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The term “repetitive head impacts” (RHI) refers to the cumulative exposure to concussive and subconcussive events. Although RHI are believed to increase risk for later-life neurological consequences (including chronic traumatic encephalopathy), quantitative analysis of this relationship has not yet been examined because of the lack of validated tools to quantify lifetime RHI exposure. The objectives of this study were: 1) to develop a metric to quantify cumulative RHI exposure from football, which we term the “cumulative head impact index” (CHII); 2) to use the CHII to examine the association between RHI exposure and long-term clinical outcomes; and 3) to evaluate its predictive properties relative to other exposure metrics (i.e., duration of play, age of first exposure, concussion history). Participants included 93 former high school and collegiate football players who completed objective cognitive and self-reported behavioral/mood tests as part of a larger ongoing longitudinal study. Using established cutoff scores, we transformed continuous outcomes into dichotomous variables (normal vs. impaired). The CHII was computed for each participant and derived from a combination of self-reported athletic history (i.e., number of seasons, position[s], levels played), and impact frequencies reported in helmet accelerometer studies. A bivariate probit, instrumental variable model revealed a threshold dose-response relationship between the CHII and risk for later-life cognitive impairment (p < 0.0001), self-reported executive dysfunction (p < 0.0001), depression (p < 0.0001), apathy (p = 0.0161), and behavioral dysregulation (p < 0.0001). Ultimately, the CHII demonstrated greater predictive validity than other individual exposure metrics.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts. CTE has been linked to disruptions in cognition, mood, and behavior. Unfortunately, the diagnosis of CTE can only be made post-mortem. Neuropathological evidence suggests limbic structures may provide an opportunity to characterize CTE in the living. Using 3 T magnetic resonance imaging, we compared select limbic brain regional volumes – the amygdala, hippocampus, and cingulate gyrus – between symptomatic former National Football League (NFL) players (n = 86) and controls (n = 22). Moreover, within the group of former NFL players, we examined the relationship between those limbic structures and neurobehavioral functioning (n = 75). The former NFL group comprised eighty-six men (mean age = 55.2 ± 8.0 years) with at least 12 years of organized football experience, at least 2 years of active participation in the NFL, and self-reported declines in cognition, mood, and behavior within the last 6 months. The control group consisted of men (mean age = 57.0 ± 6.6 years) with no history of contact-sport involvement or traumatic brain injury. All control participants provided neurobehavioral data. Compared to controls, former NFL players exhibited reduced volumes of the amygdala, hippocampus, and cingulate gyrus. Within the NFL group, reduced bilateral cingulate gyrus volume was associated with worse attention and psychomotor speed (r = 0.4 (right), r = 0.42 (left); both p < 0.001), while decreased right hippocampal volume was associated with worse visual memory (r = 0.25, p = 0.027). Reduced volumes of limbic system structures in former NFL players are associated with neurocognitive features of CTE. Volume reductions in the amygdala, hippocampus, and cingulate gyrus may be potential biomarkers of neurodegeneration in those at risk for CTE.

Factors of increased prevalence among individuals with Black racial identity (e.g., cardiovascular disease, CVD) may influence the association between exposure to repetitive head impacts (RHI) from American football and later-life neurological outcomes. Here, we tested the interaction between racial identity and RHI on neurobehavioral outcomes, brain volumetric measures, and cerebrospinal fluid (CSF) total tau (t-tau), phosphorylated tau (p-tau ), and Aβ in symptomatic former National Football League (NFL) players. 68 symptomatic male former NFL players (ages 40-69; = 27 Black, = 41 White) underwent neuropsychological testing, structural MRI, and lumbar puncture. FreeSurfer derived estimated intracranial volume (eICV), gray matter volume (GMV), white matter volume (WMV), subcortical GMV, hippocampal volume, and white matter (WM) hypointensities. Multivariate generalized linear models examined the main effects of racial identity and its interaction with a cumulative head impact index (CHII) on all outcomes. Age, years of education, Wide Range Achievement Test, Fourth Edition (WRAT-4) scores, CVD risk factors, and ε4 were included as covariates; eICV was included for MRI models. -values were false discovery rate adjusted. Compared to White former NFL players, Black participants were 4 years younger ( = 0.04), had lower WRAT-4 scores (mean difference = 8.03, = 0.002), and a higher BMI (mean difference = 3.09, = 0.01) and systolic blood pressure (mean difference = 8.15, = 0.03). With regards to group differences on the basis of racial identity, compared to White former NFL players, Black participants had lower GMV (mean adjusted difference = 45649.00, = 0.001), lower right hippocampal volume (mean adjusted difference = 271.96, = 0.02), and higher p-tau /t-tau ratio (mean adjusted difference = -0.25, = 0.01). There was not a statistically significant association between the CHII with GMV, right hippocampal volume, or p-tau /t-tau ratio. However, there was a statistically significant Race x CHII interaction for GMV ( = 2206.29, = 0.001), right hippocampal volume ( = 12.07, = 0.04), and p-tau /t-tau ratio concentrations ( = -0.01, = 0.004). Continued research on racial neurological disparities could provide insight into risk factors for long-term neurological disorders associated with American football play.

