Lack of Association of Informant-Reported Traumatic Brain Injury and Chronic Traumatic Encephalopathy.

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

Cognitive, functional, and neuropsychiatric correlates of regional tau pathology in autopsy-confirmed chronic traumatic encephalopathy.

BACKGROUND: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by hyperphosphorylated tau (p-tau) accumulation. The clinical features associated with CTE pathology are unclear. In brain donors with autopsy-confirmed CTE, we investigated the association of CTE p-tau pathology density and location with cognitive, functional, and neuropsychiatric symptoms. METHODS: In 364 brain donors with autopsy confirmed CTE, semi-quantitative p-tau severity (range: 0-3) was assessed in 10 cortical and subcortical regions. We summed ratings across regions to form a p-tau severity global composite (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). Ordinary least squares regression models examined associations between global and regional p-tau severity (separate models for each region) with each clinical scale, adjusting for age at death, racial identity, education level, and history of hypertension, obstructive sleep apnea, and substance use treatment. Ridge regression models that incorporated p-tau severity across all regions in the same model assessed which regions showed independent effects. RESULTS: The sample was predominantly American football players (333; 91.2%); 140 (38.5%) had low CTE and 224 (61.5%) had high CTE. Global p-tau severity was associated with higher (i.e., worse) scores on the cognitive and functional scales: MI ([Formula: see text] standardized = 0.02, 95%CI = 0.01-0.04), CDS ([Formula: see text] standardized = 0.02, 95%CI = 0.01-0.04), and FAQ ([Formula: see text] standardized = 0.03, 95%CI = 0.01-0.04). After false-discovery rate correction, p-tau severity in the frontal, inferior parietal, and superior temporal cortex, and the amygdala was associated with higher CDS ([Formula: see text] sstandardized = 0.17-0.29, ps < 0.01) and FAQ ([Formula: see text] sstandardized = 0.21-0.26, ps < 0.01); frontal and inferior parietal cortex was associated with higher MI ([Formula: see text] sstandardized = 0.21-0.29, ps < 0.05); frontal cortex was associated with higher BRI ([Formula: see text] standardized = 0.21, p < 0.01). Regions with effects independent of other regions included frontal cortex (CDS, MI, FAQ, BRI), inferior parietal cortex (CDS) and amygdala (FAQ). P-tau explained 13-49% of variance in cognitive and functional scales and 6-14% of variance in neuropsychiatric scales. CONCLUSION: Accumulation of p-tau aggregates, especially in the frontal cortex, are associated with cognitive, functional, and certain neurobehavioral symptoms in CTE.

Cortical-sparing chronic traumatic encephalopathy (CSCTE): a distinct subtype of CTE.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by repetitive head impacts (RHI) and pathologically defined as neuronal phosphorylated tau aggregates around small blood vessels and concentrated at sulcal depths. Cross-sectional studies suggest that tau inclusions follow a stereotyped pattern that begins in the neocortex in low stage disease, followed by involvement of the medial temporal lobe and subcortical regions with significant neocortical burden in high stage CTE. Here, we define a subset of brain donors with high stage CTE and with a low overall cortical burden of tau inclusions (mean semiquantitative value ≤1) and classify them as cortical-sparing CTE (CSCTE). Of 620 brain donors with pathologically diagnosed CTE, 66 (11%) met criteria for CSCTE. Compared to typical high stage CTE, those with CSCTE had a similar age at death and years of contact sports participation and were less likely to carry apolipoprotein ε4 (p < 0.05). CSCTE had less overall tau pathology severity, but a proportional increase of disease burden in medial temporal lobe and brainstem regions compared to the neocortex (p's < 0.001). CSCTE also had lower prevalence of comorbid neurodegenerative disease. Clinically, CSCTE participants were less likely to have dementia (p =  0.023) and had less severe cognitive difficulties (as reported by informants using the Functional Activities Questionnaire (FAQ); p < 0.001, meta-cognitional index T score; p = 0.002 and Cognitive Difficulties Scale (CDS); p < 0.001,) but had an earlier onset age of behavioral (p = 0.006) and Parkinsonian motor (p = 0.013) symptoms when compared to typical high stage CTE. Other comorbid tauopathies likely contributed in part to these differences: when cases with concurrent Alzheimer dementia or frontal temporal lobar degeneration with tau pathology were excluded, differences were largely retained, but only remained significant for FAQ (p = 0.042), meta-cognition index T score (p = 0.014) and age of Parkinsonian motor symptom onset (p = 0.046). Overall, CSCTE appears to be a distinct subtype of high stage CTE with relatively greater involvement of subcortical and brainstem regions and less severe cognitive symptoms.

