Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease found in individuals with a history of repetitive head injury (RHI) received through playing contact sports. Currently, CTE can only be diagnosed after death through the identification of perivascular neuronal hyperphosphorylated tau (pTau) pathology, found at the depth of the cortical sulcus. Although the pathognomonic lesion is found among all cases, pTau deposition is patchy and heterogeneous among individuals. To determine whether the heterogeneity of CTE masks more subtle ordering or additional disease variants, we applied the unsupervised machine learning algorithm subtype and stage inference (SuStaIn) on fully quantitative pTau density data from 26 brain regions in 207 CTE cases and 75 control cases. SuStaIn identified three distinct pathological progression subtypes: 93 cases were classified as Subtype 1 (cortical predominant) and showed dense, rapidly progressing cortical pTau akin to the classically described CTE neuropathology; Subtype 2 (cortical sparing–hippocampal enhanced) had 105 cases that exhibited a reduced cortical pTau burden that progressed slower, but also had pronounced hippocampal involvement in a CTE-specific pattern; and Subtype 3 (copathology altered) consisted of 28 older cases with higher CTE stage, was enriched for comorbid pathologies (pTDP43, Aβ, hippocampal sclerosis, and arteriolosclerosis), and had enhanced pTau in regions highly related to those additional pathologies. Clinically, impaired performance in the Functional Activities Questionnaire (FAQ) correlated with pTau regional burden and severity only in cases with Subtype 1 pathology, suggesting the enhanced cortical pTau pathology was linked to greater functional decline. Overall, these findings help characterize the heterogeneity in CTE progression, validate key pathological variants, and will be crucial for refining diagnostic criteria and advancing in-life diagnosis.

Central nervous system (CNS) associated T-cells are present in the meninges and perivascular spaces of healthy brain tissue, but their recruitment into the brain parenchyma is increased by inflammation and hyperphosphorylated tau (p-tau) accumulation. Chronic traumatic encephalopathy (CTE) is a progressive tauopathy associated with exposure to repetitive head impacts (RHI) and definitively diagnosed by the presence of a pathognomonic perivascular p-tau lesion, most commonly at the sulcal depths of the dorsolateral frontal cortex (DLF). Exposure to RHI and CTE is associated with substantial neuroinflammation; however, the involvement of T cells is unknown. Here, we used post-mortem human brain tissue to assess T-cell accumulation in the DLF of 58 individuals exposed to RHI, including 19 with neuropathologically verified Low CTE (stage I-II), 23 with neuropathologically verified High CTE (stage III-IV), and 16 without CTE, as well as 18 controls unexposed to RHI and without CTE. Multiplex immunofluorescence was utilized to label T-cells, microglia, p-tau, and synapses in the leptomeninges, sulcal gray matter, crest gray matter, and white matter. We found that infiltrating T-cells were significantly increased in the sulci across all groups compared to controls, with distinct subtypes in RHI without CTE, compared to Low or High CTE. In addition, T-cell infiltration correlated with the duration of RHI, as measured by years of sports play, and synaptic loss. Meningeal and infiltrating T-cells were elevated in sulci with p-tau depositions and spatially related to MHC2 expressing cells. Meningeal T-cells were also significantly correlated with a younger onset of behavioral symptoms. These data suggest that T-cells may play a role in the chronic inflammation and degeneration associated with RHI and CTE.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease associated with repeated head injuries (RHI) commonly experienced by contact sport athletes, military personnel, and domestic abuse victims. Despite growing recognition of CTE, the molecular mechanisms underlying disease progression remain poorly understood. This study aims to identify proteomic alterations associated with CTE pathology and clinical features to elucidate key biological pathways involved in disease pathogenesis. SomaScan 7k high-throughput proteomics was performed on 204 dorsolateral prefrontal cortex samples from the Boston University CTE Center Brain Bank. We identified differentially expressed proteins associated with CTE, hyperphosphorylated tau (ptau) pathology, duration of contact sports play, dementia status, and Cognitive Difficulty Scale (CDS) scores. Gene set enrichment analysis revealed that proteasome subunit proteins and related pathways were strongly associated with CTE progression and correlated with years of contact sports play. Reduction in ribosomal proteins and pathways was closely associated with ptau burden. Additionally, multiple models demonstrated significant alterations in MAPK-related cell signaling pathways. These findings advance our understanding of CTE progression and identify mechanisms correlated with key pathological features of the disease. Validation of these results could inform the development of diagnostics and treatments for CTE.

