National Athletic Trainers' Association Bridge Statement: Management of Sport-Related Concussion.

OBJECTIVE: To provide athletic trainers and team physicians with updated recommendations to the 2014 National Athletic Trainers' Association (NATA) concussion position statement regarding concussion management, specifically in the areas of education, assessment, prognostic factors, mental health, return to academics, physical activity, rest, treatment, and return to sport. BACKGROUND: Athletic trainers have benefited from the 2 previous NATA position statements on concussion management, and although the most recent NATA position statement is a decade old, knowledge gains in the medical literature warrant updating several (but not all) recommendations. Furthermore, in various areas of the body of literature, current evidence now exists to address items not adequately addressed in the 2014 statement, necessitating the new recommendations. This document therefore serves as a bridge from the 2014 position statement to the current state of concussion evidence, recommendations from other organizations, and discrepancies between policy and practice. RECOMMENDATIONS: These recommendations are intended to update the state of the evidence concerning the management of patients with sport-related concussion, specifically in the areas of education; assessment advances; prognostic recovery indicators; mental health considerations; academic considerations; and exercise, activity, and rehabilitation management strategies.

The Longitudinal Relationship Between Concussion History, Years of American Football Participation, and Alcohol Use Among Former National Football League Players: an NFL-LONG Study.

OBJECTIVE: Investigate the relationships between concussion history and years of football participation (repetitive head impact proxy) with alcohol use across multiple decades in former professional football players. METHODS: Participants (n = 348; mean age = 49.0 ± 9.4) completed health questionnaires in 2001 and 2019, which included self-reported concussion history and years of participation. Alcohol use frequency and amount per occasion were reported for three timepoints: during professional career, 2001, and 2019. Ordinal logistic regression models were fit to test associations of concussion history and years of participation with alcohol use at each timepoint. RESULTS: There were no significant associations between either concussion history or years of football participation with alcohol use (frequency and amount per occasion) at any timepoint. Effect estimates for concussion history and years of football participation with alcohol use were generally comparable across timepoints. CONCLUSIONS: Later life alcohol use by former American football players is not associated with concussion history or years of exposure to football.

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

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Longitudinal Associations Between Blood Biomarkers and White Matter MRI in Sport-Related Concussion: A Study of the NCAA-DoD CARE Consortium.

BACKGROUND AND OBJECTIVES: To study longitudinal associations between blood-based neural biomarkers (including total tau, neurofilament light [NfL], glial fibrillary acidic protein [GFAP], and ubiquitin C-terminal hydrolase-L1) and white matter neuroimaging biomarkers in collegiate athletes with sport-related concussion (SRC) from 24 hours postinjury to 1 week after return to play. METHODS: We analyzed clinical and imaging data of concussed collegiate athletes in the Concussion Assessment, Research, and Education (CARE) Consortium. The CARE participants completed same-day clinical assessments, blood draws, and diffusion tensor imaging (DTI) at 3 time points: 24-48 hours postinjury, point of becoming asymptomatic, and 7 days after return to play. DTI probabilistic tractography was performed for each participant at each time point to render 27 participant-specific major white matter tracts. The microstructural organization of these tracts was characterized by 4 DTI metrics. Mixed-effects models with random intercepts were applied to test whether white matter microstructural abnormalities are associated with the blood-based biomarkers at the same time point. An interaction model was used to test whether the association varies across time points. A lagged model was used to test whether early blood-based biomarkers predict later microstructural changes. RESULTS: Data from 77 collegiate athletes were included in the following analyses. Among the 4 blood-based biomarkers, total tau had significant associations with the DTI metrics across the 3 time points. In particular, high tau level was associated with high radial diffusivity (RD) in the right corticospinal tract (ß = 0.25, SE = 0.07, p FDR-adjusted = 0.016) and superior thalamic radiation (ß = 0.21, SE = 0.07, p FDR-adjusted = 0.042). NfL and GFAP had time-dependent associations with the DTI metrics. NfL showed significant associations only at the asymptomatic time point (|ß|s > 0.12, SEs <0.09, psFDR-adjusted < 0.05) and GFAP showed a significant association only at 7 days after return to play (ßs > 0.14, SEs <0.06, psFDR-adjusted < 0.05). The p values for the associations of early tau and later RD were not significant after multiple comparison adjustment, but were less than 0.1 in 7 white matter tracts. DISCUSSION: This prospective study using data from the CARE Consortium demonstrated that in the early phase of SRC, white matter microstructural integrity detected by DTI neuroimaging was associated with elevated levels of blood-based biomarkers of traumatic brain injury. Total tau in the blood showed the strongest association with white matter microstructural changes.

