Flortaucipir tau PET findings from former professional and college American football players in the DIAGNOSE CTE research project.
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ABSTRACT: Introduction
Tau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project.Method
We compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same-age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with RHI exposure; and compare players who did or did not meet diagnostic criteria for traumatic encephalopathy syndrome (TES).Results
Significantly elevated flortaucipir uptake was observed in former football players (PRO+COL) in prespecified regions (p < 0.05). Association between regional flortaucipir uptake and estimated cumulative head impact exposure was only observed in the superior frontal region in former players over 60 years old. Flortaucipir PET was not able to differentiate TES groups.Discussion
Additional studies are needed to further understand tau pathology in CTE and other individuals with a history of RHI.
SUBMITTER: Su Y
PROVIDER: S-EPMC10984430 | biostudies-literature | 2024 Mar
REPOSITORIES: biostudies-literature
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Flortaucipir tau PET findings from former professional and college American football players in the DIAGNOSE CTE research project.
Su Yi Y Protas Hillary H Luo Ji J Chen Kewei K Alosco Michael L ML Adler Charles H CH Balcer Laura J LJ Bernick Charles C Au Rhoda R Banks Sarah J SJ Barr William B WB Coleman Michael J MJ Dodick David W DW Katz Douglas I DI Marek Kenneth L KL McClean Michael D MD McKee Ann C AC Mez Jesse J Daneshvar Daniel H DH Palmisano Joseph N JN Peskind Elaine R ER Turner Robert W RW Wethe Jennifer V JV Rabinovici Gil G Johnson Keith K Tripodis Yorghos Y Cummings Jeffrey L JL Shenton Martha E ME Stern Robert A RA Reiman Eric M EM
Alzheimer's & dementia : the journal of the Alzheimer's Association 20231222 3
<h4>Introduction</h4>Tau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project.<h4>Method</h4>We compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same-age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with R ...[more]
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Project description:BackgroundExposure 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-β (Aβ) plaque formation and increases the risk for Alzheimer's disease (AD). Although the Aβ 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 Aβ plaque density, as measured by florbetapir PET. Regardless of cognitive and functional status, elevated levels of florbetapir uptake were not expected.MethodsWe 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.ResultsThere 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.ConclusionsCognitive impairment in former American football players is not associated with PET imaging of neuritic Aβ 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 registrationNCT02798185.
| S-EPMC10552261 | biostudies-literature
Project description:Exposure to repetitive head impacts in contact sports is associated with neurodegenerative disorders including chronic traumatic encephalopathy (CTE), which currently can be diagnosed only at post-mortem. American football players are at higher risk of developing CTE given their exposure to repetitive head impacts. One promising approach for diagnosing CTE in vivo is to explore known neuropathological abnormalities at post-mortem in living individuals using structural 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 = 54, 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 × 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 suggested that MRI morphometrics detect abnormalities in individuals with a history of repetitive head impact exposure that resemble the anatomic distribution of pathological findings from post-mortem CTE studies. The lack of findings associating MRI measures with exposure metrics (except for one significant relationship) or TES diagnosis and core clinical features suggested that brain morphometry must be complemented by other types of measures to characterize individuals with repetitive head impacts.
| S-EPMC11449133 | biostudies-literature
Project description:BackgroundTraumatic encephalopathy syndrome (TES) is defined as the clinical manifestation of the neuropathological entity chronic traumatic encephalopathy (CTE). A core feature of TES is neurobehavioral dysregulation (NBD), a neuropsychiatric syndrome in repetitive head impact (RHI)-exposed individuals, characterized by a poor regulation of emotions/behavior. To discover biological correlates for NBD, we investigated the association between biomarkers of inflammation (interleukin (IL)-1β, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) in cerebrospinal fluid (CSF) and NBD symptoms in former American football players and unexposed individuals.MethodsOur cohort consisted of former American football players, with (n = 104) or without (n = 76) NBD diagnosis, as well as asymptomatic unexposed individuals (n = 55) from the DIAGNOSE CTE Research Project. Specific measures for NBD were derived (i.e., explosivity, emotional dyscontrol, impulsivity, affective lability, and a total NBD score) from a factor analysis of multiple self-report neuropsychiatric measures. Analyses of covariance tested differences in biomarker concentrations between the three groups. Within former football players, multivariable linear regression models assessed relationships among log-transformed inflammatory biomarkers, proxies for RHI exposure (total years of football, cumulative head impact index), and NBD factor scores, adjusted for relevant confounding variables. Sensitivity analyses tested (1) differences in age subgroups (< 60, ≥ 60 years); (2) whether associations could be identified with plasma inflammatory biomarkers; (3) associations between neurodegeneration and NBD, using plasma neurofilament light (NfL) chain protein; and (4) associations between biomarkers and cognitive performance to explore broader clinical symptoms related to TES.ResultsCSF IL-6 was higher in former American football players with NBD diagnosis compared to players without NBD. Furthermore, elevated levels of CSF IL-6 were significantly associated with higher emotional dyscontrol, affective lability, impulsivity, and total NBD scores. In older football players, plasma NfL was associated with higher emotional dyscontrol and impulsivity, but also with worse executive function and processing speed. Proxies for RHI exposure were not significantly associated with biomarker concentrations.ConclusionSpecific NBD symptoms in former American football players may result from multiple factors, including neuroinflammation and neurodegeneration. Future studies need to unravel the exact link between NBD and RHI exposure, including the role of other pathophysiological pathways.
