Brain morphometry in former American football players: Findings from the DIAGNOSE CTE research project.

Exposure to repetitive head impacts (RHIs) in contact sports is associated with neurodegenerative disorders including chronic traumatic encephalopathy (CTE) which currently can be diagnosed only at postmortem. American football players are at higher risk of developing CTE given their exposure to RHIs. One promising approach for diagnosing CTE in vivo is to explore known neuropathological abnormalities at postmortem in living individuals using structural magnetic resonance imaging (MRI). MRI brain morphometry was evaluated in 170 male former American football players ages 45-74 years (n = 114 professional; n = 56 college) and 54 same-age unexposed asymptomatic male controls (n = 58 age range 45-74). Cortical thickness and volume of regions of interest were selected based on established CTE pathology findings and were assessed using FreeSurfer. Group differences and interactions with age and exposure factors were evaluated using a generalized least squares model. A separate logistic regression and independent multinomial model were performed to predict each Traumatic Encephalopathy Syndrome (TES) diagnosis core clinical features and provisional level of certainty for CTE pathology using brain regions of interest. Former college and professional American football players (combined) showed significant cortical thickness and/or volume reductions compared to unexposed asymptomatic controls in the hippocampus amygdala entorhinal cortex parahippocampal gyrus insula temporal pole and superior frontal gyrus. Post-hoc analyses identified group-level differences between former professional players and unexposed asymptomatic controls in the hippocampus amygdala entorhinal cortex parahippocampal gyrus insula and superior frontal gyrus. Former college players showed significant volume reductions in the hippocampus amygdala and superior frontal gyrus compared to the unexposed asymptomatic controls. We did not observe age-by-group interactions for brain morphometric measures. Interactions between morphometry and exposure measures were limited to a single significant positive association between the age of first exposure to organized tackle football and right insular volume. We found no significant relationship between brain morphometric measures and the TES diagnosis core clinical features and provisional level of certainty for CTE pathology outcomes. These findings suggest that MRI morphometrics detects abnormalities in individuals with a history of RHI exposure that resemble the anatomic distribution of pathological findings from postmortem CTE studies. The lack of findings associating MRI measures with exposure metrics (except for one significant relationship) or TES diagnosis and core clinical features suggests that brain morphometry must be complemented by other types of measures to characterize individuals with RHIs.

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.

Amyloid PET across the cognitive spectrum in former professional and college American football players: findings from the DIAGNOSE CTE Research Project.

BACKGROUND: Exposure to repetitive head impacts (RHI) in American football players can lead to cognitive impairment and dementia due to neurodegenerative disease, particularly chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE consists of perivascular aggregates of hyper-phosphorylated tau in neurons at the depths of cortical sulci. However, it is unclear whether exposure to RHI accelerates amyloid-ß (Aß) plaque formation and increases the risk for Alzheimer's disease (AD). Although the Aß neuritic plaques characteristic of AD are observed in a minority of later-stage CTE cases, diffuse plaques are more common. This study examined whether former professional and college American football players, including those with cognitive impairment and dementia, have elevated neuritic Aß plaque density, as measured by florbetapir PET. Regardless of cognitive and functional status, elevated levels of florbetapir uptake were not expected. METHODS: We examined 237 men ages 45-74, including 119 former professional (PRO) and 60 former college (COL) football players, with and without cognitive impairment and dementia, and 58 same-age men without a history of contact sports or TBI (unexposed; UE) and who denied cognitive or behavioral symptoms at telephone screening. Former players were categorized into four diagnostic groups: normal cognition, subjective memory impairment, mild cognitive impairment, and dementia. Positive florbetapir PET was defined by cortical-cerebellar average SUVR of ≥ 1.10. Multivariable linear regression and analysis of covariance (ANCOVA) compared florbetapir average SUVR across diagnostic and exposure groups. Multivariable logistic regression compared florbetapir positivity. Race, education, age, and APOE4 were covariates. RESULTS: There were no diagnostic group differences either in florbetapir average SUVR or the proportion of elevated florbetapir uptake. Average SUVR means also did not differ between exposure groups: PRO-COL (p = 0.94, 95% C.I. = [- 0.033, 0.025]), PRO-UE (p = 0.40, 95% C.I. = [- 0.010, 0.029]), COL-UE (p = 0.36, 95% CI = [0.0004, 0.039]). Florbetapir was not significantly associated with years of football exposure, cognition, or daily functioning. CONCLUSIONS: Cognitive impairment in former American football players is not associated with PET imaging of neuritic Aß plaque deposition. These findings are inconsistent with a neuropathological diagnosis of AD in individuals with substantial RHI exposure and have both clinical and medico-legal implications. TRIAL REGISTRATION: NCT02798185.

