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.

Alzheimer disease neuropathologic change (ADNC) is considered to be the most common cause of cognitive decline and dementia worldwide. ADNC level is determined using the density of neuritic plaques in combination with the topographical distribution of β-amyloid (Aβ) plaques and hyperphosphorylated tau (p-tau)-positive neurofibrillary tangles (NFTs). While cognitive decline correlates with the level of ADNC, there remains a great deal of variation in cognitive outcomes between individuals that is unaccounted for by current neuropathologic evaluation metrics. We leveraged quantitative computer-assisted positive pixel assessments to establish the neocortical p-tau burden in the middle frontal and superior temporal gyri of 61 individuals with Braak NFT stage V who had a wide range of cognitive outcomes and trajectories. Frontal and temporal neocortical p-tau burden varied between 0.2

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.

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

Alzheimer’s disease (AD) has both genetic and environmental risk factors. Gene-environment interaction may help explain some missing heritability. There is strong evidence for cigarette smoking as a risk factor for AD. To identify genetic-smoking-related associations with AD, we conducted a genome-wide association study (GWAS) assessing a SNP-smoking interaction and stratified analysis by smoking status. Lifetime smoking data were available and analyzed among 22,030 non-Hispanic White (NHW; 8,232 cases; 13,798 controls) and 3,126 African American (AFA; 921 cases; 2,205 controls) participants from the AD Genetic Consortium and the Framingham Heart Study. “Ever smoking” status was considered as a dichotomous exposure, defined by current smoking status or past history of smoking. Across 35 datasets, we conducted GWAS with two approaches: inclusion of a SNP-by-smoking interaction term and stratification by smoking status (12,080 smokers, 13,428 non-smokers). MAGEE was used to estimate SNP-by-smoking interaction effects and SAIGE was used to estimate SNP effects in stratified analysis. Age, sex, and principal components for population structure were included as covariates. METAL was used for inverse-variance weighted meta-analysis across datasets to estimate within- and cross-ancestry effects. The stratified analysis identified a genome-wide significant association among smokers in APAF1 on chromosome 12 (top SNP: rs12368451; smokers: MAF = 0.44, p = 2.2 × 10 -8 , OR = 1.20; non-smokers: MAF = 0.44, p = 0.97, OR = 1.00). Effects were present in both ancestry groups (NHW: MAF = 0.45, p = 6.1 × 10 -6 , OR = 1.16; AFA: MAF = 0.35, p = 6.6 × 10 -5 , OR = 1.46). APAF1 has been linked to gene-smoking interaction for non-AD related outcomes. A neighboring gene, ANKS1B , is highly expressed in the brain, interacts with amyloid-b precursor protein, and has shown GWAS signals for smoking initiation and cognitive ability. We also identified a genome-wide significant SNP-by-smoking interaction in the MIXL1/LIN9 region on chromosome 1 (top SNP: rs1091961, MAF = 0.35, p = 4.9 × 10 -8 , β SNP*smoking = 0.24; smokers: OR = 1.12, p = 0.0006; non-smokers: OR = 0.89, p = 0.0001). Within LIN9 , several SNPs in linkage disequilibrium with rs1091961 have shown sub-genome wide association with nicotine dependence. In this gene-smoking interaction and smoking-stratified GWAS of AD, we identified two promising loci. These findings highlight the strength of utilizing cross-ancestry datasets and considering both genetic and environmental factors together towards a personalized medicine approach to AD.

