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INTRODUCTION: Tau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project. METHOD: We compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same‐age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with RHI exposure; and compare players who did or did not meet diagnostic criteria for traumatic encephalopathy syndrome (TES). RESULTS: Significantly elevated flortaucipir uptake was observed in former football players (PRO+COL) in prespecified regions (p < 0.05). Association between regional flortaucipir uptake and estimated cumulative head impact exposure was only observed in the superior frontal region in former players over 60 years old. Flortaucipir PET was not able to differentiate TES groups. DISCUSSION: Additional studies are needed to further understand tau pathology in CTE and other individuals with a history of RHI. [ABSTRACT FROM AUTHOR]

Objective: Exposure to repetitive head impacts (RHI) is associated with later‐life cognitive symptoms and neuropathologies, including chronic traumatic encephalopathy (CTE). Cognitive decline in community cohorts is often due to multiple pathologies; however, the frequency and contributions of these pathologies to cognitive impairment in people exposed to RHI are unknown. Here, we examined the relative contributions of 13 neuropathologies to cognitive symptoms and dementia in RHI‐exposed brain donors. Methods: Neuropathologists examined brain tissue from 571 RHI‐exposed donors and assessed for the presence of 13 neuropathologies, including CTE, Alzheimer disease (AD), Lewy body disease (LBD), and transactive response DNA‐binding protein 43 (TDP‐43) inclusions. Cognitive status was assessed by presence of dementia, Functional Activities Questionnaire, and Cognitive Difficulties Scale. Spearman rho was calculated to assess intercorrelation of pathologies. Additionally, frequencies of pathological co‐occurrence were compared to a simulated distribution assuming no intercorrelation. Logistic and linear regressions tested associations between neuropathologies and dementia status and cognitive scale scores. Results: The sample age range was 18–97 years (median = 65.0, interquartile range = 46.0–76.0). Of the donors, 77.2% had at least one moderate–severe neurodegenerative or cerebrovascular pathology. Stage III–IV CTE was the most common neurodegenerative disease (43.1%), followed by TDP‐43 pathology, AD, and hippocampal sclerosis. Neuropathologies were intercorrelated, and there were fewer unique combinations than expected if pathologies were independent (p < 0.001). The greatest contributors to dementia were AD, neocortical LBD, hippocampal sclerosis, cerebral amyloid angiopathy, and CTE. Interpretation: In this sample of RHI‐exposed brain donors with wide‐ranging ages, multiple neuropathologies were common and correlated. Mixed neuropathologies, including CTE, underlie cognitive impairment in contact sport athletes. ANN NEUROL 2024;95:314–324 [ABSTRACT FROM AUTHOR]

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by hyperphosphorylated tau (p‐tau) accumulation. The clinical features of CTE are heterogeneous and their association with CTE are unclear. We investigated the association of CTE p‐tau pathology density and location with cognitive and neuropsychiatric symptoms in brain donors with autopsy‐confirmed CTE. Method: 364 brain donors with autopsy confirmed CTE were evaluated to determine the density of p‐tau pathology in 10 cortical and subcortical regions using semi‐quantitative rating scales (score range: 0‐3). We summed ratings across 10 regions to form a global composite of p‐tau severity (score range:0‐30). Informants completed standardized scales of cognition (Cognitive Difficulties Scale, CDS; BRIEF‐A Metacognition Index, MI), activities of daily living (Functional Activities Questionnaire), neurobehavioral dysregulation (BRIEF‐A Behavioral Regulation Index, BRI; Barratt Impulsiveness Scale, BIS‐11), aggression (Brown‐Goodwin Aggression Scale), depression (Geriatric Depression Scale‐15, GDS‐15), and apathy (Apathy Evaluation Scale, AES). Multivariable linear regression analyses examined the association between global p‐tau severity and p‐tau severity in each region with each of the clinical scales, controlling for age at death, racial identity, education level, hypertension history, obstructive sleep apnea history, and substance use treatment history. Result: The sample predominantly consisted of football players (333; 91.2%) and 140 (38.5%) had low CTE and 224 (61.5%) had high CTE (Table 1). Figures 1‐2 are Forrest plots of the estimated effects between regional p‐tau and clinical scales. Global p‐tau severity was associated with cognitive and functional scales: MI (beta = 0.46, 95% CI = 0.11‐0.81), CDS (beta = 1.08, 95% CI = 0.31‐1.85), and FAQ (beta = 0.32, 95% CI = 0.16‐0.49). After false‐discovery rate (FDR) correction, p‐tau in the frontal, inferior parietal, superior temporal cortex, and the amygdala was significantly associated with the CDS and FAQ; frontal and inferior parietal cortex and amygdala p‐tau also was significantly associated with MI. Frontal cortex p‐tau was significantly associated with the BRI. There were no significant associations with the other neuropsychiatric scales after FDR correction. Entorhinal cortex, hippocampus, and locus coeruleus showed no significant associations. Conclusion: Accumulation of p‐tau aggregates, especially in the frontal cortex, are a driver of cognitive, function, and certain neurobehavioral symptoms in CTE. [ABSTRACT FROM AUTHOR]