Targeted interventions and their effect on recovery in children, adolescents and adults who have sustained a sport-related concussion: a systematic review.

OBJECTIVES: We evaluated interventions to facilitate recovery in children, adolescents and adults with a sport-related concussion (SRC). DESIGN: Systematic review including risk of bias (modified Scottish Intercollegiate Guidelines Network tool). DATA SOURCES: MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase, APA PsycINFO, Cochrane Central Register of Controlled Trials, CINAHL Plus with Full Text, SPORTDiscus and Scopus searched until March 2022. STUDY ELIGIBILITY CRITERIA: (1) Original research including randomised controlled trials (RCTs), quasi-experimental designs, cohort, comparative effectiveness studies; (2) focus on SRC; (3) English; (4) peer-reviewed and (5) evaluated treatment. RESULTS: 6533 studies were screened, 154 full texts reviewed and 13 met inclusion (10 RCTs, 1 quasi-experimental and 2 cohort studies; 1 high-quality study, 7 acceptable and 5 at high risk of bias). Interventions, comparisons, timing and outcomes varied, precluding meta-analysis. For adolescents and adults with dizziness, neck pain and/or headaches >10 days following concussion, individualised cervicovestibular rehabilitation may decrease time to return to sport compared with rest followed by gradual exertion (HR 3.91 (95% CI 1.34 to 11.34)) and when compared with a subtherapeutic intervention (HR 2.91 (95% CI 1.01 to 8.43)). For adolescents with vestibular symptoms/impairments, vestibular rehabilitation may decrease time to medical clearance (vestibular rehab group 50.2 days (95% CI 39.9 to 60.4) compared with control 58.4 (95% CI 41.7 to 75.3) days). For adolescents with persisting symptoms >30 days, active rehabilitation and collaborative care may decrease symptoms. CONCLUSIONS: Cervicovestibular rehabilitation is recommended for adolescents and adults with dizziness, neck pain and/or headaches for >10 days. Vestibular rehabilitation (for adolescents with dizziness/vestibular impairments >5 days) and active rehabilitation and/or collaborative care (for adolescents with persisting symptoms >30 days) may be of benefit.

Consensus statement on concussion in sport: the 6th International Conference on Concussion in Sport-Amsterdam, October 2022.

For over two decades, the Concussion in Sport Group has held meetings and developed five international statements on concussion in sport. This 6th statement summarises the processes and outcomes of the 6th International Conference on Concussion in Sport held in Amsterdam on 27-30 October 2022 and should be read in conjunction with the (1) methodology paper that outlines the consensus process in detail and (2) 10 systematic reviews that informed the conference outcomes. Over 3½ years, author groups conducted systematic reviews of predetermined priority topics relevant to concussion in sport. The format of the conference, expert panel meetings and workshops to revise or develop new clinical assessment tools, as described in the methodology paper, evolved from previous consensus meetings with several new components. Apart from this consensus statement, the conference process yielded revised tools including the Concussion Recognition Tool-6 (CRT6) and Sport Concussion Assessment Tool-6 (SCAT6, Child SCAT6), as well as a new tool, the Sport Concussion Office Assessment Tool-6 (SCOAT6, Child SCOAT6). This consensus process also integrated new features including a focus on the para athlete, the athlete's perspective, concussion-specific medical ethics and matters related to both athlete retirement and the potential long-term effects of SRC, including neurodegenerative disease. This statement summarises evidence-informed principles of concussion prevention, assessment and management, and emphasises those areas requiring more research.

Acute evaluation of sport-related concussion and implications for the Sport Concussion Assessment Tool (SCAT6) for adults, adolescents and children: a systematic review.