Repetitive head impacts (RHI), primarily through contact sports play and military service, are a recognized risk factor for cognitive and behavioral symptoms, as well as progressive neurodegenerative diseases such as chronic traumatic encephalopathy. While altered DNA methylation has been linked to environmental exposures and neurodegeneration, its association with RHI remains unknown. In this study, we investigated whether duration of contact sports play in a community-based aging cohort is associated with altered DNA methylation patterns. Reduced representation bisulfite sequencing on human dorsolateral frontal cortex identified 461 genome-wide significant CpG sites associated with duration of contact sports play, spanning 13 genes of which the majority were hypomethylated. The hypomethylation pattern was largely replicated in an independent cohort. Notably, CAMK2B, B4GALT6, and TLR2, were hypomethylated and upregulated in the cortical sulcus of the DLFC in individuals with RHI exposure from contact sports. Furthermore, alterations of CAMK2B and B4GALT6 were observed in CTE cases. Together, these findings reveal distinct, region-specific epigenetic changes associated with contact sports exposure and provide new insights into the molecular mechanisms underlying RHI-related sequalae.

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.

Foundation models have transformed computational pathology by providing generalizable representations from large-scale histology datasets. However, existing models are predominantly trained on surgical pathology data, which is enriched for non-nervous tissue and overrepresents neoplastic, inflammatory, metabolic, and other non-neurological diseases. Neuropathology represents a markedly different domain of histopathology, characterized by unique cell types (neurons, glia, etc.), distinct cytoarchitecture, and disease-specific pathological features including neurofibrillary tangles, amyloid plaques, Lewy bodies, and pattern-specific neurodegeneration. This domain mismatch may limit the ability of general-purpose foundation models to capture the morphological patterns critical for interpreting neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and cerebellar ataxias. To address this gap, we developed NeuroFM, a foundation model trained specifically on whole-slide images of brain tissue spanning diverse neurodegenerative pathologies. NeuroFM demonstrates superior performance compared to general-purpose models across multiple neuropathology-specific downstream tasks, including mixed dementia disease classification, hippocampal region segmentation, and neurodegenerative ataxia identification encompassing cerebellar essential tremor and spinocerebellar ataxia subtypes. This work establishes that domain-specialized foundation models trained on brain tissue can better capture neuropathology-specific features than models trained on general surgical pathology datasets. By tailoring foundation models to the unique morphological landscape of neurodegenerative diseases, NeuroFM enables more accurate and reliable AI-based analysis for brain disease diagnosis and research, setting a precedent for domain-specific model development in specialized areas of digital pathology.

The unique lesion of chronic traumatic encephalopathy (CTE) is the perivascular deposition of hyperphosphorylated tau at the depth of the cortical sulci. The distribution and molecular composition of p-tau is distinct from Alzheimer’s disease (AD), but differential diagnostic challenges remain. Understanding disease differences in regional density of p-tau will inform differential diagnosis and interpretation of in vivo biomarkers. Here, we compared autopsy-confirmed CTE and AD across cortical and subcortical measurements of p-tau density. The sample included 109 brain donors with stage III/IV CTE, and 109 age (+/- 3 years) and sex similar brain donors with autopsy-confirmed AD. While the original sample was similar, there is missing data across regions due to older cases not having AT8 stains. CTE was neuropathologically diagnosed using published criteria. NIA-Reagan was used for AD. Neuropathologists used semi-quantitative rating scales (0=none, 3=severe) to evaluate p-tau severity in the dorsolateral frontal cortex (DLFC), inferior orbital frontal cortex (IFC), superior temporal cortex (STC), inferior parietal cortex (IPC), CA1, CA2, and CA4, entorhinal cortex (EC), and amygdala. Digital slide scanning of AT8 tissue was done for quantitative assessment of p-tau density in the DLFC, STC, IPC, CA1, CA2/3, CA4, and calcarine cortex. Regression and analysis of variance models compared disease groups on each outcome, controlling for age. On the semi-quantitative rating scales, those with autopsy-confirmed CTE had greater p-tau severity in the CA4-hippocampus compared with AD (OR=4.43, p=0.003); in contrast, AD had greater p-tau severity in the CA1-hippocampus (OR=0.07), EC (OR=0.10), and amygdala (OR=0.24) (ps<0.05). There were no differences for the CA2-hippocampus. Regarding cortical regions, those with AD had greater p-tau severity on the DLFC, IFC, STC, and IPC (ORs=0.03-0.16, ps<0.05). A similar pattern was found for the quantitative p-tau density data: CTE had greater p-tau density in CA4- (marginal mean difference=7.45) and CA2/3 (marginal mean difference=9.86) (ps<0.01) and AD had higher density of p-tau across the other regions (i.e., DLFC, IPC, STC, calcarine). Compared with AD, CA4-hippocampus was most affected in CTE. AD had greater p-tau density across cortical regions. Findings inform neuropathological differential diagnosis and interpretation of in vivo biomarkers in CTE and AD.

