Duration of American Football Play and Chronic Traumatic Encephalopathy.

OBJECTIVE: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to contact and collision sports, including American football. We hypothesized a dose-response relationship between duration of football played and CTE risk and severity. METHODS: In a convenience sample of 266 deceased American football players from the Veterans Affairs-Boston University-Concussion Legacy Foundation and Framingham Heart Study Brain Banks, we estimated the association of years of football played with CTE pathological status and severity. We evaluated the ability of years played to classify CTE status using receiver operating characteristic curve analysis. Simulation analyses quantified conditions that might lead to selection bias. RESULTS: In total, 223 of 266 participants met neuropathological diagnostic criteria for CTE. More years of football played were associated with having CTE (odds ratio [OR] = 1.30 per year played, 95% confidence interval [CI] = 1.19-1.41; p = 3.8 × 10-9 ) and with CTE severity (severe vs mild; OR = 1.14 per year played, 95% CI = 1.07-1.22; p = 3.1 × 10-4 ). Participants with CTE were 1/10th as likely to have played <4.5 years (negative likelihood ratio [LR] = 0.102, 95% CI = 0.100-0.105) and were 10 times as likely to have played >14.5 years (positive LR = 10.2, 95% CI = 9.8-10.7) compared with participants without CTE. Sensitivity and specificity were maximized at 11 years played. Simulation demonstrated that years played remained adversely associated with CTE status when years played and CTE status were both related to brain bank selection across widely ranging scenarios. INTERPRETATION: The odds of CTE double every 2.6 years of football played. After accounting for brain bank selection, the magnitude of the relationship between years played and CTE status remained consistent. ANN NEUROL 2020;87:116-131.

Nonhomogeneous Gadolinium Retention in the Cerebral Cortex after Intravenous Administration of Gadolinium-based Contrast Agent in Rats and Humans.

Background Gadolinium retention after repeated gadolinium-based contrast agent (GBCA) exposure has been reported in subcortical gray matter. However, gadolinium retention in the cerebral cortex has not been systematically investigated. Purpose To determine whether and where gadolinium is retained in rat and human cerebral cortex. Materials and Methods The cerebral cortex in Sprague-Dawley rats treated with gadopentetate dimeglumine (three doses over 4 weeks; cumulative gadolinium dose, 7.2 mmol per kilogram of body weight; n = 6) or saline (n = 6) was examined with antemortem MRI. Two human donors with repeated GBCA exposure (three and 15 doses; 1 and 5 months after exposure), including gadopentetate dimeglumine, and two GBCA-naive donors were also evaluated. Elemental brain maps (gadolinium, phosphorus, zinc, copper, iron) for rat and human brains were constructed by using laser ablation inductively coupled plasma mass spectrometry. Results Gadopentetate dimeglumine-treated rats showed region-, subregion-, and layer-specific gadolinium retention in the neocortex (anterior cingulate cortex: mean gadolinium concentration, 0.28 µg ∙ g-1 ± 0.04 [standard error of the mean]) that was comparable (P > .05) to retention in the allocortex (mean gadolinium concentration, 0.33 µg ∙ g-1 ± 0.04 in piriform cortex, 0.24 µg ∙ g-1 ± 0.04 in dentate gyrus, 0.17 µg ∙ g-1 ± 0.04 in hippocampus) and subcortical structures (0.47 µg ∙ g-1 ± 0.10 in facial nucleus, 0.39 µg ∙ g-1 ± 0.10 in choroid plexus, 0.29 µg ∙ g-1 ± 0.05 in caudate-putamen, 0.26 µg ∙ g-1 ± 0.05 in reticular nucleus of the thalamus, 0.24 µg ∙ g-1 ± 0.04 in vestibular nucleus) and significantly greater than that in the cerebellum (0.17 µg ∙ g-1 ± 0.03, P = .01) and white matter tracts (anterior commissure: 0.05 µg ∙ g-1 ± 0.01, P = .002; corpus callosum: 0.05 µg ∙ g-1 ± 0.02, P = .001; cranial nerve: 0.02 µg ∙ g-1 ± 0.01, P = .004). Retained gadolinium colocalized with parenchymal iron. T1-weighted MRI signal intensification was not observed. Gadolinium retention was detected in the cerebral cortex, pia mater, and pia-ensheathed leptomeningeal vessels in two GBCA-exposed human brains but not in two GBCA-naive human brains. Conclusion Repeated gadopentetate dimeglumine exposure is associated with gadolinium retention in specific regions, subregions, and layers of cerebral cortex that are critical for higher cognition, affect, and behavior regulation, sensorimotor coordination, and executive function. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Kanal in this issue.

