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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. [ABSTRACT FROM AUTHOR]

Objectives: Clinical criteria for Traumatic Encephalopathy Syndrome (ccTES) were developed for research purposes to reflect the clinical symptoms of Chronic Traumatic Encephalopathy (CTE). The aims of this study were to 1) determine whether there was an association between the research diagnosis of TES and impaired postural balance among retired professional fighters, and 2) determine repetitive head impacts (RHI) exposure thresholds among both TES positive and TES negative groups in retired professional fighters when evaluating for balance impairment. Methods: This was a pilot study evaluating postural balance among participants of the Professional Athletes Brain Health Study (PABHS). Among the cohort, 57 retired professional fighters met the criteria for inclusion in this study. A generalized linear model with generalized estimating equations was used to compare various balance measures longitudinally between fighters with and without TES. Results: A significant association was observed between a TES diagnosis and worsening performance on double-leg balance assessments when stratifying by RHI exposure thresholds. Additionally, elevated exposure to RHI was significantly associated with increased odds of developing TES; The odds for TES diagnosis were 563% (95% CI = 113, 1963; p-value = 0.0011) greater among athletes with 32 or more professional fights compared to athletes with less than 32 fights when stratifying by balance measures. Likewise, the odds for TES diagnosis were 43% (95% CI = 10, 102; p-value = 0.0439) greater with worsening double leg stance balance in athletes exposed to 32 or more fights. Conclusion: This pilot study provides preliminary evidence of a relationship between declining postural balance and a TES diagnosis among retired professional fighters with elevated RHI exposure. Further research exploring more complex assessments such as the Functional Gait Assessment may be of benefit to improve clinical understanding of the relationship between TES, RHI, and balance. [ABSTRACT FROM AUTHOR]

Background: Boxing exposes fighters to head impacts and potential traumatic brain injury (TBI). Though research has explored the neuropsychiatric consequences of contact sports, there is limited research into Excessive Daytime Sleepiness (EDS) and its relationship to other outcomes, such as impulsiveness and depression. Therefore, this study aimed to describe EDS in retired boxers using the Epworth Sleepiness Scale (ESS) and to examine how boxing and sleepiness relate to impulsiveness and depression symptomatology. Methods: 86 male retired professional boxers from the Professional Fighters Brain Health Study (PFBHS) met the inclusion criteria. Adjusted multivariable models analyzed relationships between professional boxing bouts, EDS (ESS), impulsiveness (Barratt Impulsiveness Scale Version 11 (BIS-11)), and/or depression (Patient Health Questionnaire-9 (PHQ-9)). A causal mediation analysis was performed to assess whether boxing bouts and ESS scores predicted BIS-11 and PHQ-9 scores. Results: Mean age was ∼51 years, fighters averaged ∼36 professional bouts, and ESS mean(SD) was 7.5(5.3). ESS scores were significantly associated with raw BIS-11 (Beta = 1.26, 95%CI = 0.77–1.75, p < 0.001) and ordinal PHQ-9 (OR = 1.20, 95%CI = 1.11–1.31, p < 0.001) scores in adjusted models, and the significant relationship between boxing bouts and BIS-11/PHQ-9 was mediated by ESS. Conclusions: EDS in retired male professional boxers may be strongly associated with other neuropsychiatric sequelae of TBI (impulsiveness and depression). Sleepiness; sleep; boxing; contact sports; impulsiveness; impulsivity; depression; Epworth sleepiness scale box [ABSTRACT FROM AUTHOR]

Background: Traumatic 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. Methods: Our 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. Results: CSF 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. Conclusion: Specific 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. [ABSTRACT FROM AUTHOR]