Chronic Traumatic Encephalopathy (CTE) and other neurodegenerative disorders (NDs) pose diagnostic challenges due to their diffuse and subtle pathological changes. Traditional diagnostic methods relying on manual histopathological slide inspection are labor-intensive and prone to variability, often missing subtle structural alterations. This study introduces an age-informed, attention-based multiple instance learning pipeline to predict AT8 density, a key marker of p-tau aggregation in CTE. Using Luxol Fast Blue and Hematoxylin Eosin stained images, our model identifies critical pathological regions and generates interpretable attention maps highlighting structural changes linked to tau pathology. Incorporating patient age enhances predictive accuracy and contextual understanding, addressing aging’s confounding effects. We also develop quantitative evaluation procedures for foundation models (FMs), assessing attention map smoothness, faithfulness, and robustness to perturbations like stain variability and noise. These benchmarks facilitate informed FM selection and optimization for neuropathological tasks. By enabling scalable, automated whole-slide image analysis, our approach advances digital neuropathology, supporting earlier and more precise ND diagnoses and uncovering subtle markers with potential applications in clinical imaging.

Repetitive head impacts that occur in contact/collision sports, military service, and physical violence are associated with TDP-43 pathology, and TDP-43 inclusions are frequently present in the hippocampus and frontal cortex in chronic traumatic encephalopathy (CTE). Individuals with CTE and TDP-43 inclusions are more likely to show severe cognitive impairment; however, the underlying mechanism is unknown. In amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), TDP-43 inclusions are associated with widespread gene mis-splicing and cryptic exon expression. We hypothesized that TDP-43 pathology in CTE similarly contributes to gene mis-splicing, leading to selective protein loss and neurodegeneration. A total of 212 brain donors with a history of repetitive head impacts were examined for CTE and the presence and distribution of TDP-43 inclusions. Clinical outcomes, including measures of cognitive impairment, were obtained from informants and medical records. Bulk RNA sequencing and SomaScan 7K aptamer-based proteomics were performed on the dorsolateral prefrontal cortex. After excluding those with AD, FTLD-TDP, or ALS, variable splicing events were determined using LeafCutter in those with CTE and TDP-43 inclusions in the hippocampus or frontal cortex (CTE-TDP) compared to CTE without TDP-43 in those regions (CTE). Out of 142 with CTE, 72 (51%) had TDP-43 inclusions within the hippocampus, frontal cortex, or both (CTE-TDP). Differential analysis revealed altered splicing within 836 genes in CTE-TDP compared to CTE with a false discovery rate <0.01. Of these, 23 overlapped with previously identified mis-spliced genes in ALS and FTLD-TDP. Seven of these genes had protein levels measured with SomaScan proteomics, including CAMK2B, DLGAP4, EPB41L1, NCAM1, PTPRD, RAP1GAP, and SH3KBP1. Notably, protein levels of erythrocyte membrane protein band 4.1 like 1 (EPB41L1) and RAP1 GTPase-activating protein (RAP1GAP) were significantly reduced in CTE-TDP frontal cortex compared to CTE ( p 's <0.01) and negatively correlated with both amygdala and hippocampal TDP-43 inclusions. Furthermore, decreased levels of EPB41L1 and RAP1GAP were associated with dementia adjusting for age ( p 's <0.05). Both EPB41L1 and RAP1GAP are involved in synaptic plasticity and signaling. Mis-splicing and decreased protein expression of these synapse-related genes may partially underlie the neurodegeneration and cognitive impairments in CTE with TDP-43 inclusions.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that can only be diagnosed post-mortem via pathological autopsy. The primary risk factor for CTE is a history of repetitive head impacts (RHI) received through contact sports including American football, hockey or soccer, military-related head injuries, or intimate partner violence. Recent findings have demonstrated that neuroinflammation is a critical compo-nent of early CTE pathogenesis and is likely part of the mechanism driving disease onset and progression. Additionally, the innate specificity, or ‘signature’, of a neuroinflammatory response may function as a dis-ease-specific marker for various neurodegenerative conditions. This would suggest an enormous repository of novel CTE biomarker candidates to be added to ongoing clinical trials, helping bolster diagnosis. However, few studies have truly leveraged immune mediators as candidate CTE markers. In this review, we argue and provide support that inflammatory mechanisms could serve as a viable source for novel biomarkers that are specific to CTE pathol-ogy. This includes an evaluation of inflammatory or damage-related markers such as CCL11 (C-C Motif Chem-okine Ligand 11, also known as Eotaxin-1), CCL21 (C-C Motif Chemokine Ligand 21) and GFAP (Glial Fibrillary Acidic Protein). We discuss the neuroinflammatory responses that give rise to these biomarkers in addition to the advantages and limitations of using each to diagnose CTE with particular attention to sensitivity and specifici-ty. Although further research is necessary to validate immune mediators, the latter show promise as diagnos-tic biomarkers for CTE and may also eventually serve as therapeutic targets for mitigating chronic inflamma-tion in at-risk populations.

