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Sport-related concussion (SRC) is an important public health issue. White-matter alterations after SRC are widely studied by neuroimaging approaches, such as diffusion magnetic resonance imaging (MRI). Although the exact anatomical location of the alterations may differ, significant white-matter alterations are commonly observed in long fiber tracts, but are never proven. In the present study, we performed streamline tractography to characterize the association between tract length and white-matter microstructural alterations after SRC. Sixty-eight collegiate athletes diagnosed with acute concussion (24-48 h post-injury) and 64 matched contact-sport controls were included in this study. The athletes underwent diffusion tensor imaging (DTI) in 3.0 T MRI scanners across three study sites. DTI metrics were used for tract-based spatial statistics to map white-matter regions-of-interest (ROIs) with significant group differences. Whole-brain white-mater streamline tractography was performed to extract "affected" white-matter streamlines (i.e., streamlines passing through the identified ROIs). In the concussed athletes, streamline counts and DTI metrics of the affected white-matter fiber tracts were summarized and compared with unaffected white-matter tracts across tract length in the same participant. The affected white-matter tracts had a high streamline count at length of 80-100 mm and high length-adjusted affected ratio for streamline length longer than 80 mm. DTI mean diffusivity was higher in the affected streamlines longer than 100 mm with significant associations with the Brief Symptom Inventory score. Our findings suggest that long fibers in the brains of collegiate athletes are more vulnerable to acute SRC with higher mean diffusivity and a higher affected ratio compared with the whole distribution.

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 .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.

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.Former collegiate football players (N = 57; mean age = 37.9 years [Subjective cognition was not significantly associated with any objective measures of cognitive functioning (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.

Repetitive head impact (RHI) exposure has been associated with differences in brain structure among younger active athletes, most often within the hippocampus. Studies of former athletes at early-midlife are limited. We investigated the association between RHI exposure and gray matter (GM) structure, as well as moderating factors, among former athletes in early-midlife. Former collegiate football players (n = 55; age = 37.9 + 1.5 years) completed magnetic resonance imaging to quantify GM morphometry and extensive structured interviews of RHI history (Head Impact Exposure Estimate). Linear regression models tested the association between RHI exposure and GM structures of interest. Interactions were tested for moderators: two estimates of intelligence quotient (IQ) (single word reading and picture vocabulary) and education history. Greater RHI exposure was associated with smaller hippocampal volume, β = -0.36, p = 0.004. Conversely, RHI exposure was not significantly associated with other GM outcomes ps > 0.05. Education history significantly moderated the association between RHI exposure and hippocampal volume, β = 0.31, p = 0.047. Among those with a bachelor's degree, greater RHI exposure was significantly associated with smaller hippocampal volumes, β = -0.58, p

Context Lower extremity osteoarthritis (OA) is associated with a 25% greater risk of cardiovascular disease (CVD) compared to those without OA. The prevalence of traumatic joint injuries among National Football League (NFL) players exposes these athletes to an elevated risk for osteoarthritis (OA) and potentially a greater risk of cardiovascular risk factors (CRF) and CVD. Objective To examine the association 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 health questionnaire. A sub-sample of 1,738 former players reported lifetime medical diagnoses including CVD or CRFs. Main Outcome Measure(s) Crude and adjusted prevalence ratios (PR) characterized the association between CVD or CRF with injury and/or OA diagnosis among athletes who reported 1) no history of lower extremity joint injury or surgery and no diagnosed OA, 2) athletes with a history of lower extremity joint injury or surgery and no OA diagnosed OA, and 3) athletes with a history of lower extremity joint injury or surgery and diagnosed OA. Results Neither history of lower extremity joint injury (PRadj=1.34, CI95=0.86, 2.07) nor history of lower extremity joint injury and diagnosed OA (PRadj=1.41, CI95=0.89, 2.25) were 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, CI95=1.12, 1.50) and those with lower extremity joint and diagnosed OA (PRadj=1.53, CI95=1.31, 1.78) when compared to 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.

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.