Background/Objectives: Impulsiveness is linked to cocaine history (CH) in the general population and greater fight exposure in professional fighters. Among fighters, no previous studies have quantified CH or investigated its relationship with impulsiveness. Methods: Adjusted multivariable regressions were utilized to examine the relationship between CH and impulsiveness in 335 fighters from the Professional Fighters Brain Health Study. Results: Twenty percent of fighters reported CH. CH was significantly associated with impulsiveness overall and on three subscales. Discussion/Conclusion: Cocaine's prevalence and significant association with impulsiveness in fighters merit further study. Scientific Significance: We quantify CH and demonstrate its significant association with impulsiveness in professional fighters for the first time. [ABSTRACT FROM AUTHOR]

Background: It is unknown if fluid biomarkers reflective of brain pathologies are useful in detecting and following a neurodegenerative process in individuals exposed to repetitive head impacts. This study explores the relationship between blood biomarkers and longitudinal change in cognitive function and regional brain volumes in a cohort of professional fighters. Methods: Participants are drawn from a convenience sample of active and retired professional boxers and Mixed Martial Arts fighters and a control group with no prior exposure to head impacts. 3 T MRI brain imaging, plasma samples, and computerized cognitive testing were obtained at baseline and, for a subset, annually. MRI regional volumes were extracted, along with plasma levels of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), p-tau231, and N-terminal tau (NTA). Statistical analyses were performed to assess the relationship between plasma levels and regional brain volumes and cognitive performance at baseline and longitudinally. Results: One hundred forty active boxers (mean age: 31 with standard deviation (SD) of 8), 211 active MMA (mean age of 30 with SD of 5), 69 retired boxers (mean age 49 with SD of 9), and 52 control participants (mean age 36 with SD of 12) were included in the analyses. Baseline GFAP levels were highest in the retired boxers (retired boxers v. active MMA: p = 0.0191), whereas active boxers had higher levels of NfL (active boxers v. MMA: p = 0.047). GFAP showed an increase longitudinally in retired boxers that was associated with decreasing volumes of multiple cortical and subcortical structures (e.g., hippocampus: B = − 1.25, 95% CI, − 1.65 to − 0.85) and increase in lateral ventricle size (B = 1.75, 95% CI, 1.46 to 2.04). Furthermore, performance on cognitive domains including memory, processing speed, psychomotor speed, and reaction time declined over time with increasing GFAP (e.g., processing speed: B = − 0.04, 95% CI, − 0.07 to − 0.02; reaction time: B = 0.52, 95% CI, 0.28 to 0.76). Among active fighters, increasing levels of GFAP were correlated with lower thalamic (B = − 1.42, 95% CI, − 2.34 to -0.49) and corpus callosum volumes, along with worsening scores on psychomotor speed (B = 0.14, 95% CI, 0.01 to 0.27). Conclusion: Longitudinal plasma GFAP levels may have a role in identifying individuals exposed to repetitive head impacts who are at risk of showing progressive regional atrophy and cognitive decline. [ABSTRACT FROM AUTHOR]

Background: Exposure to repetitive head impacts (RHI) in American football players can lead to cognitive impairment and dementia due to neurodegenerative disease, particularly chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE consists of perivascular aggregates of hyper-phosphorylated tau in neurons at the depths of cortical sulci. However, it is unclear whether exposure to RHI accelerates amyloid-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. Methods: We examined 237 men ages 45–74, including 119 former professional (PRO) and 60 former college (COL) football players, with and without cognitive impairment and dementia, and 58 same-age men without a history of contact sports or TBI (unexposed; UE) and who denied cognitive or behavioral symptoms at telephone screening. Former players were categorized into four diagnostic groups: normal cognition, subjective memory impairment, mild cognitive impairment, and dementia. Positive florbetapir PET was defined by cortical-cerebellar average SUVR of ≥ 1.10. Multivariable linear regression and analysis of covariance (ANCOVA) compared florbetapir average SUVR across diagnostic and exposure groups. Multivariable logistic regression compared florbetapir positivity. Race, education, age, and APOE4 were covariates. Results: There were no diagnostic group differences either in florbetapir average SUVR or the proportion of elevated florbetapir uptake. Average SUVR means also did not differ between exposure groups: PRO-COL (p = 0.94, 95% C.I. = [− 0.033, 0.025]), PRO-UE (p = 0.40, 95% C.I. = [− 0.010, 0.029]), COL-UE (p = 0.36, 95% CI = [0.0004, 0.039]). Florbetapir was not significantly associated with years of football exposure, cognition, or daily functioning. Conclusions: Cognitive impairment in former American football players is not associated with PET imaging of neuritic 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 registration: NCT02798185. [ABSTRACT FROM AUTHOR]

