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.

Chronic traumatic encephalopathy (CTE): criteria for neuropathological diagnosis and relationship to repetitive head impacts.

Over the last 17 years, there has been a remarkable increase in scientific research concerning chronic traumatic encephalopathy (CTE). Since the publication of NINDS-NIBIB criteria for the neuropathological diagnosis of CTE in 2016, and diagnostic refinements in 2021, hundreds of contact sport athletes and others have been diagnosed at postmortem examination with CTE. CTE has been reported in amateur and professional athletes, including a bull rider, boxers, wrestlers, and American, Canadian, and Australian rules football, rugby union, rugby league, soccer, and ice hockey players. The pathology of CTE is unique, characterized by a pathognomonic lesion consisting of a perivascular accumulation of neuronal phosphorylated tau (p-tau) variably alongside astrocytic aggregates at the depths of the cortical sulci, and a distinctive molecular structural configuration of p-tau fibrils that is unlike the changes observed with aging, Alzheimer's disease, or any other tauopathy. Computational 3-D and finite element models predict the perivascular and sulcal location of p-tau pathology as these brain regions undergo the greatest mechanical deformation during head impact injury. Presently, CTE can be definitively diagnosed only by postmortem neuropathological examination; the corresponding clinical condition is known as traumatic encephalopathy syndrome (TES). Over 97% of CTE cases published have been reported in individuals with known exposure to repetitive head impacts (RHI), including concussions and nonconcussive impacts, most often experienced through participation in contact sports. While some suggest there is uncertainty whether a causal relationship exists between RHI and CTE, the preponderance of the evidence suggests a high likelihood of a causal relationship, a conclusion that is strengthened by the absence of any evidence for plausible alternative hypotheses. There is a robust dose-response relationship between CTE and years of American football play, a relationship that remains consistent even when rigorously accounting for selection bias. Furthermore, a recent study suggests that selection bias underestimates the observed risk. Here, we present the advances in the neuropathological diagnosis of CTE culminating with the development of the NINDS-NIBIB criteria, the multiple international studies that have used these criteria to report CTE in hundreds of contact sports players and others, and the evidence for a robust dose-response relationship between RHI and CTE.

Associations between near end-of-life flortaucipir PET and postmortem CTE-related tau neuropathology in six former American football players.

PURPOSE: Flourine-18-flortaucipir tau positron emission tomography (PET) was developed for the detection for Alzheimer's disease. Human imaging studies have begun to investigate its use in chronic traumatic encephalopathy (CTE). Flortaucipir-PET to autopsy correlation studies in CTE are needed for diagnostic validation. We examined the association between end-of-life flortaucipir PET and postmortem neuropathological measurements of CTE-related tau in six former American football players. METHODS: Three former National Football League players and three former college football players who were part of the DIAGNOSE CTE Research Project died and agreed to have their brains donated. The six players had flortaucipir (tau) and florbetapir (amyloid) PET prior to death. All brains from the deceased participants were neuropathologically evaluated for the presence of CTE. On average, the participants were 59.0 (SD = 9.32) years of age at time of PET. PET scans were acquired 20.33 (SD = 13.08) months before their death. Using Spearman correlation analyses, we compared flortaucipir standard uptake value ratios (SUVRs) to digital slide-based AT8 phosphorylated tau (p-tau) density in a priori selected composite cortical, composite limbic, and thalamic regions-of-interest (ROIs). RESULTS: Four brain donors had autopsy-confirmed CTE, all with high stage disease (n = 3 stage III, n = 1 stage IV). Three of these four met criteria for the clinical syndrome of CTE, known as traumatic encephalopathy syndrome (TES). Two did not have CTE at autopsy and one of these met criteria for TES. Concomitant pathology was only present in one of the non-CTE cases (Lewy body) and one of the CTE cases (motor neuron disease). There was a strong association between flortaucipir SUVRs and p-tau density in the composite cortical (ρ = 0.71) and limbic (ρ = 0.77) ROIs. Although there was a strong association in the thalamic ROI (ρ = 0.83), this is a region with known off-target binding. SUVRs were modest and CTE and non-CTE cases had overlapping SUVRs and discordant p-tau density for some regions. CONCLUSIONS: Flortaucipir-PET could be useful for detecting high stage CTE neuropathology, but specificity to CTE p-tau is uncertain. Off-target flortaucipir binding in the hippocampus and thalamus complicates interpretation of these associations. In vivo biomarkers that can detect the specific p-tau of CTE across the disease continuum are needed.

Duration of American Football Play and Chronic Traumatic Encephalopathy.

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

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.

Genetics of Chronic Traumatic Encephalopathy.