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.

Twenty-Seven Year Response of South Carolina Coastal Plain Forests Affected by Hurricane Hugo.

In 1989, Hurricane Hugo inflicted catastrophic damage on approximately 1.8 million ha of forested land in South Carolina. The purpose of this study was to monitor species compositional shifts and structural changes in several forest types following the hurricane's disturbance. The immediate consequences of hurricane damage are well documented, but there are few studies based on the long-term compositional and structural changes that may result from hurricane disturbance, especially in temperate forest ecosystems. Forty-two forested plots were monitored within four study areas that received varying degrees of hurricane damage. Inventories included species, damage class, tree diameter, and regeneration. The objectives of this study were (1) to compare the recovery speed of wetland forests (e.g., bottomland hardwood swamps and cypress-tupelo swamps) to that of upland pine and hardwood forests; (2) to discover how the degree of hurricane damage can affect the timing and the pattern of forest recovery in the coastal plain; and (3) to compare individual species response patterns across different forest types and at different levels of initial damage. Over the 27-year period following the hurricane, successional pathways have been variable among plots of different forest types and intensity of initial disturbance. We have observed an expected increase in basal area (BA) following the disturbance. Sapling populations in many species have increased dramatically, and some of these populations have begun to thin in recent years. In several forest types, loblolly pine (Pinus taeda L.-not a predominant species in these sites prior to the hurricane) responded quickly and overtook some dominant species in BA and tree/sapling abundance. Several other species that were not a major component of the tree strata (wax myrtle [Morella cerifera (L.) Small], green ash [Fraxinus pennsylvanica Marsh.], and the invasive Chinese tallow [Triadica sebifera (L.) Small]) showed a large increase in sapling population. Overall, recovery speed and species resilience were specific to forest types and damage severity. The intensity and frequency of hurricanes may increase in the future as sea surface temperatures rise. Understanding how coastal forests respond to major hurricanes in the short-term and the long-term will aid us in preparing for future hurricanes and for potential changes in disturbance regimes.

White matter hyperintensities in former American football players.

INTRODUCTION: The presentation, risk factors, and etiologies of white matter hyperintensities (WMH) in people exposed to repetitive head impacts are unknown. We examined the burden and distribution of WMH, and their association with years of play, age of first exposure, and clinical function in former American football players. METHODS: A total of 149 former football players and 53 asymptomatic unexposed participants (all men, 45-74 years) completed fluid-attenuated inversion recovery magnetic resonance imaging, neuropsychological testing, and self-report neuropsychiatric measures. Lesion Segmentation Toolbox estimated WMH. Analyses were performed in the total sample and stratified by age 60. RESULTS: In older but not younger participants, former football players had greater total, frontal, temporal, and parietal log-WMH compared to asymptomatic unexposed men. In older but not younger former football players, greater log-WMH was associated with younger age of first exposure to football and worse executive function. DISCUSSION: In older former football players, WMH may have unique presentations, risk factors, and etiologies. HIGHLIGHTS: Older but not younger former football players had greater total, frontal, temporal, and parietal lobe white matter hyperintensities (WMH) compared to same-age asymptomatic unexposed men. Younger age of first exposure to football was associated with greater WMH in older but not younger former American football players. In former football players, greater WMH was associated with worse executive function and verbal memory.

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 of Playing College American Football With Long-term Health Outcomes and Mortality.