INTRODUCTION:Alzheimer's disease (AD) has genetic and environmental risk factors, including cigarette smoking. Gene-environment interactions may explain AD missing heritability. METHODS:Lifetime smoking data from 22,032 European ancestry and 3126 African ancestry participants from the Alzheimer's Disease Genetic Consortium and the Framingham Heart Study were used to conduct genome-wide single nucleotide polymorphism (SNP)-by-smoking interaction and smoking-stratified association studies. For top-ranked loci, brain-derived bulk and single nuclei RNA-sequencing were used for differential expression and colocalization analyses. RESULTS:Among smokers only, there was a genome-wide significant association in the APAF1/ANKS1B region (rs12368451; odds ratio = 1.19, 95% confidence interval: [1.12, 1.27], p = 3.0 × 10-8). Rs12368451 had expression quantitative trait locus (eQTL) activity that differed by smoking status and brain cell types but showed the most significant posterior probability (PP = 0.15) for being causal via ANKS1B expression in oligodendrocytes among smokers. DISCUSSION:Potentially causal in smokers via eQTL activity, the top SNP may alter expression of ANKS1B, which encodes amyloid beta precursor protein intracellular domain associated-1, known to regulate amyloid beta plaques. HIGHLIGHTS:Among smokers only, a novel chromosome 12 single nucleotide polymorphism (SNP) near ANKS1B was associated with Alzheimer's disease. Evidence came from European and African ancestry cohorts. RNA-sequencing analyses implicated the top SNP as causal via ANKS1B expression in oligodendrocytes. A genome-wide African ancestry-specific significant SNP-smoking interaction was observed on chromosome 6 in SLC22A23.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to exposure to repetitive head impacts (RHI), yet little is known about its pathogenesis. Applying two single-cell whole-genome sequencing methods to hundreds of neurons from prefrontal cortex of 15 individuals with CTE and 4 with RHI without CTE, we revealed increased somatic single-nucleotide variants in CTE, exhibiting a pattern previously reported in Alzheimer's disease (AD). Furthermore, we discovered high burdens of somatic small insertions and deletions in a subset of CTE individuals, resembling a known pattern, ID4, also found in AD. Our results suggest that neurons in CTE experience stereotyped mutational processes shared with AD; the absence of similar changes in RHI neurons without CTE suggests that CTE involves mechanisms beyond RHI alone.

BACKGROUND:Validity of the 2021 NINDS Traumatic Encephalopathy Syndrome (TES) criteria, proposed to diagnose chronic traumatic encephalopathy (CTE) in life, has not been assessed. METHODS:Brain donors were selected across 6 brain banks (15+ donors each), 9 repetitive head impact (RHI)/traumatic brain injury (TBI) groups (15+ donors each): college or professional American football; less than college football; college or professional contact sports, not football; less than college contact sports, not football; military combat, no contact sports; military combat and contact sports, concussion with loss of consciousness, no RHI; moderate to severe TBI, no RHI; no RHI/TBI; and 5 age groups (25+ donors each): 20-34; 35-49; 50-64; 65-79; 80+. Blinded to clinical information, neuropathologists applied NINDS/NIBIB CTE neuropathological criteria and staging (I-IV). Blinded to neuropathological information, clinicians interviewed informants and reviewed medical records, and an expert panel adjudicated TES diagnoses, including provisional levels of CTE certainty (suggestive/possible/probable). Clinical and neuropathological diagnoses were a priori dichotomized for primary and age-stratified analyses: TES with possible/probable CTE vs. no TES/TES with suggestive CTE; CTE stages II-IV vs. no CTE/stage I CTE. RESULTS:Among 193 brain donors [men: 153 (79.3%), mean age: 66.4 (SD:22.0), white race: 158 (81.9%)], 57 (29.5%) donors met clinical criteria for TES with possible/probable CTE and 42 (21.8%) donors met neuropathological criteria for CTE stages II-IV. Using neuropathological diagnosis as the gold-standard, TES criteria sensitivity, specificity, positive likelihood ratio (LR) and negative LR were overall: 0.79, 0.84, 4.9, 0.25; age 50: 0.93, 0.90, 9.6, 0.07; age <50: 0.42, 0.66, 1.22, 0.89. Twenty-four donors who met clinical but not neuropathological criteria (false-positives), had stage I CTE (5) or other pathologies including vascular disease (11), Alzheimer's disease (9), Lewy body disease (2), motor neuron disease (2) and limbic predominant age-related TDP43 encephalopathy (1). Nine donors who met neuropathological but not clinical criteria (false-negatives) had TES with suggestive CTE (3), another etiology fully explain the syndrome (4), insufficient RHI exposure (1) or inconclusive course (1). CONCLUSION:The 2021 TES criteria were sensitive and specific for CTE pathology across a range of RHI/TBI exposures, particularly above age 50, raising optimism for use in clinical care.