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.

Repetitive head impacts (RHI) sustained from contact sports are the largest risk factor for chronic traumatic encephalopathy (CTE). Currently, CTE can only be diagnosed after death and the multicellular cascade of events that trigger initial hyperphosphorylated tau (p-tau) deposition remain unclear. Further, the symptoms endorsed by young individuals with early disease are not fully explained by the extent of p-tau deposition, severely hampering development of therapeutic interventions. Here, we show that RHI exposure associates with a multicellular response in young individuals (<51 years old) prior to the onset of CTE p-tau pathology that correlates with number of years of RHI exposure. Leveraging single nucleus RNA sequencing of tissue from 8 control, 9 RHI-exposed, and 11 low stage CTE individuals, we identify SPP1+ inflammatory microglia, angiogenic and inflamed endothelial cell profiles, reactive astrocytes, and altered synaptic gene expression in excitatory and inhibitory neurons in all individuals with exposure to RHI. Surprisingly, we also observe a significant loss of cortical sulcus layer 2/3 neurons in contact sport athletes compared to controls independent of p-tau pathology. Finally, we identify TGFB1 as a potential signal mediating microglia-endothelial cell cross talk through ligand-receptor analysis. These results provide robust evidence that multiple years of RHI exposure is sufficient to induce lasting cellular alterations that may underlie p-tau deposition and help explain the early pathogenesis in young former contact sport athletes. Furthermore, these data identify specific cellular responses to repetitive head impacts that may direct future identification of diagnostic and therapeutic strategies for CTE.

Spinal cord injury (SCI) increasingly affects aged individuals, where functional impairment and mortality are highest. However, the aging-dependent mechanisms underpinning tissue damage remain elusive. Here, we find that natural killer-like T (NKLT) cells seed the intact aged human and murine spinal cord and multiply further after injury. NKLT cells accumulate in the spinal cord via C-X-C motif chemokine receptor 6 and ligand 16 signaling to clonally expand by engaging with major histocompatibility complex (MHC)-I-expressing myeloid cells. NKLT cells expressing natural killer cell granule protein 7 (Nkg7) disrupt myeloid-cell-dependent wound healing in the aged injured cord. Nkg7 deletion in mice curbs NKLT cell degranulation to normalize the myeloid cell phenotype, thus promoting tissue repair and axonal integrity. Monoclonal antibodies neutralizing CD8+ T cells after SCI enhance neurological recovery by promoting wound healing. Our results unveil a reversible role for NKG7+CD8+ NKLT cells in exacerbating tissue damage, suggesting a clinically relevant treatment for SCI.

The traditional semiquantitative (SQ) scoring system for neuropathologic assessment, although widely used, is prone to variability among assessors and does not capture the full spectrum of pathological changes. To address these limitations, digital pathology-based strategies like positive pixel quantitation or advanced artificial intelligence (AI) techniques have been developed. However, a comprehensive comparison of these measures has never been performed. Using 1412 cases from Boston University brain banks, human-driven SQ scoring was compared with computer-driven percent area-stained measures and AI-driven cellular density quantitation of tau pathology in the dorsolateral frontal cortex. When comparing each measure directly in all cases, we observed general agreement between measures. Because the full dataset included a large range of different neuropathologies, to reduce noise we performed a subanalysis in cases with the neurodegenerative disease chronic traumatic encephalopathy (CTE) and examined correlations with clinical and neuropathologic variables. While all methods demonstrated significant ability to predict CTE neuropathology, inconsistent background, noncellular elements, and artifacts increased variability for the positive pixel method. Thus, the AI-driven method was better at identifying pathological changes associated with sparse pathology. Overall, our results demonstrate important differences among neuropathologic assessment techniques and highlight the need for careful consideration when selecting analysis methods.