Background: Mixed martial arts (MMA) fighters, due to exposure to repetitive head impacts, are at risk for brain atrophy and neurodegenerative sequelae. Simultaneously, motor skills training and cognition-rich activities have been linked with larger regional brain volumes. The majority of an MMA fighter's sporting activity occurs during practice (e.g., sparring) rather than formal competition. This study, therefore, aims to be the first to explore regional brain volumes associated with sparring in MMA fighters. Methods: Ninety-four active, professional MMA fighters from the Professional Fighters Brain Health Study met inclusion criteria for this cross-sectional analysis. Adjusted multivariable regression analyses were utilized to examine the relationship between the number of sparring practice rounds per week during typical training and a select number of regional brain volumes (i.e., caudate, thalamus, putamen, hippocampus, amygdala). Results: A higher number of weekly sparring rounds during training was significantly associated with larger left (beta = 13.5 µL/round, 95% CI 2.26–24.8) and right (beta = 14.9 µL/round, 95% CI 3.64–26.2) caudate volumes. Sparring was not significantly associated with left or right thalamus, putamen, hippocampus, or amygdala volumes. Conclusions: More weekly rounds of sparring was not significantly associated with smaller volumes in any of the brain regions studied in active, professional MMA fighters. Sparring's significant association with larger caudate volume raises questions about whether fighters who spar more experience attenuated trauma-related decreases in caudate volume relative to fighters who spar less, whether fighters who spar more experience minimal or even positive changes to caudate volume, whether baseline differences in caudate size may have mediated results, or whether some other mechanism may be at play. Given limitations inherent to the cross-sectional study design, more research is needed to further explore the brain effects of sparring in MMA. [ABSTRACT FROM AUTHOR]