V alidity of the 2021 NINDS Traumatic Encephalopathy Syndrome (TES) criteria, proposed to diagnose chronic traumatic encephalopathy (CTE) in life, has not been assessed. Brain donors were selected across 6 brain banks (15+ donors each), 9 repetitive head impact (RHI)/traumatic brain injury (TBI) groups (15+ donors each): college or professional American football; less than college football; college or professional contact sports, not football; less than college contact sports, not football; military combat, no contact sports; military combat and contact sports, concussion with loss of consciousness, no RHI; moderate to severe TBI, no RHI; no RHI/TBI; and 5 age groups (25+ donors each): 20-34; 35-49; 50-64; 65-79; 80+. Blinded to clinical information, neuropathologists applied NINDS/NIBIB CTE neuropathological criteria and staging (I-IV). Blinded to neuropathological information, clinicians interviewed informants and reviewed medical records, and an expert panel adjudicated TES diagnoses, including provisional levels of CTE certainty (suggestive/possible/probable). Clinical and neuropathological diagnoses were a priori dichotomized for primary and age-stratified analyses: TES with possible/probable CTE vs. no TES/TES with suggestive CTE; CTE stages II-IV vs. no CTE/stage I CTE. Among 193 brain donors [men: 153 (79.3%), mean age: 66.4 (SD:22.0), white race: 158 (81.9%)], 57 (29.5%) donors met clinical criteria for TES with possible/probable CTE and 42 (21.8%) donors met neuropathological criteria for CTE stages II-IV. Using neuropathological diagnosis as the gold-standard, TES criteria sensitivity, specificity, positive likelihood ratio (LR) and negative LR were overall: 0.79, 0.84, 4.9, 0.25; age 50: 0.93, 0.90, 9.6, 0.07; age <50: 0.42, 0.66, 1.22, 0.89. Twenty-four donors who met clinical but not neuropathological criteria (false-positives), had stage I CTE (5) or other pathologies including vascular disease (11), Alzheimer's disease (9), Lewy body disease (2), motor neuron disease (2) and limbic predominant age-related TDP43 encephalopathy (1). Nine donors who met neuropathological but not clinical criteria (false-negatives) had TES with suggestive CTE (3), another etiology fully explain the syndrome (4), insufficient RHI exposure (1) or inconclusive course (1). The 2021 TES criteria were sensitive and specific for CTE pathology across a range of RHI/TBI exposures, particularly above age 50, raising optimism for use in clinical care.

Repetitive head impacts from amateur contact sports can lead to structural brain injuries and long-term neurodegeneration, including chronic traumatic encephalopathy (CTE). The goal of this study was to characterize the neuropathologic alterations and clinical symptoms of young amateur contact sport athletes. This case series analyzes findings from 180 brain donors younger than 30 years, including 148 (82.2%) who played only at the amateur level, from the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank. Neuropathologic evaluations, retrospective telephone clinical assessments, and online questionnaires with informants were performed blinded. Exposure was measured as years of play. Cognitive symptoms, mood disturbances, and neurobehavioral dysregulation were assessed using informant-reported athletic history and informant-completed scales. Among 180 contact sports participants (mean [SD] age, 23.14 [4.32] yrs; 166 [92.2%] male), CTE was diagnosed in 70 (38.8%; median age, 25.3 (range 17-29) yrs) who played American football, ice hockey, soccer, rugby, or wrestled. 148 were amateurs (82.2%) who played youth, high school or collegiate sports. Of the amateurs, CTE was diagnosed in 52 (35.1%) including one woman who played collegiate soccer. Most were diagnosed with mild CTE (stages I or II). Brain donors who had CTE were older ( p  <0.001, mean difference, 3.54 yrs; 95%CI, 2.44-4.63 yrs). For those who played football, duration of playing career was significantly longer in those with CTE ( p  <0.001, mean difference, 3.45 yrs; 95%CI, 1.92-4.98 years) (Table 1). Athletes with CTE had more ventricular dilatation, cavum septum pellucidum, and perivascular pigment-laden macrophages in the frontal white matter than those without CTE. Interface astrocytosis and AQP4 alterations were found in a subset with CTE (Figure 1). Cognitive and neurobehavioral symptoms were frequent among all brain donors. Suicide was the most common cause of death; there were no differences in clinical symptoms or cause of death based on CTE status. Young amateur contact sports players are at risk for structural and microstructural brain injuries, including enlarged ventricles, cavum septum pellucidum, microvascular injury, blood-brain barrier breach, interface astrocytosis, and glymphatic remodeling. Future studies are needed to clarify the association between these early structural injuries after RHI and risk for CTE.

