Repetitive Head Impact Exposure Research Articles

White Matter Hyperintensities and Microstructural Alterations in Contact Sport Athletes from Adolescence to Early Midlife.

Studies have demonstrated associations between cumulative concussion and repetitive head impact exposure (RHI) via contact sports with white matter (WM) alterations later in life. The course of WM changes associated with exposure earlier in the lifespan are unclear. This study investigated alterations in white matter (WM hyperintensity [WMH] volume and microstructural changes) associated with concussion and RHI exposure from adolescence to early midlife, as well as the interaction between exposure and age-cohort (i.e., adolescent/young adult compared to early midlife athlete cohorts) on WM outcomes. Participating football players included an adolescent/young adulthood cohort (n=82; Mage=18.41.7) and an early midlife cohort (37 former collegiate players approximately 15-years removed from sport; Mage=37.71.4). Years of football participation and number of prior concussions were exposures of interest. White matter outcomes included log-transformed manually segmented total WMH volume and neurite orientation dispersion and density imaging metrics of microstructure/organization (isotropic volume fraction[Viso], intra-cellular volume fraction[Vic], and orientation dispersion[OD]). Regression models were fit to test effects of concussion history, years of football participation, and age-cohort by years of football participation with WM outcomes. Spearman's correlations assessed associations between significant WM metrics and measures of cognitive and psychological function. A significant age-cohort by years of participation effect was observed for whole brain white matter OD, B=-0.002, SE=0.001, p=0.001. The interaction was driven by a negative association between years of participation and OD within the younger cohort, B=-0.001, SE=0.0004, p=0.008, whereas a positive association between participation and OD in the early midlife cohort, B=0.001, SE=0.0003, p=0.039, was observed. Follow-up ROI analyses showed significant interaction effects for OD in the body of the corpus callosum, genu of the corpus callosum, cingulum, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, posterior thalamic radiation (ps<0.05). Greater concussion history was significantly associated with greater Viso in the early midlife cohort, B=0.001, SE= 0.0002, p=0.010. Years of participation and concussion history were not associated with WMH volume, ps>0.05. Performance on a measure of executive function was significantly associated with years of participation, =.34, p=.04, and a trend was observed for OD, =.28, p=.09 in the early midlife cohort only. The global characterization of white matter changes associated with years of football participation were broadly similar and stable from adolescence through early midlife (i.e., microstructural alterations, but not macroscopic lesions). An inverse association between years of participation and orientation dispersion across age-cohorts may represent a process of initial recovery/reorganization proximal to sport, followed by later reduction of white matter coherence.

Online longitudinal monitoring of brain health in former contact sport athletes: A study of acceptability and ethicality

AbstractRetrospective studies reveal that retired professional football players are at an increased risk of dementia. Prospective, longitudinal evidence in athletes diverse in sex, playing level, age and sport are now needed to understand the link between contact sport and dementia. The SCORES (Screening Cognitive Outcomes after Repetitive head impact Exposure in Sport) project investigates brain health online of former contact and non‐contact sport athletes as they age. Longitudinal study success is dependent on recruitment and retention. Both are influenced by perceived acceptability of participation. The SCORES project also offers regular feedback on assessment performance to participants, which raises ethical challenges. This study was designed to explore acceptability of the SCORES project to improve recruitment, retention and ensure ethicality amongst participants. Eight participants were purposively sampled and interviewed based on Sekhon's theoretical framework for assessing acceptability. Responses were analysed deductively against this framework. Main findings were that promoting altruistic and personal benefits of participation could aid recruitment. Conversely, computer literacy and the possibility of discovering a decline in their brain health was a potential barrier. Participants identified clarity of instructions, regular non‐intrusive researcher contact, low assessment burden, emphasis on participation as voluntary and the promotion of a community as avenues towards improving retention. They identified assessment frustration and challenging assessments as possible reasons for attrition. Participants viewed feedback as both necessary and important and made suggestions for ensuring ethicality. Findings from this study demonstrate how longitudinal online studies of athletes can be improved to aid recruitment, retention and ethicality.

The Effects of Repetitive Head Impact Exposure on Mental Health Symptoms Following Traumatic Brain Injury.

