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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]

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. [ABSTRACT FROM AUTHOR]

Background: The NINDS criteria define Traumatic Encephalopathy Syndrome (TES) as the clinical manifestation of the neuropathologically diagnosed chronic traumatic encephalopathy (CTE). The core clinical features of TES include both cognitive and neuropsychiatric symptoms, the latter termed neurobehavioral dysregulation (NBD). We explored potential biological correlates of NBD by investigating fluid biomarkers of neuronal damage, astrogliosis, phosphorylated tau (pTau), neuroinflammation, and catecholamines in former American football players. Method: Our cohort consisted of former professional (PRO) and college (COL) American football players from the DIAGNOSE CTE Research Project. NBD was measured by four subscales (i.e., explosivity, emotional dyscontrol, impulsivity, affective lability) and a total NBD score, derived by factor analysis of multiple self‐report neuropsychiatric measures. Plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), CSF total tau and pTau181/231/217, as well as CSF biomarkers related to neuroinflammation (IL‐6, CRP, TNF‐α, VEGF‐A), were measured with various well‐validated immunoassay methods. Catecholamines in CSF (dopamine, 3,4‐dihydroxyphenylacetic acid, 3,4‐dihydroxyphenylalanine, noradrenaline, 3,4‐dihydroxyphenylglycol) were measured with HPLC. Multivariate linear regression models assessed the relationships between biomarkers and NBD scales, adjusted for age, BMI, race, and APOE e4, including stratification by exposure group, i.e., PRO, COL. Result: Demographics and biomarker levels are displayed in Table 1. High levels of IL‐6 were significantly associated with higher scores of all NBD subscales, independent of exposure group. Other significant relationships included plasma NfL with emotional dyscontrol and impulsivity. Within the college group, CSF pTau181 was significantly associated with emotional dyscontrol and CSF noradrenaline with explosivity, emotional dyscontrol, impulsivity, and total NBD score. (Table 2 & Figure 1). IL‐6 models were repeated with measures of cognitive dysfunction (another core feature of TES) added as covariates; these analyses again found significant relationships between IL‐6 and NBD, irrespective of cognitive functioning. Conclusion: We observed specific fluid biomarkers related to NBD in former American football players. Of note were the associations between IL‐6 and all NBD subscales (and not with cognitive functioning), suggesting that neuroinflammation may be a specific component in the expression of NBD symptoms. Future studies will investigate how these neuroinflammatory processes are related to other biomarkers, level of RHI exposure, and neuropathology. [ABSTRACT FROM AUTHOR]

Background: Repetitive head impacts (RHI) from American football can lead to tau and non‐tau pathologies that might present as white matter hyperintensities (WMH) on FLAIR MRI. In 2022, we published a study in Alzheimer's & Dementia that examined WMH and their association with risk factors and clinical function in former elite football players. That study will be presented during this symposium along with new unpublished data that used imaging and fluid biomarkers to examine etiological correlates (tau, amyloid, neurodegeneration, axonal injury, neuroinflammation) of WMH in the same cohort. Methods: The multi‐site DIAGNOSE CTE Research Project recruited 180 football players and 60 asymptomatic males without RHI ("controls"), all 45‐74 years (Table 1). Participants completed MRI, lumbar puncture, and neuropsychological testing. Lesion Segmentation Toolbox estimated FLAIR WMH, FreeSurfer derived total cortical thickness, and a diffusion pipeline derived average global FA. CSF was analyzed for p‐tau181, Aβ1‐42, NfL, and sTREM2. Tobit regressions compared football players (n = 149) and controls (n = 53) on total and regional log‐WMH and estimated the effects of years of football and age of first exposure (AFE) to football on log‐WMH. Linear regressions evaluated log‐WMH and clinical associations in football players. Structural equation modeling (SEM) examined effects between log‐WMH and cortical thickness, FA, and the CSF biomarkers. Analyses accounted for age, race, revised Framingham Stroke Risk Profile (rFSRP), body mass index, APOE ε4, and evaluation site. Results: Alosco et al. (2022) found older (i.e., 60+) but not younger football players had greater total, frontal, temporal and parietal log‐WMH compared to controls (FDR‐adjusted p‐values<0.05; Table 2). Among older football players, younger AFE was associated with greater log‐WMH (beta = ‐0.13, 95% CI = ‐0.23,‐0.02). Greater log‐WMH corresponded to worse Trails A‐B (beta = ‐4.32, 95% CI = ‐8.59,‐0.05) and List Learning Long Delay scores (beta = ‐0.56, 95% CI = ‐0.93,‐0.19). Subsequent unpublished SEM analyses in football players (Figure 1) showed the following direct effects on log‐WMH: higher rFSRP, higher CSF p‐tau181, lower FA, and reduced cortical thickness. There were no indirect effects. Compared to controls, SEM associations were stronger in football players exception for cortical thickness. Conclusions: FLAIR WMH might have unique imaging characteristics, risk factors, and pathological underpinnings in people exposed to RHI. [ABSTRACT FROM AUTHOR]

