Search

Cognitive tests of verbal fluency (VF) consist of verbalizing as many words as possible in one minute that either start with a specific letter of the alphabet or belong to a specific semantic category. These tests are widely used in neurological, psychiatric, mental health, and school settings and their validity for clinical applications has been extensively demonstrated. However, VF tests are currently administered and scored manually making them too cumbersome to use, particularly for longitudinal cognitive monitoring in large populations. The objective of the current study was to determine if automatic speech recognition (ASR) could be used for computerized administration and scoring of VF tests. We examined established techniques for constraining language modeling to a predefined vocabulary from a specific semantic category (e.g., animals). We also experimented with post-processing ASR output with confidence scoring, as well as with using speaker adaptation to improve automated VF scoring. Audio responses to a VF task were collected from 38 novice and experienced professional fighters (boxing and mixed martial arts) participating in a longitudinal study of effects of repetitive head trauma on brain function. Word error rate, correlation with manual word count and distance from manual word count were used to compare ASR-based approaches to scoring to each other and to the manually scored reference standard. Our study’s results show that responses to the VF task contain a large number of extraneous utterances and noise that lead to relatively poor baseline ASR performance. However, we also found that speaker adaptation combined with confidence scoring significantly improves all three metrics and can enable use of ASR for reliable estimates of the traditional manual VF scores. [ABSTRACT FROM AUTHOR]

Education has a protective effect against cognitive deficits following various forms of brain insult. Professional fighting (boxing and mixed martial arts) provides a model for assessing the impact of cumulative brain injuries on cognition and brain health. In the current cross-sectional observational study, we explore whether education would be protective against cognitive loss in fighters. We tested 141 professional fighters using a computerized neurocognitive battery, in addition to structural MRI. We used automated segmentation software to compute the volumes of various brain structures. We found fighters with high school education or less to show more associations between fight exposure and cognitive test scores. The relationship between brain structure volume and exposure did not differ based on education. These results are interpreted as putatively showing a protective effect of education on functional integrity in fighters, although longitudinal data and a larger sample size are required to further understand this relationship. [ABSTRACT FROM AUTHOR]

During the past ten years, dynamic functional connectivity (FC) has been extensively studied using the sliding-window method. A fixed window-size is usually selected heuristically, since no consensus exists yet on choice of the optimal window-size. Furthermore, without a known ground-truth, the validity of the computed dynamic FC remains unclear and questionable. In this study, we computed single-scale time-dependent (SSTD) window-sizes for the sliding-window method. SSTD window-sizes were based on the frequency content at every time point of a time series and were computed without any prior information. Therefore, they were time-dependent and data-driven. Using simulated sinusoidal time series with frequency shifts, we demonstrated that SSTD window-sizes captured the time-dependent period (inverse of frequency) information at every time point. We further validated the dynamic FC values computed with SSTD window-sizes with both a classification analysis using fMRI data with a low sampling rate and a regression analysis using fMRI data with a high sampling rate. Specifically, we achieved both a higher classification accuracy in predicting cognitive impairment status in fighters and a larger explained behavioral variance in healthy young adults when using dynamic FC matrices computed with SSTD window-sizes as features, as compared to using dynamic FC matrices computed with the conventional fixed window-sizes. Overall, our study computed and validated SSTD window-sizes in the sliding-window method for dynamic FC analysis. Our results demonstrate that dynamic FC matrices computed with SSTD window-sizes can capture more temporal dynamic information related to behavior and cognitive function. • Data-driven SSTD window-sizes are computed for the sliding-window dynamic functional connectivity (dFC) analysis.. • SSTD window-sizes capture time-dependent frequency information at every time-point. • DFC computed with SSTD achieves a higher accuracy in predicting impairment in fighters and explains more behavioral variance in healthy adults.. [ABSTRACT FROM AUTHOR]

Importance: Exposure to repetitive head impacts (RHI) is associated with increased risk for neurodegeneration. Accumulation of toxic proteins due to impaired brain clearance is suspected to play a role., Objective: To investigate whether perivascular space (PVS) volume is associated with lifetime exposure to RHI in individuals at risk for RHI-associated neurodegeneration., Design, Setting, and Participants: This cross-sectional study was part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project, a 7-year multicenter study consisting of 4 US study sites. Data were collected from September 2016 to February 2020 and analyses were performed between May 2021 and October 2023. After controlling for magnetic resonance image (MRI) and processing quality, former American football players and unexposed asymptomatic control participants were included in analyses., Exposure: Prior exposure to RHI while participating in American football was estimated using the 3 cumulative head impact indices (CHII-G, linear acceleration; CHII-R, rotational acceleration; and CHII, number of head impacts)., Main Outcomes and Measures: Individual PVS volume was calculated in the white matter of structural MRI. Cognitive impairment was based on neuropsychological assessment. Linear regression models were used to assess associations of PVS volume with neuropsychological assessments in former American football players. All analyses were adjusted for confounders associated with PVS volume., Results: Analyses included 224 participants (median [IQR] age, 57 [51-65] years), with 170 male former football players (114 former professional athletes, 56 former collegiate athletes) and 54 male unexposed control participants. Former football players had larger PVS volume compared with the unexposed group (mean difference, 0.28 [95% CI, 0.00-0.56]; P = .05). Within the football group, PVS volume was associated with higher CHII-R (β = 2.71 × 10-8 [95% CI, 0.50 × 10-8 to 4.93 × 10-8]; P = .03) and CHII-G (β = 2.24 × 10-6 [95% CI, 0.35 × 10-6 to 4.13 × 10-6]; P = .03). Larger PVS volume was also associated with worse performance on cognitive functioning in former American football players (β = -0.74 [95% CI, -1.35 to -0.13]; P = .04)., Conclusions and Relevance: These findings suggest that impaired perivascular brain clearance, as indicated by larger PVS volume, may contribute to the association observed between RHI exposure and neurodegeneration.