This study aimed to characterize the types and timing of repetitive head impact (RHI) exposures in individuals with moderate to severe traumatic brain injury (TBI) and to examine the effects of RHI exposures on mental health outcomes. TBI Model Systems National Database. 447 patients with moderate to severe TBI who reported RHI exposure between 2015 and 2022. Secondary data analysis. RHI exposures reported on the Ohio State University TBI Identification Method (OSU TBI-ID) were characterized by exposure category, duration, and timing relative to the index TBI. Mental health outcomes were evaluated at the 5-year follow-up assessment using the Patient Health Questionnaire-9 (PHQ-9) for depression symptoms and the Generalized Anxiety Disorder-7 (GAD-7) for anxiety symptoms. The majority of RHI exposures were sports-related (61.1%), followed by other causes (20.8%; including falls), repetitive violence/assault (18.8%), and military exposures (6.7%). Males predominantly reported sports and military exposures, while a larger proportion of females reported violence and falls. Sports exposures were most common before the index TBI, while exposures from falls and violence/abuse were most common after TBI. RHI exposures occurring after the index TBI were associated with higher levels of depression (β = 5.05; 95% CI, 1.59-8.50) and anxiety (β = 4.53; 95% CI, 1.02-8.05) symptoms than exposures before the index TBI. The findings emphasize the need to consider RHI exposures and their interaction with TBI when assessing mental health outcomes. Understanding the prevalence and challenges associated with RHI post-TBI can inform targeted interventions and improve the well-being of individuals with TBI. Preventive measures and ongoing care should be implemented to address the risks posed by RHI, particularly in individuals with prior TBI, especially surrounding fall and violence/abuse prevention.

Repetitive head impacts among professional fighters: a pilot study evaluating Traumatic Encephalopathy Syndrome and postural balance

ABSTRACT 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 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 repetitive head impact (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.

Inflammatory biomarkers for neurobehavioral dysregulation in former American football players: findings from the DIAGNOSE CTE Research Project

BackgroundTraumatic encephalopathy syndrome (TES) is defined as the clinical manifestation of the neuropathological entity chronic traumatic encephalopathy (CTE). A core feature of TES is neurobehavioral dysregulation (NBD), a neuropsychiatric syndrome in repetitive head impact (RHI)-exposed individuals, characterized by a poor regulation of emotions/behavior. To discover biological correlates for NBD, we investigated the association between biomarkers of inflammation (interleukin (IL)-1β, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) in cerebrospinal fluid (CSF) and NBD symptoms in former American football players and unexposed individuals.MethodsOur cohort consisted of former American football players, with (n = 104) or without (n = 76) NBD diagnosis, as well as asymptomatic unexposed individuals (n = 55) from the DIAGNOSE CTE Research Project. Specific measures for NBD were derived (i.e., explosivity, emotional dyscontrol, impulsivity, affective lability, and a total NBD score) from a factor analysis of multiple self-report neuropsychiatric measures. Analyses of covariance tested differences in biomarker concentrations between the three groups. Within former football players, multivariable linear regression models assessed relationships among log-transformed inflammatory biomarkers, proxies for RHI exposure (total years of football, cumulative head impact index), and NBD factor scores, adjusted for relevant confounding variables. Sensitivity analyses tested (1) differences in age subgroups (< 60, ≥ 60 years); (2) whether associations could be identified with plasma inflammatory biomarkers; (3) associations between neurodegeneration and NBD, using plasma neurofilament light (NfL) chain protein; and (4) associations between biomarkers and cognitive performance to explore broader clinical symptoms related to TES.ResultsCSF IL-6 was higher in former American football players with NBD diagnosis compared to players without NBD. Furthermore, elevated levels of CSF IL-6 were significantly associated with higher emotional dyscontrol, affective lability, impulsivity, and total NBD scores. In older football players, plasma NfL was associated with higher emotional dyscontrol and impulsivity, but also with worse executive function and processing speed. Proxies for RHI exposure were not significantly associated with biomarker concentrations.ConclusionSpecific NBD symptoms in former American football players may result from multiple factors, including neuroinflammation and neurodegeneration. Future studies need to unravel the exact link between NBD and RHI exposure, including the role of other pathophysiological pathways.

Subjective and Performance-Based Cognition and Their Associations with Head Injury History in Older Former National Football League Players.