Importance: Exposure to repetitive head impacts from playing American football (including impacts resulting in symptomatic concussions and subconcussive trauma) is associated with increased risk for later-life health problems, including cognitive and neuropsychiatric decline and neurodegenerative disease. Most research on long-term health consequences of playing football has focused on former professional athletes, with limited studies of former college players. Objectives: To estimate the prevalence of self-reported health conditions among former college football players compared with a sample of men in the general population as well as standardized mortality ratios (SMRs) among former college football players. Design, Setting, and Participants: This cohort study included data from 447 former University of Notre Dame (ND) football players aged 59 to 75 years who were seniors on the rosters from 1964 to 1980. A health outcomes survey was distributed to living players and next of kin of deceased players for whom contact information was available. The survey was completed from December 2018 to May 2019. Exposure: Participation in football at ND. Main Outcomes and Measures: Prevalence of health outcomes was compared between living former players who completed the survey and propensity score-matched participants in the Health and Retirement Study (HRS). Standardized mortality ratios of all causes and specific causes of death among all former players were compared with those among men in the general US population. Results: A total of 216 living players completed the health survey (median age, 67 years; IQR, 63-70 years) and were compared with 638 participants in the HRS (median age, 66 years; IQR, 63-70 years). Former players reported a higher prevalence of cognitive impairment (10 [5%] vs 8 [1%]; P = .02), headaches (22 [10%] vs 22 [4%]; P = .001), cardiovascular disease (70 [33%] vs 128 [20%]; P = .001), hypercholesterolemia (111 [52%] vs 182 [29%]; P = .001), and alcohol use (185 [86%] vs 489 [77%]; P = .02) and a lower prevalence of diabetes (24 [11%] vs 146 [23%]; P = .001). All-cause mortality (SMR, 0.54; 95% CI, 0.42-0.67) and mortality from heart (SMR, 0.64; 95% CI, 0.39-0.99), circulatory (SMR, 0.23; 95% CI, 0.03-0.83), respiratory (SMR, 0.13; 95% CI, 0.00-0.70), and digestive system (SMR, 0.13; 95% CI, 0.00-0.74) disorders; lung cancer (SMR, 0.26; 95% CI, 0.05-0.77); and violence (SMR, 0.10; 95% CI, 0.00-0.58) were significantly lower in the ND cohort than in the general population. Mortality from brain and other nervous system cancers was significantly higher in the ND cohort (SMR, 3.82; 95% CI, 1.04-9.77). Whereas point estimates were greater for all neurodegenerative causes (SMR, 1.42; 95% CI, 0.29-4.18), amyotrophic lateral sclerosis (SMR, 2.93; 95% CI, 0.36-10.59), and Parkinson disease (SMR, 2.07; 95% CI, 0.05-11.55), the difference did not reach statistical significance. Conclusions and Relevance: In this cohort study of former college football players, both positive and negative health outcomes were observed. With more than 800 000 former college players living in the US, additional research appears to be needed to provide stakeholders with guidance to maximize factors that improve health outcomes and minimize factors that may increase risk for later-life morbidity and mortality.

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.

Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer's disease.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease, characterized by hyperphosphorylated tau, found in individuals with a history of exposure to repetitive head impacts. While the neuropathologic hallmark of CTE is found in the cortex, hippocampal tau has proven to be an important neuropathologic feature to examine the extent of disease severity. However, the hippocampus is also heavily affected in many other tauopathies, such as Alzheimer's disease (AD). How CTE and AD differentially affect the hippocampus is unclear. Using immunofluorescent analysis, a detailed histologic characterization of 3R and 4R tau isoforms and their differential accumulation in the temporal cortex in CTE and AD was performed. CTE and AD were both observed to contain mixed 3R and 4R tau isoforms, with 4R predominating in mild disease and 3R increasing proportionally as pathological severity increased. CTE demonstrated high levels of tau in hippocampal subfields CA2 and CA3 compared to CA1. There were also low levels of tau in the subiculum compared to CA1 in CTE. In contrast, AD had higher levels of tau in CA1 and subiculum compared to CA2/3. Direct comparison of the tau burden between AD and CTE demonstrated that CTE had higher tau densities in CA4 and CA2/3, while AD had elevated tau in the subiculum. Amyloid beta pathology did not contribute to tau isoform levels. Finally, it was demonstrated that higher levels of 3R tau correlated to more severe extracellular tau (ghost tangles) pathology. These findings suggest that mixed 3R/4R tauopathies begin as 4R predominant then transition to 3R predominant as pathological severity increases and ghost tangles develop. Overall, this work demonstrates that the relative deposition of tau isoforms among hippocampal subfields can aid in differential diagnosis of AD and CTE, and might help improve specificity of biomarkers for in vivo diagnosis.