BACKGROUND Potential links between a history of sport-related concussions and later-life neurobiological and psychological brain health have been studied in former collision-sport athletes. However, empirical studies of how former athletes perceive the future of their brain health as a result of these injuries are missing. OBJECTIVES We aimed to (1) identify the extent to which former National Football League players currently have concerns about their long-term psychological and cognitive functioning as a result of concussions sustained while playing football; (2) examine whether current concerns are different than concerns they had while playing football; (3) examine the relationship between current brain health concerns and self-reported concussion history (SR-CHx); and (4) explore other important factors associated with these concerns. METHODS In this cross-sectional study, former National Football League players with a SR-CHx of one or more concussions (n = 1514; aged mean [standard deviation] = 52.3 [15.7] years) completed a general health questionnaire. Participants reported their lifetime concussion history, as well as both their current concerns and concerns while playing football (i.e., retrospective concerns) regarding the long-term effects of concussions on their memory, thinking skills, and risk of developing chronic traumatic encephalopathy. Current and retrospective concerns were self-reported on a five-point Likert scale. Four concussion history categories were created based on SR-CHx: 1-2 (n = 309); 3-5 (n = 413); 6-9 (n = 356); and 10 + (n = 436) lifetime concussions. Proportions of participants reporting each level of current and retrospective concerns were examined to identify whether concerns presently exist in these former players, and whether their current concerns are different than retrospective concerns. Next, we explored associations between current concerns and SR-CHx. RESULTS More than one-third of participants reported being currently "extremely concerned" about memory problems (36.9%), thinking skills (37.8%), and developing chronic traumatic encephalopathy (39.5%). In contrast, when asked about concerns while playing, most reported being "not at all concerned" regarding memory = 61.2%, thinking skills = 56.1%, and developing chronic traumatic encephalopathy = 71.2%. Of those who retrospectively endorsed being "not at all" or "slightly" concerned regarding memory (n = 1159/1514), thinking skills (n = 1080/1514), and developing chronic traumatic encephalopathy (n = 1219/1514), approximately half reported being currently "moderately" or "extremely" concerned about those same issues (n = 586/1159; n = 534/1080; n = 619/1219, respectively). Current concerns regarding memory (χ216 = 316.61; p

This study aimed to estimate prevalence of mild cognitive impairment (MCI) and dementia diagnoses in former National Football League (NFL) players ≥50 yr old and examine the relationships among these diagnoses and an array of predictors of long-term brain health.A cross section of former NFL players (n = 922; mean ± SD age, 64.8 ± 8.9 yr) completed a questionnaire. Prevalence of self-reported medical diagnoses of MCI and dementia was reported alongside U.S. population estimates across 5-yr age intervals (e.g., 60-64 yr). Prevalence ratios (PR) were calculated for multiple predictors of long-term brain health.Overall, MCI prevalence and dementia prevalence were n = 219(23.8%) and n = 82(8.9%), respectively. Each diagnosis was more prevalent in former NFL players across age-groups than U.S. norms, with greater disparities at relatively younger ages (e.g., 65-69 yr) compared with older ages. Greater prevalence of MCI and dementia was associated with self-reported concussion history (10+ vs 0; PRadjusted [95% CI] = 1.66 [1.02-2.71] and 2.61 [1.01-6.71], respectively); recent pain intensity (PRadjusted [95% CI] = 1.13 [1.07-1.20] and 1.15 [1.03-1.28]); and diagnoses of depression (PRadjusted [95% CI] = 2.70 [1.92-3.81] and 3.22 [1.69-6.14]), anxiety (PRadjusted [95% CI] = 1.96 [1.26-3.07] and 3.14 [1.47-6.74]), or both (PRadjusted [95% CI] = 3.11 [2.38-4.08] and 4.43 [2.71-7.25]). Higher MCI prevalence was related to sleep apnea (PRadjusted [95% CI] = 1.30 [1.06-1.60]); higher dementia prevalence was associated with age (5-yr interval, PRadjusted [95% CI] = 1.42 [1.26-1.60]) and race (non-White vs White, PRadjusted [95% CI] = 1.64 [1.07-2.53]).Self-reported MCI prevalence and dementia prevalence were higher in former NFL players than national estimates and were associated with numerous personal factors, including mood-related disorders and a high number of self-reported concussions. Predictors of higher MCI and dementia prevalence may be modifiable and warrant consideration by clinicians and researchers as potential targets to mitigate the onset of these conditions.