Age of first exposure to tackle football and chronic traumatic encephalopathy.

OBJECTIVE: To examine the effect of age of first exposure to tackle football on chronic traumatic encephalopathy (CTE) pathological severity and age of neurobehavioral symptom onset in tackle football players with neuropathologically confirmed CTE. METHODS: The sample included 246 tackle football players who donated their brains for neuropathological examination. Two hundred eleven were diagnosed with CTE (126 of 211 were without comorbid neurodegenerative diseases), and 35 were without CTE. Informant interviews ascertained age of first exposure and age of cognitive and behavioral/mood symptom onset. RESULTS: Analyses accounted for decade and duration of play. Age of exposure was not associated with CTE pathological severity, or Alzheimer's disease or Lewy body pathology. In the 211 participants with CTE, every 1 year younger participants began to play tackle football predicted earlier reported cognitive symptom onset by 2.44 years (p < 0.0001) and behavioral/mood symptoms by 2.50 years (p < 0.0001). Age of exposure before 12 predicted earlier cognitive (p < 0.0001) and behavioral/mood (p < 0.0001) symptom onset by 13.39 and 13.28 years, respectively. In participants with dementia, younger age of exposure corresponded to earlier functional impairment onset. Similar effects were observed in the 126 CTE-only participants. Effect sizes were comparable in participants without CTE. INTERPRETATION: In this sample of deceased tackle football players, younger age of exposure to tackle football was not associated with CTE pathological severity, but predicted earlier neurobehavioral symptom onset. Youth exposure to tackle football may reduce resiliency to late-life neuropathology. These findings may not generalize to the broader tackle football population, and informant-report may have affected the accuracy of the estimated effects. Ann Neurol 2018;83:886-901.

Cognitive Reserve as a Modifier of Clinical Expression in Chronic Traumatic Encephalopathy: A Preliminary Examination.

This study conducted a preliminary examination on cognitive reserve (CR) as a modifier of symptom expression in subjects with autopsy-confirmed chronic traumatic encephalopathy (CTE). The sample included 25 former professional football players neuropathologically diagnosed with CTE stage III or IV. Next of kin interviews ascertained age at cognitive and behavioral/mood symptom onset and demographic/athletic characteristics. Years of education and occupational attainment defined CR. High occupational achievement predicted later age at cognitive (p=0.02) and behavioral/mood (p=0.02) onset. Education was not an individual predictor. These preliminary findings suggest that CR may forestall the clinical manifestation of CTE.

Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football.

Importance: Players of American football may be at increased risk of long-term neurological conditions, particularly chronic traumatic encephalopathy (CTE). Objective: To determine the neuropathological and clinical features of deceased football players with CTE. Design, Setting, and Participants: Case series of 202 football players whose brains were donated for research. Neuropathological evaluations and retrospective telephone clinical assessments (including head trauma history) with informants were performed blinded. Online questionnaires ascertained athletic and military history. Exposures: Participation in American football at any level of play. Main Outcomes and Measures: Neuropathological diagnoses of neurodegenerative diseases, including CTE, based on defined diagnostic criteria; CTE neuropathological severity (stages I to IV or dichotomized into mild [stages I and II] and severe [stages III and IV]); informant-reported athletic history and, for players who died in 2014 or later, clinical presentation, including behavior, mood, and cognitive symptoms and dementia. Results: Among 202 deceased former football players (median age at death, 66 years [interquartile range, 47-76 years]), CTE was neuropathologically diagnosed in 177 players (87%; median age at death, 67 years [interquartile range, 52-77 years]; mean years of football participation, 15.1 [SD, 5.2]), including 0 of 2 pre-high school, 3 of 14 high school (21%), 48 of 53 college (91%), 9 of 14 semiprofessional (64%), 7 of 8 Canadian Football League (88%), and 110 of 111 National Football League (99%) players. Neuropathological severity of CTE was distributed across the highest level of play, with all 3 former high school players having mild pathology and the majority of former college (27 [56%]), semiprofessional (5 [56%]), and professional (101 [86%]) players having severe pathology. Among 27 participants with mild CTE pathology, 26 (96%) had behavioral or mood symptoms or both, 23 (85%) had cognitive symptoms, and 9 (33%) had signs of dementia. Among 84 participants with severe CTE pathology, 75 (89%) had behavioral or mood symptoms or both, 80 (95%) had cognitive symptoms, and 71 (85%) had signs of dementia. Conclusions and Relevance: In a convenience sample of deceased football players who donated their brains for research, a high proportion had neuropathological evidence of CTE, suggesting that CTE may be related to prior participation in football.