Enlarged perivascular spaces (ePVS) on MRI can signal impaired cerebral fluid clearance and predict dementia risk. Risk factors and biological correlates of ePVS are uncertain partially due to the lack of pathological correlation studies. Repetitive head impacts (RHI) from contact sports might represent one risk factor for ePVS, given their association with vascular pathologies and chronic traumatic encephalopathy (CTE), a neurodegenerative disease characterized by perivascular p-tau aggregates. We examined risk factors, neuropathological, and clinical correlates of antemortem MRI ePVS among brain donors exposed to RHI. The sample included 104 brain donors exposed to RHI from the UNITE brain bank. Clinical MRIs were obtained through medical record requests. A stroke neurologist used established visual rating scales (0=no ePVS, 4= >40 ePVS) to rate ePVS in the centrum semiovale (CS-ePVS) and basal ganglia (BG-ePVS) on axial T2 (n=11, 10.6%) or T1 (n=93, 89%). ePVS were coded as low (1/2) or high burden (3/4). Neuropathological diagnoses were made using established criteria. Years of football served as a proxy for duration of RHI. Antemortem dementia diagnoses were made through consensus conferences. Regression-based analyses tested the association between ePVS with years of football play, various neuropathologies, dementia status and FAQ. Analyses controlled for years from MRI scan to death. Sample characteristics are in Table 1. The most common pathological diagnosis was CTE (n=71, 68%). 34 (32.7%) and 13 (12.5%) had high CS-ePVS and BG-ePVS burden, respectively. More years of football play was associated with greater CS- (OR=1.12, 95% CI=1.03-1.22, p=0.01) and BG-ePVS (OR=1.12, 95 CI=1.01-1.24, p=0.03). Effect sizes remained when age at MRI was included for both CS- and BG-ePVS (OR=1.09) but statistical significance was diminished. Greater CS-ePVS was associated with more severe CTE, arteriosclerosis, atherosclerosis, cerebral amyloid angiopathy and Lewy body disease (Table 2). BG-ePVS was only associated with arteriosclerosis. Greater CS-ePVS were associated with increased odds for having dementia diagnosis (OR=5.41, 95% CI=1.42-20.54, p=0.01). Clinical and pathological correlations were not statistically significant when age at MRI was included. Enlarged PVS might be long-term MRI consequences of exposure to RHI, but their age independent pathological and clinical correlates in this setting remain uncertain.

ImportanceChronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impacts (RHIs). Prior research suggests a dose-response association between American football play duration and CTE risk and severity, but this association has not been studied for ice hockey. ObjectiveTo investigate associations of duration of ice hockey play with CTE diagnosis and severity, functional status, and dementia. Design, Setting, and ParticipantsThis cross-sectional study was conducted among male brain donors in the Understanding Neurological Injury and Traumatic Encephalopathy and Framingham Heart Study Brain Banks whose primary RHI exposure was from ice hockey. Donors died, brains were donated, and data were collected between July 1997 and January 2023. Data analysis was conducted from January 2023 to May 2024. ExposuresIce hockey years played as an RHI proxy. Main Outcomes and MeasuresCTE neuropathological diagnosis, cumulative phosphorylated tau (ptau) burden across 11 brain regions commonly affected in CTE, informant-reported Functional Activities Questionnaire (FAQ) score at death, and consensus dementia diagnosis were assessed. ResultsAmong 77 male donors (median [IQR] age, 51 [33-73] years), 42 individuals (54.5%) had CTE, including 27 of 28 professional players (96.4%). CTE was found in 5 of 26 donors (19.2%) who played fewer than 13 years, 14 of 27 donors (51.9%) who played 13 to 23 years, and 23 of 24 donors (95.8%) who played more than 23 years of hockey. Increased years played was associated with increased odds for CTE (odds ratio [OR] per 1-year increase, 1.34; 95% CI, 1.15-1.55; P < .001) and with increased ptau burden (SD increase per 1-year increase = 0.037; 95% CI, 0.017-0.057; P < .001) after adjusting for age at death, other contact sports played, age of first hockey exposure, concussion count, and hockey position. Simulation demonstrated that years played remained associated with CTE when years played and CTE were both associated with brain bank selection across widely ranging scenarios (median [full range] OR across all simulations, 1.34 [1.29-1.40]). Increased ptau burden was associated with FAQ score (beta standardized = 0.045; 95% CI, 0.021-0.070; P < .001) and dementia (OR per SD increase, 1.12; 95% CI, 1.01-1.26; P = .04) after adjusting for age at death, other contact sports played, hockey years played, enforcer status, age of first hockey exposure, concussion count, and hockey position. Conclusions and RelevanceIn this study of male former ice hockey players, a dose-response association was observed between hockey years played and risk and severity of CTE. Simulation suggested that brain bank selection may not bias the magnitude of outcomes in the association.