OBJECTIVES: To systematically review the scientific literature regarding the acute assessment of sport-related concussion (SRC) and provide recommendations for improving the Sport Concussion Assessment Tool (SCAT6). DATA SOURCES: Systematic searches of seven databases from 2001 to 2022 using key words and controlled vocabulary relevant to concussion, sports, SCAT, and acute evaluation. ELIGIBILITY CRITERIA: (1) Original research articles, cohort studies, case-control studies, and case series with a sample of >10; (2) ≥80% SRC; and (3) studies using a screening tool/technology to assess SRC acutely (<7 days), and/or studies containing psychometric/normative data for common tools used to assess SRC. DATA EXTRACTION: Separate reviews were conducted involving six subdomains: Cognition, Balance/Postural Stability, Oculomotor/Cervical/Vestibular, Emerging Technologies, and Neurological Examination/Autonomic Dysfunction. Paediatric/Child studies were included in each subdomain. Risk of Bias and study quality were rated by coauthors using a modified SIGN (Scottish Intercollegiate Guidelines Network) tool. RESULTS: Out of 12 192 articles screened, 612 were included (189 normative data and 423 SRC assessment studies). Of these, 183 focused on cognition, 126 balance/postural stability, 76 oculomotor/cervical/vestibular, 142 emerging technologies, 13 neurological examination/autonomic dysfunction, and 23 paediatric/child SCAT. The SCAT discriminates between concussed and non-concussed athletes within 72 hours of injury with diminishing utility up to 7 days post injury. Ceiling effects were apparent on the 5-word list learning and concentration subtests. More challenging tests, including the 10-word list, were recommended. Test-retest data revealed limitations in temporal stability. Studies primarily originated in North America with scant data on children. CONCLUSION: Support exists for using the SCAT within the acute phase of injury. Maximal utility occurs within the first 72 hours and then diminishes up to 7 days after injury. The SCAT has limited utility as a return to play tool beyond 7 days. Empirical data are limited in pre-adolescents, women, sport type, geographical and culturally diverse populations and para athletes. PROSPERO REGISTRATION NUMBER: CRD42020154787.

Joint Injury, Osteoarthritis, and Cardiovascular Disease Risk Factors in Former National Football League Athletes: An NFL-LONG Study.

CONTEXT: Individuals with lower extremity osteoarthritis (OA) have a 25% greater risk of cardiovascular disease (CVD) than those without OA. The prevalence of traumatic joint injuries among National Football League (NFL) players exposes these athletes to an elevated risk for OA and potentially a greater risk of cardiovascular risk factors (CRFs) and CVD. OBJECTIVES: To examine the associations between a history of lower extremity joint injury, lower extremity OA, and the prevalence of CRFs and CVD among former NFL athletes. DESIGN: Cross-sectional study. PATIENTS OR OTHER PARTICIPANTS: Former NFL players completed a comprehensive health questionnaire that was used in an ongoing study, the Neurologic Function Across the Lifespan: A Prospective, Longitudinal, and Translational Study for Former NFL Players (NFL-LONG). A subsample of 1738 former players reported lifetime medical diagnoses including CVD or CRFs. MAIN OUTCOME MEASURE(S): Crude and adjusted prevalence ratios (PRsadj) characterized the associations between CVD or CRFs and injury, OA diagnosis, or both among athletes who reported (1) no history of lower extremity joint injury or surgery and no diagnosed OA, (2) a history of lower extremity joint injury or surgery and no diagnosed OA, and (3) a history of lower extremity joint injury or surgery and diagnosed OA. RESULTS: Neither a history of lower extremity joint injury (PRadj = 1.34; 95% CI = 0.86, 2.07) nor a history of lower extremity joint injury and diagnosed OA (PRadj = 1.41; 95% CI = 0.89, 2.25) was significantly associated with CVD. However, CRFs were 30% and 53% more prevalent in former players with lower extremity joint injury and no diagnosed OA (PRadj = 1.30; 95% CI = 1.12, 1.50) and those with lower extremity joint injury and diagnosed OA (PRadj = 1.53; 95% CI = 1.31, 1.78), respectively, versus athletes with no history of either condition. CONCLUSIONS: The prevalence of CRFs was highest among former NFL athletes with a history of lower extremity joint injury and diagnosed OA. These findings provide insight regarding the potential pathways to chronic diseases that may be initiated by joint injury early in life.

