Proteomic Profiling of Extracellular Vesicles Separated from Plasma of Former National Football League Players at Risk for Chronic Traumatic Encephalopathy.
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ABSTRACT:
SUBMITTER: Muraoka S
PROVIDER: S-EPMC8407879 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chronic Traumatic Encephalopathy (CTE) is a tauopathy that affects individuals with a history of repetitive mild traumatic brain injury, such as American football players. Initial neuropathologic changes in CTE include perivascular deposition of phosphorylated microtubule-associated protein tau (p-tau) neurofibrillary tangles and other aggregates in neurons, astrocytes and cell processes in an irregular pattern often at the depths of the cortical sulci. In later stages, the p-tau depositions become widespread and is associated with neurodegeneration. Extracellular vesicles (EVs) are known to carry neuropathogenic molecules, most notably p-tau. We therefore examined the protein composition of EVs isolated from the cerebrospinal fluid (CSF) of former National Football League (NFL) players with cognitive and neuropsychiatric dysfunction, and an age-matched control group (CTRL) with no history of contact sports or traumatic brain injury. EVs were isolated from the CSF samples using an affinity purification kit. Total tau (t-tau) and tau phosphorylated on threonine181 (p-tau181) in CSF-derived EVs from former NFL players and CTRL participants were measured by ultrasensitive immunoassay. The t-tau and p-tau181 levels of CSF-derived EV were positively correlated with the t-tau and p-tau181 levels of total CSF in former NFL players, respectively, but not in the CTRL group. 429 unique proteins were identified from CSF-derived EVs and quantified by TMT-10 plex method. The identified protein molecules were significantly enriched for the extracellular exosome molecules, Alzheimer's disease pathway and Age/Telomere Length ontology as determined by DAVID Gene Ontology analysis. Ingenuity pathway analysis of the differentially expressed EV proteins revealed enrichment of canonical liver/retinoid X receptor activation pathway. Upstream effect analysis predicted MAPT (tau) as an upstream regulator in former NFL players. These data will be useful for understanding the EV-mediated disease spread and development of novel EV biomarkers for CTE and related disorders.
| S-EPMC6794346 | biostudies-literature
Project description:BACKGROUND:The long-term health consequences of participation in American style football (ASF) are not well understood. METHODS:We conducted a retrospective cohort study of men who had played in the NFL after 1960. Participants were studied using a standardized self-administered questionnaire designed to determine both the exposure history to ASF and the prevalence of chronic pain, sleep apnea, cardiometabolic disease, and neurocognitive impairment. Logistic regression and negative binomial regression models were used to assess associations between age, ethnicity, body-mass index during professional football career, field position, and football career duration with individual and multiple afflictions. RESULTS:In this cohort of former NFL players (n?=?3745), approximately one quarter of the eligible former players (27%) reported two or more medical afflictions (chronic pain, cardiometabolic disease, sleep apnea, or neurocognitive impairment). Career duration was significantly associated with an increase in the number of comorbidities. Age, race, and body-mass index were associated with all affliction categories, other than neurocognitive impairment, which was similarly prevalent in middle-aged players and older players. Earlier age when first playing the sport was protective against cardiometabolic affliction. CONCLUSIONS:Former NFL players report significant combinations of cross-system afflictions. Future work will be required to determine mechanistic underpinnings. However, attention to the whole player, rather than specific organ systems seems critical to improve long-term health outcomes in former ASF professional athletes.