Objective: Neurobehavioral dysregulation (NBD), a core clinical feature of traumatic encephalopathy syndrome, encompasses neuropsychiatric symptoms reported among individuals with a history of repetitive head impact exposure, including contact sport athletes. The objective of this study was to examine the construct and subconstructs of NBD through a series of factor and cluster analyses., Methods: Six clinician-scientists selected self-report questionnaire items relevant to NBD from seven available neuropsychiatric scales through a blinded voting process. These items were subjected to confirmatory factor analyses in a sample of 178 former college and professional American football players and 60 asymptomatic individuals without a history of repetitive head impact exposure. All participants were enrolled in the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Factor scores were generated on the basis of the optimal expert-informed model for NBD. Construct validity was assessed with neuropsychiatric scales not included in generation of the factor scores. Cluster analyses with NBD factor scores were used to examine symptom profiles., Results: Factor analyses confirmed that NBD was composed of four subconstructs: explosivity, emotional dyscontrol, impulsivity, and affective lability. Cluster analyses indicated four distinct symptom profiles of NBD in this group of former football players: asymptomatic (N=80, 45%), short fuse (N=33, 19%), high affective lability (N=34, 19%), and high NBD (N=31, 17%)., Conclusions: These findings characterize NBD as a multifaceted clinical construct with a heterogeneous presentation, providing a foundation for empirical work on the diagnostic criteria for traumatic encephalopathy syndrome and research on the neurobiological underpinnings of NBD., Competing Interests: Dr. Bernick has received research support from Haymon Boxing, Top Rank Promotions, and the Ultimate Fighting Championship. Dr. Geda has received funding from the Barrow Neurological Foundation, NIH (grant R01 AG057708), and Roche; and he has served on the advisory board of Lundbeck. Dr. Wethe is a cocreator of Mayo Clinic Concussion Check, which incorporates the King-Devick Test, in association with the Mayo Clinic. Dr. Katz has received royalties from Springer/Demos Publishing for a textbook on brain injury, he has served as an expert witness in legal cases involving brain injury and concussion, he has received a stipend from Encompass Health as program medical director for brain injury and chair of the annual Neurorehabilitation Conference, and he has received honoraria for a keynote address for the annual medical directors meeting of HealthSouth. Dr. Alosco has received research support from Life Molecular Imaging and the Rainwater Charitable Foundation, he has received a single-time honorarium from the Michael J. Fox Foundation, and he has received royalties from Oxford University Press. Dr. Tripodis has received financial support from the American Medical Association. Dr. Adler has served as a consultant for Avion, CND Life Sciences, Jazz, and PreCon Health. Dr. Balcer has served as editor-in-chief of the Journal of Neuro-Ophthalmology, and her spouse co-owns a patent on an N-methyl-d-aspartate receptor antibody assay. Dr. Reiman has been a compensated scientific adviser to Alkahest, Alzheon, Aural Analytics, Cognition Therapeutics Denali, Enigma, Green Valley, Retromer Therapeutics, and Vaxxinity; and he is a cofounder of, shareholder with, and adviser to ALZPath. Dr. Cummings has served as a consultant to Acadia, Actinogen, Acumen, AlphaCognition, Aprinoia, AriBio, Artery, Biogen, Biohaven, BioVie, Bristol-Myers Squib, Cassava, Cerecin, Diadem, EIP Pharma, Eisai, GAP Innovations, GemVax, Genentech, Janssen, Jocasta, Karuna, Lighthouse, Lilly, LSP/EQT, Lundbeck, Mangrove Therapeutics, Merck, NervGen, New Amsterdam, Novo Nordisk, Oligomerix, Ono, Optoceutics, Otsuka, Oxford Brain Diagnostics, PRODEO, Prothena, ReMYND, Roche, Sage Therapeutics, Signant Health, Simcere, Sinaptica, Suven, SynapseBio, TrueBinding, Vaxxinity, and Wren pharmaceutical, assessment, and investment companies; he has been supported by the Alzheimer’s Disease Drug Discovery Foundation, the Joy Chambers-Grundy Endowment, NIH (grants P20GM109025, U01NS093334, R01AG053798, P30AG072959, R35AG71476, R25AG083721), and the Ted and Maria Quirk Endowment; he owns the copyright of the Neuropsychiatric Inventory; and he is a shareholder with Acumen, Alzheon, Artery, Behrens, MedAvante-Prophase, and Vaxxinity. Dr. Stern has been a member of the Board of Directors of King-Devick Technologies, and he has received royalties for published neuropsychological tests from Psychological Assessment Resources. The other authors report no financial relationships with commercial interests.

Background: White matter signal abnormalities have been associated with traumatic brain injury (TBI) and repetitive head impacts (RHI) in contact sports (e.g. American football, rugby). However, previous studies of mixed martial arts (MMA) fighters from the Professional Fighters Brain Health Study have not found greater white matter signal abnormalities in fighters versus controls., Objective: This study aims to explore the varying white matter effects of football/rugby and MMA by analyzing how football/rugby history in mixed martial arts fighters may relate to white matter signal abnormalities, helping to further our understanding of sport-specific brain health risks., Methods: Baseline visits for 90 active, professional, male mixed martial arts fighters and 27 unexposed male controls were cross-sectionally analyzed. Wilcoxon and Kruskal-Wallis tests compared demographics and white matter signal abnormalities, and multivariable regression models examined the associations between football/rugby history and white matter signal abnormality burden in fighters, adjusting for age, education, race, fights, MRI scanner, and supratentorial volume., Results: 37/90 fighters had football/rugby history (mean: 4 years; range: 1-12 years). White matter signal abnormalities were significantly greater in fighters with football/rugby history compared to fighters without football/rugby history (Wilcoxon, p  = 0.0190). Football/rugby history was significantly associated with white matter signal abnormality burden >75 th percentile (OR: 12, CI: 3.3-61, p  < 0.001) and >50 th percentile (OR: 3.2, CI: 1.2-9.4, p  = 0.024) in fighters. Years of football/rugby were also significantly associated with white matter signal abnormalities., Conclusion: Our findings expand on previous literature by demonstrating a significant relationship between white matter signal abnormalities (WMSAs) and football/rugby history but not MMA. Furthermore, our study suggests an added risk for WMSAs in MMA fighters with a history of football/rugby. Future research should further evaluate WMSAs in contact sports, helping to inform athletes, regulatory bodies, and healthcare providers of the potential brain health risks of contact sports.