Objective: White matter hyperintensity (WMH) burden is greater, has a frontal-temporal distribution, and is associated with proxies of exposure to repetitive head impacts (RHI) in former American football players. These findings suggest that in the context of RHI, WMH might have unique etiologies that extend beyond those of vascular risk factors and normal aging processes. The objective of this study was to evaluate the correlates of WMH in former elite American football players. We examined markers of amyloid, tau, neurodegeneration, inflammation, axonal injury, and vascular health and their relationships to WMH. A group of age-matched asymptomatic men without a history of RHI was included to determine the specificity of the relationships observed in the former football players. Participants and Methods: 240 male participants aged 45-74 (60 unexposed asymptomatic men, 60 male former college football players, 120 male former professional football players) underwent semi-structured clinical interviews, magnetic resonance imaging (structural T1, T2 FLAIR, and diffusion tensor imaging), and lumbar puncture to collect cerebrospinal fluid (CSF) biomarkers as part of the DIAGNOSE CTE Research Project. Total WMH lesion volumes (TLV) were estimated using the Lesion Prediction Algorithm from the Lesion Segmentation Toolbox. Structural equation modeling, using Full-Information Maximum Likelihood (FIML) to account for missing values, examined the associations between log-TLV and the following variables: total cortical thickness, whole-brain average fractional anisotropy (FA), CSF amyloid ß42, CSF p-tau181, CSF sTREM2 (a marker of microglial activation), CSF neurofilament light (NfL), and the modified Framingham stroke risk profile (rFSRP). Covariates included age, race, education, APOE z4 carrier status, and evaluation site. Bootstrapped 95% confidence intervals assessed statistical significance. Models were performed separately for football players (college and professional players pooled; n=180) and the unexposed men (n=60). Due to differences in sample size, estimates were compared and were considered different if the percent change in the estimates exceeded 10%. Results: In the former football players (mean age=57.2, 34% Black, 29% APOE e4 carrier), reduced cortical thickness (B=-0.25, 95% CI [0.45, -0.08]), lower average FA (B=-0.27, 95% CI [-0.41, -.12]), higher p-tau181 (B=0.17, 95% CI [0.02, 0.43]), and higher rFSRP score (B=0.27, 95% CI [0.08, 0.42]) were associated with greater log-TLV. Compared to the unexposed men, substantial differences in estimates were observed for rFSRP (Bcontrol=0.02, Bfootball=0.27, 994% difference), average FA (Bcontrol=-0.03, Bfootball=-0.27, 802% difference), and p-tau181 (Bcontrol=-0.31, Bfootball=0.17, -155% difference). In the former football players, rFSRP showed a stronger positive association and average FA showed a stronger negative association with WMH compared to unexposed men. The effect of WMH on cortical thickness was similar between the two groups (Bcontrol=-0.27, Bfootball=-0.25, 7% difference). Conclusions: These results suggest that the risk factor and biological correlates of WMH differ between former American football players and asymptomatic individuals unexposed to RHI. In addition to vascular risk factors, white matter integrity on DTI showed a stronger relationship with WMH burden in the former football players. FLAIR WMH serves as a promising measure to further investigate the late multifactorial pathologies of RHI. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Patterns of cognitive impairment in former American football players are uncertain because objective neuropsychological data are lacking. This study characterized the neuropsychological test performance of former college and professional football players. Methods: One hundred seventy male former football players (n=111 professional, n=59 college; 45–74 years) completed a neuropsychological test battery. Raw scores were converted to T-scores using age, sex, and education-adjusted normative data. A T-score ≤ 35 defined impairment. A domain was impaired if 2+ scores fell in the impaired range except for the language and visuospatial domains due to the limited number of tests. Results: Most football players had subjective cognitive concerns. On testing, rates of impairments were greatest for memory (21.2% two tests impaired), especially for recall of unstructured (44.7%) versus structured verbal stimuli (18.8%); 51.8% had one test impaired. 7.1% evidenced impaired executive functions; however, 20.6% had impaired Trail Making Test B. 12.1% evidenced impairments in the attention, visual scanning, and psychomotor speed domain with frequent impairments on Trail Making Test A (18.8%). Other common impairments were on measures of language (i.e., Multilingual Naming Test [21.2%], Animal Fluency [17.1%]) and working memory (Number Span Backward [14.7%]). Impairments on our tasks of visuospatial functions were infrequent. Conclusions: In this sample of former football players (most of whom had subjective cognitive concerns), there were diffuse impairments on neuropsychological testing with verbal memory being the most frequently impaired domain. [ABSTRACT FROM AUTHOR]

Background: Patterns of cognitive impairment in former American football players are uncertain because objective neuropsychological data are lacking. This study characterized the neuropsychological test performance of former college and professional football players. Methods: One hundred seventy male former football players (n=111 professional, n=59 college; 45–74 years) completed a neuropsychological test battery. Raw scores were converted to T-scores using age, sex, and education-adjusted normative data. A T-score ≤ 35 defined impairment. A domain was impaired if 2+ scores fell in the impaired range except for the language and visuospatial domains due to the limited number of tests. Results: Most football players had subjective cognitive concerns. On testing, rates of impairments were greatest for memory (21.2% two tests impaired), especially for recall of unstructured (44.7%) versus structured verbal stimuli (18.8%); 51.8% had one test impaired. 7.1% evidenced impaired executive functions; however, 20.6% had impaired Trail Making Test B. 12.1% evidenced impairments in the attention, visual scanning, and psychomotor speed domain with frequent impairments on Trail Making Test A (18.8%). Other common impairments were on measures of language (i.e., Multilingual Naming Test [21.2%], Animal Fluency [17.1%]) and working memory (Number Span Backward [14.7%]). Impairments on our tasks of visuospatial functions were infrequent. Conclusions: In this sample of former football players (most of whom had subjective cognitive concerns), there were diffuse impairments on neuropsychological testing with verbal memory being the most frequently impaired domain. [ABSTRACT FROM AUTHOR]