Investigate the association between self-reported subjective and performance-based cognition among older (50-70 years) former professional American football players, as well as the relationship of cognitive measures with concussion history and years of football participation, as a proxy for repetitive head impact exposure. Among older former National Football League (NFL) players ( N = 172; mean age = 60.69 ± 5.64), associations of subjective (Patient Reported Outcome Measurement Information System Cognitive Function-Short Form) and performance-based cognitive measures (Brief Test of Adult Cognition by Telephone [BTACT] Executive Function and Episodic Memory indices) were assessed via univariable and multivariable regression models, with a priori covariates of depression and race. A similar univariate and multivariable regression approach assessed associations between concussion history and years of football participation with subjective and performance-based cognitive measures. In a sample subset ( n = 114), stability of subjective cognitive rating was assessed via partial correlation. Subjective ratings of cognition were significantly associated with performance-based assessment, with moderate effect sizes (episodic memory ηp2 = 0.12; executive function ηp2 = 0.178). These associations were weakened, but remained significant ( P s < 0.05), with the inclusion of covariates. Greater concussion history was associated with lower subjective cognitive function ( ηp2 = 0.114, P < 0.001), but not performance-based cognition. The strength of association between concussion history and subjective cognition was substantially weakened with inclusion of covariates ( ηp2 = 0.057). Years of participation were not associated with measures of subjective or objective cognition ( P s > 0.05). These findings reinforce the importance of comprehensive evaluation reflecting both subjective and objective measures of cognition, as well as the consideration of patient-specific factors, as part of a comprehensive neurobehavioral and health assessment of older former contact sport athletes.

Tau Positron Emission Tomography and Neurocognitive Function Among Former Professional American-Style Football Players.

American-style football (ASF) players experience repetitive head impacts that may result in chronic traumatic encephalopathy neuropathological change (CTE-NC). At present, a definitive diagnosis of CTE-NC requires the identification of localized hyperphosphorylated Tau (p-Tau) after death via immunohistochemistry. Some studies suggest that positron emission tomography (PET) with the radiotracer [18F]-Flortaucipir (FTP) may be capable of detecting p-Tau and thus establishing a diagnosis of CTE-NC among living former ASF players. To assess associations between FTP, football exposure, and objective neuropsychological measures among former professional ASF players, we conducted a study that compared former professional ASF players with age-matched male control participants without repetitive head impact exposure. Former ASF players and male controls underwent structural magnetic resonance imaging and PET using FTP for p-Tau and [11C]-PiB for amyloid-β. Former players underwent neuropsychological testing. The ASF exposure was quantified as age at first exposure, professional career duration, concussion signs and symptoms burden, and total years of any football play. Neuropsychological testing included measures of memory, executive functioning, and depression symptom severity. P-Tau was quantified as FTP standardized uptake value ratios (SUVR) and [11C]-PiB by distribution volume ratios (DVR) using cerebellar grey matter as the reference region. There were no significant differences in [18F]-FTP uptake among former ASF players (n = 27, age = 50 ± 7 years) compared with control participants (n = 11, age = 55 ± 4 years), nor did any participant have significant amyloid-β burden. Among ASF participants, there were no associations between objective measures of neurocognitive functioning and [18F]-FTP uptake. There was a marginally significant difference, however, between [18F]-FTP uptake isolated to the entorhinal cortex among players in age-, position-, and race-adjusted models (p = 0.05) that may represent an area of future investigation. The absence of increased [18F]-FTP uptake in brain regions previously implicated in CTE among former professional ASF players compared with controls questions the utility of [18F]-FTP PET for clinical evaluation in this population.

Increased spatial extent of cerebral tau PET elevations in former NFL and college football players from the DIAGNOSE CTE Research Project

AbstractBackgroundWe previously found greater spatial extent of flortaucipir (tau) PET elevations in Arizona‐Boston (DETECT) Study of 26 former National Football League (NFL) players than in 31 normal controls—using a voxel‐based Majority Count Statistics (MCS) algorithm which enabled us to detect tau PET abnormalities in the player group free from the inflated Type 1 error associated with voxel‐wise multiple comparisons (Stern et al, NEJM 2019). We now confirm this finding in a larger group of former NFL players, former college football players and asymptomatic controls without exposure to repetitive head impacts from the DIAGNOSE CTE Research Project.MethodFlortaucipir PET images were acquired in 106 former NFL players, 51 former college players, and 53 unexposed controls, 57.71+8.37 years of age. An automated algorithm (SPM12) and co‐registered MRIs were used to spatially normalize PET images into Montreal Neurological Institute template, and compute statistical brain maps of group differences in regional cerebral‐to‐cerebellar crus1 standard uptake value ratio (SUVR), controlling for the participants’ age and race with P≤0.005, uncorrected for multiple comparisons. Our MCS was then applied with 1,000 iterations to test the hypothesis that there would be a greater number of cerebral voxels with SUVR elevations in each and combined player group versus control group, as well as between the NFL versus college player groups.ResultAs predicted, the NFL, college player and aggregate player groups each had significantly more cerebral voxels with flortaucipir SUVR elevations than in the control group (postulated vs opposite directions: 53,879 vs 79, 79,552 vs 89 and 100,837 vs 86 voxels), respectively, MCS P&lt;0.001, but not between former NFL and former college players (482 versus 306, p = 0.305).ConclusionUsing a voxel based MCS analysis, former NFL and college football players have a greater spatial extent of elevations in tau PET measurements than asymptomatic controls. Additional work is needed to clarify the biological nature of these small but spatially extensive elevations, the extent to which they are related to symptom severity, cognitive performance, repetitive head impact exposure, and other risk or resilience factors, and the extent to which they are associated with subsequent clinical decline.