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease thought to be caused, in part, by repetitive head impact (RHI) exposure and characterized by phosphorylated tau deposition with varying patterns in the cerebral cortex. Flortaucipir tau PET data from the DIAGNOSE CTE Research Project was examined to investigate tau PET patterns and its relation to RHI exposure in former professional and college American football players. Method: In this study, 218 DIAGNOSE CTE participants, ages 45‐74, with flortaucipir PET were included; 104 were former National Football League players (PRO), 58 were former college football players (COL), and 56 had no history of contact sports, other exposure to RHI, or traumatic brain injury (UE). Regional flortaucipir uptake was quantified using established procedures for three previously defined statistical regions (superior frontal, left parietal, and medial temporal) and compared across the three groups. Association analyses were also performed to examine the relationship between flortaucipir uptake and exposure to RHI using the cumulative head impact index for linear acceleration g‐force (CHII‐G). The potential clinical utility of flortaucipir PET for CTE was also investigated by examining its ability to differentiate participants meeting criteria for traumatic encephalopathy syndrome (TES) and probable or possible level of certainty for CTE pathology from those who do not meet those criteria. Result: Significantly higher flortaucipir uptake was observed in former football players than in participants without RHI exposure, controlling for age and race for the superior frontal region (Fig. 1A), left parietal, and medial temporal regions. Association between regional flortaucipir uptake and CHII‐G was only observed in the superior frontal region in former players (PRO+COL) 60 years and older (Fig. 1B) and no association was observed in the full PRO+COL group. Flortaucipir PET was not able to differentiate TES groups in former football players (Fig. 1C). Conclusion: Elevated flortaucipir uptake was observed in former American football players to a group of unexposed men. The association between flortaucipir uptake and exposure to RHI may require a long latent period to manifest. Further investigation of more sensitive tau PET tracers and quantification techniques is warranted to better characterize CTE related tau pathology. [ABSTRACT FROM AUTHOR]

Background: Repetitive head impacts (RHI) from American style football (ASF) and other contact sports are a known risk factor for the neurodegenerative disease chronic traumatic encephalopathy (CTE). RHI can also lead to mixed neuropathologies that uniquely contribute to clinical symptoms. Here, we compared various types of vascular and white matter pathologies between brain donors with and without exposure to RHI from different types of contact and collision sports (CCS). Methods: The sample included 79 deceased male ASF players (RHI‐ASF) and 49 deceased male non‐ASF CCS athletes (RHI‐CCS) from the UNITE brain bank. Each RHI group had a comparison group that included similar aged (+/‐ 5 years) male brain donors without RHI from the Boston University Alzheimer's Disease Research Center and Framingham Heart Study brain banks. The modified Ischemic Injury Scale (mIIS) served as a global indicator of vascular and white matter pathologies and is a sum of hippocampal sclerosis, infarct/lacune, microinfarct, microbleeds, laminar necrosis, arteriolosclerosis, atherosclerosis of Circle of Willis, cerebral amyloid angiopathy, and white matter rarefaction. Dementia diagnoses were made during consensus conferences. Linear or logistic regression compared the RHI vs non‐RHI groups on the mIIS and its subcomponents. Logistic regression models examined the association between mIIS and dementia. Models were adjusted for age. Results: Table 1 shows sample characteristics. The RHI‐CCS group was comprised of boxers, amateur wrestlers, and ice hockey, soccer, rugby, and lacrosse players. 94 decedents had CTE, all of whom were in an RHI exposed group. Of the mIIS components, arteriolosclerosis was the most common across all groups. White matter rarefaction was also the most frequent mIIS component for both RHI groups, but not for non‐RHI groups. Compared to their respective controls, RHI‐ASF and RHI‐CCS were associated with higher mIIS scores (Table 2). Higher mIIS scores corresponded to increased odds for having dementia in both the RHI‐ASF and RHI‐CCS groups (Table 2). White matter rarefaction best discriminated both RHI groups from non‐RHI; atherosclerosis also discriminated RHI‐CCS group (Table 3). Conclusion: These results support vascular and white matter pathologies, specifically white matter rarefaction, as prominent and clinically relevant sequelae of RHI from CCS. [ABSTRACT FROM AUTHOR]