Objective: As part of a larger study dedicated to identifying speech and language biomarkers of neurological decline associated with repetitive head injury (RHI) in professional boxers and mixed martial artists (MMAs), we examined articulation rate, pausing, and disfluency in passages read aloud by participants in the Professional Athletes Brain Health Study. Setting: A large outpatient medical center specializing in neurological care. Participants, Design, and Main Measures: Passages read aloud by 60 boxers, 40 MMAs, and 55 controls were acoustically analyzed to determine articulation rate (the number of syllables produced per second), number and duration of pauses, and number and duration of disfluencies in this observational study. Results: Both boxers and MMAs differed from controls in articulation rate, producing syllables at a slower rate than controls by nearly half a syllable per second on average. Boxers produced significantly more pauses and disfluencies in passages read aloud than MMAs and controls. Conclusions: Slower articulation rate in both boxers and MMA fighters compared with individuals with no history of RHI and the increased occurrence of pauses and disfluencies in the speech of boxers suggest changes in speech motor behavior that may relate to RHI. These speech characteristics can be measured in everyday speaking conditions and by automatic recognition systems, so they have the potential to serve as effective, noninvasive clinical indicators for RHI-associated neurological decline. [ABSTRACT FROM AUTHOR]

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease thought to be caused, in part, by repetitive head impact (RHI) exposure and characterized by phosphorylated tau deposition with varying patterns in the cerebral cortex. Flortaucipir tau PET data from the DIAGNOSE CTE Research Project was examined to investigate tau PET patterns and its relation to RHI exposure in former professional and college American football players. Method: In this study, 218 DIAGNOSE CTE participants, ages 45‐74, with flortaucipir PET were included; 104 were former National Football League players (PRO), 58 were former college football players (COL), and 56 had no history of contact sports, other exposure to RHI, or traumatic brain injury (UE). Regional flortaucipir uptake was quantified using established procedures for three previously defined statistical regions (superior frontal, left parietal, and medial temporal) and compared across the three groups. Association analyses were also performed to examine the relationship between flortaucipir uptake and exposure to RHI using the cumulative head impact index for linear acceleration g‐force (CHII‐G). The potential clinical utility of flortaucipir PET for CTE was also investigated by examining its ability to differentiate participants meeting criteria for traumatic encephalopathy syndrome (TES) and probable or possible level of certainty for CTE pathology from those who do not meet those criteria. Result: Significantly higher flortaucipir uptake was observed in former football players than in participants without RHI exposure, controlling for age and race for the superior frontal region (Fig. 1A), left parietal, and medial temporal regions. Association between regional flortaucipir uptake and CHII‐G was only observed in the superior frontal region in former players (PRO+COL) 60 years and older (Fig. 1B) and no association was observed in the full PRO+COL group. Flortaucipir PET was not able to differentiate TES groups in former football players (Fig. 1C). Conclusion: Elevated flortaucipir uptake was observed in former American football players to a group of unexposed men. The association between flortaucipir uptake and exposure to RHI may require a long latent period to manifest. Further investigation of more sensitive tau PET tracers and quantification techniques is warranted to better characterize CTE related tau pathology. [ABSTRACT FROM AUTHOR]

