related symptoms are unknown. We examined the association between SUDs and CTE pathology, and cognitive and neuropsychiatric symptoms in deceased football players.MethodsThe sample included 429 deceased football players from the UNITE brain bank. CTE was neuropathologically diagnosed. Informant interviews assessed SUD history. The independent variable included substance use treatment history, an indicator of SUD less influenced by recall error. Informants completed standardized scales of cognitive function (Cognitive Difficulties Scale, Functional Activities Questionnaire, BRIEF‐A Metacognition Index [MI]), mood (Geriatric Depression Scale [GDS‐15]), and neurobehavioral dysregulation (BRIEF‐A Behavioral Regulation Index [BRI], Barratt Impulsiveness Scale [BIS‐11]). Linear or logistic regressions test the association between substance use treatment history and CTE status, cumulative p‐tau burden (sum of p‐tau severity ratings across 11 brain regions, n = 370), and each clinical scale, controlling for age and years of football play. Cumulative p‐tau burden was added as a covariate in clinical models.ResultsTables 1–3 show sample characteristics. 313/429 had autopsy‐confirmed CTE. Alcohol use disorders were more common (n = 177, 41.3%) than illicit (n = 70,16.3%) and prescription (n = 47, 11%) drug use disorders. Approx. 23% (n = 100) had a substance use treatment history, which was not associated with CTE (p = 0.21) or p‐tau burden (p = 0.14). Substance use treatment history was associated with neurobehavioral dysregulation (BRI: beta = 8.17, 95% CI = 3.92‐12.41, p<0.01; BIS‐11: beta = 8.90, 95% CI = 5.11‐12.69, p<0.01) and greater depression symptoms (GDS‐15: beta = 2.17, 95% CI = 1.08‐3.26, p<0.01). Besides the MI (beta = 5.09, 95% CI = 0.67‐9.51, p = 0.02), there was no association with cognitive scales (ps>0.05). Cumulative p‐tau burden was associated with neurobehavioral dysregulation (BRI, p<0.01) and all cognitive scales (ps<0.05).ConclusionsIn former football players, SUDs are unlikely to affect risk for CTE, but can contribute to clinical symptoms especially neurobehavioral dysregulation. These findings stress the role of tau and non‐tau causes of neurobehavioral dysregulation among football players. However, p‐tau is likely a key driver of cognitive symptoms.