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.

Repetitive head impacts (RHIs) sustained from contact sports are the largest risk factor for chronic traumatic encephalopathy (CTE)1-4. Currently, CTE can only be diagnosed after death and the events that trigger initial hyperphosphorylated tau (p-tau) deposition remain unclear2. Furthermore, the symptoms endorsed by young individuals are not fully explained by the extent of p-tau deposition2, severely hampering therapeutic interventions. Here we observed a multicellular response prior to the onset of CTE p-tau pathology that correlates with number of years of RHI exposure in young people (less than 51 years of age) with RHI exposure, the majority of whom played American football. Leveraging single-nucleus RNA sequencing of tissue from 8 control individuals, 9 RHI-exposed individuals and 11 individuals with low-stage CTE, we identify SPP1-expressing inflammatory microglia, angiogenic and inflamed endothelial cells, astrocytosis and altered synaptic gene expression in those exposed to RHI. We also observe a significant loss of cortical sulcus layer 2/3 neurons independent of p-tau pathology. Finally, we identify TGFβ1 as a potential signal that mediates microglia-endothelial cell cross talk. These results provide robust evidence that multiple years of RHI is sufficient to induce lasting cellular alterations that may underlie p-tau deposition and help explain the early pathogenesis in young former contact sport athletes. Furthermore, these data identify specific cellular responses to RHI that may direct future identification of diagnostic and therapeutic strategies for CTE.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. Genetic variation in the 17q21.31 region, containing microtubule-associated protein tau (MAPT), has been implicated in tauopathies but has not been investigated in CTE. The region includes a megabase-long inversion (H1/H2) and copy-number variations, including α, β, and γ segments, which can be characterized as nine segregating structural haplotypes. We leveraged array SNP data and a reference panel across the 17q21.31 region to impute structural haplotypes and test their association with CTE endophenotypes in 447 European ancestry brain donors with RHI exposure. The H1β1γ1 haplotype was significantly associated with dementia and semi-quantitative tau burden in multiple cortical and medial temporal regions commonly affected in CTE. H1β1γ1 differential expression analyses in dorsolateral frontal cortex implicated cis-acting genes and inflammatory pathways. Taken together, the H1β1γ1 haplotype may help explain CTE heterogeneity among those with similar RHI exposure.

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.

Background Traumatic encephalopathy syndrome (TES) is defined as the clinical manifestation of the neuropathological entity chronic traumatic encephalopathy (CTE). A core feature of TES is neurobehavioral dysregulation (NBD), a neuropsychiatric syndrome in repetitive head impact (RHI)-exposed individuals, characterized by a poor regulation of emotions/behavior. To discover biological correlates for NBD, we investigated the association between biomarkers of inflammation (interleukin (IL)-1β, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) in cerebrospinal fluid (CSF) and NBD symptoms in former American football players and unexposed individuals. Methods Our cohort consisted of former American football players, with ( n = 104) or without ( n = 76) NBD diagnosis, as well as asymptomatic unexposed individuals ( n = 55) from the DIAGNOSE CTE Research Project. Specific measures for NBD were derived (i.e., explosivity, emotional dyscontrol, impulsivity, affective lability, and a total NBD score) from a factor analysis of multiple self-report neuropsychiatric measures. Analyses of covariance tested differences in biomarker concentrations between the three groups. Within former football players, multivariable linear regression models assessed relationships among log-transformed inflammatory biomarkers, proxies for RHI exposure (total years of football, cumulative head impact index), and NBD factor scores, adjusted for relevant confounding variables. Sensitivity analyses tested (1) differences in age subgroups (< 60, ≥ 60 years); (2) whether associations could be identified with plasma inflammatory biomarkers; (3) associations between neurodegeneration and NBD, using plasma neurofilament light (NfL) chain protein; and (4) associations between biomarkers and cognitive performance to explore broader clinical symptoms related to TES. Results CSF IL-6 was higher in former American football players with NBD diagnosis compared to players without NBD. Furthermore, elevated levels of CSF IL-6 were significantly associated with higher emotional dyscontrol, affective lability, impulsivity, and total NBD scores. In older football players, plasma NfL was associated with higher emotional dyscontrol and impulsivity, but also with worse executive function and processing speed. Proxies for RHI exposure were not significantly associated with biomarker concentrations. Conclusion Specific NBD symptoms in former American football players may result from multiple factors, including neuroinflammation and neurodegeneration. Future studies need to unravel the exact link between NBD and RHI exposure, including the role of other pathophysiological pathways.

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.