Background: Repetitive head impact (RHI) exposure from the routine play of American football increases the risk of later‐life cognitive impairment and dementia from the neurodegenerative disease, chronic traumatic encephalopathy (CTE). Although neuropathological studies of CTE have found comorbid neurodegenerative and other pathologies, neuritic Aβ plaques are infrequent, particularly in early stages. However, amyloid PET imaging has not been fully characterized in cognitively impaired former American football players. Method: In this cross‐sectional, observational cohort study from the DIAGNOSE CTE Research Project, florbetapir PET mean cortical standard uptake value ratios (SUVR) and positivity (defined by average SUVR >1.10, indicative of moderate‐to‐frequent neuritic Aβ plaques), were analyzed in 119 former professional (PRO) National Football League players, 60 former college football players (COL), and 58 men unexposed (UE) to RHI who were cognitively asymptomatic. Former players were categorized into one of four diagnostic groups: cognitively normal (CN), subjective memory complaints (SMC), mild cognitive impairment (MCI), and dementia (DEM). All participants were 45‐74 yo. Multivariable linear and logistic regressions were conducted, with race, education, age, and APOE4 genotype included as covariates. A priori power calculations demonstrated adequate power to detect significant findings Result: No differences between the three exposure groups in average florbetapir SUVR or proportion of elevated florbetapir uptake were found. Pairwise group comparisons resulted in no differences in average SUVR between PRO and COL (‐0.01, 95% CI [‐0.033, 0.025], p = 0.95), PRO and UE (0.02, 95% CI [‐0.010, 0.029], p = 0.41), and COL and UE (0.02, 95% CI [0.0004, 0.039], p = 0.36). Analysis of covariance resulted in no differences among diagnostic groups (F = 0.94, p = 0.43). Neither years of playing football nor measures of cognition and daily functioning showed significant associations with florbetapir SUVR. Conclusion: Former professional and college American football players with cognitive impairment and dementia did not have elevated florbetapir amyloid PET compared to a group of men without RHI exposure. Their rates of florbetapir positivity in the football players were lower than expected for a group of men this age. These findings suggest that cognitive impairment in former elite football players may not be due to Alzheimer's disease pathology. [ABSTRACT FROM AUTHOR]

Introduction: The presentation, risk factors, and etiologies of white matter hyperintensities (WMH) in people exposed to repetitive head impacts are unknown. We examined the burden and distribution of WMH, and their association with years of play, age of first exposure, and clinical function in former American football players. Methods: A total of 149 former football players and 53 asymptomatic unexposed participants (all men, 45–74 years) completed fluid‐attenuated inversion recovery magnetic resonance imaging, neuropsychological testing, and self‐report neuropsychiatric measures. Lesion Segmentation Toolbox estimated WMH. Analyses were performed in the total sample and stratified by age 60. Results: In older but not younger participants, former football players had greater total, frontal, temporal, and parietal log‐WMH compared to asymptomatic unexposed men. In older but not younger former football players, greater log‐WMH was associated with younger age of first exposure to football and worse executive function. Discussion: In older former football players, WMH may have unique presentations, risk factors, and etiologies. Highlights: Older but not younger former football players had greater total, frontal, temporal, and parietal lobe white matter hyperintensities (WMH) compared to same‐age asymptomatic unexposed men.Younger age of first exposure to football was associated with greater WMH in older but not younger former American football players.In former football players, greater WMH was associated with worse executive function and verbal memory. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer disease (AD) is a common neurodegenerative disease, and immunomodulation offers treatment opportunities. Preclinical data suggest that intravesical Bacillus Calmette-Guerin (BCG) treatment could delay AD development. We investigated this relationship in a population-based cancer database.Sample and Methods: We queried the Surveillance, Epidemiology, and End Results-Medicare database for patients with high-risk nonmuscle-invasive bladder cancer (hrNMIBC). BCG dosage and subsequent Alzheimer diagnosis were collected through ICD-9/10 codes. Multivariable Cox regression was performed to assess the association between BCG therapy and subsequent Alzheimer diagnosis.Results: We identified 26,584 hrNMIBC patients; 51% received BCG and 8.3% were diagnosed with Alzheimer. BCG exposure was significantly associated with lower Alzheimer occurrence (hazard ratio: 0.73, P <0.05), which was dose-dependent. Increasing age, female sex, Black race, and increasing comorbidity index were significantly associated with a greater risk of subsequent Alzheimer diagnosis.Discussion: Treatment with intravesical BCG among patients with hrNMIBC was associated with a significantly lower risk for subsequent Alzheimer diagnosis, which seemed dose-dependent. [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]