| S-EPMC10854026 | biostudies-literature
Project description:American-style football (ASF) players experience repetitive head impacts that may result in chronic traumatic encephalopathy neuropathological change (CTE-NC). At present, a definitive diagnosis of CTE-NC requires the identification of localized hyperphosphorylated Tau (p-Tau) after death via immunohistochemistry. Some studies suggest that positron emission tomography (PET) with the radiotracer [18F]-Flortaucipir (FTP) may be capable of detecting p-Tau and thus establishing a diagnosis of CTE-NC among living former ASF players. To assess associations between FTP, football exposure, and objective neuropsychological measures among former professional ASF players, we conducted a study that compared former professional ASF players with age-matched male control participants without repetitive head impact exposure. Former ASF players and male controls underwent structural magnetic resonance imaging and PET using FTP for p-Tau and [11C]-PiB for amyloid-β. Former players underwent neuropsychological testing. The ASF exposure was quantified as age at first exposure, professional career duration, concussion signs and symptoms burden, and total years of any football play. Neuropsychological testing included measures of memory, executive functioning, and depression symptom severity. P-Tau was quantified as FTP standardized uptake value ratios (SUVR) and [11C]-PiB by distribution volume ratios (DVR) using cerebellar grey matter as the reference region. There were no significant differences in [18F]-FTP uptake among former ASF players (n = 27, age = 50 ± 7 years) compared with control participants (n = 11, age = 55 ± 4 years), nor did any participant have significant amyloid-β burden. Among ASF participants, there were no associations between objective measures of neurocognitive functioning and [18F]-FTP uptake. There was a marginally significant difference, however, between [18F]-FTP uptake isolated to the entorhinal cortex among players in age-, position-, and race-adjusted models (p = 0.05) that may represent an area of future investigation. The absence of increased [18F]-FTP uptake in brain regions previously implicated in CTE among former professional ASF players compared with controls questions the utility of [18F]-FTP PET for clinical evaluation in this population.
| S-EPMC10458363 | 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:ImportanceParticipation in American-style football (ASF) has been linked to chronic traumatic encephalopathy neuropathological change (CTE-NC), a specific neuropathologic finding that can only be established at autopsy. Despite being a postmortem diagnosis, living former ASF players may perceive themselves to have CTE-NC. At present, the proportion and clinical correlates of living former professional ASF athletes with perceived CTE who report suicidality are unknown.ObjectiveTo determine the proportion, clinical correlates, and suicidality of living former professional ASF players with perceived CTE.Design, setting, and participantsA cross-sectional study within the Football Players Health Study at Harvard University was conducted from 2017 to 2020. Using electronic and paper surveys, this population-based study included former ASF players who contracted with a professional league from 1960 to 2020 and volunteered to fill out a baseline survey. Data for this study were analyzed from June 2023 through March 2024.ExposuresData included demographics, football-related exposures (eg, position, career duration), and current health problems (anxiety, attention-deficit/hyperactivity disorder, depression, diabetes, emotional and behavioral dyscontrol symptoms, headache, hyperlipidemia, hypertension, low testosterone level, pain, sleep apnea, and subjective cognitive function).Main outcomes and measuresThe proportion of participants reporting perceived CTE. Univariable and multivariable models were used to determine clinical and suicidality correlates of perceived CTE.ResultsAmong 4180 former professional ASF players who volunteered to fill out a baseline survey, 1980 (47.4%) provided follow-up data (mean [SD] age, 57.7 [13.9] years). A total of 681 participants (34.4%) reported perceived CTE. Subjective cognitive difficulties, low testosterone level, headache, concussion signs and symptoms accrued during playing years, depressive/emotional and behavioral dyscontrol symptoms, pain, and younger age were significantly associated with perceived CTE. Suicidality was reported by 171 of 681 participants with perceived CTE (25.4%) and 64 of 1299 without perceived CTE (5.0%). After adjusting for established suicidality predictors (eg, depression), men with perceived CTE remained twice as likely to report suicidality (odds ratio, 2.06; 95% CI, 1.36-3.12; P < .001).Conclusions and relevanceThis study found that approximately one-third of living former professional ASF players reported perceived CTE. Men with perceived CTE had an increased prevalence of suicidality and were more likely to have health problems associated with cognitive impairment compared with men without perceived CTE. Perceived CTE represents a novel risk factor for suicidality and, if present, should motivate the diagnostic assessment and treatment of medical and behavioral conditions that may be misattributed to CTE-NC.