Incorporation of concussion history as part of the LIfestyle for BRAin Health (LIBRA) modifiable factors risk score and associations with cognition in older former National Football League players.

OBJECTIVE: Investigate associations between the LIfestyle for BRAin Health (LIBRA) risk score with odds of mild cognitive impairment (MCI) diagnosis and cognitive function, incorporating concussion history. METHODS: Former National Football League (NFL) players (N = 1050; mean age = 64.8 ± 9.0-years) completed initial testing for integration of concussion history into LIBRA scores (i.e., modified-LIBRA) and completed the Brief Test of Adult Cognition by Telephone (BTACT). Modified-LIBRA score (including concussion history) associations with odds of MCI and cognitive dysfunction were assessed via logistic and linear regression. RESULTS: The highest quartile LIBRA scores were six times more likely to have a diagnosis of MCI compared to the lowest quartile (OR = 6.27[3.61, 10.91], p < 0.001). Modified-LIBRA scores significantly improved model fit for odds of MCI above original LIBRA scores (χ2 (1) = 7.76, p = 0.005) and accounted for a greater fraction of variance in executive function (ΔR2  = 0.02, p = 0.003) and episodic memory (ΔR2  = 0.02, p = 0.002). CONCLUSIONS: Modified-LIBRA score, incorporating concussion history, may help monitoring risk status in former contact sport athletes, by targeting modifiable, lifestyle-related risk factors.

Changes in resting state networks in high school football athletes across a single season.

OBJECTIVE: The aim of this pilot cohort study was to examine changes in the organization of resting-state brain networks in high school football athletes and its relationship to exposure to on-field head impacts over the course of a single season. METHODS: Seventeen male high school football players underwent functional magnetic resonance imaging and computerized neurocognitive testing (CNS Vital Signs) before the start of contact practices and again after the conclusion of the season. The players were equipped with helmet accelerometer systems (Head Impact Telemetry System) to record head impacts in practices and games. Graph theory analysis was applied to study intranetwork local efficiency and strength of connectivity within six anatomically defined brain networks. RESULTS: We observed a significant decrease in the local efficiency (-24.9 ± 51.4%, r = 0.7, p < 0.01) and strength (-14.5 ± 26.8%, r = 0.5, p < 0.01) of functional connectivity within the frontal lobe resting-state network and strength within the parietal lobe resting-state network (-7.5 ± 17.3%, r = 0.1, p < 0.01), as well as a concomitant increase in the local efficiency (+55.0 +/- 59.8%, r = 0.5, p < 0.01) and strength (+47.4 +/- 47.3%, r = 0.5, p < 0.01) within the mediotemporal networks. These alterations in network organization were associated with changes in performance on verbal memory (p < 0.05) and executive function (p < 0.05). We did not observe a significant relationship between the frequency or cumulative magnitude of impacts sustained during the season and neurocognitive or imaging outcomes (p > 0.05). CONCLUSION: Our findings suggest the efficiency and strength of resting-state networks are altered across a season of high school football, but the association of exposure levels to subconcussive impacts is unclear. ADVANCES IN KNOWLEDGE: The efficiency of resting-state networks is dynamic in high school football athletes; such changes may be related to impacts sustained during the season, though further study is needed.

Measurement implications on the association between self-reported concussion history and depression: An NFL-LONG study.

ObjectiveThis study examined how associations of self-reported concussion history and depression vary based on different variable characterizations. Methods Former NFL players (n = 1,697) completed a General Health Survey, indicating the number of concussions they sustained during their football career and whether a physician had diagnosed them with depression, and the PROMIS 4-item Depression scale. Self-reported concussion history was characterized as: a 3-category variable (0, 1-2, 3+) with (1) indicator variables and (2) as an ordinal variable; a 5-category variable (0, 1-2, 3-5, 6-9, 10+) with (3) indicator variables and (4) as an ordinal variable; and (5) the original interval scale (0, 1, 2,…, 10, 10+). Depression was characterized as: (1) physician diagnosis (yes/no); and the PROMIS 4-item Depression scale treated as: (2) the original T-score variable and (3) using a cut-off of a T-score >60 versus ≤60. Regression models with various combinations of the characterizations, while adjusting for age, race/ethnicity, education, pain interference, and stress level, estimated prevalence ratios and mean differences for binary and continuous outcomes, respectively. Concussion history-related effect estimates were compared across all models. Results Self-reported concussion history emerged as a significant predictor of each depression measure. With a higher number of concussions reported, be it via the categories or the interval scale, stronger associations between self-reported concussion history and depression were observed. Conclusions The various approaches to characterize self-reported concussion history and depression provided evidence of significant associations between the two variables, with the degree of association varying based on characterization of each construct.