Objectives: Determine, through video reviews, how often concussions occur in combat sport matches, what influence they have on the outcome, and how well non-physician personnel can be trained to recognize concussions. Methods: This is a retrospective video analysis by an 8-person panel of 60 professional fights (30 boxing and 30 mixed martial arts). Through video review, physician and non-physician personnel recorded details about each probable concussion and determined if and when they would have stopped the fight compared to the official stoppage time. Results: A concussion was recorded in 47/60 fights. The mean number of concussions per minute of fight time was 0.061 (0.047 for boxers and 0.085 for MMA). When stratifying by outcome of the bout, the mean number of concussions per minute for the winner was 0.010 compared to the loser at 0.111 concussions per minute. The fighter that sustained the first concussion ultimately lost 98% of the time. The physician and non-physician raters had high agreement regarding the number of concussions that occurred to each fighter per match. The physician raters judged that 24 of the 60 fights (11 boxing [37%]; 13 MMA [43%]) should have been stopped sooner than what occurred. Conclusion: Recognizing that the concussions often occur in combat sport matches, that the losing fighter almost always is concussed first and tends to sustain more concussions during the fight, along with the demonstration that non-physician personnel can be taught to recognize concussion, may guide policy changes that improve brain health in combat sports. [ABSTRACT FROM AUTHOR]

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been neuropathologically diagnosed in brain donors exposed to repetitive head impacts, including boxers and American football, soccer, ice hockey, and rugby players. CTE cannot yet be diagnosed during life. In December 2015, the National Institute of Neurological Disorders and Stroke awarded a seven-year grant (U01NS093334) to fund the "Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project." The objectives of this multicenter project are to: develop in vivo fluid and neuroimaging biomarkers for CTE; characterize its clinical presentation; refine and validate clinical research diagnostic criteria (i.e., traumatic encephalopathy syndrome [TES]); examine repetitive head impact exposure, genetic, and other risk factors; and provide shared resources of anonymized data and biological samples to the research community. In this paper, we provide a detailed overview of the rationale, design, and methods for the DIAGNOSE CTE Research Project. Methods: The targeted sample and sample size was 240 male participants, ages 45–74, including 120 former professional football players, 60 former collegiate football players, and 60 asymptomatic participants without a history of head trauma or participation in organized contact sports. Participants were evaluated at one of four U.S. sites and underwent the following baseline procedures: neurological and neuropsychological examinations; tau and amyloid positron emission tomography; magnetic resonance imaging and spectroscopy; lumbar puncture; blood and saliva collection; and standardized self-report measures of neuropsychiatric, cognitive, and daily functioning. Study partners completed similar informant-report measures. Follow-up evaluations were intended to be in-person and at 3 years post-baseline. Multidisciplinary diagnostic consensus conferences are held, and the reliability and validity of TES diagnostic criteria are examined. Results: Participant enrollment and all baseline evaluations were completed in February 2020. Three-year follow-up evaluations began in October 2019. However, in-person evaluation ceased with the COVID-19 pandemic, and resumed as remote, 4-year follow-up evaluations (including telephone-, online-, and videoconference-based cognitive, neuropsychiatric, and neurologic examinations, as well as in-home blood draw) in February 2021. Conclusions: Findings from the DIAGNOSE CTE Research Project should facilitate detection and diagnosis of CTE during life, and thereby accelerate research on risk factors, mechanisms, epidemiology, treatment, and prevention of CTE. Trial registration: NCT02798185 [ABSTRACT FROM AUTHOR]

