In vivo biomarkers that can detect long-term neuropathologies from repetitive head impact (RHI) exposure are needed, especially for the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). Here, we evaluated plasma p -tau217 as a potential biomarker for CTE p -tau pathology, and examined the concordance between plasma p -tau217 and Aβ pathology in an at-risk for CTE sample. The sample included 180 male former football players (120 professional, 60 college), and 56 asymptomatic men without RHI (i.e., controls). Participants completed blood draws, 18F-florbetapir (Aβ+=SUVR≥1.10), and 18F-flortaucipir PET. Traumatic encephalopathy syndrome (TES) diagnoses were made. Single molecule array for plasma p -tau217 (ALZpath) was performed (≥0.6 cutoff used to maximize sensitivity). Nine participants had post-mortem tissue. ANCOVA examined group differences in p -tau217 (football vs controls; TES-CTE no, TES-CTE suggestive, TES-CTE possible/probable). Multivariable regression models tested associations between p -tau217 and florbetapir/flortaucipir PET. Covariates included age, race and APOE e4 . Sample characteristics are in Table 1. p -tau217 concentrations were higher in former football players compared to controls (est. marginal mean difference=-0.217, p  = 0.005). There were no group differences in Aβ-PET SUVR. No differences were found across TES-CTE certainty levels. In football players, higher p -tau217 was associated with higher Aβ-PET SUVR (B=1.380, 95%CI[0.597-2.155], p  = 0.001) but not when Aβ+ ( n  = 17) participants and those with kidney/liver disease ( n  = 5) were excluded. Aβ+ participants had the highest p -tau217 (Figure 1). When compared against Aβ-PET, several false Aβ-positives (high p -tau217, Aβ-) were identified, including one extreme outlier (assay related) and a cluster of Aβ- participants with p -tau217 between 0.60–1.0. There were no associations with flortaucipir SUVR (frontal, mesial temporal, left parietal). Two extreme p -tau217 outliers had autopsy-confirmed CTE stage III (AD-, Table 2). Of the remaining donors, all were AD- and four had CTE (stages II-IV) with ptau217 between 0.125-0.449. Plasma p -tau217 has usefulness in quantifying Aβ pathology but restricted utility for detection of CTE. In this at-risk for CTE sample, p -tau217 and Aβ-PET were associated at the group level. At the individual level, false Aβ-positives (and negatives) existed, including Aβ- participants with high p -tau217. We will explore whether this discrepancy is due to disease or peripheral interference with the N-terminal binding in p -tau assays.

OBJECTIVE:Subjective cognitive complaints (SCC) can precede cognitive decline and are associated with demographic, exposure, lifestyle, and psychological factors. Prevalences of SCC and their correlates in individuals with repetitive head impacts (RHI) are poorly understood. This study characterized SCC in former elite American football players by frequency, mood and behavioral correlates, concordance with informant reports, and associations with neuropsychological test performance, cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI) markers of neurodegeneration. METHOD:Former American football players (n = 180) completed measures of global and domain-specific SCC, neuropsychiatric symptom questionnaires, neuropsychological testing, lumbar puncture, and MRI. Elastic net regression evaluated the relative importance of potential SCC correlates. Intraclass correlation coefficients measured concordance between self and informant reports. Multiple linear regressions tested associations between SCC and verbal memory and executive functioning scores. CSF Aβ1-42, p-tau181, t-tau, neurofilament light (NfL), hippocampal volume, and regional cortical thickness were examined for their potential associations with SCC. RESULTS:Rates of SCC ranged from 43 to 77% depending on the domain. Symptoms of depression, impulsivity, and anxiety were strongly associated with SCC. Self- and informant-reported SCC showed moderate inter-rater agreement. Adjusting for age, race, education, APOE ϵ4 carrier status, and depressive symptoms, SCC were associated with lower objective verbal memory and executive functioning performance. SCC were associated with lower parahippocampal cortical thickness but not with hippocampal volume or any of the measured CSF tests. CONCLUSIONS:SCC are strongly associated with neuropsychiatric factors in former American football players. SCC may also be a marker of cognitive decline and neurodegeneration.