To examine the stability of former National Football League (NFL) players' recall of professional football concussion.Two-hundred-and-nine former NFL players (ceasing football participation before/in 2001) completed surveys in 2001, 2010, and 2019 and reported the number of concussions sustained during their professional careers (0, 1 … 10,10). Participants were categorized into four 'recall stability' groups, based upon concussion recall [e.g., 'Same' (same number recalled), 'Increased' (more recalled than in prior time point)]. In 2019, participants completed measures of functioning (e.g., PROMIS Cognitive Function, Anxiety, Depression). Fleiss Kappa and generalized linear mixed models (GLMM)-based ordinal measures Kappa assessed stability across time points. 'Recall stability group' functioning scores were compared.Overall, 45.9% recalled more concussions over time; 14.8% reported the same number. Fleiss Kappa and GLMM-based ordinal measures Kappa suggested fair (0.22, 95% CI: 0.26, 0.38) and moderate stability (0.41, 95% CI: 0.35, 0.46), respectively. Higher cognitive functioning (P = 0.002), lower anxiety (P = 0.003), and lower depression (P = 0.007) were observed in the 'Same' vs 'Increased' groups.Despite subtle time-based variations in reporting, professional football concussion history recall was relatively stable. Better cognitive and psychological functioning was associated with greater stability in concussion recall.

Primary care providers (PCPs) are evaluating increasing numbers of concussions, but it is unknown how often they are documenting concussion-specific history and physical examination findings vital for this process. This study reviews clinical documentation to determine how PCPs are evaluating concussed patients. PCPs often did not document important aspects of concussion history, including dizziness (48%), nausea (48%), vision changes (54%), cognitive complaints (54%), emotional changes (83%), sleep difficulties (84%), and neck pain (87%). Additionally, they often did not document important aspects of a concussion physical examination, including detailed neurologic examination (73%), clinical cognitive assessment (87%), balance testing (59%), and neck evaluation (54%). Omitting these parts of the history and physical examination could result in a premature return to play.

ObjectiveTo identify subgroups of former National Football League (NFL) players using latent profile analysis (LPA) and examine their associations with total years of participation (TYP) and self-reported lifetime sport-related concussion history (SR-CHx).MethodsFormer NFL players (N=686) aged 50–70 years, with an average 18.0 TYP (±4.5) completed a questionnaire. SR-CHx distributions included: low (0–3; n=221); intermediate (4–8; n=209) and high (9+; n=256). LPA measures included: Quality of Life in Neurological Disorders Emotional–Behavioral Dyscontrol, Patient Reported Outcomes Measurement Information System Cognitive Function, Emotional Support, Self-Efficacy, Meaning and Purpose, Physical Function, Pain Interference, Participation in Social Roles and Activities, Anxiety, Depression, Fatigue, and Sleep Disturbance. Demographic, medical/psychiatric history, current psychosocial stressors, TYP and SR-CHx were compared across latent profiles (LPs).ResultsA five profile solution emerged: (LP1) global higher functioning (GHF; 26.5%); (LP2) average functioning (10.2%); (LP3) mild somatic (pain and physical functioning) concerns (22.0%); (LP4) somatic and cognitive difficulties with mild anxiety (SCA; 27.5%); LP5) global impaired functioning (GIF; 13.8%). The GIF and SCA groups reported the largest number ofe- medical/psychiatric conditions and higher psychosocial stressor levels. SR-CHx was associated with profile group (χ2(8)=100.38, pConclusionsFive distinct profiles of self-reported functioning were identified among former NFL players. Several comorbid factors (ie, medical/psychiatric diagnoses and psychosocial stressors) and SR-CHx were associated with greater neurobehavioural and psychosocial dysfunction.