Introduction: This clinical trial evaluates the efficacy and safety of a 6‐week course of daily neuroAD™ therapy. Methods: 131 subjects between 60 and 90 years old, unmedicated for Alzheimer's disease (AD), or on stable doses of an acetylcholinesterase inhibitor and/or memantine, with Mini–Mental State Examination scores between 18 and 26, clinical dementia rating scale scores of 1 or 2, enrolled for a prospective, randomized, double‐blind, sham‐controlled, multicenter clinical trial. Structural brain MRIs were obtained for transcranial magnetic stimulation targeting. Baseline Alzheimer's disease assessment scale—cognitive (ADAS‐Cog) and Clinical Global Impression of Change were assessed. 129 participants were randomized to active treatment plus standard of care (SOC) or sham treatments plus SOC. Results: Subjects with baseline ADAS‐Cog ≤ 30 (~85% of study population) showed a statistically significant benefit favoring active over sham. Responder analysis showed 31.7% participants in the active group with ≤ −4 point improvement on ADAS‐Cog versus 15.4% in the sham group. Discussion: neuroAD™ Therapy System provides a low‐risk therapeutic benefit for patients with milder AD (baseline ADAS‐Cog ≤30) beyond pharmacologic SOC. [ABSTRACT FROM AUTHOR]

Objective: Depression, neuropathology, and cognitive decline are commonly observed with repetitive head injuries (RHIs).We examined whether in boxers (a) clinically significant depression is associated with structural brain changes and cognition; (b) minimal symptoms of depression moderate the relations among RHI and brain volumes and cognition; and (c) baseline depression is associated with longitudinal cognitive changes. Setting: Clinical Research Center. Participants: A total of 205 male professional boxers. Design: Cross-sectional and longitudinal (subsample: n = 45; first visit to follow-up range = 1-6 years; mean = 2.61 years).Main Measures: Patient Health Questionnaire- 9 depression; CNS Vital Signs cognitive battery; brain imaging. Results: Clinically significant depression was associated with smaller regional volumes in insula, cingulate, orbitofrontal cortex, thalami, and middle corpus-callosum subregions; and with poorer verbal memory and psychomotor speed performance. Depression symptoms moderated the relations between RHI and bilateral thalami, left hippocampus, left medial orbitofrontal cortex, and bilateral insula volumes; but not cognition. Baseline depression was associated with poorer psychomotor speed and reaction time longitudinally and improved verbal memory performance longitudinally. Conclusion: Clinical depression is associated with volumetric and cognitive changes occasioning RHI exposure, and even minimal depressive symptoms may moderate the relations between exposure and brain volumes in key regions. Longitudinally, there is preliminary evidence that depression precedes cognitive changes. [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]