INTRODUCTION:Chronic traumatic encephalopathy (CTE) is a tauopathy linked to repetitive head impacts. Factors influencing brain regional susceptibility to tau deposition and spreading remain unclear. METHODS:We used three datasets: [18F]flortaucipir positron emission tomography (PET) in 157 former professional American football players and 53 controls (DIAGNOSE CTE); cortical myelin water fractions (MWF) in 50 healthy individuals (Myelin Water Atlas); and white matter (WM) tract MWF and functional connectivity (FC) in 100 healthy individuals (Human Connectome Project). We tested associations between tau-PET uptake and covariance in football players and typical cortical gray matter (GM) MWF, WM tract MWF, and FC. RESULTS:Cortical regions with lower typical GM MWF showed higher tau-PET uptake (β = -0.399, p = 0.001). WM tracts with lower typical MWF were associated with higher tau-PET covariance (β = -0.238, p < 0.001). Higher typical FC was associated with higher tau-PET covariance (β = 0.447, p < 0.001). DISCUSSION:In former football players at risk for CTE, regional susceptibility to tau deposition may be driven by low myelin and high FC.

INTRODUCTION:Repetitive head impacts (RHIs) have been linked to later life neurodegeneration, yet the in vivo structural correlates of cumulative biomechanical loading remain unclear. We examined whether regional ventricular morphology in former American football players reflects exposure burden and traumatic encephalopathy syndrome (TES) classification. METHODS:Participants included 170 male former football players and 54 age-matched asymptomatic male controls from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Subject-specific manual segmentation quantified lateral ventricle, inferior horn, third ventricle, and fourth ventricle volumes. Group and exposure associations were tested using generalized least squares models. RESULTS:Former players showed larger left inferior lateral ventricle volume than controls, with the largest effects among professional players. Greater cumulative linear and rotational acceleration exposure was associated with enlargement across lateral ventricular and inferior horn regions. DISCUSSION:Regional ventricular enlargement may represent an in vivo marker of cumulative biomechanical loading after RHI exposure.

Although the younger age of first exposure (AFE) to American football has not been associated with neurodegenerative pathology, AFE has been associated with clinical symptoms. However, the literature is mixed. We examined the association between AFE to football and clinical outcomes before and after age 60 at death, to isolate the potential role of decreased neuropathological resilience in older age. This study included 677 deceased male football players who donated their brains to the Understanding Neurologic Injury and Traumatic Encephalopathy Brain Bank. Informants completed modified scales assessing cognition, function, behavior, and neuropsychiatric features with dementia adjudicated through consensus conferences. Regressions tested the association between AFE and dementia, chronic traumatic encephalopathy (CTE) pathology, and each scale, adjusted for multiple testing. Analyses were stratified by age 60, adjusting for age at death, duration of play, and neuropathology. Most donors (mean age = 60.9, standard deviation = 19.8) played college or professional football (n = 509, 76%). CTE was the most prevalent neuropathology (n = 471, 70%). AFE was not associated with neurodegenerative disease pathology. Among those older than 60 at death, younger AFE was associated with cognitive composite score impairment (odds ratio: 0.897, 95% confidence interval [CI]: 0.814-0.988, p = 0.027) and worse cognitive (beta: 0.04, 95% CI: 0.01-0.069, p = 0.009), neurobehavioral (beta: 0.032, 95% CI: 0.002-0.062, p = 0.035), and neuropsychiatric (beta: 0.032, 95% CI: 0.00-0.064, p = 0.048) composite scores. Younger AFE was only associated with worse informant-reported clinical outcomes in older deceased football players, independent of neurodegeneration. Our findings offer a potential explanation for the mixed literature on AFE and clinical outcomes. The effects of AFE may only manifest in older adults when cognitive reserve is depleted, neuropathological resilience is reduced, or age-related vulnerabilities interact with prior head injury exposure, worsening clinical outcomes.