Relative Contributions of Mixed Pathologies to Cognitive and Functional Symptoms in Brain Donors Exposed to Repetitive Head Impacts.

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.

Imaging Brain Injury in Former National Football League Players.

Importance: Pilot studies that involved early imaging of the 18 kDa translocator protein (TSPO) using positron emission tomography (PET) indicated high levels of TSPO in the brains of active or former National Football League (NFL) players. If validated further in larger studies, those findings may have implications for athletes involved in collision sport. Objective: To test for higher TSPO that marks brain injury and repair in a relatively large, unique cohort of former NFL players compared with former elite, noncollision sport athletes. Design, Setting, and Participants: This cross-sectional study used carbon 11-labeled N,N-diethyl-2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide positron emission tomography ([11C]DPA-713 PET) data from former NFL players within 12 years of last participation in the NFL and elite noncollision sport athletes from across the US. Participants were enrolled between April 2018 and February 2023. Main outcomes and measures: Regional [11C]DPA-713 total distribution volume from [11C]DPA-713 PET that is a measure of regional brain TSPO; regional brain volumes on magnetic resonance imaging; neuropsychological performance, including attention, executive function, and memory domains. Results: This study included 27 former NFL players and 27 former elite, noncollision sport athletes. Regional TSPO levels were higher in former NFL players compared with former elite, noncollision sport athletes (unstandardized ß coefficient, 1.08; SE, 0.22; 95% CI, 0.65 to 1.52; P < .001). The magnitude of the group difference depended on region, with largest group differences in TSPO in cingulate and frontal cortices as well as hippocampus. Compared with noncollision sport athletes, former NFL players performed worse in learning (mean difference [MD], -0.70; 95% CI, -1.14 to -0.25; P = .003) and memory (MD, -0.77; 95% CI, -1.24 to -0.30; P = .002), with no correlation between total gray matter TSPO and these cognitive domains. Conclusions and relevance: In this cross-sectional study using [11C]DPA-713 PET, higher brain TSPO was found in former NFL players compared with noncollision sport athletes. This finding is consistent with neuroimmune activation even after cessation of NFL play. Future longitudinal [11C]DPA-713 PET and neuropsychological testing promises to inform whether neuroimmune-modulating therapy may be warranted.

Neuropathologic and Clinical Findings in Young Contact Sport Athletes Exposed to Repetitive Head Impacts.