Mild traumatic brain injury (mTBI) remains a diagnostic challenge and therefore strategies for objective assessment of neurological function are key to limiting long-term sequelae. Current assessment methods are not optimal in austere environments such as athletic fields; therefore, we developed an immersive tool, the Display Enhanced Testing for Cognitive Impairment and mTBI (DETECT) platform, for rapid objective neuropsychological (NP) testing. The objectives of this study were to assess the ability of DETECT to accurately identify neurocognitive deficits associated with concussion and evaluate the relationship between neurocognitive measures and subconcussive head impacts. DETECT was used over a single season of two high school and two college football teams. Study participants were instrumented with Riddell Head Impact Telemetry (HIT) sensors and a subset tested with DETECT immediately after confirmed impacts for different combinations of linear and rotational acceleration. A total of 123 athletes were enrolled and completed baseline testing. Twenty-one players were pulled from play for suspected concussion and tested with DETECT. DETECT was 86.7% sensitive (95% confidence interval [CI]: 59.5%, 98.3%) and 66.7% specific (95% CI: 22.3%, 95.7%) in correctly identifying athletes with concussions (15 of 21). Weak but significant correlations were found between complex choice response time (processing speed and divided attention) and both linear (Spearman rank correlation coefficient 0.262, p = 0.02) and rotational (Spearman coefficient 0.254, p = 0.03) acceleration on a subset of 76 players (113 DETECT tests) with no concussion symptoms. This study demonstrates that DETECT confers moderate to high sensitivity in identifying acute cognitive impairment and suggests that football impacts that do not result in concussion may negatively affect cognitive performance immediately following an impact. Specificity, however, was not optimal and points to the need for additional studies across multiple neurological domains. Given the need for more objective concussion screening in triage situations, DETECT may provide a solution for mTBI assessment.

Background: Repeat sports-related concussive/subconcussive injury (RC/SCI) is related to memory impairment. Objective & Methods: We sought to determine memory differences between persons with RC/SC...

ObjectiveTo study longitudinal recovery trajectories of white matter after sports-related concussion (SRC) by performing diffusion tensor imaging (DTI) on collegiate athletes who sustained SRC.MethodsCollegiate athletes (n = 219, 82 concussed athletes, 68 contact-sport controls, and 69 non–contact-sport controls) were included from the Concussion Assessment, Research and Education Consortium. The participants completed clinical assessments and DTI at 4 time points: 24 to 48 hours after injury, asymptomatic state, 7 days after return-to-play, and 6 months after injury. Tract-based spatial statistics was used to investigate group differences in DTI metrics and to identify white-matter areas with persistent abnormalities. Generalized linear mixed models were used to study longitudinal changes and associations between outcome measures and DTI metrics. Cox proportional hazards model was used to study effects of white-matter abnormalities on recovery time.ResultsIn the white matter of concussed athletes, DTI-derived mean diffusivity was significantly higher than in the controls at 24 to 48 hours after injury and beyond the point when the concussed athletes became asymptomatic. While the extent of affected white matter decreased over time, part of the corpus callosum had persistent group differences across all the time points. Furthermore, greater elevation of mean diffusivity at acute concussion was associated with worse clinical outcome measures (i.e., Brief Symptom Inventory scores and symptom severity scores) and prolonged recovery time. No significant differences in DTI metrics were observed between the contact-sport and non–contact-sport controls.ConclusionsChanges in white matter were evident after SRC at 6 months after injury but were not observed in contact-sport exposure. Furthermore, the persistent white-matter abnormalities were associated with clinical outcomes and delayed recovery time.

Evaluating acute sport-related concussion (SRC) differs among providers, who apply international consensus and national guidelines variably. Retrospective medical record review was completed for 889 outpatients aged 7 to 18 years, diagnosed with SRC from 2014 to 2017. Associations between board-certified sports medicine fellowship (SMF) training status and assessment of concussion-specific history and physical examination items were tested using nonparametric χ tests. Differential odds (by fellowship training status) of using history and physical examination items were assessed using multivariable logistic regression modeling. Each SRC history and physical examination items were assessed in higher proportions by SMFs, as compared with non-SMFs, statistically significant for all tested items with the exception of headache history. SMFs demonstrated higher odds of detailed neurologic examinations and clinical cognitive testing compared with non-SMFs, after adjusting for patient and physician characteristics. Physicians caring for concussed patients should seek continuing education opportunities aligning them with training provided to sports medicine fellows.