Post-traumatic neurodegeneration and chronic traumatic encephalopathy.

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity around the world. Concussive and subconcussive forms of closed-head injury due to impact or blast neurotrauma represent the most common types of TBI in civilian and military settings. It is becoming increasingly evident that TBI can lead to persistent, long-term debilitating effects, and in some cases, progressive neurodegeneration and chronic traumatic encephalopathy (CTE). The epidemiological literature suggests that a single moderate-to-severe TBI may be associated with accelerated neurodegeneration and increased risk of Alzheimer's disease, Parkinson's disease, or motor neuron disease. However, the pathologic phenotype of these post-traumatic neurodegenerations is largely unknown and there may be pathobiological differences between post-traumatic disease and the corresponding sporadic disorder. By contrast, the pathology of CTE is increasingly well known and is characterized by a distinctive pattern of progressive brain atrophy and accumulation of hyperphosphorylated tau neurofibrillary and glial tangles, dystrophic neurites, 43 kDa TAR DNA-binding protein (TDP-43) neuronal and glial aggregates, microvasculopathy, myelinated axonopathy, neuroinflammation, and white matter degeneration. Clinically, CTE is associated with behavioral changes, executive dysfunction, memory deficits, and cognitive impairments that begin insidiously and most often progress slowly over decades. Although research on the long-term effects of TBI is advancing quickly, the incidence and prevalence of post-traumatic neurodegeneration and CTE are unknown. Critical knowledge gaps include elucidation of pathogenic mechanisms, identification of genetic risk factors, and clarification of relevant variables-including age at exposure to trauma, history of prior and subsequent head trauma, substance use, gender, stress, and comorbidities-all of which may contribute to risk profiles and the development of post-traumatic neurodegeneration and CTE. This article is part of a Special Issue entitled 'Traumatic Brain Injury'.

Chronic traumatic encephalopathy: a neurodegenerative consequence of repetitive traumatic brain injury.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that develops as a result of repetitive mild traumatic brain injury. Chronic traumatic encephalopathy is characterized by a unique pattern of accumulation of hyperphosphorylated tau in neurons and astrocytes. The tau abnormalities begin focally and perivascularly at the depths of the cerebral sulci, spread to the superficial layers of the adjacent cortex, and eventually become widespread throughout the medial temporal lobes, diencephalon, and brainstem. Abnormalities in 43 kDa TAR DNA-binding protein are also found in most cases of CTE. To date, CTE can only be diagnosed by postmortem neuropathological examination, although there are many ongoing research studies examining imaging techniques and biomarkers that might prove to have diagnostic utility. Currently, the incidence and prevalence of CTE are unknown, although great strides are being made to better understand the clinical symptoms and signs of CTE. Further research is critically needed to better identify the genetic and environmental risk factors for CTE as well as potential rehabilitation and therapeutic strategies.

Interface astrogliosis in contact sport head impacts and military blast exposure.

Exposure to military blast and repetitive head impacts (RHI) in contact sports is associated with increased risk of long-term neurobehavioral sequelae and cognitive deficits, and the neurodegenerative disease chronic traumatic encephalopathy (CTE). At present, the exact pathogenic mechanisms of RHI and CTE are unknown, and no targeted therapies are available. Astrocytes have recently emerged as key mediators of the multicellular response to head trauma. Here, we investigated interface astrogliosis in blast and impact neurotrauma, specifically in the context of RHI and early stage CTE. We compared postmortem brain tissue from former military veterans with a history of blast exposure with and without a neuropathological diagnosis of CTE, former American football players with a history of RHI with and without a neuropathological diagnosis of CTE, and control donors without a history of blast, RHI exposure or CTE diagnosis. Using quantitative immunofluorescence, we found that astrogliosis was higher at the grey-white matter interface in the dorsolateral frontal cortex, with mixed effects at the subpial surface and underlying cortex, in both blast and RHI donors with and without CTE, compared to controls. These results indicate that certain astrocytic alterations are associated with both impact and blast neurotrauma, and that different astroglial responses take place in distinct brain regions.

Characterization of Detergent Insoluble Proteome in Chronic Traumatic Encephalopathy.