Background: There is a current lack of any composite measure for the effective tracking and monitoring of clinical change in individuals exposed to repetitive head impacts (RHI). The aim of this study is to create a composite instrument for the purposes of detecting change over time in cognitive and behavioral function in individuals exposed to RHI. Methods: The data to derive the composite instrument came from the Professional Fighters Brain Health Study (PFBHS), a longitudinal study of active and retired professional fighters [boxers and mixed martial arts (MMA) fighters] and healthy controls. Participants in the PFBHS underwent assessment on an annual basis that included computerized cognitive testing and behavioral questionnaires. Multivariate logistic regression models were employed to compare active fighters (n = 117) with controls (n = 22), and retired fighters (n = 26) with controls to identify the predictors that could be used to differentiate the groups over time. In a second step, linear discriminant analysis was performed to derive the linear discriminant coefficients for the three groups by using the predictors from the two separate logistic regression models. Results: The composite scale is a weighted linear value of 12 standardized scores consisting of both current and yearly change scores in domains including: processing speed, choice reaction time, semantic fluency, letter fluency, and Barrett Impulsiveness Scale. Because the weighting of values differed between active and retired fighters, two versions emerged. The mean and standard deviation ratio (MSDR) showed that the new index had better sensitivity compared to the individual measures, with the ratio of MSDR of the new index to that of the existing measures of at least 1.84. Conclusion: With the increasing need for tools to follow individuals exposed to RHI and the potential of clinical trials on the horizon for CTE, the RHICI is poised to serve as an initial approach to a composite clinical measure. [ABSTRACT FROM AUTHOR]

Amyloid- β (A β ) is the target in many clinical trials for Alzheimer's disease (AD). Preclinical AD patients are heterogeneous with regards to different backgrounds and diagnosis. Accurately predicting A β status of participants by using machine learning (ML) models based on easily accessible data, could improve the effectiveness of AD clinical trials. We will develop optimal ML models for each subpopulation stratified by sex and disease stages using sub scores from screening neurological tests. Data from the AD Neuroimaging Initiative (ADNI) were used to build the ML models, for three groups: individuals with significant memory concern, early mild cognitive impairment (MCI), and late MCI. Data were further separated into 6 groups by disease stage (3 levels) and sex (2 categories). The outcome was defined as the A β status confirmed by the PET imaging, and the features include demographic data, newly identified risk factors, screening tests, and the domain scores from screening tests. Monte Carlo simulation studies were used together with k-fold cross-validation technique to compute model performance metric. We also develop a new feature selection method based on the stochastic ordering to avoiding searching all possible combinations of features. Accuracy of the identified optimal model for SMC male was over 90% by using domain scores, and accuracy for LMCI female was above 86%. Domain scores can improve the ML model prediction as compared to the total scores. Accurate ML prediction models can identify the proper population for AD clinical trials. [ABSTRACT FROM AUTHOR]

Previous neuroimaging studies have identified structural brain abnormalities in active professional fighters with repetitive head trauma and correlated these changes with fighters' neuropsychological impairments. However, functional brain changes in these fighters derived using neuroimaging techniques remain unclear. In this study, both static and dynamic functional connectivity alterations were investigated (1) between healthy normal control subjects (NC) and fighters and (2) between non-impaired and impaired fighters. Resting-state fMRI data were collected on 35 NC and 133 active professional fighters, including 68 impaired fighters and 65 non-impaired fighters, from the Professional Fighters Brain Health Study at our center. Impaired fighters performed worse on processing speed (PSS) tasks with visual-attention and working-memory demands. The static functional connectivity (sFC) matrix was estimated for every pair of regions of interest (ROI) using a subject-specific parcellation. The dynamic functional connectivity (dFC) was estimated using a sliding-window method, where the variability of each ROI pair across all windows represented the temporal dynamics. A linear regression model was fitted for all 168 subjects, and different t-contrast vectors were used for between-group comparisons. An association analysis was further conducted to evaluate FC changes associated with PSS task performances without creating artificial impairment group-divisions in fighters. Following corrections for multiple comparisons using network-based statistics, our study identified significantly reduced long-range frontal-temporal, frontal-occipital, temporal-occipital, and parietal-occipital sFC strengths in fighters than in NCs, corroborating with previously observed structural damages in corresponding white matter tracts in subjects experiencing repetitive head trauma. In impaired fighters, significantly decreased sFC strengths were found among key regions involved in visual-attention, executive and cognitive process, as compared to non-impaired fighters. Association analysis further reveals similar sFC deficits to worse PSS task performances in all 133 fighters. With our choice of dFC indices, we were not able to observe any significant dFC changes beyond a trend-level increased temporal variability among similar regions with weaker sFC strengths in impaired fighters. Collectively, our functional brain findings supplement previously reported structural brain abnormalities in fighters and are important to comprehensively understand brain changes in fighters with repetitive head trauma. [ABSTRACT FROM AUTHOR]