Background and Objectives: Exposure to repetitive head impacts (RHI) is linked to the development of chronic traumatic encephalopathy (CTE), which can only be diagnosed at post-mortem. The presence of a cavum septum pellucidum (CSP) is a common finding in post-mortem studies of confirmed CTE and in neuroimaging studies of individuals exposed to RHI. This study examines CSP in living former American football players, investigating its association with RHI exposure, traumatic encephalopathy syndrome (TES) diagnosis, and provisional levels of certainty for CTE pathology., Methods: Data from the DIAGNOSE CTE Research Project were used to compare the presence and ratio of CSP in former American football players (n = 175), consisting of former college (n = 58) and former professional players (n = 117), and asymptomatic unexposed controls without RHI exposure (n = 55). We further evaluated potential associations between CSP measures and cumulative head impact index (CHII) measures (frequency, linear acceleration, and rotational force), a TES diagnosis (yes/no), and a provisional level of certainty for CTE pathology (suggestive, possible, and probable)., Results: Former American football players exhibited a higher CSP presence and ratio than unexposed asymptomatic controls. Among player subgroups, professional players showed a greater CSP ratio than former college players and unexposed asymptomatic controls. Among all football players, CHII rotational forces correlated with an increased CSP ratio. No significant associations were found between CSP measures and diagnosis of TES or provisional levels of certainty for CTE pathology., Discussion: This study confirms previous findings, highlighting a greater prevalence of CSP and a greater CSP ratio in former American football players compared with unexposed asymptomatic controls. In addition, former professional players showed a greater CSP ratio than college players. Moreover, the relationship between estimates of CHII rotational forces and CSP measures suggests that cumulative frequency and strength of rotational forces experienced in football are associated with CSP. However, CSP does not directly correlate with TES diagnosis or provisional levels of certainty for CTE, indicating that it may be a consequence of RHI associated with rotational forces. Further research, especially longitudinal studies, is needed for confirmation and to explore changes over time., Competing Interests: C.H. Adler consulted for Avion, CND Life Sciences, Jazz, and PreCon Health; LJB is Editor-in-Chief of the Journal of Neuro-Ophthalmology and is a paid consultant to Biogen (Cambridge, MA, USA); C. Bernick receives research support from the Ultimate Fighting Championship, Top Rank promotions, Haymon Boxing, Las Vegas Raiders, and Professional Bull Riders. He is a paid consultant for Aurora Concussion Therapy Systems, Inc. (St. Paul, MN); A.P. Lin consulted for Agios, BioMarin, and Moncton MRI. He is a co-founder of BrainSpec, Inc; J.L. Cummings has provided consultation to Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren Therapeutics, Biogen, Biohaven, Cassava, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, Prothena, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience, and Unlearn AI pharmaceutical, assessment, and investment companies; E.M. Reiman is a compensated scientific advisor for Alkahest, Alzheon, Aural Analytics, Denali, Green Valley, Retromer Therapeutics, and Vaxxinity and is a cofounder of ALZPath; R.A. Stern is a paid consultant to Biogen (Cambridge, MA, USA) and Lundbeck (Copenhagen, Denmark). He is a member of the Board of Directors of King-Devick Technologies, Inc. (Chicago, IL, USA), and he receives royalties for published neuropsychological tests from Psychological Assessment Resources, Inc. (Lutz, FL, USA). He has been a member of the Medical Science Committee for the National Collegiate Athletic Association Student-Athlete Concussion Injury Litigation; I.K. Koerte receives funding for a collaborative project from Abbott Inc. She receives royalties for book chapters. Her spouse is an employee at Siemens AG and a stockholder of Siemens AG and Siemens Healthineers. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: Obstructive sleep apnea (SA) is common in older men and a contributor to negative cognitive, psychiatric, and brain health outcomes. Little is known about SA in those who played contact sports and are at increased risk of neurodegenerative disease(s) and other neuropathologies associated with repetitive head impacts (RHI). In this study, we investigated the frequency of diagnosed and witnessed SA and its contribution to clinical symptoms and tau pathology using PET imaging among male former college and former professional American football players., Methods: The sample included 120 former National Football League (NFL) players, 60 former college players, and 60 asymptomatic men without exposure to RHI (i.e., controls). Diagnosed SA was self-reported, and all participants completed the Mayo Sleep Questionnaire (MSQ, informant version), the Epworth Sleepiness Scale (ESS), neuropsychological testing, and tau (flortaucipir) PET imaging. Associations between sleep indices (diagnosed SA, MSQ items, and the ESS) and derived neuropsychological factor scores, self-reported depression (Beck Depression Inventory-II [BDI-II]), informant-reported neurobehavioral dysregulation (Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A] Behavioral Regulation Index [BRI]), and tau PET uptake, were tested., Results: Approximately 36.7% of NFL players had diagnosed SA compared with 30% of the former college football players and 16.7% of the controls. Former NFL players and college football players also had higher ESS scores compared with the controls. Years of football play was not associated with any of the sleep metrics. Among the former NFL players, diagnosed SA was associated with worse Executive Function and Psychomotor Speed factor scores, greater BDI-II scores, and higher flortaucipir PET standard uptake value ratios, independent of age, race, body mass index, and APOE ε4 gene carrier status. Higher ESS scores correlated with higher BDI-II and BRIEF-A BRI scores. Continuous positive airway pressure use mitigated all of the abovementioned associations. Among the former college football players, witnessed apnea and higher ESS scores were associated with higher BRIEF-A BRI and BDI-II scores, respectively. No other associations were observed in this subgroup., Discussion: Former elite American football players are at risk of SA. Our findings suggest that SA might contribute to cognitive, neuropsychiatric, and tau outcomes in this population. Like all neurodegenerative diseases, this study emphasizes the multifactorial contributions to negative brain health outcomes and the importance of sleep for optimal brain health., Competing Interests: The authors report no relevant disclosures. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2024 American Academy of Neurology.)

Exposure to repetitive head impacts (RHIs) in contact sports is associated with neurodegenerative disorders including chronic traumatic encephalopathy (CTE) which currently can be diagnosed only at postmortem. American football players are at higher risk of developing CTE given their exposure to RHIs. One promising approach for diagnosing CTE in vivo is to explore known neuropathological abnormalities at postmortem in living individuals using structural magnetic resonance imaging (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 = 58 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-by-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 suggest that MRI morphometrics detects abnormalities in individuals with a history of RHI exposure that resemble the anatomic distribution of pathological findings from postmortem CTE studies. The lack of findings associating MRI measures with exposure metrics (except for one significant relationship) or TES diagnosis and core clinical features suggests that brain morphometry must be complemented by other types of measures to characterize individuals with RHIs., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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.