| S-EPMC6640629 | biostudies-literature
Project description:ImportancePilot studies that involved early imaging of the 18 kDa translocator protein (TSPO) using positron emission tomography (PET) indicated high levels of TSPO in the brains of active or former National Football League (NFL) players. If validated further in larger studies, those findings may have implications for athletes involved in collision sport.ObjectiveTo test for higher TSPO that marks brain injury and repair in a relatively large, unique cohort of former NFL players compared with former elite, noncollision sport athletes.Design, setting, and participantsThis cross-sectional study used carbon 11-labeled N,N-diethyl-2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide positron emission tomography ([11C]DPA-713 PET) data from former NFL players within 12 years of last participation in the NFL and elite noncollision sport athletes from across the US. Participants were enrolled between April 2018 and February 2023.Main outcomes and measuresRegional [11C]DPA-713 total distribution volume from [11C]DPA-713 PET that is a measure of regional brain TSPO; regional brain volumes on magnetic resonance imaging; neuropsychological performance, including attention, executive function, and memory domains.ResultsThis study included 27 former NFL players and 27 former elite, noncollision sport athletes. Regional TSPO levels were higher in former NFL players compared with former elite, noncollision sport athletes (unstandardized β coefficient, 1.08; SE, 0.22; 95% CI, 0.65 to 1.52; P < .001). The magnitude of the group difference depended on region, with largest group differences in TSPO in cingulate and frontal cortices as well as hippocampus. Compared with noncollision sport athletes, former NFL players performed worse in learning (mean difference [MD], -0.70; 95% CI, -1.14 to -0.25; P = .003) and memory (MD, -0.77; 95% CI, -1.24 to -0.30; P = .002), with no correlation between total gray matter TSPO and these cognitive domains.Conclusions and relevanceIn this cross-sectional study using [11C]DPA-713 PET, higher brain TSPO was found in former NFL players compared with noncollision sport athletes. This finding is consistent with neuroimmune activation even after cessation of NFL play. Future longitudinal [11C]DPA-713 PET and neuropsychological testing promises to inform whether neuroimmune-modulating therapy may be warranted.
| S-EPMC10616723 | biostudies-literature
Project description:BackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been associated with a history of repetitive head impacts. The neuropathological diagnosis is based on a specific pattern of tau deposition with minimal amyloid-beta deposition that differs from other disorders, including Alzheimer's disease. The feasibility of detecting tau and amyloid deposition in the brains of living persons at risk for CTE has not been well studied.MethodsWe used flortaucipir positron-emission tomography (PET) and florbetapir PET to measure deposition of tau and amyloid-beta, respectively, in the brains of former National Football League (NFL) players with cognitive and neuropsychiatric symptoms and in asymptomatic men with no history of traumatic brain injury. Automated image-analysis algorithms were used to compare the regional tau standardized uptake value ratio (SUVR, the ratio of radioactivity in a cerebral region to that in the cerebellum as a reference) between the two groups and to explore the associations of SUVR with symptom severity and with years of football play in the former-player group.ResultsA total of 26 former players and 31 controls were included in the analysis. The mean flortaucipir SUVR was higher among former players than among controls in three regions of the brain: bilateral superior frontal (1.09 vs. 0.98; adjusted mean difference, 0.13; 95% confidence interval [CI], 0.06 to 0.20; P<0.001), bilateral medial temporal (1.23 vs. 1.12; adjusted mean difference, 0.13; 95% CI, 0.05 to 0.21; P<0.001), and left parietal (1.12 vs. 1.01; adjusted mean difference, 0.12; 95% CI, 0.05 to 0.20; P = 0.002). In exploratory analyses, the correlation coefficients in these three regions between the SUVRs and years of play were 0.58 (95% CI, 0.25 to 0.79), 0.45 (95% CI, 0.07 to 0.71), and 0.50 (95% CI, 0.14 to 0.74), respectively. There was no association between tau deposition and scores on cognitive and neuropsychiatric tests. Only one former player had levels of amyloid-beta deposition similar to those in persons with Alzheimer's disease.ConclusionsA group of living former NFL players with cognitive and neuropsychiatric symptoms had higher tau levels measured by PET than controls in brain regions that are affected by CTE and did not have elevated amyloid-beta levels. Further studies are needed to determine whether elevated CTE-associated tau can be detected in individual persons. (Funded by Avid Radiopharmaceuticals and others.).