Importance: Young contact sport athletes may be at risk for long-term neuropathologic disorders, including chronic traumatic encephalopathy (CTE). Objective: To characterize the neuropathologic and clinical symptoms of young brain donors who were contact sport athletes. Design, Setting, and Participants: This case series analyzes findings from 152 of 156 brain donors younger than 30 years identified through the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank who donated their brains from February 1, 2008, to September 31, 2022. Neuropathologic evaluations, retrospective telephone clinical assessments, and online questionnaires with informants were performed blinded. Data analysis was conducted between August 2021 and June 2023. Exposures: Repetitive head impacts from contact sports. Main Outcomes and Measures: Gross and microscopic neuropathologic assessment, including diagnosis of CTE, based on defined diagnostic criteria; and informant-reported athletic history and informant-completed scales that assess cognitive symptoms, mood disturbances, and neurobehavioral dysregulation. Results: Among the 152 deceased contact sports participants (mean [SD] age, 22.97 [4.31] years; 141 [92.8%] male) included in the study, CTE was diagnosed in 63 (41.4%; median [IQR] age, 26 [24-27] years). Of the 63 brain donors diagnosed with CTE, 60 (95.2%) were diagnosed with mild CTE (stages I or II). Brain donors who had CTE were more likely to be older (mean difference, 3.92 years; 95% CI, 2.74-5.10 years) Of the 63 athletes with CTE, 45 (71.4%) were men who played amateur sports, including American football, ice hockey, soccer, rugby, and wrestling; 1 woman with CTE played collegiate soccer. For those who played football, duration of playing career was significantly longer in those with vs without CTE (mean difference, 2.81 years; 95% CI, 1.15-4.48 years). Athletes with CTE had more ventricular dilatation, cavum septum pellucidum, thalamic notching, and perivascular pigment-laden macrophages in the frontal white matter than those without CTE. Cognitive and neurobehavioral symptoms were frequent among all brain donors. Suicide was the most common cause of death, followed by unintentional overdose; there were no differences in cause of death or clinical symptoms based on CTE status. Conclusions and Relevance: This case series found that young brain donors exposed to repetitive head impacts were highly symptomatic regardless of CTE status, and the causes of symptoms in this sample are likely multifactorial. Future studies that include young brain donors unexposed to repetitive head impacts are needed to clarify the association among exposure, white matter and microvascular pathologic findings, CTE, and clinical symptoms.

Leveraging football accelerometer data to quantify associations between repetitive head impacts and chronic traumatic encephalopathy in males.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impacts (RHI), but the components of RHI exposure underlying this relationship are unclear. We create a position exposure matrix (PEM), composed of American football helmet sensor data, summarized from literature review by player position and level of play. Using this PEM, we estimate measures of lifetime RHI exposure for a separate cohort of 631 football playing brain donors. Separate models examine the relationship between CTE pathology and players' concussion count, athletic positions, years of football, and PEM-derived measures, including estimated cumulative head impacts, linear accelerations, and rotational accelerations. Only duration of play and PEM-derived measures are significantly associated with CTE pathology. Models incorporating cumulative linear or rotational acceleration have better model fit and are better predictors of CTE pathology than duration of play or cumulative head impacts alone. These findings implicate cumulative head impact intensity in CTE pathogenesis.

Decreased myelin proteins in brain donors exposed to football-related repetitive head impacts.

American football players and other individuals exposed to repetitive head impacts can exhibit a constellation of later-life cognitive and neuropsychiatric symptoms. While tau-based diseases such as chronic traumatic encephalopathy can underpin certain symptoms, contributions from non-tau pathologies from repetitive head impacts are increasingly recognized. We examined cross-sectional associations between myelin integrity using immunoassays for myelin-associated glycoprotein and proteolipid protein 1 with risk factors and clinical outcomes in brain donors exposed to repetitive head impacts from American football. Immunoassays for myelin-associated glycoprotein and proteolipid protein 1 were conducted on dorsolateral frontal white matter tissue samples of 205 male brain donors. Proxies of exposure to repetitive head impacts included years of exposure and age of first exposure to American football play. Informants completed the Functional Activities Questionnaire, Behavior Rating Inventory of Executive Function-Adult Version (Behavioral Regulation Index), and Barratt Impulsiveness Scale-11. Associations between myelin-associated glycoprotein and proteolipid protein 1 with exposure proxies and clinical scales were tested. Of the 205 male brain donors who played amateur and professional football, the mean age was 67.17 (SD = 16.78), and 75.9% (n = 126) were reported by informants to be functionally impaired prior to death. Myelin-associated glycoprotein and proteolipid protein 1 correlated with the ischaemic injury scale score, a global indicator of cerebrovascular disease (r = -0.23 and -0.20, respectively, Ps < 0.01). Chronic traumatic encephalopathy was the most common neurodegenerative disease (n = 151, 73.7%). Myelin-associated glycoprotein and proteolipid protein 1 were not associated with chronic traumatic encephalopathy status, but lower proteolipid protein 1 was associated with more severe chronic traumatic encephalopathy (P = 0.03). Myelin-associated glycoprotein and proteolipid protein 1 were not associated with other neurodegenerative disease pathologies. More years of football play was associated with lower proteolipid protein 1 [beta = -2.45, 95% confidence interval (CI) [-4.52, -0.38]] and compared with those who played <11 years of football (n = 78), those who played 11 or more years (n = 128) had lower myelin-associated glycoprotein (mean difference = 46.00, 95% CI [5.32, 86.69]) and proteolipid protein 1 (mean difference = 24.72, 95% CI [2.40, 47.05]). Younger age of first exposure corresponded to lower proteolipid protein 1 (beta = 4.35, 95% CI [0.25, 8.45]). Among brain donors who were aged 50 or older (n = 144), lower proteolipid protein 1 (beta = -0.02, 95% CI [-0.047, -0.001]) and myelin-associated glycoprotein (beta = -0.01, 95% CI [-0.03, -0.002]) were associated with higher Functional Activities Questionnaire scores. Lower myelin-associated glycoprotein correlated with higher Barratt Impulsiveness Scale-11 scores (beta = -0.02, 95% CI [-0.04, -0.0003]). Results suggest that decreased myelin may represent a late effect of repetitive head impacts that contributes to the manifestation of cognitive symptoms and impulsivity. Clinical-pathological correlation studies with prospective objective clinical assessments are needed to confirm our findings.