Objective: Repetitive head impacts in professional fighting commonly lead to head injuries. Increased exposure to repetitive head trauma, measured by the number of professional fights and years of fighting, has been associated with slower processing speed and smaller brain volumes. The impact of win-loss outcomes has been investigated in other sports, with several studies suggesting that individuals on losing teams experience more head injuries. Here, the authors hypothesized that fighters with a worse fight record would exhibit poorer brain health outcomes., Methods: The Professional Fighters Brain Health Study examined changes in neuropsychiatric symptoms, regional brain volume, and cognition among professional boxers and mixed martial arts fighters. These data were used to evaluate the relationship between win-loss ratios and brain health outcomes among professional fighters (N=212) by using validated neuropsychiatric symptom and cognitive measures and MRI data., Results: Retired fighters with a better record demonstrated more impulsiveness (B=0.21, df=48) and slower processing speed (B=-0.42, df=31). More successful fighters did not perform better than fighters with worse records on any neuropsychiatric or cognitive test. Retired fighters with better fight records had smaller brain volumes in the subcortical gray matter, anterior corpus callosum, left and right hippocampi, left and right amygdala, and left thalamus. More successful active fighters had a smaller left amygdala volume., Conclusions: These findings suggest that among retired fighters, a better fight record was associated with greater impulsiveness, slower processing speed, and smaller brain volume in certain regions. This study shows that even successful fighters experience adverse effects on brain health., Competing Interests: Dr. Bernick has received research support from Haymon Boxing, Top Rank Promotions, and the Ultimate Fighting Championship. The other authors report no financial relationships with commercial interests.

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., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Composite scores have been increasingly used in trials for Alzheimer's disease (AD) to detect disease progression, such as the AD Composite Score (ADCOMS) in the lecanemab trial., Objective: To develop a new composite score to improve the prediction of outcome change., Methods: We proposed to develop a new composite score based on the statistical model in the ADCOMS, by removing duplicated sub-scales and adding the model selection in the partial least squares (PLS) regression., Results: The new AD composite S core with variable S election (ADSS) includes 7 cognitive sub-scales. ADSS can increase the sensitivity to detect disease progression as compared to the existing total scores, which leads to smaller sample sizes using the ADSS in trial designs., Conclusions: ADSS can be utilized in AD trials to improve the success rate of drug development with a high sensitivity to detect disease progression in early stages., Competing Interests: JC has provided consultation to Acadia, Actinogen, Alkahest, AlphaCognition, Aprinoia, AriBio, Biogen, BioVie, Cassava, Cerecin, Corium, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, GAP Innovations, Grifols, Janssen, Karuna, Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Optoceutics, Ono, Otsuka, PRODEO, Prothena, ReMYND, Resverlogix, Roche, Sage Therapeutics, Signant Health, Simcere, Sunbird Bio, Suven, SynapseBio, TrueBinding, and Vaxxinity pharmaceutical, assessment, and investment companies. All other authors have nothing to disclose., (© 2024 – The authors. Published by IOS Press.)

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., (© 2024. The Author(s).)

Background and Objectives: Recent data link exposure to repetitive head impacts (RHIs) from American football with increased white matter hyperintensity (WMH) burden. WMH might have unique characteristics in the context of RHI beyond vascular risk and normal aging processes. We evaluated biological correlates of WMH in former American football players, including markers of amyloid, tau, inflammation, axonal injury, neurodegeneration, and vascular health., Methods: Participants underwent clinical interviews, MRI, and lumbar puncture as part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Structural equation modeling tested direct and indirect effects between log-transformed total fluid-attenuated inversion recovery (FLAIR) lesion volumes (TLV) and the revised Framingham stroke risk profile (rFSRP), MRI-derived global metrics of cortical thickness and fractional anisotropy (FA), and CSF levels of amyloid β 1-42 , p-tau 181 , soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and neurofilament light. Covariates included age, race, education, body mass index, APOE ε4 carrier status, and evaluation site. Models were performed separately for former football players and a control group of asymptomatic men unexposed to RHI., Results: In 180 former football players (mean age = 57.2, 36% Black), higher log(TLV) had direct associations with the following: higher rFSRP score (B = 0.26, 95% CI 0.07-0.40), higher p-tau 181 (B = 0.17, 95% CI 0.01-0.43), lower FA (B = -0.28, 95% CI -0.42 to -0.13), and reduced cortical thickness (B = -0.25, 95% CI -0.45 to -0.08). In 60 asymptomatic unexposed men (mean age = 59.3, 40% Black), there were no direct effects on log(TLV) (rFSRP: B = -0.03, 95% CI -0.48 to 0.57; p-tau 181 : B = -0.30, 95% CI -1.14 to 0.37; FA: B = -0.07, 95% CI -0.48 to 0.42; or cortical thickness: B = -0.28, 95% CI -0.64 to 0.10). The former football players showed stronger associations between log(TLV) and rFSRP (1,069% difference in estimates), p-tau 181 (158%), and FA (287%) than the unexposed men., Discussion: Risk factors and biological correlates of WMH differed between former American football players and asymptomatic unexposed men. In addition to vascular health, p-tau 181 and diffusion tensor imaging indices of white matter integrity showed stronger associations with WMH in the former football players. FLAIR WMH may have specific risk factors and pathologic underpinnings in RHI-exposed individuals.

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., (© 2023 The American Academy of Addiction Psychiatry (AAAP).)

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., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Due to current limitations in diagnosing chronic traumatic encephalopathy (CTE) clinically, traumatic encephalopathy syndrome (TES) has been proposed as the clinical presentation of suspected CTE. This study aimed to determine whether there was an association between a clinical diagnosis of TES and subsequent temporal decline in cognitive or MRI volumetric measures., Methods: This was a secondary analysis of the Professional Athletes Brain Health Study (PABHS), inclusive of active and retired professional fighters older than 34 years. All athletes were adjudicated as TES positive (TES+) or TES negative (TES-) based on the 2021 clinical criteria. General linear mixed models were used to compare MRI regional brain volumes and cognitive performance between groups., Results: A total of 130 fighters met inclusion criteria for consensus conference. Of them, 52 fighters (40%) were adjudicated as TES+. Athletes with a TES+ diagnosis were older and had significantly lower education. Statistically significant interactions and between-group total mean differences were found in all MRI volumetric measurements among the TES+ group compared with those among the TES- group. The rate of volumetric change indicated a significantly greater increase for lateral (estimate = 5,196.65; 95% CI = 2642.65, 7750.66) and inferior lateral ventricles (estimate = 354.28; 95% CI = 159.90, 548.66) and a decrease for the hippocampus (estimate = -385.04, 95% CI = -580.47, -189.62), subcortical gray matter (estimate = -4,641.08; 95% CI = -6783.98, -2498.18), total gray matter (estimate = -26492.00; 95% CI = -50402.00, -2582.32), and posterior corpus callosum (estimate = -147.98; 95% CI = -222.33, -73.62). Likewise, the rate of cognitive decline was significantly greater for reaction time (estimate = 56.31; 95% CI = 26.17, 86.45) and other standardized cognitive scores in the TES+ group., Discussion: The 2021 TES criteria clearly distinguishes group differences in the longitudinal presentation of volumetric loss in select brain regions and cognitive decline among professional fighters 35 years and older. This study suggests that a TES diagnosis may be useful in professional sports beyond football, such as boxing and mixed martial arts. These findings further suggest that the application of TES criteria may be valuable clinically in predicting cognitive decline., (© 2023 American Academy of Neurology.)