Background: Fosgonimeton (ATH‐1017) is a positive modulator of HGF/MET, a key neurotrophic pathway impaired in Alzheimer's disease (AD). Neuronal MET expression is decreased in the cortex and hippocampus, which may contribute to synaptic loss, neurodegeneration, and functional decline. ACT‐AD seeks to replicate and extend the previously shown improvement of event‐related potential (ERP) P300 latency in AD patients demonstrated in an 8‐day randomized, placebo‐controlled, double‐blind Phase 1 trial. ERP P300 latency is a noninvasive, objective, quantitative biomarker of cognitive performance without learning effects. Method: ACT‐AD is a Phase 2, 26‐week, randomized, double‐blind, placebo‐controlled, parallel group trial in patients with a clinical diagnosis of mild to moderate AD. Patients enrolled were aged 55‐85 years, had a mini‐mental state examination (MMSE) score of 14‐24, a Clinical Dementia Rating global score of 1 or 2 at screening, a syndromal clinical diagnosis of probable AD according to McKhann et al. (Alzheimers Dement. 2011), and were treatment‐naïve or receiving stable acetylcholinesterase inhibitor therapy. Patients were randomized (1:1:1) to placebo or fosgonimeton at doses of 40 or 70 mg, administered subcutaneously once daily. The trial is powered for the primary endpoint, change in ERP P300 latency. Secondary endpoints include ADAS‐Cog11, ADCS‐CGIC and ADCS‐ADL23. The relationship of ERP P300 latency with cognition, memory and executive function, as well as pharmacokinetics, and safety will also be analyzed. Result: In total, 77 patients with mild to moderate AD were randomized, with a mean (SD) age of 71.4 (7.3) years, 50.6% female, and mean (SD) baseline MMSE score of 19.5 (3.1). ApoE4 carriers made up 56% of the population, with 42% as noncarriers and 2% unknown. Conclusion: The double‐blind period of ACT‐AD is ongoing and estimated to complete in May 2022, with results available in June 2022. First analyses will be presented at the annual 2022 AAIC congress. This study is sponsored by Athira Pharma, registered at Clinicaltrials.gov: NCT04491006, and supported by a grant from the National Institute on Aging of the National Institutes of Health under Award Number R01AG06268. [ABSTRACT FROM AUTHOR]

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is characterized by perivascular foci of phosphorylated tau (p‐tau) notably in the depths of sulci, with varying patterns in the cerebral cortex. Prior studies show elevated flortaucipir (FTP) PET binding in former American professional football players(PRO). However, the association of p‐tau with clinical measures remains unclear using regional FTP SUVR as early signs of CTE related tau pathology. Graph theory (GT) takes advantages of the spatial variability in p‐tau load and allows the integration of regional measures to define GT based measures. Here we examine the GT based measures in two CTE cohorts to evaluate their utility in assessing p‐tau related pathology in CTE. Method: The graph procedure was optimized in FTP PET images in a group of 26 PRO with reported cognitive and/or behavorial symptoms and 30 asymptomatic controls without a history of traumatic brain injury (the DETECT Study) and identified the GT measure, entorhinal tau strength, as the target metric with the best group separation between PRO and controls. The optimized graph procedures were then applied to the DIAGNOSE CTE Research Project dataset (99 former PRO, 51 former college football players [COL], and 52 controls without exposure to repetitive head impacts [CTL]) and we examined entorhinal tau strength's ability to differentiate the exposure groups and relationship to consensus based diagnoses of Traumatic Encephalopathy Syndrome (TES), the clinical syndrome associated with CTE. Result: Entorhinal tau strength was significantly different among the three exposure groups (p=0.0001) similar to regional SUVR measures (Figure 1). Regional SUVR did not differentiate players (PRO+COL) with and without TES, while entorhinal tau strength approached although did not reach significance (Figure 2). Entorhinal tau strength is the only FTP measure that showed significant differences (p=0.006) between those players with cognitive impairment and players without (Figure 3). Conclusion: While there is still considerable overlap in between‐group measurements, GT based entorhinal tau strength, is potentially more sensitive in detecting tau changes in players with and without TES. Additional studies are necessary to clarify the value of this new measure in detecting underlying CTE pathology. [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]