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.

Characterizing tau deposition in chronic traumatic encephalopathy (CTE): utility of the McKee CTE staging scheme.

Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive head impacts (RHI) that has been neuropathologically diagnosed in American football players and other contact sport athletes. In 2013, McKee and colleagues proposed a staging scheme for characterizing the severity of the hyperphosphorylated tau (p-tau) pathology, the McKee CTE staging scheme. The staging scheme defined four pathological stages of CTE, stages I(mild)-IV(severe), based on the density and regional deposition of p-tau. The objective of this study was to test the utility of the McKee CTE staging scheme, and provide a detailed examination of the regional distribution of p-tau in CTE. We examined the relationship between the McKee CTE staging scheme and semi-quantitative and quantitative assessments of regional p-tau pathology, age at death, dementia, and years of American football play among 366 male brain donors neuropathologically diagnosed with CTE (mean age 61.86, SD 18.90). Spearman's rho correlations showed that higher CTE stage was associated with higher scores on all semi-quantitative and quantitative assessments of p-tau severity and density (p's < 0.001). The severity and distribution of CTE p-tau followed an age-dependent progression: older age was associated with increased odds for having a higher CTE stage (p < 0.001). CTE stage was independently associated with increased odds for dementia (p < 0.001). K-medoids cluster analysis of the semi-quantitative scales of p-tau across 14 regions identified 5 clusters of p-tau that conformed to increasing CTE stage (stage IV had 2 slightly different clusters), age at death, dementia, and years of American football play. There was a predilection for p-tau pathology in five regions: dorsolateral frontal cortex (DLF), superior temporal cortex, entorhinal cortex, amygdala, and locus coeruleus (LC), with CTE in the youngest brain donors and lowest CTE stage restricted to DLF and LC. These findings support the usefulness of the McKee CTE staging scheme and demonstrate the regional distribution of p-tau in CTE.

Late contributions of repetitive head impacts and TBI to depression symptoms and cognition.

OBJECTIVE: To test the hypothesis that repetitive head impacts (RHIs), like those from contact sport play and traumatic brain injury (TBI) have long-term neuropsychiatric and cognitive consequences, we compared middle-age and older adult participants who reported a history of RHI and/or TBI with those without this history on measures of depression and cognition. METHODS: This cross-sectional study included 13,323 individuals (mean age, 61.95; 72.5% female) from the Brain Health Registry who completed online assessments, including the Ohio State University TBI Identification Method, the Geriatric Depression Scale (GDS-15), and the CogState Brief Battery and Lumos Labs NeuroCognitive Performance Tests. Inverse propensity-weighted linear regressions accounting for age, sex, race/ethnicity, and education tested the effects of RHI and TBI compared to a non-RHI/TBI group. RESULTS: A total of 725 participants reported RHI exposure (mostly contact sport play and abuse) and 7,277 reported TBI (n = 2,604 with loss of consciousness [LOC]). RHI (ß, 1.24; 95% CI, 0.36-2.12), TBI without LOC (ß, 0.43; 95% CI, 0.31-0.54), and TBI with LOC (ß, 0.75; 95% CI, 0.59-0.91) corresponded to higher GDS-15 scores. While TBI with LOC had the most neuropsychological associations, TBI without LOC had a negative effect on CogState Identification (ß, 0.004; 95% CI, 0.001-0.01) and CogState One Back Test (ß, 0.004; 95% CI, 0.0002-0.01). RHI predicted worse CogState One Back Test scores (ß, 0.02; 95% CI, -0.01 to 0.05). There were RHI × TBI interaction effects on several neuropsychological subtests, and participants who had a history of both RHI and TBI with LOC had the greatest depression symptoms and worse cognition. CONCLUSIONS: RHI and TBI independently contributed to worse mid- to later-life neuropsychiatric and cognitive functioning.