Objective: Incidence of concussions and report of symptoms are greater among women across sports. While structural brain changes and cognitive declines are associated with repetitive head impact (RHI), the role of sex is not well-understood. This study aimed to determine if there is a moderating effect of sex on the relationship the number of professional fights has with cognitive functioning and regional brain volumes in a cohort of boxers, mixed martial artists, and martial artists. Methods: A total of 55 women were matched with 55 men based on age, years of education, ethnicity, and fighting style. Cognition was assessed via the CNS Vital Signs computerized cognitive battery and supplemental measures. Structural brain scans, demographic data, and number of professional fights (NoPF) were also considered. The matched pairs were compared via analysis of covariance, accounting for total brain volume. Within-subject moderation models were utilized to assess the moderating effect of sex on the relationship between NoPF and brain volumes and cognitive performance. Results: Men were observed to have poorer performance on measures of psychomotor speed when compared to women. On a series of analyses assessing the role of sex as a moderator of the relationship between NoPF and regional brain volumes/cognitive performance, a significant moderation effect was observed across multiple measures of cognitive functioning, such that men had poorer performance. Differences in numerous regional brain volumes were also observed, such that the relationship between NoPF and brain volumes was steeper among men. Conclusion: Sex was observed to be an important moderator in the relationship between NoPF, aspects of cognitive functioning, and volumes of numerous brain regions, suggesting that sex differences in neuroanatomic and cognitive response to RHI deserve further attention. [ABSTRACT FROM AUTHOR]

The long-term effects of repetitive head impacts have been recognized for close to a century. What is now referred to as chronic traumatic encephalopathy (CTE) was first described by Martland in 1928 in a series of boxers. Over the years, several important articles were published, including Critchley's 1957 report where he introduced the term "chronic traumatic encephalopathy," Robert's study in 1969 which provided evidence of the prevalence of neurological impairment in retired fighters, and Corsellis' initial description of the pathology of CTE. However, what brought public attention to the issue of CTE in sports were the postmortem findings of CTE pathology in professional American football players, initially reported by Omalu and subsequently in a large series by McKee. There is now standardization of pathological criteria for CTE and recognition that it can be seen across all activities that involve repetitive head impacts. [ABSTRACT FROM AUTHOR]

It has long been established that fighting sports such as boxing and mixed martial arts can lead to head injury. Prior work from this group on the Professional Fighters Brain Health Study found that exposure to repetitive head impacts is associated with lower brain volumes and decreased processing speed in fighters. Current and previously licensed professional fighters were recruited, divided into active and retired cohorts, and matched with a control group that had no prior experience in sports with likely head trauma. This study examined the relationship between age of first exposure (AFE) to fighting sports and brain structure (MRI regional volume), cognitive performance (CNS Vital Signs, iComet C3), and clinical neuropsychiatric symptoms (PHQ-9, Barratt Impulsiveness Scale). Brain MRI data showed significant correlations between earlier AFE and smaller bilateral hippocampal and posterior corpus callosum volumes for both retired and active fighters. Earlier AFE in active fighters was correlated with decreased processing speed and decreased psychomotor speed. Retired fighters showed a correlation between earlier AFE and higher measures of depression and impulsivity. Overall, the results help to inform clinicians, governing bodies, parents, and athletes of the risks associated with beginning to compete in fighting sports at a young age. [ABSTRACT FROM AUTHOR]