INTRODUCTION Subjective cognitive complaints (SCC) can precede Alzheimer's disease and related dementias. SCC in the absence of objective impairment is termed subjective cognitive decline (SCD). This study aimed to characterize SCC and SCD among a sample of aging individuals with and without prior repetitive head impact (RHI) exposure, the former of whom are at risk for chronic traumatic encephalopathy (CTE). METHODS RHI‐exposed (N = 167) and non–RHI‐exposed (N = 317) Boston University Alzheimer's Disease Research Center (ADRC) participants and their informants completed subjective measures assessing memory and executive function. Participants completed objective tests of these domains. RESULTS RHI exposure was associated with greater self‐ and informant‐reported SCC and with over four‐fold increased odds of SCD among cognitively unimpaired participants (odds ratio = 4.10, p < 0.001). SCC was associated with objective measures in RHI and non‐RHI participants. DISCUSSION Among RHI‐exposed individuals, SCC align with objective cognitive performance. SCD warrants investigation as potential early indicator of RHI‐related neuropathologies. Highlights Subjective cognitive complaints (SCC) are common after repetitive head impacts (RHI). RHI status is associated with increased odds of subjective cognitive decline (SCD). Neuropsychiatric symptoms are associated with SCC in RHI‐exposed individuals. SCC may indicate underlying post‐traumatic neuropathology in RHI‐exposed individuals.

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. The relationship between the components of repetitive head impacts and chronic traumatic encephalopathy (CTE) remains unclear. Here, the authors use American football helmet sensor data to show that duration of play, cumulative head impacts and linear and rotational accelerations are significantly associated with CTE pathology.

Thalamic atrophy has been associated with exposure to repetitive head impacts (RHI) in professional fighters. The aim of this study is to investigate whether or not age at first exposure (AFE) to RHI is associated with thalamic volume in symptomatic former National Football League (NFL) players at risk for chronic traumatic encephalopathy (CTE). Eighty-six symptomatic former NFL players (mean age = 54.9 ± 7.9 years) were included. T1-weighted data were acquired on a 3T magnetic resonance imager, and thalamic volumes were derived using FreeSurfer. Mood and behavior, psychomotor speed, and visual and verbal memory were assessed. The association between thalamic volume and AFE to playing football and to number of years playing was calculated. Decreased thalamic volume was associated with more years of play (left: p = 0.03; right: p = 0.03). Younger AFE was associated with decreased right thalamic volume (p = 0.014). This association remained significant after adjusting for total years of play. Decreased left thalamic volume was associated with worse visual memory (p = 0.014), whereas increased right thalamic volume was associated with fewer mood and behavior symptoms (p = 0.003). In our sample of symptomatic former NFL players at risk for CTE, total years of play and AFE were associated with decreased thalamic volume. The effect of AFE on right thalamic volume was almost twice as strong as the effect of total years of play. Our findings confirm previous reports of an association between thalamic volume and exposure to RHI. They suggest further that younger AFE may result in smaller thalamic volume later in life.

Youth football players may incur hundreds of repetitive head impacts (RHI) in one season. Our recent research suggests that exposure to RHI during a critical neurodevelopmental period prior to age 12 may lead to greater later-life mood, behavioral, and cognitive impairments. Here, we examine the relationship between age of first exposure (AFE) to RHI through tackle football and later-life corpus callosum (CC) microstructure using magnetic resonance diffusion tensor imaging (DTI). Forty retired National Football League (NFL) players, ages 40–65, were matched by age and divided into two groups based on their AFE to tackle football: before age 12 or at age 12 or older. Participants underwent DTI on a 3 Tesla Siemens (TIM-Verio) magnet. The whole CC and five subregions were defined and seeded using deterministic tractography. Dependent measures were fractional anisotropy (FA), trace, axial diffusivity, and radial diffusivity. Results showed that former NFL players in the AFE <12 group had significantly lower FA in anterior three CC regions and higher radial diffusivity in the most anterior CC region than those in the AFE ≥12 group. This is the first study to find a relationship between AFE to RHI and later-life CC microstructure. These results suggest that incurring RHI during critical periods of CC development may disrupt neurodevelopmental processes, including myelination, resulting in altered CC microstructure.