Quantitative proteomics of postmortem human brain can identify dysfunctional proteins that contribute to neurodegenerative disorders like Alzheimer disease (AD) and frontotemporal dementia. Similar studies in chronic traumatic encephalopathy (CTE) are limited, therefore we hypothesized that proteomic sequencing of CTE frontal cortex brain homogenates from varying CTE pathologic stages may provide important new insights into this disorder. Quantitative proteomics of control, CTE and AD brains was performed to characterize differentially expressed proteins, and we identified over 4000 proteins in CTE brains, including significant enrichment of the microtubule associated protein tau. We also found enrichment and pathologic aggregation of RNA processing factors as seen previously in AD, supporting the previously recognized overlap between AD and CTE. In addition to these similarities, we identified CTE-specific enrichment of proteins which increase with increasing severity of CTE pathology. NADPH dehydrogenase quinone 1 (NQO1) was one of the proteins which showed significant enrichment in CTE and also correlated with increasing CTE stage. NQO1 demonstrated neuropathologic correlation with hyperphosphorylated tau in glial cells, mainly astrocytes. These results demonstrate that quantitative proteomic analysis of CTE postmortem human brain can identify disease relevant findings and novel cellular pathways involved in CTE pathogenesis.

Variation in TMEM106B in chronic traumatic encephalopathy.

The genetic basis of chronic traumatic encephalopathy (CTE) is poorly understood. Variation in transmembrane protein 106B (TMEM106B) has been associated with enhanced neuroinflammation during aging and with TDP-43-related neurodegenerative disease, and rs3173615, a missense coding SNP in TMEM106B, has been implicated as a functional variant in these processes. Neuroinflammation and TDP-43 pathology are prominent features in CTE. The purpose of this study was to determine whether genetic variation in TMEM106B is associated with CTE risk, pathological features, and ante-mortem dementia. Eighty-six deceased male athletes with a history of participation in American football, informant-reported Caucasian, and a positive postmortem diagnosis of CTE without comorbid neurodegenerative disease were genotyped for rs3173615. The minor allele frequency (MAF = 0.42) in participants with CTE did not differ from previously reported neurologically normal controls (MAF = 0.43). However, in a case-only analysis among CTE cases, the minor allele was associated with reduced phosphorylated tau (ptau) pathology in the dorsolateral frontal cortex (DLFC) (AT8 density, odds ratio [OR] of increasing one quartile = 0.42, 95% confidence interval [CI] 0.22-0.79, p = 0.008), reduced neuroinflammation in the DLFC (CD68 density, OR of increasing one quartile = 0.53, 95% CI 0.29-0.98, p = 0.043), and increased synaptic protein density (ß = 0.306, 95% CI 0.065-0.546, p = 0.014). Among CTE cases, TMEM106B minor allele was also associated with reduced ante-mortem dementia (OR = 0.40, 95% CI 0.16-0.99, p = 0.048), but was not associated with TDP-43 pathology. All case-only models were adjusted for age at death and duration of football play. Taken together, variation in TMEM106B may have a protective effect on CTE-related outcomes.

Lewy Body Pathology and Chronic Traumatic Encephalopathy Associated With Contact Sports.

Traumatic brain injury has been associated with increased risk of Parkinson disease and parkinsonism, and parkinsonism and Lewy body disease (LBD) can occur with chronic traumatic encephalopathy (CTE). To test whether contact sports and CTE are associated with LBD, we compared deceased contact sports athletes (n = 269) to cohorts from the community (n = 164) and the Boston University Alzheimer disease (AD) Center (n = 261). Participants with CTE and LBD were more likely to have ß-amyloid deposition, dementia, and parkinsonism than CTE alone (p < 0.05). Traditional and hierarchical clustering showed a similar pattern of LBD distribution in CTE compared to LBD alone that was most frequently neocortical, limbic, or brainstem. In the community-based cohort, years of contact sports play were associated with neocortical LBD (OR = 1.30 per year, p = 0.012), and in a pooled analysis a threshold of >8 years of play best predicted neocortical LBD (ROC analysis, OR = 6.24, 95% CI = 1.5-25, p = 0.011), adjusting for age, sex, and APOE ɛ4 allele status. Clinically, dementia was significantly associated with neocortical LBD, CTE stage, and AD; parkinsonism was associated with LBD pathology but not CTE stage. Contact sports participation may increase risk of developing neocortical LBD, and increased LBD frequency may partially explain extrapyramidal motor symptoms sometimes observed in CTE.