Importance Parkinsonism is associated with traumatic brain injury and chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head impact (RHI) exposure, but the neuropathologic substrates that underlie parkinsonism in individuals with CTE are yet to be defined. Objective To evaluate the frequency of parkinsonism in individuals with CTE and the association of RHI and neuropathologic substrates with parkinsonism in these individuals. Design, Setting, and Participants This cross-sectional study included brain donors with neuropathologically diagnosed CTE without other significant neurodegenerative disease and with information on parkinsonism from the Understanding Neurologic Injury and Traumatic Encephalopathy brain bank between July 2015 and May 2022. Exposure Years of contact sports participation as a proxy for RHI. Main Outcomes and Measures The main outcomes were frequency of parkinsonism in individuals with CTE and associations between (1) RHI with substantia nigra (SN) Lewy bodies (LBs) and neurofibrillary tangles (NFTs); (2) LBs, NFTs, and arteriolosclerosis with SN neuronal loss; and (3) SN neuronal loss, LBs, NFTs, and arteriolosclerosis with parkinsonism, tested by age-adjusted logistic regressions. Results Of 481 male brain donors with neuropathologically diagnosed CTE, parkinsonism occurred frequently in individuals with CTE (119 [24.7%]; 362 [75.3%] did not have parkinsonism). Participants with parkinsonism had a higher mean (SD) age at death (71.5 [13.0] years) than participants without parkinsonism (54.1 [19.3] years) (P < .001) and higher rates of dementia (104 [87.4%] vs 105 [29.0%]), visual hallucinations (45 [37.8%] vs 51 [14.1%]), and probable rapid eye movement sleep behavior disorder (52 [43.7%] vs 58 [16.0%]) (P < .001 for all). Participants with parkinsonism had a more severe CTE stage (eg, stage IV: 35 [29.4%] vs 39 [10.8%]) and nigral pathology than those without parkinsonism (NFTs: 50 of 117 [42.7%] vs 103 of 344 [29.9%]; P = .01; neuronal loss: 61 of 117 [52.1%] vs 59 of 344 [17.1%]; P < .001; and LBs: 28 of 116 [24.1%] vs 20 of 342 [5.8%]; P < .001). Years of contact sports participation were associated with SN NFTs (adjusted odds ratio [AOR], 1.04; 95% CI, 1.00-1.07; P = .03) and neuronal loss (AOR, 1.05; 95% CI, 1.01-1.08; P = .02). Nigral neuronal loss (AOR, 2.61; 95% CI, 1.52-4.47; P < .001) and LBs (AOR, 2.29; 95% CI, 1.15-4.57; P = .02) were associated with parkinsonism. However, SN neuronal loss was associated with SN LBs (AOR, 4.48; 95% CI, 2.25-8.92; P < .001), SN NFTs (AOR, 2.51; 95% CI, 1.52-4.15; P < .001), and arteriolosclerosis (AOR, 2.27; 95% CI, 1.33-3.85; P = .002). In American football players, regression analysis demonstrated that SN NFTs and neuronal loss mediated the association between years of play and parkinsonism in the context of CTE (beta, 0.012; 95% CI, 0.001-0.038). Conclusions and Relevance In this cross-sectional study of contact sports athletes with CTE, years of contact sports participation were associated with SN tau pathology and neuronal loss, and these pathologies were associated with parkinsonism. Repetitive head impacts may incite neuropathologic processes that lead to symptoms of parkinsonism in individuals with CTE.