Many studies have investigated the imaging sequelae of repetitive head trauma with mixed results, particularly with regard to the detection of intracranial white matter changes (WMCs) and cerebral microhemorrhages (CMHs) on ≤3 Tesla (T) field magnetic resonance imaging (MRI). 7T MRI, which has recently been approved for clinical use, is more sensitive at detecting lesions associated with multiple neurological diagnoses. In this study, we sought to determine whether 7T MRI would detect more WMCs and CMHs than 3T MRI in 19 professional fighters, 16 patients with single TBI, versus 82 normal healthy controls (NHCs). Fighters and patients with TBI underwent both 3T and 7T MRI; NHCs underwent either 3T ( n  = 61) or 7T ( n  = 21) MRI. Readers agreed on the presence/absence of WMCs in 88% (84 of 95) of 3T MRI studies (Cohen's kappa, 0.76) and in 93% (51 of 55) of 7T MRI studies (Cohen's kappa, 0.79). Readers agreed on the presence/absence of CMHs in 96% (91 of 95) of 3T MRI studies (Cohen's kappa, 0.76) and in 96% (54 of 56) of 7T MRI studies (Cohen's kappa, 0.88). The number of WMCs detected was greater in fighters and patients with TBI than NHCs at both 3T and 7T. Moreover, the number of WMCs was greater at 7T than at 3T for fighters, patients with TBI, and NHCs. There was no difference in the number of CMHs detected with 7T MRI versus 3T MRI or in the number of CMHs observed in fighters/patients with TBI versus NHCs. These initial findings suggest that fighters and patients with TBI may have more WMCs than NHCs and that the improved voxel size and signal-to-noise ratio at 7T may help to detect these changes. As 7T MRI becomes more prevalent clinically, larger patient populations should be studied to determine the cause of these WMCs., Competing Interests: C.B.: UFC, Top Rank promotions, and Haymon Boxing provide research support. S.J.: financial support from Siemens (travel, research grant); Eisai; Monteris; and St Jude (none of these activities are related to this article)., (© Jonathan K. Lee et al., 2023; Published by Mary Ann Liebert, Inc.)

Objective: To examine the characteristics of those who fulfil the recent National Institute of Neurological Disease and Stroke (NINDS) Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome (TES) and test whether they show differences in MRI-based regional brain volumes, cognitive domains, and certain plasma biomarkers., Methods: Professional fighters 35 years of age or older and/or retired were included. Participants were categorised as either having TES (TES+) or not (non-TES). TES+ participants were further subtyped by their cognitive profile. Multiple linear regression models were used to compare MRI-based regional brain volumes, cognitive performance, plasma tau and neurofilament light levels between TES- and TES+ groups., Results: 176 participants (110 boxers and 66 MMA) were included in the analysis. 72 (41%)/176 were categorised as having TES, the likelihood of TES increasing with age. TES+ participants tended to be boxers, started fighting at a younger age, had more professional fights and knocked out more frequently. The TES+ group had lower regional brain volumes including both grey and white matter structures. TES+ also had lower scores on simple and choice reaction time, psychomotor speed and Trails A ., Conclusion: The new TES criteria does distinguish a group of fighters with differences in regional brain volumes and reduced cognitive function. Our findings support the use of the NINDS criteria for TES in further research of the long-term effects of repetitive head impacts., Competing Interests: Competing interests: Dr Bernick has received research funding for the Professional Athletes Brain Health Study from UFC, Top Rank promotions, Belator promotions and Haymon Boxing. The other authors do not have any competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2022 the Alzheimer's Association.)

Background and Objectives: This study compares longitudinal changes in cognitive functioning and brain structures in male fighters who transitioned to an inactive fighting status without any further exposure to repetitive head impacts (RHIs) and fighters remaining active with continual exposure to RHIs., Methods: Participants were recruited from the Professional Fighters Brain Health Study. At time point (TP)1, all fighters were active, with continual exposure to RHIs. At TP2, fighters were considered "transitioned" if they had no sanctioned professional fights and had not been sparring for the past 2 years. Fighters were considered "active" if they continued to train and compete. All fighters underwent cognitive testing and 3T MRI at both TPs. A subset of our fighters (50%) underwent blood sampling for the characterization of neurofilament light (NfL) levels at both TPs. Linear mixed-effect models were applied to investigate the potentially different longitudinal trajectories (interaction effect between group and time) of cognitive function measures, NfL levels, and regional thickness measures (derived from structural MRI) between transitioned and active fighters., Results: Forty-five male transitioned fighters (aged 31.69 ± 6.27 years [TP1]; 22 boxers, 22 mixed martial artists, and 1 martial artist) and 45 demographically matched male active fighters (aged 30.24 ± 5.44 years [TP1]; 17 boxers, 27 mixed martial artists, and 1 martial artist) were included in the analyses. Significantly different longitudinal trajectories between transitioned and active fighters were observed in verbal memory ( p FDR = 4.73E-04), psychomotor speed ( p FDR = 4.73E-04), processing speed ( p FDR = 3.90E-02), and NfL levels ( p = 0.02). Transitioned fighters demonstrated longitudinally improved cognitive functioning and decreased NfL levels, and active fighters demonstrated declines in cognitive performance and stable NfL levels. Of 68 cortical regions inspected, 54 regions demonstrated a consistently changing trajectory, with thickness measures stabilizing on a group level for transitioned fighters and subtly declining over time for active fighters., Discussion: After fighters' cessation of RHI exposure, cognitive function and brain thickness measures may stabilize and blood NfL levels may decline. This study could be a starting point to identify potential predictors of individuals who are at a higher risk of RHI-related long-term neurologic conditions., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