Purpose This study aimed to quantify the Head Impact Telemetry (HIT) System's impact detection and location measurement accuracy using an impact biomechanics data set paired with video of high school football special teams plays. Methods The head impact biomechanics data set and video were collected from 22 high school football players, wearing HIT System instrumented helmets, competing in 218 special teams plays over a single high school football season. We used two separate video analysis approaches. To quantify the impact detection accuracy, we evaluated the video for head impacts independently of the impact data collection triggers collected by the HIT System. Video-observed impacts matched to valid and invalid head impacts by the HIT System algorithm were categorized as true positives, false positives, false negatives, and true negatives. To quantify impact location accuracy, we analyzed video-synchronized head impacts for impact location independent of the HIT System's impact location measurement and quantified the estimated percent agreement of impact location between the HIT System recorded impact location and the impact location observed on video. Results The HIT System's impact-filtering algorithm had 69% sensitivity, 72% specificity, and 70% accuracy in categorizing true and non-head impact data collection triggers. The HIT System agreed with video-observed impact locations on 64% of the 129 impacts we analyzed (unweighted k = 0.43, 95% confidence interval = 0.31-0.54). Conclusion This work provides data on the HIT System's impact detection and location accuracy during high school football special teams plays using game video analysis that has not been previously published. Based on our data, we believe that the HIT System is useful for estimating population-based impact location distributions for special teams plays.

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.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 hours 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.A total of 140 athletes with concussion (79.3% male; aged 18.71 ± 1.10 years, mean ± SD) and 21 non-concussed athletes (76.2% male; 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 of 0.954 (95% confidence interval: 0.922‒0.986). Specifically, after 6 h of injury, the individual area under the curve of plasma erythrocyte membrane protein band 4.1 (EPB41) and alpha-synuclein were 0.956 and 0.875, respectively. The combination of EPB41 and alpha-synuclein provided the best area under the curve (1.000), which suggests this combination of candidate plasma biomarkers is best for diagnosing concussion in athletes after 6 h of injury.Our data suggest that proteomic profiling may provide novel diagnostic protein markers and that a combination of EPB41 and alpha-synuclein is the most predictive biomarker of concussion after 6 h of injury.

Background and Purpose: Postmortem and experimental studies indicate a potential association between repeated concussions and stroke risk in older contact sport athletes. We examined the relationship between concussion and stroke history in former National Football League players aged ≥50 years. Methods: Former professional football players aged ≥50 years who played ≥1 year in the National Football League were enrolled in the cross-sectional study. Indirect standardization was used to calculate overall and decade-specific standardized prevalence ratios. Logistic regression using Firth’s bias reduction method examined the association between lifetime concussion history 0 (n=119; 12.2%), 1 to 2 (n=152; 15.5%), 3 to 5 (n=242; 24.7%), 6 to 9 (201; 20.5%), and 10+(n=265; 27.1%) and stroke. Adjusted odds ratios for stroke were calculated for concussion history groups, age, and coronary artery disease and/or myocardial infarction. Results: The 979 participants who met inclusion criteria had a mean age of 65.0±9.0 years (range, 50–99). The prevalence of stroke was 3.4% (n=33), significantly lower than expected based on rates of stroke in US men aged 50 and over (standardized prevalence ratio=0.56, Z= −4.56, P Conclusions: The prevalence of stroke among former National Football League players aged ≥50 years was lower than the general population, with significantly increased risk among those with 10 or more prior concussions. Findings add to the evidence suggesting that traumatic brain injuries are associated with increased risk of stroke. Clinically, management of cardio- and cerebrovascular health may be pertinent to those with a history of multiple prior concussions.