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impacts (RHI) like those from American football. Causes of cognitive and neuropsychiatric symptoms (e.g., neurobehavioral dysregulation) in CTE are unclear. Substance use disorders (SUDs) are common among individuals with autopsy‐confirmed CTE, but their association with CTE and related symptoms are unknown. We examined the association between SUDs and CTE pathology, and cognitive and neuropsychiatric symptoms in deceased football players. Methods: The sample included 429 deceased football players from the UNITE brain bank. CTE was neuropathologically diagnosed. Informant interviews assessed SUD history. The independent variable included substance use treatment history, an indicator of SUD less influenced by recall error. Informants completed standardized scales of cognitive function (Cognitive Difficulties Scale, Functional Activities Questionnaire, BRIEF‐A Metacognition Index [MI]), mood (Geriatric Depression Scale [GDS‐15]), and neurobehavioral dysregulation (BRIEF‐A Behavioral Regulation Index [BRI], Barratt Impulsiveness Scale [BIS‐11]). Linear or logistic regressions test the association between substance use treatment history and CTE status, cumulative p‐tau burden (sum of p‐tau severity ratings across 11 brain regions, n = 370), and each clinical scale, controlling for age and years of football play. Cumulative p‐tau burden was added as a covariate in clinical models. Results: Tables 1–3 show sample characteristics. 313/429 had autopsy‐confirmed CTE. Alcohol use disorders were more common (n = 177, 41.3%) than illicit (n = 70,16.3%) and prescription (n = 47, 11%) drug use disorders. Approx. 23% (n = 100) had a substance use treatment history, which was not associated with CTE (p = 0.21) or p‐tau burden (p = 0.14). Substance use treatment history was associated with neurobehavioral dysregulation (BRI: beta = 8.17, 95% CI = 3.92‐12.41, p<0.01; BIS‐11: beta = 8.90, 95% CI = 5.11‐12.69, p<0.01) and greater depression symptoms (GDS‐15: beta = 2.17, 95% CI = 1.08‐3.26, p<0.01). Besides the MI (beta = 5.09, 95% CI = 0.67‐9.51, p = 0.02), there was no association with cognitive scales (ps>0.05). Cumulative p‐tau burden was associated with neurobehavioral dysregulation (BRI, p<0.01) and all cognitive scales (ps<0.05). Conclusions: In former football players, SUDs are unlikely to affect risk for CTE, but can contribute to clinical symptoms especially neurobehavioral dysregulation. These findings stress the role of tau and non‐tau causes of neurobehavioral dysregulation among football players. However, p‐tau is likely a key driver of cognitive symptoms. [ABSTRACT FROM AUTHOR]