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., Competing Interests: C.B. has served as an advisor for Optina Diagnostics. P.G. (in the last 3 y) has provided consulting to AstraZeneca, Astellas Pharma, Bayer, Bristol Myers Squibb, Clovis Oncology, Dyania Health, Driver, EMD Serono, Exelixis, Foundation Medicine, Guardant Health, Genentech/Roche, Genzyme, GlaxoSmithKline, Heron Therapeutics, Immunomedics/Gilead, Infinity Pharmaceuticals, Janssen, Merck & Co., Mirati Therapeutics, Pfizer, QED Therapeutics, Regeneron Pharmaceuticals, Seattle Genetics, 4D Pharma PLC, UroGen; his institution has received research funding from Bavarian Nordic, Bristol Myers Squibb, Clovis Oncology, Debiopharm, EMD Serono, GlaxoSmithKline, Immunomedics, Kure It Cancer Research, Merck & Co., Mirati Therapeutics, Pfizer, QED Therapeutics. J.L.G. has received research funding from FerGene Pharmaceuticals Inc. J.L.W. has received research funding from Alto Biosciences, Nucleix, Merck and Janssen, and he has served as a consultant to Sanofi Genzyme. He has also received royalties from up to date. The remaining authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The search for disease modifying therapies in Alzheimers disease (AD) has recently led to promising results but also revealed design issues in clinical trials themselves. Of particular importance is the potential statistical challenges that can arise when dosages change after an interim analysis, which is not uncommon in contemporary AD trials. Following the recent Aducanumab trials, we sought to study the implications of dose changes on the statistical power of an AD trial. We conducted extensive simulations to calculate statistical power when the relationship between treatment effect size and time is linear or non-linear, and the investigated drug has delayed treatment effect or not. Statistical power depends on many design factors including the dose change time, correlation, population homogeneity, and treatment effect time. We recommend that researchers conduct simulation studies at the interim analysis to justify the modified sample size and/or follow-up time modification meanwhile the type I and II error rates are controlled., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

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., Competing Interests: CB has received research funding from the Ultimate Fighters Championship, Top Rank promotions, Haymon Boxing, and Bellator/Spike TV. JA has authored intellectual property related to the C3 Logix software. JC has provided consultation to Acadia, Actinogen, AgeneBio, Alkahest, Alzheon, Annovis, Avanir, Axsome, Biogen, Cassava, Cerecin, Cerevel, Cognoptix, Cortexyme, EIP Pharma, Eisai, Foresight, Gemvax, Green Valley, Grifols, Hisun, Karuna, MapLight, Novo Nordisk, Nutricia, Orion, Otsuka, ReMYND, Resverlogix, Roche, Samumed, Samus Therapeutics, Third Rock, Signant Health, Sunovion, Suven, and United Neuroscience pharmaceutical and assessment companies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bernick, Shan, Bennett, Alberts and Cummings.)

Objective: To develop evidence-informed, expert consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE)., Methods: A panel of 20 expert clinician-scientists in neurology, neuropsychology, psychiatry, neurosurgery, and physical medicine and rehabilitation, from 11 academic institutions, participated in a modified Delphi procedure to achieve consensus, initiated at the First National Institute of Neurological Disorders and Stroke Consensus Workshop to Define the Diagnostic Criteria for TES , April, 2019. Before consensus, panelists reviewed evidence from all published cases of CTE with neuropathologic confirmation, and they examined the predictive validity data on clinical features in relation to CTE pathology from a large clinicopathologic study (n = 298)., Results: Consensus was achieved in 4 rounds of the Delphi procedure. Diagnosis of TES requires (1) substantial exposure to repetitive head impacts (RHIs) from contact sports, military service, or other causes; (2) core clinical features of cognitive impairment (in episodic memory and/or executive functioning) and/or neurobehavioral dysregulation; (3) a progressive course; and (4) that the clinical features are not fully accounted for by any other neurologic, psychiatric, or medical conditions. For those meeting criteria for TES, functional dependence is graded on 5 levels, ranging from independent to severe dementia. A provisional level of certainty for CTE pathology is determined based on specific RHI exposure thresholds, core clinical features, functional status, and additional supportive features, including delayed onset, motor signs, and psychiatric features., Conclusions: New consensus diagnostic criteria for TES were developed with a primary goal of facilitating future CTE research. These criteria will be revised as updated clinical and pathologic information and in vivo biomarkers become available., (© 2021 American Academy of Neurology.)

Traumatic brain injury (TBI) is a common source of functional impairment among athletes, military personnel, and the general population. Professional fighters in both boxing and mixed martial arts (MMA) are at particular risk for repetitive TBI and may provide valuable insight into both the pathophysiology of TBI and its consequences. Currently, effects of fighter weight class on brain volumetrics (regional and total) and functional outcomes are unknown. Fifty-three boxers and 103 MMA fighters participating in the Professional Fighters Brain Health Study (PRBHS) underwent volumetric magnetic resonance imaging (MRI) and neuropsychological testing. Fighters were divided into lightweight (≤139.9 lb), middleweight (140.0-178.5 lb), and heavyweight (>178.5 lb). Compared with lightweight fighters, heavyweights displayed greater yearly reductions in regional brain volume (boxers: bilateral thalami; MMA: left thalamus, right putamen) and functional performance (boxers: processing speed, simple and choice reaction; MMA: Trails A and B tests). Lightweights suffered greater reductions in regional brain volume on a per-fight basis (boxers: left thalamus; MMA: right putamen). Heavyweight fighters bore greater yearly burden of regional brain volume and functional decrements, possibly related to differing fight dynamics and force of strikes in this division. Lightweights demonstrated greater volumetric decrements on a per-fight basis. Although more research is needed, greater per-fight decrements in lightweights may be related to practices of weight-cutting, which may increase vulnerability to neurodegeneration post-TBI. Observed decrements associated with weight class may result in progressive impairments in fighter performance, suggesting interventions mitigating the burden of TBI in professional fighters may both improve brain health and increase professional longevity., Competing Interests: Dr. Charles Bernick receives research funding support (see Funding Information section above). The remaining authors declare no relevant conflicts of interest., (© Michael J.C. Bray et al., 2021; Published by Mary Ann Liebert, Inc.)