| S-EPMC6636818 | biostudies-literature
Project description:Athletes with injury-related pain, especially National Football League (NFL) players, are at increased risk for opioid use and misuse which may result in medical, psychiatric and social problems. This is the first study to evaluate the intersection of sports pain and opioid use and misuse among former NFL players.A telephone survey of 644 retired NFL players from the 2009 Retired Players Association Directory was conducted (53.4% completion rate) from March to August 2010.Over half (52%) used opioids during their NFL career with 71% reporting misuse. Additionally, 15% of NFL misusers currently misused vs. 5% among players who used just as prescribed during their NFL career. Prevalence of current opioid use was 7%-3 times the rate of the general population. Multivariate analyses indicated that significant NFL pain increased the adjusted odds (AOR) of any current opioid use vs. non-use (AOR 6.76, 95%CI 2.88-15.87), as did moderate to severe mental impairment (AOR 1.88, 95%CI 1.19-2.98) and heavy drinking in the past week (AOR 2.15, 95%CI 1.17-3.98). Undiagnosed concussions singly predicted current misuse vs. use just as prescribed (AOR 4.25, 95%CI 1.12-16.22). Three variables predicted current misuse vs. non-use: significant pain (AOR 8.33, 95%CI 1.98-35.04), undiagnosed concussions (AOR 3.51, 95%CI 1.98-35.04) and heavy drinking (AOR 3.48, 95%CI 1.63-7.41).Players who misused during their NFL career were most likely to misuse currently compared to others. Current misuse was associated with more NFL pain, undiagnosed concussions and heavy drinking. Longitudinal studies are needed to determine the long term effects of opioid misuse among athletes.
| S-EPMC3095672 | biostudies-literature
Project description:Ascending aortic dimensions are slightly larger in young competitive athletes compared with sedentary controls, but rarely >40 mm. Whether this finding translates to aortic enlargement in older, former athletes is unknown. This cross-sectional study involved a sample of 206 former National Football League (NFL) athletes compared with 759 male subjects from the DHS-2 (Dallas Heart Study-2; mean age of 57.1 and 53.6 years, respectively, P<0.0001; body surface area of 2.4 and 2.1 m2, respectively, P<0.0001). Midascending aortic dimensions were obtained from computed tomographic scans performed as part of a NFL screening protocol or as part of the DHS. Compared with a population-based control group, former NFL athletes had significantly larger ascending aortic diameters (38±5 versus 34±4 mm; P<0.0001). A significantly higher proportion of former NFL athletes had an aorta of >40 mm (29.6% versus 8.6%; P<0.0001). After adjusting for age, race, body surface area, systolic blood pressure, history of hypertension, current smoking, diabetes mellitus, and lipid profile, the former NFL athletes still had significantly larger ascending aortas (P<0.0001). Former NFL athletes were twice as likely to have an aorta >40 mm after adjusting for the same parameters. Ascending aortic dimensions were significantly larger in a sample of former NFL athletes after adjusting for their size, age, race, and cardiac risk factors. Whether this translates to an increased risk is unknown and requires further evaluation.
| S-EPMC5728154 | biostudies-literature
Project description:To analyze neurodegenerative causes of death, specifically Alzheimer disease (AD), Parkinson disease, and amyotrophic lateral sclerosis (ALS), among a cohort of professional football players.This was a cohort mortality study of 3,439 National Football League players with at least 5 pension-credited playing seasons from 1959 to 1988. Vital status was ascertained through 2007. For analysis purposes, players were placed into 2 strata based on characteristics of position played: nonspeed players (linemen) and speed players (all other positions except punter/kicker). External comparisons with the US population used standardized mortality ratios (SMRs); internal comparisons between speed and nonspeed player positions used standardized rate ratios (SRRs).Overall player mortality compared with that of the US population was reduced (SMR 0.53, 95% confidence interval [CI] 0.48-0.59). Neurodegenerative mortality was increased using both underlying cause of death rate files (SMR 2.83, 95% CI 1.36-5.21) and multiple cause of death (MCOD) rate files (SMR 3.26, 95% CI 1.90-5.22). Of the neurodegenerative causes, results were elevated (using MCOD rates) for both ALS (SMR 4.31, 95% CI 1.73-8.87) and AD (SMR 3.86, 95% CI 1.55-7.95). In internal analysis (using MCOD rates), higher neurodegenerative mortality was observed among players in speed positions compared with players in nonspeed positions (SRR 3.29, 95% CI 0.92-11.7).The neurodegenerative mortality of this cohort is 3 times higher than that of the general US population; that for 2 of the major neurodegenerative subcategories, AD and ALS, is 4 times higher. These results are consistent with recent studies that suggest an increased risk of neurodegenerative disease among football players.