Importance:Repetitive head impacts (RHI) from American football have been associated with later-life cognitive and neuropsychiatric changes. Findings have been limited by small samples, focus on elite players, and lack of appropriate control groups. Objective:To assess the association between American football participation and cognitive and neuropsychiatric function in men 40 years or older. Design, Setting, and Participants:In this cross-sectional study, online data from male football players in the Head Impact & Trauma Surveillance Study (HITSS) were collected between March 7, 2022, and April 9, 2025. In a subanalysis, football players were matched to Brain Health Registry controls without RHI. Exposures:RHI proxies, including self-reported total years of football play, highest level of play, position, and age of first exposure. Main Outcomes and Measures:Linear regression models with multiway cluster-robust SEs compared performance of players vs controls on computerized cognitive tests (Cambridge Automated Neuropsychological Battery Paired Associates Learning Test First Attempt Memory Score [PALFAMS] and Total Errors Adjusted [PALTEA]), subjective cognitive concerns (Everyday Cognition Scale [ECog]), and depressive symptoms (Geriatric Depression Scale 15 [GDS-15]). Multivariable linear regressions, analyses of covariance, and binary logistic regression models tested associations between RHI proxies and PALFAMS, PALTEA, ECog, GDS-15, and additional neuropsychiatric (Behavior Rating Inventory of Executive Function-Adult [BRIEF-A] Behavioral Regulation Index [BRI]) and cognitive (BRIEF-A Meta-Cognition Index [MI]) measures. Models were adjusted for age, race, educational level, and vascular risk. Results:The study sample included 3970 male former American football players (mean [SD] age, 55.93 [10.00] years) enrolled in HITSS. Two substudies were performed: (1) all 3970 football players and (2) 943 players and controls (mean [SD] age, 58.46 [10.37] years), including 661 football players and 282 Brain Health Registry controls. Overall, all study participants were highly educated (561 [85%] had a ≥4-year degree). Compared with controls, players had worse scores on PALFAMS (B = -0.64; 95% CI, -1.23 to 0.05; β = -0.15; P = .03), PALTEA (B = 0.31; 95% CI, 0.07-0.54; β = 0.18; P = .01), ECog (B = 0.11; 95% CI, 0.07-0.15; β = 0.38; P < .001), and GDS-15 (B = 0.62; 95% CI, 0.39-0.86; β = 0.37; P < .001). Among the 3970 total players (mean [SD] years of education, 16.11 [2.20]), professional players had worse scores than college and high school or youth players. Years of play was associated with higher ECog (B = 0.006; 95% CI, 0.003-0.009; adjusted P < .001), MI (B = 0.17; 95% CI, 0.02-0.32; adjusted P = .04), BRI (B = 0.27; 95% CI, 0.16-0.37; adjusted P < .001), GDS-15 (B = 0.03; 95% CI, 0.009-0.04; adjusted P = .003), and PALTEA (B = 0.03; 95% CI, 0.004-0.06; adjusted P = .04) scores. Conclusions and Relevance:In this cross-sectional study of former American football players, prior American football participation was associated with worse later-life cognitive and neuropsychiatric function. These findings support a dose-response association with years and level of play, providing context to help clinicians and researchers assess the risk of symptoms among former players.

Importance:In vivo biomarkers for detecting neuropathologies from repetitive head impacts (RHI), including chronic traumatic encephalopathy (CTE), are needed. Objective:To evaluate the utility of plasma phosphorylated tau 217 (p-tau217), assess its performance as a beta-amyloid (Aβ) biomarker in participants with RHI exposure at risk for CTE, and explore concordance with CTE neuropathology in a postmortem subsample. Design, Setting, and Participants:This longitudinal, multicenter, case-control study used data from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of CTE (DIAGNOSE CTE) Research Project, collected from September 2016 to October 2023. Participants were former American football players (case participants) and asymptomatic men unexposed to RHI (control participants). A subsample had available neuropathologic data. Exposures:RHI, traumatic encephalopathy syndrome (TES) diagnoses, and levels of CTE certainty. Main Outcomes and Measures:Plasma p-tau217 (classified as positive [≥0.63 pg/mL], intermediate [0.40-0.62 pg/mL], and negative [<0.40 pg/mL]), Aβ-positron emission tomography (PET; 18F-florbetapir; with Aβ-positive defined as a standardized uptake value ratio [SUVR] ≥1.10), and tau-PET (18F-flortaucipir). TES diagnoses were assigned by multidisciplinary consensus conference. Analyses of postmortem brains controlled for age, race, and APOE ε4 status. Results:Among 231 participants (mean [SD] age, 57.75 [8.25] years), 177 were former football players (117 professional and 60 college) and 54 were unexposed participants. Former football players had higher baseline mean (SD) p-tau217 concentrations than unexposed participants (0.35 [0.26] pg/mL vs 0.27 [0.14] pg/mL; P = .008), although this was driven by a higher proportion of Aβ-PET-positive participants among former players. Plasma p-tau217 increased over time across the sample (B = 0.207 [95% CI, 0.117-0.298]; P < .001), with no significant time × exposure group interactions. Among football players, p-tau217 showed no time × group interactions with TES diagnosis, TES-CTE certainty, or RHI metrics. Higher p-tau217 concentration correlated with higher global Aβ-PET SUVR (B = 0.058 [95% CI, 0.053-3.501; P = .01), with a few discordant cases (5 participants were p-tau217-negative and Aβ-PET-positive; 7 participants were p-tau217-positive and Aβ-PET-negative). P-tau217 had similar areas under the curve for projecting Aβ-PET positivity as cerebrospinal fluid (CSF) p-tau181/Aβ42 and CSF Aβ40/42 measures (p-tau217: AUC, 0.88 [95% CI, 0.80-0.96]; CSF p-tau181/Aβ42: AUC, 0.89 [95% CI, 0.79-1.00]; CSF Aβ40/42: AUC, 0.85 [95% CI, 0.72-0.98]). Among 9 brain donors, 6 had CTE (stages II-IV; none with Alzheimer disease). Seven had negative or intermediate p-tau217, concordant with Aβ-PET. Two p-tau217 outliers with stage III CTE had normal concentrations upon additional testing. Conclusions and Relevance:The findings of this study suggest that plasma p-tau217 concentration is unlikely to be useful for the detection of CTE, but it does show utility for ruling out Aβ pathology in participants at risk for CTE.