Investigating the association between subjective and objective performance-based cognitive function among former collegiate football players.

OBJECTIVE: Studies have observed variable associations of prior contact sport participation with subjective and objective measures of cognitive function. This study directly investigated the association between subjective self-report and objective performance-based cognition among former collegiate football players, as well as its relationship to self-reported concussion history. METHODS: Former collegiate football players (N = 57; mean age = 37.9 years [SD = 1.49]) retired from sport 15-years prior were enrolled. Linear regression models examined associations between subjective cognition (Quality of Life in Neurological Disorders Cognitive Functioning-Short Form), and performance on a neuropsychological battery. Domain specific (executive function) metrics of subjective (Behavior Rating Inventory of Executive Function-Adult) and objective cognition were also exclusively examined. Associations between self-reported concussion history with subjective and objective measures were tested. Potential influential factors (sleep quality and distress) were included as covariates. RESULTS: Subjective cognition was not significantly associated with any objective measures of cognitive functioning (p's > .05). Greater self-reported concussion history was inversely associated with subjective cognition (B = -2.49, p = .004), but not objective performance-based cognition (p's > .05). Distress was significantly related to all metrics of subjective cognition (p's < .001) as well as performance on delayed recall and verbal fluency (p's < .05). Sleep quality was only significantly related to timed visuospatial sequencing (p = .033). CONCLUSIONS: Reliance on self-reported measures of cognitive functioning alone is insufficient when assessing cognition in former contact sport athletes. Assessment of other factors known to influence subjective cognitive complaints should also be examined in determining the presence of cognitive deficits.

A dominance analysis of subjective cognitive complaint comorbidities in former professional football players with and without mild cognitive impairment.

OBJECTIVES: Subjective cognitive difficulties (SCDs) are associated with factors commonly reported in older adults and former contact sport athletes, regardless of objective cognitive decline. We investigated the relative contribution of these factors to SCD in former National Football League (NFL)-players with and without a diagnosis of mild cognitive impairment (MCI). METHODS: Former NFL players (n = 907) aged ≥ 50 years (mean = 64.7 ± 8.9), with (n = 165) and without (n = 742) a diagnosis of MCI completed health questionnaires. Multivariable regression and dominance analyses determined the relative importance of SCD factors on SCD: 1) depression, 2) anxiety, 3) sleep disturbance, 4) pain interference, 5) ability to participate in social roles and activities, 6) stress-related events, 7) fatigue, 8) concussion history, and 9) education. SCD outcomes included Neuro-QoL Emotional-Behavioral Dyscontrol and the PROMIS Cognitive Function. Fisher's z-transformation compared comorbid contributing factors to SCD across MCI and non-MCI groups. RESULTS: Complete dominance of anxiety was established over most comorbid factors across the MCI and non-MCI groups. Fatigue also exhibited complete dominance over most comorbid factors, though its influence in the MCI group was less robust (general dominance). Average contributions to variance accounted for by comorbid factors to ratings of SCD across MCI and non-MCI groups did not statistically differ (Z-statistics <1.96, ps>.05). CONCLUSIONS: Anxiety and fatigue are the most robust factors associated with SCD in former professional football players across various combinations of clinical presentations (different combinations of comorbid factors), regardless of documented cognitive impairment. Self-reported deficits may be less reliable in detecting objective impairment in the presence of these factors, with multidimensional assessment being ideal.

Relating American Football Age of First Exposure to Patient-Reported Outcomes and Medical Diagnoses Among Former National Football League Players: An NFL-LONG study.