| S-EPMC4098841 | biostudies-other
Project description:PurposeThe purpose of this study was to determine return-to-play (RTP), performance and career survivorship for National Football League (NFL) athletes sustaining pectoralis major (PM) injuries with comparison among grades of injury and between nonoperative and operative management.MethodsPublicly available data from the 1998-2020 NFL seasons were reviewed to identify athletes with PM injuries. Athlete characteristics were collected 1 season before and 2 seasons after injury. Percent of total games played in a season, player efficiency rating (PER), and Pro Football Focus (PFF) grades were compared for the preinjury season and 2 postinjury seasons. Kaplan-Meier survivorship plots were computed for RTP and postinjury career length, whereas a log-rank test was used to compare survivorship differences.ResultsIn total, 258 PM injuries were reported at a mean age of 27.1 ± 3.3 years. A total of 126 surgical repairs occurred in 48.8% (n = 126) of injuries, with athletes undergoing repair possessing a lower RTP rate and longer time to RTP compared to athletes treated conservatively (P < .001). Survival analysis revealed shorter career length for athletes sustaining PM tears compared to strains (P < .001), although no difference in career length was appreciated on the basis of injury management (P = .980). Defensive linemen and wide receivers had lower PER during their second postinjury seasons (P = .019 and .030, respectively), whereas defensive linemen had lower PFF grades during their second post-injury seasons (P = .044).ConclusionNFL athletes requiring PM repair may experience a lower likelihood of RTP, and longer RTP timing, likely because of higher-grade injuries. Defensive linemen and wide receivers experiencing PM injuries are at risk for diminished performance post-injury. Career length does not appear to be affected based on injury management.Level of evidenceLevel III, cohort study.
| S-EPMC8365217 | biostudies-literature
Project description:ImportancePlayers of American football may be at increased risk of long-term neurological conditions, particularly chronic traumatic encephalopathy (CTE).ObjectiveTo determine the neuropathological and clinical features of deceased football players with CTE.Design, setting, and participantsCase 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.ExposuresParticipation in American football at any level of play.Main outcomes and measuresNeuropathological 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.ResultsAmong 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 relevanceIn 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.
| S-EPMC5807097 | biostudies-literature
Project description:ImportanceLong-term adverse health outcomes, particularly those associated with repetitive head impacts, are of growing concern among US-style football players in the US and Canada.ObjectiveTo assess whether exposure to repetitive head impacts during a professional football career is associated with an increase in the risk of all-cause mortality.Design, setting, and participantsThis retrospective cohort study included 13 912 players in the 1969 to 2017 National Football League (NFL) seasons. All cause-mortality up until July 1, 2018, was included. Data collection was performed from July 13, 2017, to July 1, 2018, as reported in the Pro Football Reference.ExposuresThe main exposure was a professional football cumulative head impact index (pfCHII). The pfCHII was measured by combining cumulative padded practice time and games played summed during seasons of play reported in the Pro Football Reference and a player position risk adjustment from helmet accelerometer studies.Main outcomes and measuresDemographic characteristics except for the pfCHII were calculated for 14 366 players with complete follow-up. The pfCHII was calculated for 13 912 players (eliminating the 454 specials teams players). Cox proportional hazards regression was used to compare hazard ratios (HRs) of death by repetitive head impacts. Analyses were unadjusted and adjusted for birth year, body mass index, and height.ResultsAmong 14 366 NFL players who had follow-up for analysis, the mean (SD) age was 47.3 (14.8) years, the mean (SD) body mass index was 29.6 (3.9), and 763 of 14 366 players (5.3%) had died. Among 13 912 players in the pfCHII analysis, the median pfCHII was 32.63 (interquartile range, 13.71-66.12). A 1-log increase in pfCHII was significantly associated with an increased hazard of death for the 1969 to 2017 seasons (HR, 2.02; 95% CI, 1.21-3.37; P = .01) after adjustment. The quadratic pfCHII was also statistically significant (HR, 0.91; 95% CI, 0.85-0.98; P = .01), indicating that the hazard of death increased at a decreasing rate, whereas the pfCHII increased.Conclusions and relevanceThe findings suggest that an increase in repetitive head impacts is associated with an increased hazard of death among NFL players. Reduction in repetitive head impacts from playing football or other activities through additional rule and equipment changes may be associated with reduced mortality.
| S-EPMC7215260 | biostudies-literature