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.

BACKGROUND AND OBJECTIVES:Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with exposure to repetitive head impacts, including from contact sports and military service. Although CTE case reports have commonly described aggression during midlife, recent studies failed to show associations between CTE tau burden and aggression. First-degree family history of mental illness (1°FHMI) is a well-established risk factor of aggression. We tested the hypothesis that CTE pathology moderates the association between 1°FHMI and aggression, providing an explanation for the lack of association previously observed. METHODS:This was a retrospective examination of consecutive, deceased, male brain donors with repetitive head impact exposure from the Understanding Neurologic Injury and Traumatic Encephalopathy Study at Boston University from 2014 to 2021. Neuropathologists diagnosed CTE using established National Institute of Neurological Disorders and Stroke criteria. Informants were administered the Brown-Goodwin Assessment for Lifetime History of Aggression (BGLHA) and were queried regarding 1°FHMI. Exploratory factor analysis evaluated BGLHA factor structure. Stratified by CTE status, linear regression analyses examined relationships between 1°FHMI and standardized adult BGLHA scores and factor scores. Models were adjusted for race, age at death, education, years of contact sport play, military history, substance use treatment history, psychologically traumatic event history, and BGLHA childhood score. RESULTS:Among 845 brain donors, the mean age at death was 60.3 (SD = 19.6) years. 589 donors (69.7%) had CTE, and 383 donors (45.3%) had a 1°FHMI. 1°FHMI was significantly associated with standardized adult BGLHA scores in those with CTE, but not in those without CTE (CTE present: β = 0.16, 95% CI 0.02-0.29; CTE absent: β = 0.10, 95% CI -0.12 to 0.32). The largest effects were observed among those with CTE, aged 40-59 years (CTE present: β = 0.64, 95% CI 0.32-0.96; CTE absent: β = 0.05, 95% CI -0.44 to 0.54), particularly for BGLHA factors of emotional dysregulation/impulsiveness (CTE present: β = 1.68, 95% CI 0.78-2.58; CTE absent: β = 0.09, 95% CI -1.20 to 1.37) and antisocial behavior (CTE present: β = 1.56, 95% CI 0.64-2.47; CTE absent: β = 0.10, 95% CI -1.19 to 1.40). DISCUSSION:Among brain donors exposed to repetitive head impacts, CTE pathology moderated the effect of 1°FHMI on BGLHA scores, with the largest effects in midlife. Predisposition to mental illness and CTE pathology may increase risk of aggression beyond each risk factor's additive effects. Prospective studies are needed to confirm these results.

Repetitive head impacts (RHIs) from football are associated with the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). It is unclear whether a history of traumatic brain injury (TBI) is sufficient to precipitate CTE neuropathology. We examined the association between TBI and CTE neuropathology in 580 deceased individuals exposed to RHIs from football. TBI history was assessed using a modified version of the Ohio State University TBI Identification Method Short Form administered to informants. There were 22 donors who had no TBI, 213 who had at least one TBI without loss of consciousness (LOC), 345 who had TBI with LOC, and, of those with a history of TBI with LOC, 36 who had at least one moderate-to-severe TBI (msTBI, LOC >30 min). CTE neuropathology was diagnosed in 405. There was no association between CTE neuropathology status or severity and TBI with LOC (odds ratio [OR] = 0.95, 95% confidence interval [CI] = 0.64-1.41; OR = 1.22, 95% CI = 0.71-2.09) or msTBI (OR = 0.70, 95% CI = 0.33-1.50; OR = 1.01, 95% CI = 0.30-3.41). There were no associations with other neurodegenerative or cerebrovascular pathologies examined. TBI with LOC and msTBI were not associated with CTE neuropathology in this sample of brain donors exposed to RHIs from American football.