| S-EPMC11420824 | biostudies-literature
Project description:Objectives: To identify novel targets for neurorehabilitation of people with a remote history of multiple concussions by: (1) comprehensively characterizing neuropsychiatric and cognitive functioning in former professional football players, with a focus on executive functions; (2) distinguishing concussion-related findings from pre-morbid/cohort characteristics of professional football players; and, (3) exploring the relationship between executive functions and neuropsychiatric symptoms. Participants: Sixty-one high-functioning former professional football players and 31 age- and sex-matched control participants without history of concussion or participation in contact sports. Design: Between-groups analyses. Main measures: Neuropsychiatric. Personality Assessment Inventory (PAI) clinical scales plus the Aggression treatment consideration scale; the Mini International Neuropsychiatric Interview (MINI). Cognitive. Comprehensive clinical neuropsychological battery assessing domains of verbal and visuospatial attention; speed of processing and memory; current and estimated pre-morbid IQ; and, executive functioning, including two experimental measures that were novel for this population (i.e., response inhibition and inconsistency of responding on a go/no-go task). Results: (1) Compared to control participants, former professional football players scored significantly higher on the PAI Depression, Mania, and Aggression scales, and significantly lower on response inhibition. (2) Relative to controls, former players with >3 concussions ( x ¯ = 6 . 1 ), but not former players with ≤ 3 concussions ( x ¯ = 2 . 0 ), showed (i) significantly higher scores on the PAI Depression scale, (ii) significantly more MINI clinical diagnoses overall, and manic/hypomanic episodes specifically, and (iii) significantly poorer executive function. (3) Mediation analysis revealed that concussion exposure had a significant indirect effect on PAI Depression, Mania, and Aggression via inconsistency of responding on the go/no-go task. Conclusions: Notable impairments to neuropsychiatric functioning and worse performance on a sensitive experimental measure of executive function were observed; these were related to both concussion history and pre-morbid (cohort) factors. Therefore, neuropsychiatric and executive functioning should be carefully assessed in those with a remote history of multiple concussions. Moreover, former players' neuropsychiatric symptoms were associated with inconsistency of responding; this suggests that treatments targeted at response inconsistency could help to mitigate neuropsychiatric dysfunction.