Applying the Bradford Hill Criteria for Causation to Repetitive Head Impacts and Chronic Traumatic Encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with a history of repetitive head impacts (RHI). CTE was described in boxers as early as the 1920s and by the 1950s it was widely accepted that hits to the head caused some boxers to become "punch drunk." However, the recent discovery of CTE in American and Australian-rules football, soccer, rugby, ice hockey, and other sports has resulted in renewed debate on whether the relationship between RHI and CTE is causal. Identifying the strength of the evidential relationship between CTE and RHI has implications for public health and medico-legal issues. From a public health perspective, environmentally caused diseases can be mitigated or prevented. Medico-legally, millions of children are exposed to RHI through sports participation; this demographic is too young to legally consent to any potential long-term risks associated with this exposure. To better understand the strength of evidence underlying the possible causal relationship between RHI and CTE, we examined the medical literature through the Bradford Hill criteria for causation. The Bradford Hill criteria, first proposed in 1965 by Sir Austin Bradford Hill, provide a framework to determine if one can justifiably move from an observed association to a verdict of causation. The Bradford Hill criteria include nine viewpoints by which to evaluate human epidemiologic evidence to determine if causation can be deduced: strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy. We explored the question of causation by evaluating studies on CTE as it relates to RHI exposure. Through this lens, we found convincing evidence of a causal relationship between RHI and CTE, as well as an absence of evidence-based alternative explanations. By organizing the CTE literature through this framework, we hope to advance the global conversation on CTE mitigation efforts.

Association of APOE Genotypes and Chronic Traumatic Encephalopathy.