Background:Traumatic encephalopathy syndrome (TES) is a clinical research construct used to identify individuals at risk for chronic traumatic encephalopathy (CTE) following exposure to repetitive head impacts (RHI). Adjudication of TES relies on clinical features such as progressive cognitive impairment and neurobehavioral dysregulation. Blood-based biomarkers and structural neuroimaging abnormalities have been associated with TES but are not part of the criteria. This study evaluated whether TES identification was associated with the combined contribution of cognitive performance, blood biomarkers, and structural neuroimaging measures across two well-characterized cohorts. Methods:Participants included 158 professional fighters from the Professional Athletes Brain Health Study and 149 former American football players from The DIAGNOSE CTE Research Project. Three indices were constructed representing complementary domains: a cognitive index reflecting cohort-specific cognitive features, a blood biomarker index including plasma neurofilament light chain, glial fibrillary acidic protein, total tau, tau phosphorylated at amino acid 231, and APOE-ε4 carrier status, and an imaging index comprising volumetric MRI measures of subcortical structures, ventricles, and corpus callosum subregions. Grouped weighted quantile sum regression models were estimated within each cohort to evaluate associations between these indices and TES while adjusting for age, race, competition status, and RHI exposure. Results:Multidomain models demonstrated improved model performance compared with single-domain models in both cohorts (PABHS: AUC=0.91, PPV=0.80; DIAGNOSE CTE: AUC=0.84, PPV=0.85). Biomarker and imaging indices contributed additional information across cohorts, although imaging contributions were more prominent in fighters whereas blood biomarker associations were stronger in football players. Conclusion:TES in RHI-exposed athletes was associated with a convergent clinicobiological profile observed across two independent cohorts with distinct exposure patterns. These findings support multidomain analytic frameworks for evaluating correlated biological signals in RHI-exposed populations and may inform future studies of TES and CTE.

BACKGROUND:Cumulative head trauma, encompassing repetitive head impacts (RHI) and traumatic brain injury (TBI), has been associated with later-life neurodegenerative disease. Studies on parkinsonism/Parkinson's disease (PD) have evaluated RHI and TBI in isolation, yielding mixed results. Cumulative head trauma may better predict PD risk. OBJECTIVE:To examine independent and cumulative effects of RHI through soccer participation and TBI history on PD diagnosis and age at diagnosis. METHODS:We used a cross-sectional cohort design with data from the Fox Insight study. Participants completed self-report questionnaires on PD diagnosis, TBI (no TBI, TBI with loss of consciousness [LOC], TBI without LOC), and sport participation. Multivariable logistic regressions examined the effects of soccer, TBI group, and their interaction on PD diagnosis. Cox proportional hazards examined associations with time to PD diagnosis. Covariates included age, sex, race, education, income, body mass index, heart disease/diabetes, and family PD history. RESULTS:Among 1231 participants (mean[SD] age = 66.12[10.60]), 278 played soccer (953 non-contact and collision sport [CCS] athletes). Participants reported no TBI (390[33%]), TBI without LOC (495[43%]), or TBI with LOC (258[23%]). Overall, 768(62%) reported a PD diagnosis (mean[SD] age at diagnosis = 59.02[9.86]). A significant soccer × TBI interaction indicated that soccer players with TBI with LOC had 2.6× higher odds of PD compared to non-CCS athletes without TBI (OR [95% CI] = 2.600[1.085-6.305], P = 0.033). Former soccer players with TBI with LOC had a 15.6% higher hazard of early PD diagnosis (HR = 1.469, P = 0.027) compared to non-CCS athletes with no TBI. CONCLUSION:Cumulative head trauma (RHI + TBI) increased PD risk and lowered age at onset. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Repetitive head impacts (RHI) from contact and collision sports have been associated with later-life cognitive and neurobehavioral impairments, as well as neurodegenerative conditions such as chronic traumatic encephalopathy (CTE). RHI-associated clinical sequelae among female former soccer players, specifically, are not well understood. This cross-sectional study aimed to examine the relationship of RHI exposure proxies (e.g., total years of soccer play, concussion history, highest level of play, and estimated cumulative heading frequency) with clinical measures (e.g., subjective cognitive complaints, objective cognitive performance, behavioral dysregulation, and depressive symptoms) among 2,732 women, aged 40 years or above, enrolled in the Head Impact and Trauma Surveillance Study (HITSS), all of whom formerly played organized soccer. HITSS participants completed an online battery that elicited self-reported cognitive and behavioral complaints and depressive symptoms, and that assessed cognitive performing via computerized tests. Multivariable linear regression models estimated associations between soccer-related RHI proxies and outcome measures, adjusting for age and education. Among the former soccer players, longer duration of soccer play, higher level of play, greater estimated cumulative heading frequency, and concussion history were significantly associated with worse self-reported cognitive functioning, greater behavioral dysregulation, and elevated depressive symptom severity. Apart from a single association between concussion history and PAL FAMS performance, we found no other associations between RHI proxies and objective cognitive test performance. Among middle-aged women who played organized soccer, cumulative RHI exposure was associated with small but statistically significant effects for measures of subjective cognitive complaints, behavioral functioning, and depressive symptoms. Continued monitoring of this large cohort of female former soccer players will improve understanding of long-term consequences of soccer play.