Potential links between a history of sport-related concussions and later-life neurobiological and psychological brain health have been studied in former collision-sport athletes. However, empirical studies of how former athletes perceive the future of their brain health as a result of these injuries are missing.We aimed to (1) identify the extent to which former National Football League players currently have concerns about their long-term psychological and cognitive functioning as a result of concussions sustained while playing football; (2) examine whether current concerns are different than concerns they had while playing football; (3) examine the relationship between current brain health concerns and self-reported concussion history (SR-CHx); and (4) explore other important factors associated with these concerns.In this cross-sectional study, former National Football League players with a SR-CHx of one or more concussions (n = 1514; aged mean [standard deviation] = 52.3 [15.7] years) completed a general health questionnaire. Participants reported their lifetime concussion history, as well as both their current concerns and concerns while playing football (i.e., retrospective concerns) regarding the long-term effects of concussions on their memory, thinking skills, and risk of developing chronic traumatic encephalopathy. Current and retrospective concerns were self-reported on a five-point Likert scale. Four concussion history categories were created based on SR-CHx: 1-2 (n = 309); 3-5 (n = 413); 6-9 (n = 356); and 10 + (n = 436) lifetime concussions. Proportions of participants reporting each level of current and retrospective concerns were examined to identify whether concerns presently exist in these former players, and whether their current concerns are different than retrospective concerns. Next, we explored associations between current concerns and SR-CHx.More than one-third of participants reported being currently "extremely concerned" about memory problems (36.9%), thinking skills (37.8%), and developing chronic traumatic encephalopathy (39.5%). In contrast, when asked about concerns while playing, most reported being "not at all concerned" regarding memory = 61.2%, thinking skills = 56.1%, and developing chronic traumatic encephalopathy = 71.2%. Of those who retrospectively endorsed being "not at all" or "slightly" concerned regarding memory (n = 1159/1514), thinking skills (n = 1080/1514), and developing chronic traumatic encephalopathy (n = 1219/1514), approximately half reported being currently "moderately" or "extremely" concerned about those same issues (n = 586/1159; n = 534/1080; n = 619/1219, respectively). Current concerns regarding memory (χFormer National Football League players reported significant concerns regarding the potential effects of their prior concussions on long-term brain health, and these concerns are more prevalent now than when they were playing football. Cognitive and mental health concerns are readily identifiable targets for clinical intervention. Clinicians working with former players may wish to explore the extent to which individual players experience these concerns, the nature and depth of these concerns, and the impact of these concerns on the player's functioning and well-being.

Sport-related concussions can result from a single high magnitude impact that generates concussive symptoms, repeated subconcussive head impacts aggregating to generate concussive symptoms, or a combined effect from the two mechanisms. The array of symptoms produced by these mechanisms may be clinically interpreted as a sport-related concussion. It was hypothesized that head impact exposure resulting in concussion is influenced by severity, total number, and frequency of subconcussive head impacts. The influence of total number and magnitude of impacts was previously explored, but frequency was investigated to a lesser degree. In this analysis, head impact frequency was investigated over a new metric called 'time delta', the time difference from the first recorded head impact of the day until the concussive impact. Four exposure metrics were analyzed over the time delta to determine whether frequency of head impact exposure was greater for athletes on their concussion date relative to other dates of contact participation. Those metrics included head impact frequency, head impact accrual rate, risk weighted exposure (RWE), and RWE accrual rate. Athletes experienced an elevated median number of impacts, RWE, and RWE accrual rate over the time delta on their concussion date compared to non-injury sessions. This finding suggests elevated frequency of head impact exposure on the concussion date compared to other dates that may precipitate the onset of concussion. National Institute of Neurological Disorders and Stroke of the National Institutes of Health [1R01NS126449]; Grand Alliance Concussion Assessment, Research, and Education (CARE) Consortium - National Collegiate Athletic Association (NCAA); Department of Defense (DOD); Office of the Assistant Secretary of Defense for Health Affairs [W81XWH-14-2-0151]; Veterans Affairs Medical Research Published version Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number 1R01NS126449. This publication was also made possible with support from the Grand Alliance Concussion Assessment, Research, and Education (CARE) Consortium, funded in part by the National Collegiate Athletic Association (NCAA) and the Department of Defense (DOD). The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Psychological Health and Traumatic Brain Injury Program under Award NO W81XWH-14-2-0151. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense (DHP funds). This study was also supported by Veterans Affairs Medical Research. The authors would also like to thank Jody Harland, MS, Janetta Matesan, BA, Michael Menser, Larry Riggen, MS (Indiana University School of Medicine); Ashley Rettmann, BS, Nicole L'Heureux, MBA (University of Michigan); Melissa Koschnitzke, MA (Medical College of Wisconsin); Michael Jarrett, MBA, Vibeke Brinck, MS and Bianca Byrne, BA (Quesgen); Melissa Baker, BS (Datalys Center for Sports Injury Research and Prevention); and the research and medical staff at each of the CARE participation sites. The team would also like to acknowledge the HIT System operators that participated in this study: Julia Ford (UNC), Philippe Gagnon-Joseph (UNC), Miranda Kruse (UNC), Gus Hendricks (UCLA), Quinn Lukens (UW), Brett Griesemer (VT), Alex Black (VT), Lewis Young (VT), Dom Calhoun (USAFA), Mike Aderman (USMA), Sean Roach (USMA), and Jeremy Ross (USMA).