Contact or Collision Sport History, Repetitive Neurotrauma, and Patient-Reported Outcomes in Early to Midadulthood.

Data on the early to midlife effects of repetitive neurotrauma on patient-reported outcomes have been delimited to homogeneous samples of male athletes without comparison groups or accounting for modifying factors such as physical activity. To determine the effect of contact or collision sport participation and repetitive neurotrauma on patient-reported outcomes among early to middle-aged adults. Cross-sectional study. Research laboratory. A total of 113 adults (53 [46.9%] men, 60 [53.1%] women; age = 34.88 ± 11.80 years) in 4 groups: (1) physically inactive individuals with no repetitive head impact (RHI) exposure (NON); (2) noncontact sport athletes and nonathletes with no RHI exposure who were currently physically active (NCA); (3) former high-risk sport athletes with an RHI history who were physically active (HRS); and (4) former rugby players with prolonged RHI exposure who remained physically active. The 12-Item Short-Form Health Survey (SF-12), Apathy Evaluation Scale-self-rated version (AES-S), Satisfaction With Life Scale (SWLS), and Sport Concussion Assessment Tool-5th Edition (SCAT5) Symptom and Symptom Severity Checklist. The NON group had worse self-rated physical function than the NCA group as assessed by the SF-12 physical component summary (P = .03) and worse self-rated apathy (AES-S) and satisfaction with life (SWLS) than the NCA (P = .03 for both) and HRS groups (P = .03 and P = .040, respectively). We observed no group differences for self-rated mental health (SF-12 mental component summary; P = .26) or symptoms (SCAT5; P = .42). Career duration was not associated with any patient-reported outcomes. A history of contact or collision sport participation and career duration did not negatively affect patient-reported outcomes in physically active, early to middle-aged adults. However, physical inactivity status was negatively associated with patient-reported outcomes in these individuals in the absence of an RHI history.

Comparison of Various Metrics of Repetitive Head Impact Exposure And Their Associations With Neurocognition in Collegiate-Aged Athletes.

Characterize the levels of various metrics of repetitive head impacts (RHI) in contact (CS) and non-contact (NCS) sport athletes and determine the extent to which they are associated with fluid cognition. Collegiate-aged athletes (n = 176) completed semi-structured interviews about participation in contact sport. RHI was operationalized based on current sport (CS/NCS), the cumulative number of years of participation, age at first exposure (AFE), and based on recently proposed traumatic encephalopathy syndrome (TES) categories. The NIH Toolbox Cognition Battery assessed fluid cognition. General linear models compared RHI metrics between CS and NCS athletes and tested associations of RHI measures with fluid cognition. CS athletes had more years of RHI exposure, higher rates of "extensive" exposure based on TES criteria, and were more likely to have AFE before age 12 relative to NCS (ps < .001). A subset of NCS athletes, however, reported prior RHI at levels categorized as being "extensive" based on TES criteria (5%), while a larger minority had AFE before 12 (34%). No adverse associations of RHI and fluid cognition were observed (ps > .05). Across all RHI metrics, more or earlier RHI was associated with better episodic memory (ps ≤ .05). Secondary analyses showed this effect was driven by women. Current results find no evidence that RHI in collegiate-aged athletes is associated with worse neurocognition. Although there was extensive overlap among RHI measures, results demonstrate that categorizing athletes based on their current sport undercounts the lifetime RHI exposure in many NCS athletes.

Differences in head impact biomechanics between playing positions in Canadian high school football players

ABSTRACT The objective of this study was to compare head impact magnitudes and time between impacts among positions in Canadian high-school football. Thirty nine players from two high-school football teams were recruited and assigned a position profile: Profile 1 (quarterback, receiver, defensive back, kicker), Profile 2 (linebacker, running back), and Profile 3 (linemen). Players wore instrumented mouthguards to measure peak magnitudes of linear and angular acceleration and velocity for each head impact throughout the season. A principal component analysis reduced the dimensionality of biomechanical variables, resulting in one principal component (PC1) score assigned to every impact. Time between impacts was calculated by subtracting the timestamps of subsequent head impacts within a session. Significant differences in PC1 scores and time between impacts occurred between playing position profiles (ps<0.001). Post-hoc comparisons determined that PC1 was greatest in Profile 2, followed by Profiles 1 and 3. Time between impacts was lowest in Profile 3, followed by Profiles 2 and 1. This study delivers a new method of reducing the multidimensionality of head impact magnitudes and suggests different Canadian high-school football playing positions experience different head impact magnitudes and frequencies, which is important for monitoring concussion and repetitive head impact exposure.