Chronic traumatic encephalopathy (CTE) is a progressive brain disease linked to repetitive head impacts (RHI), often incurred from contact sports, and can lead to dementia. Here, we investigated the association between RHI and white matter/vascular neuropathologies and their relative contribution to dementia status in deceased men 50 + years old with and without exposure to RHI from various types of contact and collision sports. Our sample included two RHI groups from the UNITE brain bank: (1) American Football players (RHI-AF, n  = 79), and (2) non-AF contact and collision sport athletes (e.g., boxing, rugby; RHI-CCS, n  = 49). Controls included similarly aged (± 5 years) male brain donors without RHI. A modified ischemic injury scale (mIIS) served as a global measure of white matter and vascular neuropathologies, encompassing nine subcomponents. Dementia was determined through diagnostic consensus conference based on interviews with families. Using linear regression models controlling for age at death, mIIS was different in RHI-AF versus non-RHI only ( p  = 0.036). Subsequent logistic regression of each mIIS subcomponent, controlling for age at death, demonstrated that worse white matter rarefaction (RHI-AF; Beta = 1.42, [95% CI 2.03–8.43]; RHI-CCS; Beta = 1.93, [95% CI 2.35–20.17]) and hippocampal sclerosis (RHI-AF; Beta = 2.01, [95% CI 2.69–20.81]; RHI-CCS; Beta = 2.19, [95% CI 2.49–32.10]) was more common in RHI groups from their controls. Further, logistic regressions found that higher global mIIS correlated with increased odds of dementia in only the RHI-AF group ( p  = 0.02), driven by white matter rarefaction ( β  = 0.94, [95% CI 1.66–4.00]) and hippocampal sclerosis ( β  = 1.08, [95% CI 1.35–6.42]). There were similar findings in RHI-CCS group for odds of dementia ( p  = 0.048), including white matter rarefaction ( β  = 0.68, [95% CI 1.22–3.21], p  = 0.05). Overall, these results demonstrate that white matter  rarefaction and hippocampal sclerosis are linked to RHI exposure across all types of contact sports. Further, these pathologies contribute to dementia independent of p-tau pathology in American football players.

Cerebral amyloid angiopathy (CAA) consists of beta-amyloid deposition in the walls of the cerebrovasculature and is commonly associated with Alzheimer’s disease (AD). However, the association of CAA with repetitive head impacts (RHI) and with chronic traumatic encephalopathy (CTE) is unknown. We evaluated the relationship between RHI from contact sport participation, CTE, and CAA within a group of deceased contact sport athletes (n = 357), a community-based cohort (n = 209), and an AD cohort from Boston University AD Center (n = 241). Unsupervised hierarchal cluster analysis demonstrated a unique cluster (n = 11) with increased CAA in the leptomeningeal vessels compared to the intracortical vessels (p < 0.001) comprised of participants with significantly greater frequencies of CTE (7/11) and history of RHI. Overall, participants with CTE (n = 251) had more prevalent (p < 0.001) and severe (p = 0.010) CAA within the frontal leptomeningeal vessels compared to intracortical vessels. Compared to those with AD, participants with CTE had more severe CAA in frontal than parietal lobes (p < 0.001) and more severe CAA in leptomeningeal than intracortical vessels (p = 0.002). The overall frequency of CAA in participants with CTE was low, and there was no significant association between contact sport participation and the presence of CAA. However, in those with CAA, a history of contact sports was associated with increased CAA severity in the frontal leptomeningeal vessels (OR = 4.01, 95% CI 2.52–6.38, p < 0.001) adjusting for AD, APOE ε4 status, and age. Participants with CAA had increased levels of sulcal tau pathology and decreased levels of the synaptic marker PSD-95 (p’s < 0.05), and CAA was a predictor of dementia (OR = 1.75, 95% CI 1.02–2.99, p = 0.043) adjusting for age, sex, and comorbid pathology. Overall, contact sport participation and CTE were associated with more severe frontal and leptomeningeal CAA, and CAA was independently associated with worse pathological and clinical outcomes.

INTRODUCTION This studyexamined the independent contribution of chronic traumatic encephalopathy (CTE) neuropathology to symptoms. METHODS The sample included 614 brain donors with (n = 366) and without (n = 248) autopsy‐confirmed CTE. Brain donors with other major neurodegenerative disease diagnoses were excluded. Informants completed cognitive and neuropsychiatric measures. Dementia was determined during diagnostic consensus conferences. RESULTS CTE stage IV (of IV) was associated with 4.48 (95% confidence interval [CI] = 1.97–10.90) increased odds of having dementia. CTE stage III had an odds ratio of 2.12 (95% CI = 1.91–3.77). Higher CTE stage was associated with greater informant‐reported cognitive symptoms (p < 0.01). There were no associations with mood/behavioral scales. DISCUSSION CTE stage III/IV neuropathology was associated with dementia and cognitive symptoms: those with stage IV were 4.5 times more likely to have dementia than those without CTE. It is uncertain if low‐stage CTE clinically manifests, and mood/behavioral symptoms likely have multifactorial causes and/or a fluctuating course. Highlights Stage III and IV chronic traumatic encephalopathy (CTE) are independently associated with increased odds of having dementia. Higher CTE stage was associated with greater informant‐reported cognitive symptoms. Stage I and II CTE were not associated with cognitive symptoms or dementia. CTE of any severity was not associated with informant‐reported mood or behavioral symptoms.