Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impacts (RHI), but the components of RHI exposure underlying this relationship are unclear. We create a position exposure matrix (PEM), composed of American football helmet sensor data, summarized from literature review by player position and level of play. Using this PEM, we estimate measures of lifetime RHI exposure for a separate cohort of 631 football playing brain donors. Separate models examine the relationship between CTE pathology and players’ concussion count, athletic positions, years of football, and PEM-derived measures, including estimated cumulative head impacts, linear accelerations, and rotational accelerations. Only duration of play and PEM-derived measures are significantly associated with CTE pathology. Models incorporating cumulative linear or rotational acceleration have better model fit and are better predictors of CTE pathology than duration of play or cumulative head impacts alone. These findings implicate cumulative head impact intensity in CTE pathogenesis.

BackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. We previously showed that duration of American football play is associated with risk and severity of CTE pathology. Helmet accelerometers have been used previously to examine frequency, linear acceleration, and rotational acceleration of hits sustained across youth, high school, and college football. Here we projected this data onto former American football playing brain donors to examine the relationship between cumulative frequency of hits, linear acceleration, and rotational acceleration during players’ athletic careers and CTE pathology.Method656 former American football playing brain donors from the Veterans Affairs‐Boston University‐Concussion Legacy Foundation Brain Bank were examined for CTE pathology and severity. Years and position of play at each level (youth, high school, college, professional) were acquired through retrospective clinical interviews with brain donors next‐of‐kin. From a literature search of studies using helmet accelerometers, we calculated the mean frequency of hits, linear acceleration (g‐force), and rotational acceleration (rad/sec2) for one year of play at each level‐position combination. These values were projected onto brain donors’ career exposure to derive cumulative frequency of head impacts (CHII), cumulative linear acceleration (CHII‐G), and cumulative rotational acceleration (CHII‐R). Separate logistic regression models examined the relationship of years of play, CHII, CHII‐G, and CHII‐R on CTE status and severity (low vs. high), adjusting for age at death.ResultThe mean (SD) age at death was 59.7 (20.1) and 451 (68.8%) had CTE pathology. Each cumulative measure was significantly associated with presence of CTE (p’s<.001) and severity of CTE (p’s<.001). Based on ROC analyses, CHII‐R (AUC=0.765, p<.001) and CHII‐G (AUC= 0.758, p<.001) performed significantly better than years of play (AUC=0.716) in classifying CTE pathology, and there was no difference between years of play and CHII (AUC=0.698, p=0.25). Similar relationships were observed for CTE severity. Model fit and cross‐validation statistics were also consistent (Table 2).ConclusionAmong former American football playing brain donors, cumulative linear and rotational acceleration were better predictors of CTE pathology than duration of play or cumulative hits. The findings suggest head impact intensity is an important factor in developing CTE pathology.

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.