Amyloid-[Formula: see text] (A[Formula: see text]) 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[Formula: see text] 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[Formula: see text] 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.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Zhuang, Mishra, Nandy, Yang, Sreenivasan, Bennett, Bernick and Cordes.)

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., (Copyright © 2020 Bennett, Stephen, Bernick, Shan and Banks.)

Objective: Repetitive head impacts (RHIs) in combat sports are associated with cognitive decline and brain volume reduction. While fighting style differences between boxers, mixed martial artists (MMAs), and martial artists (MAs) have resulted in a broader spectrum of injury, the effects of RHIs on MAs relative to other fighters have not yet been explored. This study aimed to determine a differential effect of fighting style on cognition and brain., Setting: A large outpatient medical center specializing in neurological care., Participants, Design, and Main Measures: In total, 40 MAs, 188 boxers, and 279 MMAs were compared on baseline measures of subcortical regional brain volumes, after controlling for total brain volumes, and cognitive performance., Results: Significant differences between MAs, MMAs, and boxers were observed in subcortical brain structure volumes and cognitive measures. MMAs and MAs consistently had larger volumes and higher scores than boxers. Fighting style significantly moderated the relationship between the number of professional fights and the volumes of various subcortical brain structures and performance on a measure of processing speed at baseline., Conclusions: Differences in RHIs across fighting styles may be of clinical significance. Exploring changes over time within the MA, boxer, and MMA cohorts may provide insight into longer-term discrepancies in subcortical regional brain volumes and cognitive functioning across fighting styles.

Objective: This study tests the hypothesis that certain MRI-based regional brain volumes will show reductions over time in a cohort exposed to repetitive head impacts (RHI)., Methods: Participants were drawn from the Professional Fighters Brain Health Study, a longitudinal observational study of professional fighters and controls. Participants underwent annual 3T brain MRI, computerized cognitive testing, and blood sampling for determination of neurofilament light (NfL) and tau levels. Yearly change in regional brain volume was calculated for several predetermined cortical and subcortical brain volumes and the relationship with NfL and tau levels determined., Results: A total of 204 participants who had at least 2 assessments were included in the analyses. Compared to controls, the active boxers had an average yearly rate of decline in volumes of the left thalamus (102.3 mm 3 /y [ p = 0.0004], mid anterior corpus callosum (10.2 mm 3 /y [ p = 0.018]), and central corpus callosum (16.5 mm 3 /y [ p = <0.0001]). Retired boxers showed the most significant volumetric declines compared to controls in left (32.1 mm 3 /y [ p = 0.002]) and right (30.6 mm 3 /y [ p = 0.008]) amygdala and right hippocampus (33.5 mm 3 /y [ p = 0.01]). Higher baseline NfL levels were associated with greater volumetric decline in left hippocampus and mid anterior corpus callosum., Conclusion: Volumetric loss in different brain regions may reflect different pathologic processes at different times among individuals exposed to RHI., (© 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

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.

Introduction: New treatments for neurodegenerative disease are urgently needed, and clinical trial methods are an essential component of new drug development. Although a parallel-group study design for neurological disorder clinical trials is commonly used to test the effectiveness of a new treatment as compared to placebo, it does not efficiently use information from the on-going study to increase the success rate of a trial or to stop a trial earlier when the new treatment is indeed ineffective., Methods: We review some recent advances in designs for clinical trials, including futility designs and adaptive designs., Results: Futility designs and noninferiority designs are used to test the nonsuperiority and the noninferiority of a new treatment, respectively. We provide some guidance on using these two designs and analyzing data from these studies properly. Adaptive designs are increasingly used in clinical trials to improve the flexibility and efficiency of trials with the potential to reduce resources, time, and costs. We review some typical adaptive designs and new statistical methods to handle the statistical challenges from adaptive designs., Discussion: Statistical advances in clinical trial designs may be helpful to shorten study length and benefit more patients being treated with a better treatment during the discovery of new therapies for neurological disorders. Advancing statistical underpinnings of neuroscience research is a critical aspect of the core activities supported by the Center of Biomedical Research Excellence award supporting the Center for Neurodegeneration and Translational Neuroscience.

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., (© 2017 The British Psychological Society.)

Repeated head trauma experienced by active professional fighters results in various structural, functional and perfusion damage. However, whether there are common regions of structural and perfusion damage due to fighting and whether these structural and perfusion differences are associated with neuropsychological measurements in active professional fighters is still unknown. To that end, T1-weighted and pseudocontinuous arterial spin labeling MRI on a group of healthy controls and active professional fighters were acquired. Voxelwise group comparisons, in a univariate and multivariate sense, were performed to investigate differences in gray and white matter density (GMD, WMD) and cerebral blood flow (CBF) between the two groups. A significantly positive association between global GMD and WMD was obtained with psychomotor speed and reaction time, respectively, in our cohort of active professional fighters. In addition, regional WMD deficit was observed in a cluster encompassing bilateral pons, hippocampus, and thalamus in fighters (0.49 ± 0.04 arbitrary units (a.u.)) as compared to controls (0.51 ± 0.05a.u.). WMD in the cluster of active fighters was also significantly associated with reaction time. Significantly lower CBF was observed in right inferior temporal lobe with both partial volume corrected (46.9 ± 14.93 ml/100 g/min) and non-partial volume corrected CBF maps (25.91 ± 7.99 ml/100 g/min) in professional fighters, as compared to controls (65.45 ± 22.24 ml/100 g/min and 35.22 ± 12.18 ml/100 g/min respectively). A paradoxical increase in CBF accompanying right cerebellum and fusiform gyrus in the active professional fighters (29.52 ± 13.03 ml/100 g/min) as compared to controls (19.43 ± 12.56 ml/100 g/min) was observed with non-partial volume corrected CBF maps. Multivariate analysis with both structural and perfusion measurements found the same clusters as univariate analysis in addition to a cluster in right precuneus. Both partial volume corrected and non-partial volume corrected CBF of the cluster in the thalamus had a significantly positive association with the number of fights. In addition, GMD of the cluster in right precuneus was significantly associated with psychomotor speed in our cohort of active professional fighters. Our results suggest a heterogeneous pattern of structural and CBF deficits due to repeated head trauma in active professional fighters. This finding indicates that investigating both structural and CBF changes in the same set of participants may help to understand the pathophysiology and progression of cognitive decline due to repeated head trauma.