Effects of contact/collision sport history on gait in early- to mid-adulthood

BackgroundTo determine the effect of contact/collision sport participation on measures of single-task (ST) and dual-task (DT) gait among early- to middle-aged adults. MethodsThe study recruited 113 adults (34.88 ± 11.80 years, (mean ± SD); 53.0% female) representing 4 groups. Groups included (a) former non-contact/collision athletes and non-athletes who are not physically active (n = 28); (b) former non-contact/collision athletes who are physically active (n = 29); (c) former contact/collision sport athletes who participated in high-risk sports and are physically active (n = 29); and (d) former rugby players with prolonged repetitive head impact exposure history who are physically active (n = 27). Gait parameters were collected using inertial measurement units during ST and DT gait. DT cost was calculated for all gait parameters (double support, gait speed, and stride length). Groups were compared first using one-way analysis of covariance. Then a multiple regression was performed for participants in the high-risk sport athletes and repetitive head impact exposure athletes groups only to predict gait outcomes from contact/collision sport career duration. ResultsThere were no significant differences between groups on any ST, DT, or DT cost outcomes (p > 0.05). Contact/collision sport duration did not predict any ST, DT, or DT cost gait outcomes. ConclusionYears and history of contact/collision sport participation does not appear to negatively affect or predict neurobehavioral function in early- to mid-adulthood among physically active individuals.

Leveraging American football helmet accelerometer data to estimate associations between cumulative repetitive head impact exposure and chronic traumatic encephalopathy

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. We previously showed that duration of American football play is associated with risk and severity of CTE pathology. Helmet accelerometers have been used previously to examine frequency, linear acceleration, and rotational acceleration of hits sustained across youth, high school, and college football. Here we projected this data onto former American football playing brain donors to examine the relationship between cumulative frequency of hits, linear acceleration, and rotational acceleration during players’ athletic careers and CTE pathology.Method656 former American football playing brain donors from the Veterans Affairs‐Boston University‐Concussion Legacy Foundation Brain Bank were examined for CTE pathology and severity. Years and position of play at each level (youth, high school, college, professional) were acquired through retrospective clinical interviews with brain donors next‐of‐kin. From a literature search of studies using helmet accelerometers, we calculated the mean frequency of hits, linear acceleration (g‐force), and rotational acceleration (rad/sec2) for one year of play at each level‐position combination. These values were projected onto brain donors’ career exposure to derive cumulative frequency of head impacts (CHII), cumulative linear acceleration (CHII‐G), and cumulative rotational acceleration (CHII‐R). Separate logistic regression models examined the relationship of years of play, CHII, CHII‐G, and CHII‐R on CTE status and severity (low vs. high), adjusting for age at death.ResultThe mean (SD) age at death was 59.7 (20.1) and 451 (68.8%) had CTE pathology. Each cumulative measure was significantly associated with presence of CTE (p’s&lt;.001) and severity of CTE (p’s&lt;.001). Based on ROC analyses, CHII‐R (AUC=0.765, p&lt;.001) and CHII‐G (AUC= 0.758, p&lt;.001) performed significantly better than years of play (AUC=0.716) in classifying CTE pathology, and there was no difference between years of play and CHII (AUC=0.698, p=0.25). Similar relationships were observed for CTE severity. Model fit and cross‐validation statistics were also consistent (Table 2).ConclusionAmong former American football playing brain donors, cumulative linear and rotational acceleration were better predictors of CTE pathology than duration of play or cumulative hits. The findings suggest head impact intensity is an important factor in developing CTE pathology.

Associations of lifetime concussion history and repetitive head impact exposure with resting-state functional connectivity in former collegiate American football players: An NCAA 15-year follow-up study.