Background: Professional boxers and Mixed Martial Arts (MMA) fighters regularly sustain blunt force trauma to the head leading to Traumatic Brain Injury (TBI) and concussion; therefore, fighters are at high risk for chronic traumatic encephalopathy and neurodegenerative disease. Family history of dementia (fhD) may significantly modulate fighter response to TBI. Genetic polymorphisms associated with dementia have been reported to modulate an individual's response to brain injury and to influence emotionality, risk‐taking, and cognition. A recent study in male college athletes found that fhD predisposed athletes to poorer recovery after concussion and to decrements in impulse control following injury. Furthermore, in a population‐based cohort study from the Netherlands, researchers found that parental history of dementia led to increased rates of depression in mid‐life. The present study aims to investigate how fhD in fighters may relate to history of symptomatic concussions, depression, and impulsivity. Methods: Using data from the Professional Fighters Brain Health Study (longitudinal cohort study of fighters), we included active, professional boxers and MMA fighters (n = 198) for cross‐sectional analyses. The latest study visits with available data were utilized to generate multivariate regression analyses examining the number of self‐reported symptomatic concussions in a fighter's career, Patient Health Questionnaire (PHQ)‐9 scores, and Barratt Impulsiveness Scale Version 11 (BIS‐11) scores, adjusting for age, sex, education, and number of professional fights. Results: FhD was significantly associated with more symptomatic concussions during one's career (p<0.05), higher PHQ‐9 scores (p<0.01), and higher BIS‐11 scores (p<0.01). Conclusions: Our findings suggest that professional boxers and MMA fighters with fhD may be more likely to experience symptomatic concussions, depression, and impulsivity during their active fighting career. We postulate that fhD may predispose fighters to experience a higher burden of neuropsychiatric symptoms after sustaining a TBI, potentially due to differences in the brain's response to injury. These findings may be used to advise those with fhD to minimize possible exposures to TBI and to educate fighters with fhD regarding risks of chronic neurotrauma exposure. Future research should evaluate potential genetic and/or molecular mechanisms behind these trends and behavioral outcomes associated with the sequelae of TBI in those with fhD. [ABSTRACT FROM AUTHOR]

Professional boxing is associated with a risk of chronic neurological injury, with up to 20–50% of former boxers exhibiting symptoms of chronic brain injury. Chronic traumatic brain injury encompasses a spectrum of disorders that are associated with long-term consequences of brain injury and remains the most difficult safety challenge in modern-day boxing. Despite these concerns, traditional guidelines used for return to sport participation after concussion are inconsistently applied in boxing. Furthermore, few athletic commissions require either formal consultation with a neurological specialist (i.e. neurologist, neurosurgeon, or neuropsychologist) or formal neuropsychological testing prior to return to fight. In order to protect the health of boxers and maintain the long-term viability of a sport associated with exposure to repetitive head trauma, we propose a set of specific requirements for brain safety that all state athletic commissions would implement. [ABSTRACT FROM PUBLISHER]

Background: Repetitive head impacts from American football have been associated with long‐term cognitive symptoms. The late neuropsychological profiles of this population is not well‐characterized. Research has relied on retrospective informant reports and/or has been small samples of former professional players. We describe objective neuropsychological test performance in former college and professional American football players. Methods: Male (45‐74 years) former National Football League (n=107) and college football players (n=59) from the DIAGNOSE‐CTE Research Project completed a neuropsychological test battery, Functional Activities Questionnaire (FAQ) and Quick Dementia Rating Scale (QDRS). Neuropsychological test scores were converted to T‐scores using age, sex, and/or education‐adjusted normative data. T‐scores<35 defined impairment. Participants were enrolled across the spectrum of symptom severity (asymptomatic to dementia). Individuals without decisional capacity were excluded. Participants with missing data (n=4) and who scored <45 on Test of Memory Malingering Trial 2 (n=10) were excluded. Results: 108 (65.1%) identified as White and 53 (31.9%) as Black. Mean education years was 16.76 (SD=1.48). Fourteen (8.4%) and 6 (3.6%) reported diagnostic history of ADHD and learning disability, respectively. Average Montreal Cognitive Assessment score was 24.96 (SD=3.17); 85 (51.2%) scored <26. Impairment rates were highest for learning and episodic memory. On Neuropsychological Assessment Battery List Learning, 29.5% were impaired on Immediate recall, 36.1% on Short Delay, and 44.0% on Long Delay Recall. Impairment rates for Craft Story Immediate and Delayed Recall (Paraphrase) were 15.7% and 18.7%, respectively. 19.9% and 15.7% were impaired on learning and delayed recall of the Brief Visuospatial Memory Test‐Revised. Impairments were frequent on the Multilingual Naming Test (20.5%), Trail Making Test Parts B (19.3%) and A (18.1%), Animal Fluency (15.7%), and Number Span Backward (15.1%). Impairments were less common (<10%) for phonemic fluency, planning, basic attention, and visual‐perceptual abilities, Mean FAQ was 3.11 (SD=5.14); 23 (13.9%) had an FAQ >9. Based on QDRS scores, 66 (39.8%) had mild cognitive impairment, 44 (26.5%) mild dementia, and 6 (3.6%) moderate dementia. Conclusions: In these former American football players, neuropsychological impairments were most frequent in episodic memory, followed by confrontation naming and executive function. Further research is needed to delineate this population's unique neuropsychological profile. [ABSTRACT FROM AUTHOR]