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.

BACKGROUND AND OBJECTIVES:The link between repetitive head impact (RHI) exposure, later-life cognitive decline, and neurobehavioral dysregulation (NBD) is not well understood. Recent work has implicated inflammation and limbic dysfunction as relevant RHI correlates. Our goal was to integrate plasma and CSF inflammatory biomarkers, structural brain imaging, and clinical measures in former elite American football players to better understand reasons for RHI-related cognitive and neurobehavioral changes. METHODS:Participants were from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project, which recruited male former college/professional football players with RHI and asymptomatic unexposed (UE) controls with no history of contact sports, military combat, or traumatic brain injury/concussion. Our study focused on plasma/CSF inflammatory biomarkers (interleukin [IL]-6, tumor necrosis factor [TNF]-α, glial fibrillary acidic protein), limbic white matter (WM) microstructure (diffusion tensor imaging: fractional anisotropy [FA], mean diffusivity [MD]), and clinical measures (memory, executive function, NBD). Hierarchical linear regressions assessed change in variance explained (ΔR2) among inflammation, WM, and clinical outcomes in former football players. Post hoc analyses tested whether associations differed by group (football vs UE; group interactions) or were stronger in football players considered at highest risk of CTE. RESULTS:Our sample included 223 men (n = 170 football players: age 57.2 ± 8.1 years, 33% non-Hispanic/Black; n = 53 UE participants: age 59.4 ± 8.6 years, 34% non-Hispanic/Black). In football players, higher inflammation was associated with lower limbic FA (plasma IL-6: ΔR2 = 0.03 [0.001-0.09], p = 0.03; CSF IL-6: ΔR2 = 0.03 [-0.01 to 0.11], p = 0.03; plasma TNF-α: ΔR2 = 0.05 [0.01-0.11], p = 0.003) and higher limbic MD (CSF IL-6: ΔR2 = 0.06 [0.007-0.15], p = 0.01). Inflammation was more strongly related to limbic WM microstructure in football players than in UE participants. Worse WM microstructure was associated with worse memory in football players (FA: ΔR2 = 0.05 [0.003-0.14], p = 0.007; MD: ΔR2 = 0.07, p = 0.003 [0.008-0.16]). Most of the observed associations were stronger in the CTE probable subgroup. There were no direct associations between plasma or CSF markers of inflammation and cognition. DISCUSSION:In former elite football players, elevated plasma and CSF inflammatory markers were associated with poorer limbic WM microstructure, which in turn related to worse cognition. Given the limbic system's role in cognition and behavior, inflammation may be a modifiable target for RHI-related neurodegeneration. Limitations include the cross-sectional design and limited generalizability to other contact sports, lower levels of play, female athletes, or other RHI sources.