Background: Repetitive head impacts (RHI) from American football and other sources are associated with the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). Moderate‐to‐severe traumatic brain injury (msTBI) has been suggested to be sufficient to precipitate CTE. Yet, this evidence is based on small case series of msTBI and the interplay between msTBI and RHI on CTE risk is unknown. We modeled the associations between msTBI history and years of American football play (proxy for RHI exposure duration) on CTE neuropathology among deceased American football players. Methods: The sample included 471 deceased male football players from the UNITE brain bank, all 40+ years old. Informants of donors were administered the Ohio State University TBI Identification Method to assess TBI history. Loss of consciousness (LOC) for 30+ minutes defined msTBI. CTE was neuropathologically diagnosed and staged using published criteria. Outcomes included CTE status, CTE severity (low vs high), and cumulative p‐tau burden—summary of semi‐quantitative ratings of p‐tau severity across 11 brain regions (n = 402). Binary or linear regressions tested the association between msTBI and each outcome, controlling for age and years of football. A years of play x msTBI history interaction term was examined. Results: Tables 1‐2 shows sample characteristics (mean age = 67.89, SD = 12.70; 15.7% Black). Of the sample, 114 (24.2%) had a msTBI history. Years since last TBI with LOC was 37.16 (SD = 18.66) years. 344 (73.0%) had autopsy‐confirmed CTE. There was no association between msTBI and CTE status (OR = 1.38, 95% CI = 0.81,2.33, p = 0.24), CTE severity (OR = 0.77, CI = 0.41,1.44, p = 0.41), or cumulative p‐tau burden (beta = ‐1.03, 95% CI = ‐2.77,0.71, p = 0.25). In contrast, years of football play was associated with CTE status (OR = 1.15, 95% CI = 1.10,1.21, p<0.01), CTE severity (OR = 1.14, 95% CI = 1.08,1.21, p<0.01), and cumulative p‐tau burden (beta = 0.44, 95% CI = 0.32,0.56, p<0.01). There were no years of play x msTBI interaction effects (ps>0.05). Conclusions: msTBI history was not associated with CTE neuropathology, nor did it modify the effect of years of football play on CTE status and severity. These findings argue against msTBI as a contributor to CTE in the setting of RHI. Examination of age at msTBI and msTBI frequency, as well as non‐CTE neuropathological correlates of msTBI are next steps. [ABSTRACT FROM AUTHOR]

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. We previously showed that duration of American football play is associated with risk and severity of CTE pathology. Helmet accelerometers have been used previously to examine frequency, linear acceleration, and rotational acceleration of hits sustained across youth, high school, and college football. Here we projected this data onto former American football playing brain donors to examine the relationship between cumulative frequency of hits, linear acceleration, and rotational acceleration during players' athletic careers and CTE pathology. Method: 656 former American football playing brain donors from the Veterans Affairs‐Boston University‐Concussion Legacy Foundation Brain Bank were examined for CTE pathology and severity. Years and position of play at each level (youth, high school, college, professional) were acquired through retrospective clinical interviews with brain donors next‐of‐kin. From a literature search of studies using helmet accelerometers, we calculated the mean frequency of hits, linear acceleration (g‐force), and rotational acceleration (rad/sec2) for one year of play at each level‐position combination. These values were projected onto brain donors' career exposure to derive cumulative frequency of head impacts (CHII), cumulative linear acceleration (CHII‐G), and cumulative rotational acceleration (CHII‐R). Separate logistic regression models examined the relationship of years of play, CHII, CHII‐G, and CHII‐R on CTE status and severity (low vs. high), adjusting for age at death. Result: The mean (SD) age at death was 59.7 (20.1) and 451 (68.8%) had CTE pathology. Each cumulative measure was significantly associated with presence of CTE (p's<.001) and severity of CTE (p's<.001). Based on ROC analyses, CHII‐R (AUC=0.765, p<.001) and CHII‐G (AUC= 0.758, p<.001) performed significantly better than years of play (AUC=0.716) in classifying CTE pathology, and there was no difference between years of play and CHII (AUC=0.698, p=0.25). Similar relationships were observed for CTE severity. Model fit and cross‐validation statistics were also consistent (Table 2). Conclusion: Among former American football playing brain donors, cumulative linear and rotational acceleration were better predictors of CTE pathology than duration of play or cumulative hits. The findings suggest head impact intensity is an important factor in developing CTE pathology. [ABSTRACT FROM AUTHOR]