BACKGROUND: The age of first exposure (AFE) to American football participation is a growing concern for late-life function. Mixed evidence exists surrounding AFE and may be attributed to varied methods employed across studies. OBJECTIVE: To examine the associations between AFE to American football participation with measures of cognitive, behavioral, and physical function and brain-related medical diagnoses across age categories among former National Football League players. METHODS: We conducted a cross-sectional survey of 1784 former players (age: 52.3 ± 16.3 years, AFE: 11.3 ± 2.9 years, years of football: 17.5 ± 4.5 years, 86.9% ≥ one lifetime concussion). Players completed a general health questionnaire recording demographics, football playing history (including AFE), and diagnoses (anxiety, depression, any form of dementia, mild cognitive impairment). Players completed Patient-Reported Outcomes Measurement Information System (PROMIS) measures assessing domains of cognitive and physical function, anxiety, depression, sleep disturbance, pain interference, and emotional-behavioral dyscontrol. Multivariable linear and binomial regression models were used to examine the associations of AFE and age with PROMIS outcomes and diagnoses, respectively. RESULTS: No significant AFE by age interactions were detected for PROMIS outcomes (p ≥ 0.066) or diagnoses (p ≥ 0.147). Younger AFE associated with higher PROMIS scores of anxiety (B = - 0.22, p = 0.016), depression (B = - 0.22, p = 0.010), sleep disturbances (B = - 0.16, p = 0.007), pain interference (B = - 0.19, p = 0.014), and emotional-behavioral dyscontrol (B = - 0.22, p = 0.019). Age was associated with all PROMIS outcomes (p ≤ 0.042). AFE was not associated with the prevalence of anxiety, depression, dementia, or mild cognitive impairment (p ≥ 0.449), while age was (p ≤ 0.013). CONCLUSIONS: AFE was significantly associated with PROMIS outcomes, albeit low-strength associations (i.e., effect sizes), but not with diagnoses. Our findings indicate AFE is a significant but minor contributing factor for health-related quality of life in this cohort. Future work should incorporate additional characterizations of cumulative head impacts and related factors when examining long-term outcomes associated with football participation.

Are EPB41 and alpha-synuclein diagnostic biomarkers of sport-related concussion? Findings from the NCAA and Department of Defense CARE Consortium.

BACKGROUND: Current protein biomarkers are only moderately predictive at identifying individuals with mild traumatic brain injury or concussion. Therefore, more accurate diagnostic markers are needed for sport-related concussion. METHODS: This was a multicenter, prospective, case-control study of athletes who provided blood samples and were diagnosed with a concussion or were a matched non-concussed control within the National Collegiate Athletic Association-Department of Defense Concussion Assessment, Research, and Education Consortium conducted between 2015 and 2019. The blood was collected within 48 h of injury to identify protein abnormalities at the acute and subacute timepoints. Athletes with concussion were divided into 6 h post-injury (0-6 h post-injury) and after 6 h post-injury (7-48 h post-injury) groups. We applied a highly multiplexed proteomic technique that used a DNA aptamers assay to target 1305 proteins in plasma samples from athletes with and without sport-related concussion. RESULTS: A total of 140 athletes with concussion (79.3% males; aged 18.71 ± 1.10 years, mean ± SD) and 21 non-concussed athletes (76.2% males; 19.14 ± 1.10 years) were included in this study. We identified 338 plasma proteins that significantly differed in abundance (319 upregulated and 19 downregulated) in concussed athletes compared to non-concussed athletes. The top 20 most differentially abundant proteins discriminated concussed athletes from non-concussed athletes with an area under the curve (AUC) of 0.954 (95% confidence interval: 0.922‒0.986). Specifically, after 6 h of injury, the individual AUC of plasma erythrocyte membrane protein band 4.1 (EPB41) and alpha-synuclein (SNCA) were 0.956 and 0.875, respectively. The combination of EPB41 and SNCA provided the best AUC (1.000), which suggests this combination of candidate plasma biomarkers is the best for diagnosing concussion in athletes after 6 h of injury. CONCLUSION: Our data suggest that proteomic profiling may provide novel diagnostic protein markers and that a combination of EPB41 and SNCA is the most predictive biomarker of concussion after 6 h of injury.

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.