The objective of this study was to examine associations of lifetime concussion history (CHx) and an advanced metric of lifetime repetitive head impact exposure with resting-state functional connectivity (rsFC) across the whole-brain and among large-scale functional networks (Default Mode; Dorsal Attention; and Frontoparietal Control) in former collegiate football players. Individuals who completed at least one year of varsity collegiate football were eligible to participate in this observational cohort study (n = 48; aged 36-41 years; 79.2% white/Caucasian; 12.5±4.4 years of football played; all men). Individuals were excluded if they reported history/suspicion of psychotic disorder with active symptoms, contraindications to participation in study procedures (e.g., MRI safety concern), or inability to travel. Each participant provided concussion and football playing histories. Self-reported concussion history was analyzed in two different ways based on prior research: dichotomous "High" (≥3 concussions; n = 28) versus "Low" (<3 concussions; n = 20); and four ordinal categories (0-1 concussion [n = 19]; 2-4 concussions [n = 8]; 5-7 concussions [n = 9]; and ≥8 concussions [n = 12]). The Head Impact Exposure Estimate (HIEE) was calculated from football playing history captured via structured interview. Resting-state fMRI and T1-weighted MRI were acquired and preprocessed using established pipelines. Next, rsFC was calculated using the Seitzman et al., (2020) 300-ROI functional atlas. Whole-brain, within-network, and between-network rsFC were calculated using all ROIs and network-specific ROIs, respectively. Effects of CHx and HIEE on rsFC values were examined using separate multivariable linear regression models, with a-priori α set to 0.05. We observed no statistically significant associations between rsFC outcomes and either CHx or HIEE (ps ≥ .12). Neither CHx nor HIEE were associated with neural signatures that have been observed in studies of typical and pathological aging. While CHx and repetitive head impacts have been associated with changes in brain health in older former athletes, our preliminary results suggest that associations with rsFC may not be present in early midlife former football players.

Perivascular Space Morphology Is Affected By Career Exposure In Special Operations Forces Combat Soldiers

Special Operations Forces (SOF) combat Soldiers are at high risk for repetitive blast and head impact exposure. These exposures may predispose SOF combat Soldiers to acute brain injuries and subsequent chronic manifestations including sleep disorders reported by 40% of US Service Members. Studying brain morphology such as perivascular spaces (PVS) may illustrate a strong intersection between brain glymphatic system function and sleep quality. Cerebral PVS are glymphatic system passageways normally serving to clear brain metabolic waste during sleep. Increasing MRI visible PVS number and volume are a possible pathogenesis for neurodegenerative disorders. PURPOSE: To determine the association between PVS morphological characteristics and career stage in SOF combat Soldiers. METHODS: Healthy asymptomatic SOF combat Soldiers (age=33.0±4.1yrs) cross-sectionally participated in this study at two career stages: baseline (n=141) and in-career (n=76). We collected whole brain 3D T2-weighted magnetic resonance imaging (MRI) on a Siemens 3T Biograph mMR or 3T MAGNETOM Prisma with equivalent settings (TR/TE = 3200/400ms, slice thickness = 1mm, FoV = 256mm x 256 mm). We segmented the PVS using validated multi-scale deep convolutional encoder-decoder neural networks. All images were skull stripped and registered to a custom brain atlas using Advanced Normalization Tools to identify only PVS clusters within cerebral white matter. We quantified PVS number and volume. The PVS outcome variables were non-normally distributed. As such, we employed nonparametric Mann Whitney U tests to compare the two career stage groups. RESULTS: Median (IQR) data were as follows: PVS number = 37.0 (44.0); PVS volume = 647mm3 (972mm3). In-career SOF combat Soldiers had greater PVS number (z = 2.56, P = 0.01) and PVS volume (z = 2.28, P = 0.02). CONCLUSIONS: In-career SOF combat Soldiers (typically older) show higher segmented PVS number and volume compared to baseline cohort. Also, our PVS findings may indicate impairments with clearing brain wastes suggesting sleep interventions may be warranted in SOF combat Soldier populations who experience continued exposures to combat and training. Measuring the PVS may be an important outcome in determining the efficacy of sleep studies in this population. Funded by US Special Operations Command.

Association Between Head Impact Biomechanics and Physical Load in College Football.