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.

Over the last 17 years, there has been a remarkable increase in scientific research concerning chronic traumatic encephalopathy (CTE). Since the publication of NINDS–NIBIB criteria for the neuropathological diagnosis of CTE in 2016, and diagnostic refinements in 2021, hundreds of contact sport athletes and others have been diagnosed at postmortem examination with CTE. CTE has been reported in amateur and professional athletes, including a bull rider, boxers, wrestlers, and American, Canadian, and Australian rules football, rugby union, rugby league, soccer, and ice hockey players. The pathology of CTE is unique, characterized by a pathognomonic lesion consisting of a perivascular accumulation of neuronal phosphorylated tau (p-tau) variably alongside astrocytic aggregates at the depths of the cortical sulci, and a distinctive molecular structural configuration of p-tau fibrils that is unlike the changes observed with aging, Alzheimer’s disease, or any other tauopathy. Computational 3-D and finite element models predict the perivascular and sulcal location of p-tau pathology as these brain regions undergo the greatest mechanical deformation during head impact injury. Presently, CTE can be definitively diagnosed only by postmortem neuropathological examination; the corresponding clinical condition is known as traumatic encephalopathy syndrome (TES). Over 97% of CTE cases published have been reported in individuals with known exposure to repetitive head impacts (RHI), including concussions and nonconcussive impacts, most often experienced through participation in contact sports. While some suggest there is uncertainty whether a causal relationship exists between RHI and CTE, the preponderance of the evidence suggests a high likelihood of a causal relationship, a conclusion that is strengthened by the absence of any evidence for plausible alternative hypotheses. There is a robust dose–response relationship between CTE and years of American football play, a relationship that remains consistent even when rigorously accounting for selection bias. Furthermore, a recent study suggests that selection bias underestimates the observed risk. Here, we present the advances in the neuropathological diagnosis of CTE culminating with the development of the NINDS–NIBIB criteria, the multiple international studies that have used these criteria to report CTE in hundreds of contact sports players and others, and the evidence for a robust dose–response relationship between RHI and CTE.

Although we have greatly increased our ability to identify the presence of neurodegenerative pathology during life, additional techniques and targets are still needed to increase diagnostic specificity. Recently, it has become evident that the neuroinflammatory response might be tailored towards distinct diseases resulting in disease specific “neuroinflammatory signatures”. Therefore, a detailed comparison of neuroinflammatory molecules present among distinct neurodegenerative diseases could provide novel information of disease specific therapeutic targets or differential biomarkers. To better examine potential neuroinflammatory signatures, a 71 immune-related protein multiplex ELISA panel was utilized to analyze anterior cingulate grey matter from 127 individuals neuropathologically diagnosed with Alzheimer’s disease (AD), but chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease (AGD). A partial least square regression analysis was used for unbiased clustering and identifying proteins that were distinctly correlated with each disease correcting for age and gender. Receiver operator characteristic and binary logistic regression analyses were then used to examine the ability of each candidate protein to distinguish diseases. Validation in postmortem cerebrospinal fluid (CSF) from 15 AD and 14 CTE cases was performed to determine if candidate proteins could act as possible biomarkers. Finally, histology was performed using candidate proteins to visualize cell type expression for better understanding of potential mechanistic pathways. Five clusters of neuroimmune proteins were identified and compared to determine if clusters were specific to distinct disease. Each cluster was found to correlate with either CTE, AD, PSP, CBD, or AGD. When examining which proteins were the strongest driver of each cluster, it was observed the most distinctive protein for CTE was CCL21, AD was FLT3L, and PSP was IL13. Individual proteins that were specific to CBD and AGD were not observed. CCL21 was observed to be elevated in CTE CSF compared to AD, further validating the use as possible biomarkers. Overall, these results highlight that different neuroinflammatory responses might underlie unique mechanisms in related neurodegenerative pathologies. Additionally, the use of distinct neuroinflammatory signatures could help differentiate between neuropathologies and act as novel biomarker candidate to increase specificity for in-life diagnoses.