Importance: Repetitive head impact (RHI) exposure is the chief risk factor for chronic traumatic encephalopathy (CTE). However, the occurrence and severity of CTE varies widely among those with similar RHI exposure. Limited evidence suggests that the APOEε4 allele may confer risk for CTE, but previous studies were small with limited scope. Objective: To test the association between APOE genotype and CTE neuropathology and related endophenotypes. Design, Setting, and Participants: This cross-sectional genetic association study analyzed brain donors from February 2008 to August 2019 from the Veterans Affairs-Boston University-Concussion Legacy Foundation Brain Bank. All donors had exposure to RHI from contact sports or military service. All eligible donors were included. Analysis took place between June 2020 and April 2022. Exposures: One or more APOEε4 or APOEε2 alleles. Main Outcomes and Measures: CTE neuropathological status, CTE stage (0-IV), semiquantitative phosphorylated tau (p-tau) burden in 11 brain regions (0-3), quantitative p-tau burden in the dorsolateral frontal lobe (log-transformed AT8+ pixel count per mm2), and dementia. Results: Of 364 consecutive brain donors (100% male; 53 [14.6%] self-identified as Black and 311 [85.4%] as White; median [IQR] age, 65 [47-77] years) 20 years or older, there were 294 individuals with CTE and 70 controls. Among donors older than 65 years, APOEε4 status was significantly associated with CTE stage (odds ratio [OR], 2.34 [95% CI, 1.30-4.20]; false discovery rate [FDR]-corrected P = .01) and quantitative p-tau burden in the dorsolateral frontal lobe (ß, 1.39 [95% CI, 0.83-1.94]; FDR-corrected P = 2.37 × 10-5). There was a nonsignificant association between APOEε4 status and dementia (OR, 2.64 [95% CI, 1.06-6.61]; FDR-corrected P = .08). Across 11 brain regions, significant associations were observed for semiquantitative p-tau burden in the frontal and parietal cortices, amygdala, and entorhinal cortex (OR range, 2.45-3.26). Among football players, the APOEε4 association size for CTE stage was similar to playing more than 7 years of football. Associations were significantly larger in the older half of the sample. There was no significant association for CTE status. Association sizes were similar when donors with an Alzheimer disease neuropathological diagnosis were excluded and were reduced but remained significant after adjusting for neuritic and diffuse amyloid plaques. No associations were observed for APOEε2 status. Models were adjusted for age at death and race. Conclusions and Relevance: APOEε4 may confer increased risk for CTE-related neuropathological and clinical outcomes among older individuals with RHI exposure. Further work is required to validate these findings in an independent sample.

Association Between Antemortem FLAIR White Matter Hyperintensities and Neuropathology in Brain Donors Exposed to Repetitive Head Impacts.

BACKGROUND AND OBJECTIVES: Late neuropathologies of repetitive head impacts from contact sports can include chronic traumatic encephalopathy (CTE) and white matter degeneration. White matter hyperintensities (WMH) on fluid-attenuated inversion recovery (FLAIR) MRI scans are often viewed as microvascular disease from vascular risk, but might have unique underlying pathologies and risk factors in the setting of repetitive head impacts. We investigated the neuropathologic correlates of antemortem WMH in brain donors exposed to repetitive head impacts. The association between WMH and repetitive head impact exposure and informant-reported cognitive and daily function were tested. METHODS: This imaging-pathologic correlation study included symptomatic male decedents exposed to repetitive head impacts. Donors had antemortem FLAIR scans from medical records and were without evidence of CNS neoplasm, large vessel infarcts, hemorrhage, or encephalomalacia. WMH were quantified using log-transformed values for total lesion volume (TLV), calculated using the lesion prediction algorithm from the Lesion Segmentation Toolbox. Neuropathologic assessments included semiquantitative ratings of white matter rarefaction, cerebrovascular disease, hyperphosphorylated tau (p-tau) severity (CTE stage, dorsolateral frontal cortex), and ß-amyloid (Aß). Among football players, years of play was a proxy for repetitive head impact exposure. Retrospective informant-reported cognitive and daily function were assessed using the Cognitive Difficulties Scale (CDS) and Functional Activities Questionnaire (FAQ). Regression models controlled for demographics, diabetes, hypertension, and MRI resolution. Statistical significance was defined as p ≤ 0.05. RESULTS: The sample included 75 donors: 67 football players and 8 nonfootball contact sport athletes or military veterans. Dementia was the most common MRI indication (64%). Fifty-three (70.7%) had CTE at autopsy. Log TLV was associated with white matter rarefaction (odds ratio [OR] 2.32, 95% confidence interval [CI] 1.03, 5.24; p = 0.04), arteriolosclerosis (OR 2.38, 95% CI 1.02, 5.52; p = 0.04), CTE stage (OR 2.58, 95% CI 1.17, 5.71; p = 0.02), and dorsolateral frontal p-tau severity (OR 3.03, 95% CI 1.32, 6.97; p = 0.01). There was no association with Aß. More years of football play was associated with log TLV (unstandardized ß 0.04, 95% CI 0.01, 0.06; p = 0.01). Greater log TLV correlated with higher FAQ (unstandardized ß 4.94, 95% CI 0.42, 8.57; p = 0.03) and CDS scores (unstandardized ß 15.35, 95% CI -0.27, 30.97; p = 0.05). DISCUSSION: WMH might capture long-term white matter pathologies from repetitive head impacts, including those from white matter rarefaction and p-tau, in addition to microvascular disease. Prospective imaging-pathologic correlation studies are needed. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence of associations between FLAIR white matter hyperintensities and neuropathologic changes (white matter rarefaction, arteriolosclerosis, p-tau accumulation), years of American football play, and reported cognitive symptoms in symptomatic brain donors exposed to repetitive head impacts.