Head impacts and physical exertion are ubiquitous in American football, but the relationship between these factors is poorly understood across a competitive season or even within an individual session. Gameplay characteristics, including player position and session type, may contribute to these relationships but have not been prospectively examined. The current study aimed to determine if an association exists between head impact biomechanics and physical load metrics. We prospectively studied college football players during the 2017–2021 football seasons across representative playing positions (15 offensive and defensive linemen, 11 linebackers and tight ends, and 15 defensive backs, running backs, and receivers). Participants wore halters embedded with Catapult Vector GPS monitoring systems to quantify player load and participant helmets were equipped with the Head Impact Telemetry System to quantify head impact biomechanics and repetitive head impact exposure (RHIE). Generalized linear models and linear regression models were employed to analyze in-session and season-long outcomes, while addressing factors such as player position and session type on our data. Player load was associated with RHIE (p < 0.001). Season-long player load predicted season-long RHIE (R2 = 0.31; p < 0.001). Position group affected in-session player load (p = 0.025). Both player load and RHIE were greater in games than in practices (p < 0.001), and position group did not affect RHIE (p = 0.343). Physical load burden was associated with RHIE within sessions and across an entire season. Session type affected both RHIE and player load, while position group only affected player load. Our data point to tracking physical load burden as a potential proxy for monitoring anticipated RHIE during the season.

Serum neurofilament light in professional soccer players: goal on safety.

Sports-related concussion (SRC) is a subset of mild traumatic brain injuries occurring in contact sports. Most people recover spontaneously, but in retired professional players, the risk for neurodegenerative diseases is increased. A biomarker, such as neurofilament light chains (NfL), would help to address this issue and demonstrate sports' safety. Assessing NfL in professional soccer players may be the best way to investigate if repetitive head-impact exposure in the typical lower and asymptomatic range is harmful. To evaluate whether the NfL in serum is a sensitive biomarker to detect mild brain injury in professional soccer players. Thirty-six soccer players belonging to a professional Italian team underwent serum NfL assessment using ultrasensitive single-molecule array technology. Sixteen healthy nonathletic controls were also enrolled. Differences between groups and changes over time, considering pre-season vs. season, were considered. Serum NfL concentrations were comparable in the soccer professional players (median [interquartile range], 6.44pg/mL [4.60-8.27] and controls (6.50pg/mL [5.26-7.04]), with a median difference of - 0.06pg/mL (95% CI -1.36 to 1.18), p = 0.957. No significant differences according to players' role (goalkeeper, defender, midfielder or forward) or according to timing of sampling (pre-season vs. season) were found. These results suggest that professional soccer, even when played at the highest level of competition, may be considered safe. Future studies assessing serum NfL levels after soccer-related concussions should be carried out, to evaluate their usefulness as a return-to-play marker avoiding second impact syndrome.

Plasma P-tau181 and P-tau217 in Patients With Traumatic Encephalopathy Syndrome With and Without Evidence of Alzheimer Disease Pathology.

Traumatic encephalopathy syndrome (TES) has overlapping clinical symptoms with Alzheimer disease (AD). AD pathology commonly co-occurs with chronic traumatic encephalopathy (CTE) pathology. There are currently no validated CTE biomarkers. AD-specific biomarkers such as plasma P-tau181 and P-tau217 may help to identify patients with TES who have AD pathology. We measured plasma P-tau181 and P-tau217 (Meso Scale Discovery electrochemiluminescence) in patients with TES, mild cognitive impairment/dementia with biomarker-confirmed AD ("AD"), and healthy controls ("HC"). Patients underwent amyloid-beta (Aβ)-PET and a subset underwent tau-PET using [18F]Flortaucipir. We compared plasma P-tau levels controlling for age and sex and also performed AUC analyses to evaluate the accuracy of group differentiation. In patients with TES, we evaluated associations between plasma P-tau, years of repetitive head impact exposure, and tau-PET. Four TES patients with autopsy-confirmed CTE were described qualitatively. The sample included 131 participants (TES, N = 18; AD, N = 65; HC, N = 48). Aβ(+) patients with TES (N = 10), but not Aβ(-) TES, had significantly higher plasma P-tau levels than HC (P-tau181: p < 0.001, d = 1.34; P-tau217: p < 0.001, d = 1.59). There was a trend for Aβ(+) TES having higher plasma P-tau than Aβ(-) TES (P-tau181: p = 0.06, d = 1.06; P-tau217: p = 0.09, d = 0.93). AUC analyses showed good classification of Aβ(+) TES from HC for P-tau181 (AUC = 0.87 [0.71-1.00]) and P-tau217 (AUC = 0.93 [0.86-1.00]). Plasma P-tau217 showed fair differentiation of Aβ(+) TES from Aβ(-) TES (AUC = 0.79 [0.54-1.00], p = 0.04), whereas classification accuracy of P-tau181 was slightly lower and not statistically significant (AUC = 0.71 [0.46-0.96], p = 0.13). Patients with AD had higher tau-PET tracer uptake than Aβ(+) TES and were well differentiated using P-tau181 (AUC = 0.81 [0.68-0.94]) and P-tau217 (AUC = 0.86 [0.73-0.98]). Plasma P-tau correlated with the tau-PET signal in Aβ(+) TES but not in Aβ(-) TES, and there was no association between plasma P-tau and years of repetitive head impact exposure. TES patients with severe CTE and no AD at autopsy had low P-tau181 and P-tau217 levels. Measuring P-tau181 and P-tau217 in plasma may be a feasible and scalable fluid biomarker for identifying AD pathology in TES. Low plasma P-tau levels may be used to increase clinical suspicion of CTE over AD as a primary pathology in TES. Currently, there is no support for P-tau181 or P-tau217 as in vivo biomarkers of CTE tau. Larger studies of patients with pathologically confirmed CTE are needed. This study provides Class III evidence that (1) among patients with TES and abnormal Aβ-PET scans, elevated plasma P-tau can differentiate between affected individuals and HCs; (2) low plasma P-tau may help identify patients with TES who do not have Alzheimer; and (3) plasma P-tau181 and P-tau217 are not useful biomarkers of patients with TES who do not have AD.