The 2025 Leon Thal Summit convened an international panel of clinicians, neuroscientists, neuropathologists, and neuroimaging specialists to evaluate the current state of biomarker development for chronic traumatic encephalopathy (CTE) and to outline priorities for advancing translational research for this important area. Discussions integrated emerging findings from longitudinal cohorts, new molecular and neuroimaging approaches, expanding post mortem evidence, and evolving insights into exposure biology and genetic modifiers. Consensus themes emphasized the need for biomarkers that detect CTE-specific tau proteoforms, integration of existing imaging and fluid markers into traumatic encephalopathy syndrome research criteria, and refinement of multimodal magnetic resonance imaging and blood-based tools that capture early CTE pathology. The group underscored the importance of coordinated, longitudinal clinicopathological studies and collaborative research frameworks to validate candidate biomarkers and accelerate progress toward accurate diagnosis, disease monitoring, and therapeutic development for individuals at risk for or exhibiting signs of CTE.

Repetitive head impacts sustained during American football have been associated with neuropathological changes such as white matter shear injuries. However, the impact of specific factors, such as age of first exposure and cumulative head impact burden, on white matter integrity remains unclear. This study investigated in vivo white matter microstructural changes using diffusion tensor imaging and tract-based spatial statistics in 165 male former American football players (mean age 57.3 years, range 45-74) and 52 unexposed asymptomatic male controls (mean age 59.4 years, range 45-74) in the DIAGNOSE CTE Research Project. Compared to controls, former football players exhibited significantly higher fractional anisotropy (FA) in 1.97% of the white matter skeleton (1552 voxels; Cohen's d = 0.587) and higher tissue-corrected FA (FAt) in 1.48% of the white matter skeleton (1004 voxels; Cohen's d = 0.616). No significant differences were observed for mean diffusivity, axial diffusivity, radial diffusivity, or free water between football players and controls. Among football players, there were no significant differences in the white matter microstructure between players diagnosed with traumatic encephalopathy syndrome and those without the diagnosis. Lower FA was significantly associated with older age (P < 0.00001) and an earlier age of first exposure to tackle football (P < 0.01), while lower FAt was associated with greater cumulative head impact burden, specifically higher linear acceleration (P < 0.04) and rotational force (P < 0.02). This study highlights the influential role of exposure factors on white matter microstructure in former American football players, as well as the utility of diffusion tensor imaging to aid in characterizing the long-term effects of repetitive head impacts in contact sport athletes.

Importance:Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact exposure. CTE can only be diagnosed post mortem, and the antemortem neuropsychological profile is poorly understood, hindering accurate diagnosis before death. Objective:To characterize antemortem neuropsychological test performance of former National Football League (NFL) players with autopsy-confirmed CTE. Design, Setting, and Participants:This retrospective case series included former NFL players who completed an antemortem neuropsychological evaluation and had autopsy-confirmed CTE. Data were collected between January 1, 2017, and April 30, 2025. Statistical analysis was performed from September 2025 to June 2026. Exposure:CTE neuropathology, defined by the National Institute of Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering consensus panel. Main Outcomes and Measures:Neuropsychological test performance, neuropathologic diagnoses, and semiquantitative phosphorylated tau (p-tau) pathology across 11 brain regions were examined. Raw scores were converted to z scores using age, sex, and/or education level-based normative data. Test results with z scores of -1.5 or less were categorized as impaired; domains with 2 or more impaired test results were considered impaired. Results:The primary analytic sample included 33 men (mean [SD] age at death, 65.4 [13.3] years; mean [SD] time between testing and death, 2.4 [1.6] years), 25 with high- and 8 with low-stage CTE. Learning and memory was most impaired (17 of 27 [63.0%]), followed by executive function (15 of 29 [51.7%]) and language (12 of 29 [41.4%]). High-stage CTE participants generally had worse scores than low-stage CTE participants. Greater global p-tau burden was associated with worse learning and memory performance (B = -0.40; 95% CI, -0.70 to -0.09; P = .01). Findings were similar after excluding 9 participants with co-occurring Alzheimer disease or frontotemporal lobar degeneration tau. Conclusions and Relevance:In this retrospective case series of NFL players with autopsy-confirmed CTE, memory, executive function, and language impairments were common, and p-tau burden was associated with worse memory performance. Findings provide insight into the expected CTE neuropsychological profile and may help advance diagnosis before death.