Incidence of and Mortality From Amyotrophic Lateral Sclerosis in National Football League Athletes.

Importance: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease; understanding ALS risk factors is a critical public health issue. Objectives: To evaluate the incidence of and mortality from ALS in National Football League (NFL) athletes and to describe characteristics associated with ALS within this cohort. Design, Setting, and Participants: This population-based cohort study included all 19 423 NFL athletes who debuted between 1960 and 2019 and played 1 or more professional game. It was conducted between October 3, 2020, and July 19, 2021. Exposure: Participation in the NFL, including playing 1 or more professional games. Main Outcomes and Measures: Cases of ALS and death information were identified based on public records from NFL statistics aggregators, news reports, obituaries, and National Death Index results. The standardized incidence ratio and the standardized mortality ratio were calculated based on data acquired from surveillance studies of ALS accounting for age, sex, and race. Secondary analyses examined the association of body mass index, NFL career duration, race, birth location, and markers of fame, using a nested case-control design, matching athletes with ALS to athletes without ALS, by NFL debut year. Results: A total of 19 423 male former and current NFL players (age range, 23-78 years) were included in this cohort study and were followed up for a cumulative 493 168 years (mean [SD] follow-up, 30.6 [13.7] years). Thirty-eight players received a diagnosis of ALS, and 28 died during the study time frame, representing a significantly higher incidence of ALS diagnosis (standardized incidence ratio, 3.59; 95% CI, 2.58-4.93) and mortality (standardized mortality ratio, 3.94; 95% CI, 2.62-5.69) among NFL players compared with the US male population, adjusting for age and race. Among NFL athletes, nested-case-control analyses found that those who received a diagnosis of ALS had significantly longer careers (mean [SD] duration, 7.0 [3.9] years) than athletes without ALS (mean [SD] duration, 4.5 [3.6] years; odds ratio, 1.2; 95% CI, 1.1-1.3). There were no differences in ALS status based on proxies of NFL fame, body mass index, position played, birth location, or race. Conclusions and Relevance: The age-, sex-, and race-adjusted incidence of and mortality from ALS among all NFL players who debuted between 1960 and 2019 were nearly 4 times as high as those of the general population. Athletes with a diagnosis of ALS had longer NFL careers than those without ALS, suggesting an association between NFL duration of play and ALS. The identification of these risk factors for ALS helps to inform the study of pathophysiological mechanisms responsible for this fatal neurodegenerative disease.

Structural MRI profiles and tau correlates of atrophy in autopsy-confirmed CTE.