Although chronic traumatic encephalopathy (CTE) garners substantial attention in the media and there have been marked scientific advances in the last few years, much remains unclear about the role of genetic risk in CTE. Two athletes with comparable contact-sport exposure may have varying amounts of CTE neuropathology, suggesting that other factors, including genetics, may contribute to CTE risk and severity. In this review, we explore reasons why genetics may be important for CTE, concepts in genetic study design for CTE (including choosing controls, endophenotypes, gene by environment interaction, and epigenetics), implicated genes in CTE (including APOE, MAPT, and TMEM106B), and whether predictive genetic testing for CTE should be considered.

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

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

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

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

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

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

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.

American Football Play and Parkinson Disease Among Men.

Importance: Parkinsonism and Parkinson disease (PD) are known to result from repetitive head impacts from boxing. Repetitive head impacts from American football may also be associated with increased risk of neurodegenerative pathologies that cause parkinsonism, yet in vivo research on the association between football play and PD is scarce and limited by small samples and equivocal findings. Objective: To evaluate the association between football participation and self-reported parkinsonism or PD diagnosis. Design, Setting, and Participants: This cross-sectional study leveraged data from the online Fox Insight study. Participants completed online questionnaires and self-reported whether they currently had a diagnosis of Parkinson disease or parkinsonism by a physician or other health care professional. In November 2020, the Boston University Head Impact Exposure Assessment was launched for data collection on repetitive head impacts. Data used for this manuscript were obtained from the Fox Insight database on June 9, 2022. A total of 1875 men who endorsed playing any organized sport were included. Former athletes were divided into those who participated in football (n = 729 [38.9%]) and those who participated in other sports (reference group). Exposures: Self-reported participation in football, duration and level of football play, age at first exposure. Main Outcomes and Measures: Logistic regression tested associations between PD status and history of football play, duration of football play, highest level played, and age at first exposure, controlling for age, education, history of diabetes or heart disease, body mass index, history of traumatic brain injury with loss of consciousness, and family history of PD. Results: In this sample of 1875 men (mean [SD] age, 67.69 [9.84] years) enriched for parkinsonism or PD (n = 1602 [85.4%]), 729 (38.9%) played football (mean [SD] duration, 4.35 [2.91] years). History of playing football was associated with higher odds of having a parkinsonism or PD diagnosis (odds ratio [OR], 1.61; 95% CI, 1.19-2.17). Among the entire sample, longer duration of play was associated with higher odds of having a parkinsonism or PD diagnosis (OR, 1.12; 95% CI, 1.06-1.19). Among football players, longer duration of football play (OR, 1.12; 95% CI, 1.02-1.23) and higher level of play (OR, 2.93; 95% CI, 1.28-6.73) were associated with higher odds of having parkinsonism or PD. Conclusions and Relevance: In this cross-sectional study of participants enriched for PD, participation in football was associated with higher odds of having a reported parkinsonism or PD diagnosis.

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.

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

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

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.

The neuropathology of chronic traumatic encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head trauma, including concussion and subconcussion. CTE was first recognized in boxers nearly a century ago as "dementia pugilistica" or "punch drunk," but has been recently identified in contact sports athletes (including American football, ice hockey, soccer, baseball, rugby, boxing, and wrestling) and military veterans exposed to blast. Similar to many other neurodegenerative diseases, CTE is diagnosed conclusively only by neuropathologic examination of brain tissue. CTE is characterized by the buildup of hyperphosphorylated tau as neurofibrillary tangles, abnormal neurites, and inclusions in astrocytes around small blood vessels with a tendency to occur in clusters at the sulcal depths of the cortex. Using the McKee criteria, a consensus panel of expert neuropathologists confirmed CTE as a unique neurodegenerative disease with a pathognomonic CTE lesion that has only been found in individuals exposed to brain trauma. Recently, 177 instances of CTE were reported in a convenience sample of 202 former American football players, including 110 of 111 former National Football League players (99%), 48 of 53 former college football players (91%), and 3 of 14 former high school players (21%), by far the largest case series ever reported. Significant increases in active microglia and inflammation also occur after repetitive head impact injury and in CTE. A preliminary study showed that inflammatory cytokines were elevated in the brain tissue and cerebrospinal fluid of individuals with pathologically confirmed CTE compared to controls and individuals with Alzheimer disease, which may some day be useful in diagnosis of CTE during life. Although many fundamental questions remain to be answered regarding CTE, postmortem analysis of tissue from brain donors and tissue-based research have accelerated and expanded our current understanding of CTE and its pathogenesis. Guided by the neuropathologic findings, current research efforts are underway to develop biomarkers to diagnose CTE and effective ways to treat the disorder during life.

Variation in TMEM106B in chronic traumatic encephalopathy.

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

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

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