Background: Little is known about sleep in those with a history of contact sports, who are at increased risk for neurodegenerative disease(s). Sleep disruption and disorders are increasingly recognized as having a bidirectional relationship with Alzheimer's disease neuropathology. Here, we investigated self‐reported sleep disruption and disorders in male former college and professional American football players. Method: 116 former National Football League (NFL) players, 60 former college football players, and 60 asymptomatic men without a history of traumatic brain injury or repetitive head impacts (controls), all between 45‐74 years, completed the Mayo Sleep Questionnaire (MSQ) which includes the Epworth Sleepiness Scale (ESS). Former American football players were enrolled across the spectrum of symptom severity (asymptomatic to mild dementia). Using binary logistic regression or analysis of covariance, comparisons (controlling for age, racial identity, body mass index, APOE e4 status) on each of the MSQ items and the ESS were made between each of the study groups. Result: Compared to controls, former NFL players were more likely to restless legs (OR = 7.32, 95% CI = 1.63‐32.97*), sleepwalking (OR = 8.65, 95% CI = 1.08‐69.22*), observed apnea (OR = 2.25, 95% CI = 1.04‐4.85*), lower alertness levels (marginal mean diff. = 0.90**) and had higher ESS (marginal mean diff. = 2.37**). Former college football players reported greater sleep disturbances compared with controls: restless legs (OR = 10.82, 95% CI = 1.86‐62.89**), sleepwalking (OR = 10.45, 95% CI = 1.12‐97.58*), alertness levels (marginal mean diff. = 1.48**) and ESS (marginal mean diff. = 2.76*). There were no college vs control differences for observed apnea. There were no differences between former NFL players and former college football players on any sleep metric. **p<.005, *p<.05. Conclusion: Sleep disturbances may be an important factor to investigate in those with a history of participation in American football. [ABSTRACT FROM AUTHOR]

Background: Dementia is associated with microvascular disease of the retina. In this study, we examine whether cognitive status (normal cognition, mild cognitive impairment, and dementia) is associated with albuminuria, a microvascular disorder of the kidney.Study Design: Cross-sectional analysis.Setting& Participants: 2,316 participants from the Cardiovascular Health Cognition Study who underwent brain magnetic resonance imaging and testing for albuminuria.Predictor: Doubling of albuminuria.Outcome: Dementia defined according to neuropsychological and clinical evaluation.Measurements: Multinomial logistic modeling was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of dementia and mild cognitive impairment with doubling of albuminuria compared with the odds with normal cognition.Results: 283 participants (12.2%) had dementia, 344 (14.9%) had mild cognitive impairment, and 1,689 (72.9%) had normal cognition. Compared with participants with normal cognition, doubling of albuminuria was associated with increased odds of dementia (OR, 1.22; 95% CI, 1.15 to 1.29). Adjustment for prevalent cardiovascular disease and cardiovascular risk factors, lipid levels, C-reactive protein level, estimated glomerular filtration rate, and apolipoprotein E-4 genotype attenuated this association, but it remained statistically significant (OR, 1.12; 95% CI, 1.03 to 1.22). Mild cognitive impairment was associated with albuminuria on unadjusted analysis, but not with adjustment for other factors.Limitations: Results are cross-sectional; causality cannot be imputed.Conclusions: The odds of dementia increased in the presence of albuminuria. These findings suggest a role of shared susceptibility for microvascular disease in the brain and kidney in older adults. [ABSTRACT FROM AUTHOR]