| S-EPMC6696977 | biostudies-literature
Project description:BackgroundExposure to repetitive head impacts (RHI) is associated with an increased risk of later-life neurobehavioral dysregulation and neurodegenerative disease. The underlying pathomechanisms are largely unknown.PurposeTo investigate whether RHI exposure is associated with later-life corpus callosum (CC) microstructure and whether CC microstructure is associated with plasma total tau and neuropsychological/neuropsychiatric functioning.Study typeRetrospective cohort study.PopulationSeventy-five former professional American football players (age 55.2 ± 8.0 years) with cognitive, behavioral, and mood symptoms.Field strength/sequenceDiffusion-weighted echo-planar MRI at 3 T.AssessmentSubjects underwent diffusion MRI, venous puncture, neuropsychological testing, and completed self-report measures of neurobehavioral dysregulation. RHI exposure was assessed using the Cumulative Head Impact Index (CHII). Diffusion MRI measures of CC microstructure (i.e., free-water corrected fractional anisotropy (FA), trace, radial diffusivity (RD), and axial diffusivity (AD)) were extracted from seven segments of the CC (CC1-7), using a tractography clustering algorithm. Neuropsychological tests were selected: Trail Making Test Part A (TMT-A) and Part B (TMT-B), Controlled Oral Word Association Test (COWAT), Stroop Interference Test, and the Behavioral Regulation Index (BRI) from the Behavior Rating Inventory of Executive Function, Adult version (BRIEF-A).Statistical testsDiffusion MRI metrics were tested for associations with RHI exposure, plasma total tau, neuropsychological performance, and neurobehavioral dysregulation using generalized linear models for repeated measures.ResultsRHI exposure was associated with increased AD of CC1 (correlation coefficient (r) = 0.32, P < 0.05) and with increased plasma total tau (r = 0.34, P < 0.05). AD of the anterior CC1 was associated with increased plasma total tau (CC1: r = 0.30, P < 0.05; CC2: r = 0.29, P < 0.05). Higher trace, AD, and RD of CC1 were associated with better performance (P < 0.05) in TMT-A (trace, r = 0.33; AD, r = 0.31; and RD, r = 0.28) and TMT-B (trace, r = 0.31; RD, r = 0.34). Higher FA and AD of CC2 were associated with better performance (P < 0.05) in TMT-A (FA, r = 0.36; AD, r = 0.28), TMT-B (FA, r = 0.36; AD, r = 0.27), COWAT (FA, r = 0.36; AD, r = 0.32), and BRI (AD, r = 0.29).Data conclusionThese results suggest an association among RHI exposure, CC microstructure, plasma total tau, and clinical functioning in former professional American football players.Level of evidence3 Technical Efficacy Stage: 1.
| S-EPMC8633029 | biostudies-literature
Project description:ObjectivesCareer duration is often used as a metric of neurotrauma exposure in studies of elite athletes. However, as a proxy metric, career length may not accurately represent causal factors, and associations with health outcomes may be susceptible to selection effects. To date, relationships between professional American-style football (ASF) career length and postcareer health remain incompletely characterised.MethodsWe conducted a survey-based cross-sectional cohort study of former professional ASF players. Flexible regression methods measured associations between self-reported career duration and four self-reported health conditions: pain, arthritis, mood and cognitive symptoms. We also measured associations between career duration and four self-reported ASF exposures: prior concussion signs and symptoms (CSS), performance enhancing drugs, intracareer surgeries and average snaps per game. Models were adjusted for age and race.ResultsAmong 4189 former players (52±14 years of age, 39% black, 34% lineman position), the average career length was 6.7±3.9 professional seasons (range=1-20+). We observed inverted U-shaped relationships between career duration and outcomes (all p<0.001), indicating that adverse health effects were more common among men with intermediate career durations than those with shorter or longer careers. Similar findings were observed for play-related exposures (eg, CSS and snaps).ConclusionsRelationships between ASF career duration and subsequent health status are non-linear. Attenuation of the associations among longer career players may reflect selection effects and suggest career length may serve as a poor proxy for true causal factors. Findings highlight the need for cautious use of career duration as a proxy exposure metric in studies of former athletes.
| S-EPMC11503077 | biostudies-literature
Project description:AbstractThe burden of pain is unequal across demographic groups, with broad and persisting race differences in pain-related outcomes in the United States. Members of racial and ethnic minorities frequently report more pervasive and severe pain compared with those in the majority, with at least some disparity attributable to differences in socioeconomic status. Whether race disparities in pain-related health outcomes exist among former professional football players is unknown. We examined the association of race with pain outcomes among 3995 former professional American-style football players who self-identified as either Black or White. Black players reported more intense pain and higher levels of pain interference relative to White players, even after controlling for age, football history, comorbidities, and psychosocial factors. Race moderated associations between several biopsychosocial factors and pain; higher body mass index was associated with more pain among White but not among Black players. Fatigue and psychosocial factors were more strongly related to pain among Black players relative to White players. Collectively, the substantial social and economic advantages of working as a professional athlete did not seem to erase race-related disparities in pain. We highlight an increased burden of pain among elite Black professional football players and identify race-specific patterns of association between pain and biopsychosocial pain risk factors. These findings illuminate potential future targets of interventions that may serve to reduce persistent disparities in the experience and impact of pain.
| S-EPMC10502895 | biostudies-literature