Objectives: Cumulative head trauma may alter brain structure and function. We explored the relationship between exposure variables, cognition and MRI brain structural measures in a cohort of professional combatants., Methods: 224 fighters (131 mixed martial arts fighters and 93 boxers) participating in the Professional Fighters Brain Health Study, a longitudinal cohort study of licensed professional combatants, were recruited, as were 22 controls. Each participant underwent computerised cognitive testing and volumetric brain MRI. Fighting history including years of fighting and fights per year was obtained from self-report and published records. Statistical analyses of the baseline evaluations were applied cross-sectionally to determine the relationship between fight exposure variables and volumes of the hippocampus, amygdala, thalamus, caudate, putamen. Moreover, the relationship between exposure and brain volumes with cognitive function was assessed., Results: Increasing exposure to repetitive head trauma measured by number of professional fights, years of fighting, or a Fight Exposure Score (FES) was associated with lower brain volumes, particularly the thalamus and caudate. In addition, speed of processing decreased with decreased thalamic volumes and with increasing fight exposure. Higher scores on a FES used to reflect exposure to repetitive head trauma were associated with greater likelihood of having cognitive impairment., Conclusions: Greater exposure to repetitive head trauma is associated with lower brain volumes and lower processing speed in active professional fighters., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by a distinct pattern of hyperphosphorylated tau (p-tau). Thought to be caused by repetitive concussive and subconcussive injuries, CTE is considered largely preventable. The majority of neuropathologically confirmed cases have occurred in professional contact sport athletes (eg, boxing, football). A recent post-mortem case series has magnified concerns for the public's health following its identification in six high school level athletes. CTE is diagnosed with certainty only following a post-mortem autopsy. Efforts to define the etiology and clinical progression during life are ongoing. The goal of this article is to characterize the clinical concepts associated with short- and long-term effects of repetitive traumatic brain injury, with a special emphasis on new clinical diagnostic criteria for CTE. Utilizing these new diagnostic criteria, two cases of neuropathologically confirmed CTE, one in a professional football player and one in a professional boxer, are reported. Differences in cerebellar pathology in CTE confirmed cases in boxing and football are discussed., (© 2015 International Society of Neuropathology.)

Repetitive head trauma is a risk factor for Alzheimer's disease and is the primary cause of chronic traumatic encephalopathy. However, little is known about the natural history of, and risk factors for, chronic traumatic encephalopathy or about means of early detection and intervention. The Professional Fighters Brain Health Study is a longitudinal study of active professional fighters (boxers and mixed martial artists), retired professional fighters, and controls matched for age and level of education. The main objective of the Professional Fighters Brain Health Study is to determine the relationships between measures of head trauma exposure and other potential modifiers and changes in brain imaging and neurological and behavioral function over time. The study is designed to extend over 5 years, and we anticipate enrollment of more than 400 boxers and mixed martial artists. Participants will undergo annual evaluations that include 3-tesla magnetic resonance imaging scanning, computerized cognitive assessments, speech analysis, surveys of mood and impulsivity, and blood sampling for genotyping and exploratory biomarker studies. Statistical models will be developed and validated to predict early and progressive changes in brain structure and function. A composite fight exposure index, developed as a summary measure of cumulative traumatic exposure, shows promise as a predictor of brain volumes and cognitive function.

Background: Factors that affect the rate of progression of Alzheimer disease (AD) need to be considered in the clinical trial designs of potential disease-modifying therapies., Objective: To determine the influence of age on AD course in a clinical trial setting., Design: Pooled cohort study from 3 AD clinical trials of 18-month duration conducted by the Alzheimer Disease Cooperative Study group., Setting: Alzheimer disease research centers from across the United States., Patients: Four hundred seventy-one subjects with mild to moderate AD assigned to the placebo arm of 3 clinical trials., Main Outcome Measures: The relationships between baseline age and rate of change in the Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-cog) 11, Mini-Mental State Examination, Clinical Dementia Rating scale Sum of Boxes score, Alzheimer Disease Cooperative Study–activities of daily living scale, and Neuropsychiatric Inventory were analyzed using a mixed-effect regression model. Sample size calculation for possible future AD clinical trials lasting 18 months using the results of the change in ADAS-cog 11 by tertiles of age groups., Results: Older age at baseline was associated with a slower rate of decline in the ADAS-cog 11 and the Mini-Mental State Examination scores. Almost twice as many subjects aged 80 years and older compared with those aged younger than 70 years would be required to demonstrate a 30% treatment effect on the ADAS-cog 11 in an 18-month AD trial., Conclusion: Subject age is an important factor to consider when defining the study population in and analyzing data from AD trials of potential disease-modifying therapies.

Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P(combined) = 3.2 × 10(-8)). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10(-9)) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5' UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.

Background and Purpose: To determine whether progression of MRI-defined vascular disease predicts subsequent vascular events in the elderly., Methods: The Cardiovascular Health Study, a longitudinal cohort study of vascular disease in the elderly, allows us to address this question because its participants had 2 MRI scans≈5 years apart and have been followed for ≈9 years since the follow-up scan for incident vascular events., Results: Both MRI-defined incident infarcts and worsened white matter grade were significantly associated with heart failure, stroke, and death, but not transient ischemic attacks, angina, or myocardial infarction. Strongest associations occurred when both incident infarcts and worsened white matter grade were present for heart failure (hazard ratio, 1.79; 95% confidence interval, 1.18-2.73), stroke (hazard ratio, 2.58; 95% confidence interval, 1.53-4.36), death (hazard ratio, 1.69; 95% confidence interval, 1.28-2.24), and cardiovascular death (hazard ratio, 1.97; 95% confidence interval, 1.24-3.14)., Conclusions: Progression of MRI-defined vascular disease identifies elderly people at increased risk for subsequent heart failure, stroke, and death. Whether aggressive risk factor management would reduce risk is unknown.

This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of key scientific and public-policy needs identified in this document will be incorporated by the Alzheimer Study Group into a broader National Alzheimer's Strategic Plan, which will be presented to the 111th Congress and the Obama administration in March 2009. The Alzheimer's Strategic Plan is expected to include additional recommendations for governance, family support, healthcare, and delivery of social services.

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.