Importance:Accurate prediction of chronic traumatic encephalopathy (CTE) remains challenging in life. Objective:To assess the reliability and validity of the NINDS traumatic encephalopathy syndrome (TES) criteria to predict CTE pathology in life. Design:Clinicopathological Diagnostic/Prognostic Study. Setting:Six brain banks with varied recruitment criteria. Participants:Brain donors were selected across 6 brain banks (15+ donors each), 5 age groups spanning ages 20 to 80+ (25+ donors each) and 9 repetitive head impact (RHI)/traumatic brain injury (TBI) groups (15+ donors each): (1) college or professional American football; (2) less than college football; (3) college or professional contact sports, non-football; (4) less than college contact sports, non-football; (5) military combat, no contact sports; (6) military combat and contact sports; (7) concussion with loss of consciousness, no RHI; (8) moderate to severe TBI, no RHI; (9) no RHI/TBI. Exposures:Blinded to neuropathological information, clinicians reviewed prospective study and medical records and conducted informant interviews, and an expert panel adjudicated TES diagnoses, including provisional levels of certainty for CTE pathology (suggestive/possible/probable). TES diagnoses were a priori dichotomized: TES with possible/probable CTE (CTE pos/prob ) vs. no TES/TES with suggestive CTE (CTE sug ). Main Outcomes and Measures:Blinded to clinical information, neuropathologists applied NINDS/NIBIB CTE neuropathological criteria and staging (I-IV). CTE diagnoses were a priori dichotomized: stages II-IV vs. no CTE/stage I. Results:Among 193 brain donors [men:153 (79.3%), mean age:66.4 (SD:22.0)], 57 (29.5%) donors met clinical criteria for CTE pos/prob and 42 (21.8%) donors met neuropathological criteria for CTE stages II-IV. There was high agreement between panelists for CTE pos/prob vs. no TES/CTE sug (ICC:0.95, 95%CI:0.88-0.97). CTE pos/prob sensitivity, specificity, positive likelihood ratio (LR) and negative LR for CTE stages II-IV were: 0.77 (95%CI:0.64-0.89), 0.84 (95%CI:0.78-0.90), 4.8 (95%CI:3.02-7.61), 0.28 (95%CI:0.15-0.50); age≥50:0.90 (95%CI:0.80-1), 0.90 (95%CI:0.85-0.96), 9.2 (95%CI:4.9-17.27), 0.11 (95%CI:0.04-0.33). All younger false positives (age<50; n=13) had a mental health, substance use and/or pain disorder. All older false positives (age≥50; n=11) had non-CTE neurodegenerative and vascular pathologies. Among 10 false negatives, 8 had stage II CTE. Conclusions and Relevance:The NINDS TES criteria demonstrated good reliability, sensitivity and specificity, and provided moderate to large evidence to both rule out and rule in CTE pathology, particularly above age 50. Key Points:Question: What is the validity of the NINDS consensus diagnostic criteria for traumatic encephalopathy syndrome (TES) for predicting chronic traumatic encephalopathy (CTE) neuropathology?Findings: In this clinicopathological diagnostic/prognostic study that included brain donors from varied brain banks, head impact exposures and ages, TES criteria sensitivity, specificity, positive likelihood ratio (LR) and negative LR were 0.77, 0.84, 4.8 and 0.28 with improved performance above age≥50 (0.90, 0.90, 9.2, 0.11).Meaning: The NINDS TES criteria were sensitive and specific for CTE neuropathology across varied head impact exposures, particularly above age 50.

BACKGROUND AND OBJECTIVES:Former American football players exposed to repetitive head impacts (RHI) are at a risk of chronic traumatic encephalopathy (CTE), but chronic pain, polypharmacy, and extensive orthopedic surgeries may also contribute to cognitive and behavioral symptoms. This study evaluated associations between chronic pain, centrally acting medications (CAMs), and orthopedic surgeries with cognitive and behavioral symptoms among former American football players. METHODS:The sample included former professional (PRO) and collegiate (COL) football players and unexposed, asymptomatic men (UE) from DIAGNOSE CTE. Number of CAMs, orthopedic surgeries, and average pain scores were compared between the groups. Among former football players, logistic regression tested associations between CAMs, average pain score, and orthopedic surgeries with diagnoses of cognitive impairment and neurobehavioral dysregulation (NBD) using traumatic encephalopathy syndrome (TES) research criteria. Linear regression tested associations between CAMs, average pain score, and orthopedic surgeries with the Montreal Cognitive Assessment (MoCA) and behavioral and mood symptom scales. Covariates included age, education, race, and total years of football. RESULTS:The study included 236 men (120 PRO, 60 COL, 56 UE). The mean ages were 59.1 (PRO), 53.5 (COL) and 59.6 (UE) years. PRO and COL used more CAMs (mean PRO = 0.76, COL = 1.14, UE = 0.14), had higher average pain scores (PRO = 4.22, COL = 3.21, UE = 1.05), and more orthopedic surgeries than the UE (mean PRO = 2.76, COL = 1.22, UE = 0.34). CAMs and average pain scores were associated with increased odds of consensus diagnosed NBD (CAMs OR = 2.15, 95% CI 1.53 to 3.26; average pain score OR = 1.55, 95% CI 1.32 to 1.85). CAMs and average pain scores were associated with increased measures of impulsivity, depression, anxiety, behavioral regulation, and aggression. CAMs and average pain scores were not associated with consensus diagnosed cognitive impairment, but CAMs were negatively associated with MoCA score (estimate = -0.47, 95% CI -0.81 to -0.13). There was no association between number of orthopedic surgeries and cognition or NBD. DISCUSSION:CAMs and chronic pain are associated with NBD and CAMs are associated with reduced MoCA scores in former American football players.