Football Players' Perceptions of Future Risk of Concussion and Concussion-Related Health Outcomes.

Concussion is increasingly recognized as a risk of participation in contact and collision sports. There have been few examinations of athletes' perceptions of their susceptibility to concussion or concussion-related health consequences. We examine college football players' perceptions of their risk of sustaining a concussion and concussion-related health consequences in their future, whether these perceptions change over time, and how concussion history is related to perceived future risk of concussion and concussion-related health consequences. A survey was administered to National Collegiate Athletic Association Division I Football Championship Series athletes on 10 teams in 2013 and to nine of those teams in 2014. Athletes answered questions assessing their perceptions of concussion and potential concussion-related health consequences. Approximately 40% of athletes believed there was a strong possibility that they would sustain a concussion in the future, while approximately one-in-four thought a concussion would make them miss a few games. About one-in-10 athletes predicted dementia, Alzheimer's disease, or chronic traumatic encephalopathy would develop from concussions. These beliefs were stronger among athletes who had sustained previous concussions. Across the two years studied, athletes' perceptions of the risk of concussion and missing a few games because of concussion decreased significantly. Overall, a substantial proportion of college football players believe they will have long-term health consequences as a result of sustaining sport-related concussions. The true incidence and prevalence of many of these outcomes are unknown. Further research is needed to determine whether athletes have an accurate perception of the risks of these outcomes developing.

CCL11 is increased in the CNS in chronic traumatic encephalopathy but not in Alzheimer's disease.

CCL11, a protein previously associated with age-associated cognitive decline, is observed to be increased in the brain and cerebrospinal fluid (CSF) in chronic traumatic encephalopathy (CTE) compared to Alzheimer's disease (AD). Using a cohort of 23 deceased American football players with neuropathologically verified CTE, 50 subjects with neuropathologically diagnosed AD, and 18 non-athlete controls, CCL11 was measured with ELISA in the dorsolateral frontal cortex (DLFC) and CSF. CCL11 levels were significantly increased in the DLFC in subjects with CTE (fold change = 1.234, p < 0.050) compared to non-athlete controls and AD subjects with out a history of head trauma. This increase was also seen to correlate with years of exposure to American football (ß = 0.426, p = 0.048) independent of age (ß = -0.046, p = 0.824). Preliminary analyses of a subset of subjects with available post-mortem CSF showed a trend for increased CCL11 among individuals with CTE (p = 0.069) mirroring the increase in the DLFC. Furthermore, an association between CSF CCL11 levels and the number of years exposed to football (ß = 0.685, p = 0.040) was observed independent of age (ß = -0.103, p = 0.716). Finally, a receiver operating characteristic (ROC) curve analysis demonstrated CSF CCL11 accurately distinguished CTE subjects from non-athlete controls and AD subjects (AUC = 0.839, 95% CI 0.62-1.058, p = 0.028). Overall, the current findings provide preliminary evidence that CCL11 may be a novel target for future CTE biomarker studies.

Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy.

The chronic effects of repetitive head impacts (RHI) on the development of neuroinflammation and its relationship to chronic traumatic encephalopathy (CTE) are unknown. Here we set out to determine the relationship between RHI exposure, neuroinflammation, and the development of hyperphosphorylated tau (ptau) pathology and dementia risk in CTE. We studied a cohort of 66 deceased American football athletes from the Boston University-Veteran's Affairs-Concussion Legacy Foundation Brain Bank as well as 16 non-athlete controls. Subjects with a neurodegenerative disease other than CTE were excluded. Counts of total and activated microglia, astrocytes, and ptau pathology were performed in the dorsolateral frontal cortex (DLF). Binary logistic and simultaneous equation regression models were used to test associations between RHI exposure, microglia, ptau pathology, and dementia. Duration of RHI exposure and the development and severity of CTE were associated with reactive microglial morphology and increased numbers of CD68 immunoreactive microglia in the DLF. A simultaneous equation regression model demonstrated that RHI exposure had a significant direct effect on CD68 cell density (p < 0.0001) and ptau pathology (p < 0.0001) independent of age at death. The effect of RHI on ptau pathology was partially mediated through increased CD68 positive cell density. A binary logistic regression demonstrated that a diagnosis of dementia was significantly predicted by CD68 cell density (OR = 1.010, p = 0.011) independent of age (OR = 1.055, p = 0.007), but this effect disappeared when ptau pathology was included in the model. In conclusion, RHI is associated with chronic activation of microglia, which may partially mediate the effect of RHI on the development of ptau pathology and dementia in CTE. Inflammatory molecules may be important diagnostic or predictive biomarkers as well as promising therapeutic targets in CTE.