BACKGROUND: Chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy, cannot currently be diagnosed during life. Atrophy patterns on magnetic resonance imaging could be an effective in vivo biomarker of CTE, but have not been characterized. Mechanisms of neurodegeneration in CTE are unknown. Here, we characterized macrostructural magnetic resonance imaging features of brain donors with autopsy-confirmed CTE. The association between hyperphosphorylated tau (p-tau) and atrophy on magnetic resonance imaging was examined. METHODS: Magnetic resonance imaging scans were obtained by medical record requests for 55 deceased symptomatic men with autopsy-confirmed CTE and 31 men (n = 11 deceased) with normal cognition at the time of the scan, all >60 years Three neuroradiologists visually rated regional atrophy and microvascular disease (0 [none]-4 [severe]), microbleeds, and cavum septum pellucidum presence. Neuropathologists rated tau severity and atrophy at autopsy using semi-quantitative scales. RESULTS: Compared to unimpaired males, donors with CTE (45/55=stage III/IV) had greater atrophy of the orbital-frontal (mean diff.=1.29), dorsolateral frontal (mean diff.=1.31), superior frontal (mean diff.=1.05), anterior temporal (mean diff.=1.57), and medial temporal lobes (mean diff.=1.60), and larger lateral (mean diff.=1.72) and third (mean diff.=0.80) ventricles, controlling for age at scan (ps<0.05). There were no effects for posterior atrophy or microvascular disease. Donors with CTE had increased odds of a cavum septum pellucidum (OR = 6.7, p < 0.05). Among donors with CTE, greater tau severity across 14 regions corresponded to greater atrophy on magnetic resonance imaging (beta = 0.68, p < 0.01). CONCLUSIONS: These findings support frontal-temporal atrophy as a magnetic resonance imaging finding of CTE and show p-tau accumulation is associated with atrophy in CTE.

Validity of the 2014 traumatic encephalopathy syndrome criteria for CTE pathology.

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.

Association of probable REM sleep behavior disorder with pathology and years of contact sports play in chronic traumatic encephalopathy.

Probable rapid eye movement (REM) sleep behavior disorder (pRBD) is a synucleinopathy-associated parasomnia in which loss of REM sleep muscle atonia results in motor behavior during REM sleep, including dream enactment. Traumatic brain injury is independently associated with increased risk of pRBD and Lewy body disease, and both pRBD and Lewy body disease are often observed in chronic traumatic encephalopathy (CTE). However, the frequency and pathological substrate of pRBD in CTE have not been formally studied and remain unknown. Of the total sample of 247 men, age at death of 63.1 ± 18.8 years (mean ± SD), 80 [32%] were determined by informant report to have symptoms of pRBD. These participants had played more years of contact sports (18.3 ± 11.4) than those without pRBD (15.1 ± 6.5; P = 0.02) and had an increased frequency of Lewy body disease (26/80 [33%] vs 28/167 [17%], P = 0.005). Of the 80 participants with pRBD, 54 [68%] did not have Lewy body disease; these participants were more likely to have neurofibrillary tangles and pretangles in the dorsal and median raphe (41 of 49 [84%] non-LBD participants with pRBD symptoms vs 90 of 136 [66%] non-LBD participants without pRBD symptoms, P = 0.02), brainstem nuclei with sleep regulatory function. Binary logistic regression modeling in the total study sample showed that pRBD in CTE was associated with dorsal and median raphe nuclei neurofibrillary tangles (OR = 3.96, 95% CI [1.43, 10.96], P = 0.008), Lewy body pathology (OR = 2.36, 95% CI [1.18, 4.72], P = 0.02), and years of contact sports participation (OR = 1.04, 95% CI [1.00, 1.08], P = 0.04). Overall, pRBD in CTE is associated with increased years of contact sports participation and may be attributable to Lewy body and brainstem tau pathologies.

Chronic Traumatic Encephalopathy: Advocacy and Communicating with the Public.

Over the past 40 years, advocacy groups have been instrumental in raising awareness for neurodegenerative diseases such as Alzheimer's disease. More recently, advocates have emerged to educate about sports concussions and chronic traumatic encephalopathy (CTE), including the Concussion Legacy Foundation (CLF). CTE is a neurodegenerative disease caused in part by repetitive head impacts (RHI). While the majority of CTE research has focused on studying former American football players, CTE has also been found in military personnel, victims of domestic violence, and contact sport athletes from high school to professional levels of play. Advocates' many goals include creating a culture of brain donation and modifying youth contact sports to decrease RHI. Here, we provide the first review of CTE advocacy, summarize the accomplishments of the CLF, and consider the connections between CTE advocacy, research, and legislation over the last decade.