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.

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

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.

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.

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 (β = 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.

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 3-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 = 0.0112), 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 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.

Objective: To describe the clinical and neuropathological features of second-impact syndrome (SIS). Background: Young amateur contact sport athletes die every year from SIS. SIS is a catastrophic brain injury believed to result from a second head impact occurring after incomplete recovery from a previous head trauma. Case studies have reported on the clinical features of SIS, but pathobiological mechanisms are unknown and no study has described the neuropathology of SIS. Design/Methods: This is a case report of a 17-year-old healthy female whose brain was donated to the Veteran’s Affairs-Boston University-Concussion Legacy Foundation brain bank as part of ongoing research investigating the consequences of repetitive head impacts (RHI). Clinical interviews with the subject’s parents ascertained demographic, clinical, athletic, and RHI exposure history. Medical records supplemented the clinical interview. Parents provided consent to disseminate the findings to the scientific community. Results: Subject experienced 3 blows to the head within a single week while playing rugby. Two concussions, separated by 2 days, resulted in post-concussion symptoms (e.g., tinnitus, headache, fatigue). Two days later, she sustained a third head impact. Within minutes, she developed seizures, rapid unresponsiveness, and was hospitalized (Glasgow Coma Scale = 3). Urgent head CT showed generalized cerebral edema, 3 mm midline shift, and a small subdural hemorrhage. Despite hemicraniectomy, she died 5 days later from worsening edema and uncal herniation. Neuropathological examination revealed an acute superior temporal contusion, resolving hemorrhagic axonal injury with digestion chambers in the subcortical u-fibers and hippocampal stem, perivascular nests of activated microglia and lymphocytes, and anoxic-ischemic encephalopathy. Conclusions: This is the first case study to report the clinical and neuropathological features of SIS. Larger autopsy samples are needed to systematically identify clinicopathological correlates of SIS to facilitate research on risk factors and preventative strategies (e.g., return-to-play guidelines) to prevent unnecessary fatalities in young athletes. Study Supported by: This work was supported by the National Institute of Neurological Disorders and Stroke (1U01NS086659-01, U01NS093334, R01NS078337, R56NS078337), Department of Defense (W81XWH-13-2-0064), Department of Veterans Affairs, the Veterans Affairs Biorepository (CSP 501), the National Institute of Aging Boston University Alzheimer’s Disease Center (P30AG13846; supplement 0572063345–5), Department of Defense Peer Reviewed Alzheimer’s Research Program (DoD-PRARP #13267017), the National Institute of Aging Boston University Framingham Heart Study (R01AG1649), the National Operating Committee on Standards for Athletic Equipment and the Concussion Legacy Foundation. This work was also supported by unrestricted gifts from the Andlinger Foundation, the WWE and the NFL. Michael L. Alosco and research reported in this publication is supported by the National Institutes of Health under grant number 1F32NS096803-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Jesse Mez is supported by the National Institutes of Health under grant number K23 AG046377. Funding sources did not have restrictions on the design and conduct of the study, collection, management, analysis, and interpretation of data, or the preparation, review, or approval of the manuscript, or decision to submit the manuscript for publication. Disclosure: Dr. Mian has nothing to disclose. Dr. Alosco has nothing to disclose. Dr. Mez has nothing to disclose. Dr. Kiernan has nothing to disclose. Dr. Daneshvar has nothing to disclose. Dr. Nowinski has nothing to disclose. Dr. Kowall has nothing to disclose. Dr. Stern has received personal compensation for activities with Biogen, Avanir Pharmaceuticals, the NCAA, and Eli Lilly. Dr. Stern has received royalty payments from Psychological Assessment Resources, Inc. Dr. Stern has received research support from Avid Radiopharmaceuticals, Amarantus, Eisai, and Eli Lilly. Dr. Katz has nothing to disclose. Dr. Cantu has nothing to disclose. Dr. McKee has nothing to disclose.

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.