Long‐term traumatic brain injury due to repeated head impacts (RHI) has been shown to be a risk factor for neurodegenerative disorders, characterized by a loss in cognitive performance. Establishing the correlation between changes in the white matter (WM) structural connectivity measures and neuropsychological test scores might help to identify the neural correlates of the scores that are used in daily clinical setting to investigate deficits due to repeated head blows. Hence, in this study, we utilized high angular diffusion MRI (dMRI) of 69 cognitively impaired and 70 nonimpaired active professional fighters from the Professional Fighters Brain Health Study, and constructed structural connectomes to understand: (a) whether there is a difference in the topological WM organization between cognitively impaired and nonimpaired active professional fighters, and (b) whether graph‐theoretical measures exhibit correlations with neuropsychological scores in these groups. A dMRI derived structural connectome was constructed for every participant using brain regions defined in AAL atlas as nodes, and the product of fiber number and average fractional anisotropy of the tracts connecting the nodes as edges. Our study identified a topological WM reorganization due to RHI in fighters prone to cognitive decline that was correlated with neuropsychological scores. Furthermore, graph‐theoretical measures were correlated differentially with neuropsychological scores between groups. We also found differentiated WM connectivity involving regions of hippocampus, precuneus, and insula within our cohort of cognitively impaired fighters suggesting that there is a discernible WM topological reorganization in fighters prone to cognitive decline. [ABSTRACT FROM AUTHOR]

Objective: For concussions to be effectively managed in sports, they need to be correctly identified and reported. The extent to which professional athletes correctly recognize concussions, and their willingness to report symptoms, is not yet well understood. Given the risk of head injuries leading to concussions across combat sports, insight into professional fighters' knowledge and reporting of concussive symptoms is essential to improve concussion management. Methods: To investigate understanding and reporting patterns of concussions sustained while training or competing, 257 fighters completed a self-report questionnaire assessing self-perception of concussion knowledge, trust of ringside medical providers, and reported number of previous head injuries. Fighting history, including number of knockouts, was obtained from self-report (amateur) and published (professional) records. Results: Significant gaps in fighters' perceived knowledge of concussion symptoms and long-term effects of multiple concussions emerged. Approximately 40% of fighters reported returning to training or competition the same day a head injury was sustained, while 21% of fighters endorsed concealing symptoms of head injury from medical providers and coaches. Conclusions: Confusion surrounding terms used to describe head injuries amongst fighters (e.g., concussions, knockouts), coupled with limited understanding of concussive symptoms and a desire to return to competition, likely contributes to significant underreporting of symptoms. [ABSTRACT FROM AUTHOR]

This research was motivated by a clinical trial design for a cognitive study. The pilot study was a matched-pairs design where some data are missing, specifically the missing data coming at the end of the study. Existing approaches to determine sample size are all based on asymptotic approaches (e.g., the generalized estimating equation (GEE) approach). When the sample size in a clinical trial is small to medium, these asymptotic approaches may not be appropriate for use due to the unsatisfactory Type I and II error rates. For this reason, we consider the exact unconditional approach to compute the sample size for a matched-pairs study with incomplete data. Recommendations are made for each possible missingness pattern by comparing the exact sample sizes based on three commonly used test statistics, with the existing sample size calculation based on the GEE approach. An example from a real surgeon-reviewers study is used to illustrate the application of the exact sample size calculation in study designs. [ABSTRACT FROM AUTHOR]

Combat sports are growing in popularity, viewership, and participation. The nature of these sports involves repetitive head contact, yet unlike most other professional contact sports, there are no endorsed guidelines or mandates for graduated and systematic return to play following concussion. Here, we review the literature related to concussion and fighting sports, and propose guidelines for concussion management and safe return to play following concussion. [ABSTRACT FROM AUTHOR]