Dual-Task Gait Performance Following Head Impact Exposure in Male and Female Collegiate Rugby Players.

BackgroundGait impairments have been well-studied in concussed athletes. However, the sex-specific effect of cumulative head impacts on gait is not well understood. When a cognitive task is added to a walking task, dual-task gait assessments can help amplify deficits in gait and are representative of tasks in everyday life. Dual-task cost is the difference in performance from walking (single-task) to walking with a cognitive load (dual-task).PurposeThe objectives of this study were to explore the differences between sexes in 1) dual-task gait metrics, 2) gait metric changes from pre-season to post-concussion and post-season, and 3) the dual-task costs associated with gait metrics.Study DesignCross-sectional studyMethodsOver two seasons, 77 female athlete-seasons and 64 male athlete-seasons from collegiate club rugby teams participated in this study. Subjects wore inertial sensors and completed walking trials with and without a cognitive test at pre-season, post-season, and post-concussion (if applicable).ResultsFemales athletes showed improvement in cadence (mean = 2.7 step/min increase), double support time (mean = -0.8% gait cycle time decrease), gait speed (mean = 0.1 m/s increase), and stride length (mean = 0.2 m increase) in both task conditions over the course of the season (p < 0.030). Male athletes showed no differences in gait metrics over the course of the season, except for faster gait speeds and longer stride lengths in the dual-task condition (p < 0.034). In all four gait characteristics, at baseline and post-season, females had higher dual-task costs (mean difference = 4.4, p < 0.003) than the males.ConclusionsThis results of this study showed little evidence suggesting a relationship between repetitive head impact exposure and gait deficits. However, there are sex-specific differences that should be considered during the diagnosis and management of sports-related concussion.Level of EvidenceLevel 2b

A Preclinical Rodent Model for Repetitive Subconcussive Head Impact Exposure in Contact Sport Athletes.

Repetitive subconcussive head impact exposure has been associated with clinical and MRI changes in some non-concussed contact sport athletes over the course of a season. However, analysis of human tolerance for repeated head impacts is complicated by concussion and head impact exposure history, genetics, and other personal factors. Therefore, the objective of the current study was to develop a rodent model for repetitive subconcussive head impact exposure that can be used to understand injury mechanisms and tolerance in the human. This study incorporated the Medical College of Wisconsin Rotational Injury Model to expose rats to multiple low-level head accelerations per day over a 4-week period. The peak magnitude of head accelerations were scaled from our prior human studies of contact sport athletes and the number of exposures per day were based on the median (moderate exposure) and 95th percentile (high exposure) number of exposures per day across the human sample. Following the exposure protocol, rats were assessed for cognitive deficits, emotional changes, blood serum levels of axonal injury biomarkers, and histopathological evidence of injury. High exposure rats demonstrated cognitive deficits and evidence of anxiety-like behaviors relative to shams. Moderate exposure rats did not demonstrate either of those behaviors. Similarly, high exposure rats had histopathological evidence of gliosis [i.e., elevated Iba1 intensity and glial fibrillary acidic protein (GFAP) volume relative to shams] in the basolateral amygdala and other areas. Blood serum levels of neurofilament light (NFL) demonstrated a dose response relationship with increasing numbers of low-level head acceleration exposures with a higher week-to-week rate of NFL increase for the high exposure group compared to the moderate exposure group. These findings demonstrate a cumulative effect of repeated low-level head accelerations and provide a model that can be used in future studies to better understand mechanisms and tolerance for brain injury resulting from repeated low-level head accelerations, with scalable biomechanics between the rat and human.