Objective: To present clinical and neuropathological features of chronic traumatic encephalopathy (CTE) in a young, former high school soccer player. Background: CTE is a neurodegenerative disease that currently only can be diagnosed neuropathologically. It is associated with exposure to repetitive head impacts (RHI), usually from contact sports. CTE has been observed in fewer than 10 soccer players, all of whom played semi-professionally or professionally. Design/Methods: As part of the Understanding Neurological Injury and Traumatic Encephalopathy (UNITE) Study, a panel of clinicians, blinded to neuropathology, makes clinical consensus diagnoses, based on detailed retrospective informant interviews, using published criteria, including proposed CTE clinical research criteria. Here, we present an instructive case of a 24-year-old former soccer player. Results: He played soccer from age 4 until his senior year of high school. He suffered approximately 20 concussions, of which 19 were soccer-related. In high school, he developed headaches and attentional difficulties. In college, he had intermittent depressive episodes, mild memory impairment and problematic substance use. He left college before graduating and lived with his parents. They observed angry outbursts, self-mutilation, passive suicidal ideation, poor decision making and ongoing substance use. He died from an accidental overdose. Panel members supported bipolar disorder as a primary diagnosis, and CTE and substance use disorder as possible contributing diagnoses. Neuropathological examination showed hyperphosphorylated tau containing neurofibrillary tangles and neurites around small blood vessels that were diagnostic of CTE based on NINDS/NIBIB neuropathological criteria. Conclusions: To our knowledge, this is the youngest soccer player diagnosed with CTE and the first case to have only played high school-level soccer. Although CTE should be considered in the differential diagnosis of a young adult with extensive RHI exposure and persistent mood and behavioral symptoms, prospective studies are needed before we can infer the likelihood of CTE in this setting. Disclosure: Dr. Phalen has nothing to disclose. Dr. Alosco has nothing to disclose. Dr. Kiernan has nothing to disclose. Dr. Montenigro has nothing to disclose. Dr. Solomon has nothing to disclose. Dr. Stern has received personal compensation for activities with Biogen, Avanir Pharmaceuticals, the NCAA, and Eli Lilly. Dr. Stern has received royalty payments from Psychological Assessment Resources, Inc. Dr. Stern has received research support from Avid Radiopharmaceuticals, Amarantus, Eisai, and Eli Lilly. Dr. Katz has nothing to disclose. Dr. McKee has nothing to disclose. Dr. Mez has nothing to disclose.

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

Objective: To investigate whether APOEɛ4 is a risk factor for chronic traumatic encephalopathy (CTE) severity. Background: CTE is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI). CTE has distinct neuropathology consisting of perivascular hyperphosphorylated tau (ptau) deposition. All cases of neuropathologically confirmed CTE have had a history of RHI exposure; however, only a subset exposed to RHI develop CTE, suggesting a role for genetic risk factors. There is mixed evidence suggesting that APOEɛ4 confers risk for CTE, but it is unknown whether APOEɛ4 is a risk factor for ptau severity in CTE or whether this effect is modified by RHI exposure. Design/Methods: 110 autopsy-confirmed CTE cases of European ancestry from the VA-BU-CLF Brain Bank were evaluated for CTE stage (1–4, 4 most severe). Informants were asked about participants’ years of organized football played. We assessed the relationship between APOEɛ4 (0–2 alleles) and CTE stage. Among football players only (n= 85), we assessed the interaction of APOEɛ4 with years of play. Age of death was controlled for in each model. Results: APOEɛ4 was significantly associated with CTE stage (OR=2.99 for an increase in 1 stage, p=0.006). Among football players, the interaction between APOEɛ4 and years of play was significantly associated with CTE stage (p=0.024). In analyses stratified by median years of play (high ≥ 14 years, low Conclusions: Among people with CTE, APOEɛ4 may be a risk factor for disease severity with a larger effect at low levels of RHI exposure. Disclosure: Dr. Verscaj has nothing to disclose. Dr. Abdolmohammadi has nothing to disclose. Dr. Kiernan has nothing to disclose. Dr. Chung has nothing to disclose. Dr. Crary has nothing to disclose. Dr. Stein has nothing to disclose. Dr. Farrer has nothing to disclose. Dr. McKee has nothing to disclose. Dr. Mez has nothing to disclose.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease associated with exposure to repetitive head impacts (RHI), including American football. Although most pathologically confirmed cases of CTE had a history of RHI, how exposure relates to neuropathology is not known. We hypothesized that as cumulative RHI exposure increased, CTE risk would correspondingly increase. In a convenience sample of 163 deceased former American football players from the Veterans Affairs-Boston University-Concussion Legacy Foundation Brain Bank, we retrospectively determined participants’ duration of play (in years), player positions, levels of play, and concussion number. We estimated each participant's cumulative impacts using published football helmet sensor data. To circumvent errors in measuring cumulative impact, we used instrumental variable methods to evaluate this variable, assigning duration of play as the instrument. Analyses were adjusted for age at death. 134 of 163 participants met neuropathological diagnostic criteria for CTE. Those with CTE played an average of 7 years longer than those without CTE, with odds of diagnosis 25% higher per additional year played (OR=1.25, 95% CI, 1.11–1.40). In the instrumental variable analyses, those with CTE had an average of 3,300 more head impacts with odds of diagnosis 64% higher per 1,000 additional impacts (OR=1.64; 95% CI, 1.28–2.36). Concussion number was not significantly associated with CTE risk. The odds of having CTE at death nearly double with every 3 additional years of play. Estimated cumulative impacts, regardless of whether symptoms are present (concussion), predict CTE risk. Brain banks suffer from marked selection bias and these results should be interpreted cautiously until they can be replicated.

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.

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

April 28, 2017April 18, 2017Free AccessChronic Traumatic Encephalopathy in a 24-year-old former soccer player (P6.165)Joseph Phalen, Michael Alosco, Patrick Kiernan, Philip Montenigro, Todd Solomon, Robert Stern, Douglas Katz, Ann McKee, and Jesse MezAuthors Info & AffiliationsApril 18, 2017 issue88 (16_supplement)https://doi.org/10.1212/WNL.88.16_supplement.P6.165 Letters to the Editor

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

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