Clinical and Neuropathological Correlates of Substance Use in American Football Players

Article type: Research Article

Authors: Walsh, Michael^a | Uretsky, Madeline^a | Tripodis, Yorghos^{a; b; c} | Nowinski, Christopher J.^{b; d} | Rasch, Abigail^b | Bruce, Hannah^a | Ryder, Megan^b | Martin, Brett M.^{a; b; e} | Palmisano, Joseph N.^{a; b; e} | Katz, Douglas I.^{b; f} | Dwyer, Brigid^{b; f} | Daneshvar, Daniel H.^{b; g; h} | Walley, Alexander Y.ⁱ | Kim, Theresa W.ⁱ | Goldstein, Lee E.^{a; b; j; k; l; m} | Stern, Robert A.^{a; b; n; o} | Alvarez, Victor E.^{a; b; p; q; r; s} | Huber, Bertrand Russell^{a; b; p; q} | McKee, Ann C.^{a; b; k; p; q; r; s} | Stein, Thor D.^{a; b; k; p; q; r; s} | Mez, Jesse^{a; b; s} | Alosco, Michael L.^{a; b; o; *}

Affiliations: [a] Department of Neurology, Boston University Alzheimer’s Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA | [b] Department of Neurology, Boston University CTE Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA | [c] Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA | [d] Concussion Legacy Foundation, Boston, MA, USA | [e] Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, MA, USA | [f] Braintree Rehabilitation Hospital, Braintree, MA, USA | [g] Department of Physical Medicine and Rehabilitation, Massachusetts General Hospital, Boston, MA, USA | [h] Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Boston, MA, USA | [i] Grayken Center for Addiction, Clinical Addiction Research and Education Unit, Section of General Internal Medicine, Boston Medical Center, and Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA | [j] Department of Radiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA | [k] Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA | [l] Department of Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA | [m] Departments of Biomedical, Electrical & Computer Engineering, Boston University College of Engineering, Boston, MA, USA | [n] Department of Neurosurgery, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA | [o] Department of Anatomy & Neurobiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA | [p] U.S. Department of Veteran Affairs, VA Boston Healthcare System, Jamaica Plain, MA, USA | [q] National Center for PTSD, VA Boston Healthcare, Jamaica Plain, MA, USA | [r] VA Bedford Healthcare System, Bedford, MA, USA | [s] Framingham Heart Study, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA

Correspondence: [*] Correspondence to: Michael L Alosco, PhD, 72 E Concord Street, Instructional Building, L-5, Boston, MA 02118, USA. Tel.: +1 617-358-6029; E-mail: malosco@bu.edu.

Abstract: Background:Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy more frequently found in deceased former football players. CTE has heterogeneous clinical presentations with multifactorial causes. Previous literature has shown substance use (alcohol/drug) can contribute to Alzheimer’s disease and related tauopathies pathologically and clinically. Objective:To examine the association between substance use and clinical and neuropathological endpoints of CTE. Methods:Our sample included 429 deceased male football players. CTE was neuropathologically diagnosed. Informant interviews assessed features of substance use and history of treatment for substance use to define indicators: history of substance use treatment (yes vs no, primary variable), alcohol severity, and drug severity. Outcomes included scales that were completed by informants to assess cognition (Cognitive Difficulties Scale, BRIEF-A Metacognition Index), mood (Geriatric Depression Scale-15), behavioral regulation (BRIEF-A Behavioral Regulation Index, Barratt Impulsiveness Scale-11), functional ability (Functional Activities Questionnaire), as well as CTE status and cumulative p-tau burden. Regression models tested associations between substance use indicators and outcomes. Results:Of the 429 football players (mean age = 62.07), 313 (73%) had autopsy confirmed CTE and 100 (23%) had substance use treatment history. Substance use treatment and alcohol/drug severity were associated with measures of behavioral regulation (FDR-p-values<0.05, ΔR2 = 0.04–0.18) and depression (FDR-p-values<0.05, ΔR2 = 0.02–0.05). Substance use indicators had minimal associations with cognitive scales, whereas p-tau burden was associated with all cognitive scales (p-values <0.05). Substance use treatment had no associations with neuropathological endpoints (FDR-p-values>0.05). Conclusions:Among deceased football players, substance use was common and associated with clinical symptoms.

Keywords: Alcohol use, Alzheimer’s disease, chronic traumatic encephalopathy, dementia, repetitive head impacts, substance use, traumatic brain injury

DOI: 10.3233/JAD-240300

Journal: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 971-986, 2024