Introduction: Validity of the 2014 traumatic encephalopathy syndrome (TES) criteria, proposed to diagnose chronic traumatic encephalopathy (CTE) in life, has not been assessed. Methods: A total of 336 consecutive brain donors exposed to repetitive head impacts from contact sports, military service, and/or physical violence were included. Blinded to clinical information, neuropathologists applied National Institute on Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering CTE criteria. Blinded to neuropathological information, clinicians interviewed informants and reviewed medical records. An expert panel adjudicated TES diagnoses. Results: A total of 309 donors were diagnosed with TES; 244 donors had CTE pathology. TES criteria demonstrated sensitivity and specificity of 0.97 and 0.21, respectively. Cognitive (odds ratio [OR] = 3.6; 95% confidence interval [CI]: 1.2–5.1), but not mood/behavior or motor symptoms, were significantly associated with CTE pathology. Having Alzheimer's disease (AD) pathology was significantly associated with reduced TES accuracy (OR = 0.27; 95% CI: 0.12–0.59). Discussion: TES criteria provided good evidence to rule out, but limited evidence to rule in, CTE pathology. Requiring cognitive symptoms in revised criteria and using AD biomarkers may improve CTE pathology prediction. [ABSTRACT FROM AUTHOR]

Background: Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. The clinical presentation of CTE can include cognitive impairment, with progression to dementia. Currently, CTE can only be definitively diagnosed postmortem; most reports of the associated clinical syndrome come from retrospective informant interviews. In this setting, characterizing the clinical course can be biased because donors may have died from causes unrelated to CTE. To minimize this selection pressure and more accurately report average age of dementia and death in CTE, we identified brain donors with high stage CTE who died from neurodegenerative disease. Method: Donors with RHI exposure from contact sports and/or military service were eligible for the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank. CTE neuropathological diagnosis and staging were assessed using validated criteria. Dementia diagnosis was determined by clinical consensus and dementia onset age was defined as the age that informants first reported functional impairment on a standardized scale of activities of daily living (Functional Activities Questionnaire, FAQ). Causes of death were determined from medical records, death certificate review, and informant interviews. Donors with a neuropathological diagnosis of high stage CTE (III or IV) and a neurodegenerative cause of death were included in the current study. Result: 186 donors met inclusion criteria. Football was the most common type of RHI exposure (172; 92.5%). Mean age of dementia onset was 70.2 (SD = 7.4; range = 48‐93) and the mean age of death was 77.1 (SD = 7.8; range = 54‐97). Mean time from dementia diagnosis to death was 6.9 years (SD = 4.6; range = 0‐24). 136 donors (73.1%) had other comorbid neurodegenerative diseases, including 84 (45.4%) with Alzheimer's disease, 58 (31.2%) with Lewy body disease, and 28 (15.1%) with frontotemporal lobar degeneration. Compared to donors with CTE and comorbid neurodegenerative diseases, donors with CTE but without comorbid neurodegenerative diseases did not significantly differ in age at dementia onset, age at death, and time from dementia diagnosis to death. Conclusion: Among brain donors with high stage CTE who died from neurodegenerative disease, approximately 75% had late onset‐dementia (i.e., age of dementia onset >65 years) and died within 10 years of dementia diagnosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Chronic traumatic encephalopathy (CTE) has been linked to participation in contact sports such as boxing and American football. CTE results in a progressive decline of memory and cognition, as well as depression, suicidal behavior, poor impulse control, aggressiveness, parkinsonism, and, eventually, dementia. In some individuals, it is associated with motor neuron disease, referred to as chronic traumatic encephalomyelopathy, which appears clinically similar to amyotrophic lateral sclerosis. Results of neuropathologic research has shown that CTE may be more common in former contact sports athletes than previously believed. It is believed that repetitive brain trauma, with or possibly without symptomatic concussion, is responsible for neurodegenerative changes highlighted by accumulations of hyperphosphorylated tau and TDP‐43 proteins. Given the millions of youth, high school, collegiate, and professional athletes participating in contact sports that involve repetitive brain trauma, as well as military personnel exposed to repeated brain trauma from blast and other injuries in the military, CTE represents an important public health issue. Focused and intensive study of the risk factors and in vivo diagnosis of CTE will potentially allow for methods to prevent and treat these diseases. Research also will provide policy makers with the scientific knowledge to make appropriate guidelines regarding the prevention and treatment of brain trauma in all levels of athletic involvement as well as the military theater. [ABSTRACT FROM AUTHOR]