OBJECTIVES:To determine the range of possible prevalences of chronic traumatic encephalopathy (CTE) at death among National Football League (NFL) players and examine the association between CTE severity and risk of dementia. DESIGN:Retrospective population based cohort study. SETTING:NFL players from the era of hard-shell helmets (post-1949) in the US, including brain donors to the UNITE (Understanding Neurologic Injury and Traumatic Encephalopathy) and UCSF ADRC (University of California, San Francisco Alzheimer's Disease Research Center) brain banks. PARTICIPANTS:1712 former NFL players who died during 2008-21, of whom 338 donated their brains for neuropathological evaluation. Personal information and causes of death according to the National Death Index (NDI) were obtained for all NFL players who died during the study period. Neuropathologists masked to clinical and playing histories assessed postmortem CTE diagnosis and stage IV CTE. Clinicians, masked to neuropathological status, reviewed donors' medical records and informant based clinical histories, to adjudicate a dementia diagnosis. MAIN OUTCOME MEASURES:The main outcome measures were the minimum (number of donors with CTE/total number of NFL deaths) and maximum (1-(number of donors without CTE/total number of NFL deaths)) CTE prevalence at death during the study period and the six years (2016-21) when brain donation was most frequent. To account for selection pressure of brain donation status, inverse probability weighting was used to estimate the association between stage IV CTE and study clinician diagnosed dementia. RESULTS:Among 1712 NFL players who died, 338 (19.7%) players' brains were studied, 315 (93.2%) of whom had a diagnosis of CTE; thus, among all 1712 NFL players who died, the possible CTE prevalence at death ranged between 18.5% and 98.7%. The possible prevalence at death during 2016 to 2021, when brain donation was most frequent, ranged between 24.5% and 97.7%. Among brain donors, 104 (30.8%) had stage IV CTE, 202 (59.8%) had study clinician diagnosed dementia (dementia onset: 63.4 years, standard deviation (SD) 12.5; death: 73.1 years, SD 10.5), and 63 (18.6%) had neurodegenerative disease listed as primary cause of death. In donors, stage IV CTE was associated with study clinician diagnosed dementia (risk ratio 1.44, 95% confidence interval 1.16 to 1.78; P<0.001). Only 40.6% of donors (n=82) with study clinician diagnosed dementia had neurodegenerative disease listed as the primary or secondary cause of death. CONCLUSIONS:At minimum, nearly a quarter of all former NFL players who died during 2016-21 had CTE neuropathology at death. Among NFL player brain donors, dementia diagnosed based on records before death was common and associated with stage IV CTE.

INTRODUCTION:Repetitive head impacts (RHI) from contact sports may cause a unique pattern of white matter hyperintensities (WMH) on T2-weighted fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), termed RHI-associated WMH (RHI-WMH). These lesions are punctate, circular, and located at the gray-white matter boundary, an area vulnerable to trauma-related damage. METHODS:We investigated the association of RHI with these lesions in two aging cohorts: (1) former American football players versus asymptomatic unexposed men and (2) individuals with RHI from various contact sports versus non-RHI participants. RHI-WMH were assessed using visual ratings and a novel automated quantification pipeline. RESULTS:Individuals with RHI had greater RHI-WMH by both detection methods in both cohorts. RHI-WMH were associated with plasma neurofilament light and p-tau231, and flortaucipir positron emission tomography (PET) uptake. DISCUSSION:RHI-WMH may represent a new supportive biomarker for the detection of RHI-related neuropathologies later in life.