The neuropathology of chronic traumatic encephalopathy.

Repetitive brain trauma is associated with a progressive neurological deterioration, now termed as chronic traumatic encephalopathy (CTE). Most instances of CTE occur in association with the play of sports, but CTE has also been reported in association with blast injuries and other neurotrauma. Symptoms of CTE include behavioral and mood changes, memory loss, cognitive impairment and dementia. Like many other neurodegenerative diseases, CTE is diagnosed with certainty only by neuropathological examination of brain tissue. CTE is a tauopathy characterized by the deposition of hyperphosphorylated tau (p-tau) protein as neurofibrillary tangles, astrocytic tangles and neurites in striking clusters around small blood vessels of the cortex, typically at the sulcal depths. Severely affected cases show p-tau pathology throughout the brain. Abnormalities in phosphorylated 43 kDa TAR DNA-binding protein are found in most cases of CTE; beta-amyloid is identified in 43%, associated with age. Given the importance of sports participation and physical exercise to physical and psychological health as well as disease resilience, it is critical to identify the genetic risk factors for CTE as well as to understand how other variables, such as stress, age at exposure, gender, substance abuse and other exposures, contribute to the development of CTE.

Frequency of head-impact-related outcomes by position in NCAA division I collegiate football players.

Concussions and subconcussive impacts sustained in American football have been associated with short- and long-term neurological impairment, but differences in head impact outcomes across playing positions are not well understood. The American Medical Society for Sports Medicine has identified playing position as a key risk factor for concussion in football and one for which additional research is needed. This study examined variation in head impact outcomes across primary football playing positions in a group of 730 National Collegiate Athletic Association Division I Football Championship Series athletes, using a self-report questionnaire. Although there were no significant differences between position groups in the number of diagnosed concussions during the 2012 football season, there were significant differences between groups in undiagnosed concussions (p=0.008) and "dings" (p<0.001); offensive linemen reported significantly higher numbers than most other positions. Significant differences were found between position groups in the frequencies of several postimpact symptoms, including dizziness (p<0.001), headache (p<0.001), and seeing stars (p<0.001) during the 2012 football season, with offensive linemen reporting significantly more symptoms compared to most other groups. There were also positional differences in frequency of returning to play while symptomatic (p<0.001) and frequency of participating in full-contact practice (p<0.001). Offensive linemen reported having returned to play while experiencing symptoms more frequently and participating in more full-contact practices than other groups. These findings suggest that offensive linemen, a position group that experiences frequent, but low-magnitude, head impacts, develop more postimpact symptoms than other playing positions, but do not report these symptoms as a concussion.

Assessing clinicopathological correlation in chronic traumatic encephalopathy: rationale and methods for the UNITE study.

INTRODUCTION: Chronic traumatic encephalopathy (CTE) is a progressive neurodegeneration associated with repetitive head impacts. Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) is a U01 project recently funded by the National Institute of Neurological Disorders and Stroke and the National Institute of Biomedical Imaging and Bioengineering. The goal of the UNITE project is to examine the neuropathology and clinical presentation of brain donors designated as "at risk" for the development of CTE based on prior athletic or military exposure. Here, we present the rationale and methodology for UNITE. METHODS: Over the course of 4 years, we will analyze the brains and spinal cords of 300 deceased subjects who had a history of repetitive head impacts sustained during participation in contact sports at the professional or collegiate level or during military service. Clinical data are collected through medical record review and retrospective structured and unstructured family interviews conducted by a behavioral neurologist or neuropsychologist. Blinded to the clinical data, a neuropathologist conducts a comprehensive assessment for neurodegenerative disease, including CTE, using published criteria. At a clinicopathological conference, a panel of physicians and neuropsychologists, blinded to the neuropathological data, reaches a clinical consensus diagnosis using published criteria, including proposed clinical research criteria for CTE. RESULTS: We will investigate the validity of these clinical criteria and sources of error by using recently validated neuropathological criteria as a gold standard for CTE diagnosis. We also will use statistical modeling to identify diagnostic features that best predict CTE pathology. CONCLUSIONS: The UNITE study is a novel and methodologically rigorous means of assessing clinicopathological correlation in CTE. Our findings will be critical for developing future iterations of CTE clinical diagnostic criteria.