Context Ankle injuries are common at all levels of American football, and retired National Football League (NFL) players have a high prevalence of osteoarthritis (OA), but little is known about how ankle injuries influence OA prevalence and daily activities in this population or how surgical interventions for such injuries alter the risk of OA. Objective To examine (1) the association of ankle-injury history with OA prevalence, (2) the association of surgical intervention after ankle injury with OA prevalence, and (3) the relationships among ankle injuries, reported OA, and daily activities in retired NFL players. Design Case-control study. Setting Survey. Patients or Other Participants Data from the Retired NFL Players General Health Survey. Main Outcome Measure(s) We created a 7-category main exposure variable that differentiated respondents by football-related ankle injury and surgical intervention. Multivariable binomial regression models were used to estimate prevalence ratios and 95% confidence intervals. Among those reporting OA, we examined the distribution of responses regarding whether OA affected daily activities. Results Among the 2446 respondents, 920 participants experienced OA in any joint during their lifetime. Compared with those reporting no ankle injuries, the prevalence of OA was higher among those with a history of ankle injury. Also, the prevalence of OA was higher among those who had undergone surgery versus those who had not. The number of retired NFL players who reported that OA often affected their daily activities increased with the number of ankle injuries. Conclusions Among former NFL players, a history of ankle injury increased the prevalence of OA. More ankle injuries increased the probability that OA negatively affected daily activities. Future prospective research is needed to better determine the influence of surgical intervention at the ankle or foot on OA.

Context: Concussion management is moving from passive rest strategies to active interventions, including aerobic exercise therapy. Little information is available regarding the feasibility and adherence of these programs. Objectives: To determine whether an aerobic exercise training program intended for rehabilitation in people with concussion is feasible. Healthy, nonconcussed subjects were studied in this phase 1 trial. Design: Phase 1 parallel-group, randomized controlled trial in a sample of healthy (nonconcussed), recreationally active university students. Setting: Laboratory. Patients: 40 healthy university students. Methods: Participants were equally randomized to acute concussion therapy intervention (ACTIVE) training or nontraining groups. All participants completed maximal cardiopulmonary exercise tests on a stationary cycle ergometer at 2 test sessions approximately 14 days apart. During this 2-week study period, ACTIVE training participants completed six 30-minute cycling sessions, progressing from 60% to 80% of the participant’s individualized maximal oxygen consumption. A subset of participants (NACTIVE = 12, Nnontraining = 11) wore physical activity monitors throughout the 2-week study period. Main Outcomes Measures: Study protocol and randomization effectiveness, exercise safety and adherence, and progressive intensity of the ACTIVE training procedures. Results: No adverse events occurred during any exercise sessions. Twelve ACTIVE training participants (60%) completed all training sessions, and every participant completed at least 4 sessions. Heart rate increased throughout the training period (P P = .20). Conclusions: University-aged students were adherent to the ACTIVE training protocol. Future research should investigate the safety and feasibility of aerobic training programs in acutely concussed individuals to determine their appropriateness as a clinical rehabilitation strategy.

Researchers have been collecting head impact data from instrumented football players to characterize the biomechanics of concussion for the past 15 years, yet the link between biomechanical input and clinical outcome is still not well understood. We have previously shown that even though concussive biomechanics might be unremarkable in large datasets of head impacts, the impacts causing injury are of high magnitude for the concussed individuals relative to their impact history. This finding suggests a need to account for differences in tolerance at the individual level. In this study, we identified control subjects for our concussed subjects who demonstrated traits we believed were correlated to factors thought to affect injury tolerance, including height, mass, age, race, and concussion history. A total of 502 college football players were instrumented with helmet-mounted accelerometer arrays and provided complete baseline assessment data, 44 of which sustained a total of 49 concussion. Biomechanical measures quantifying impact frequency and acceleration magnitude were compared between groups. On average, we found that concussed subjects experienced 93.8 more head impacts (p = 0.0031), 10.2 more high magnitude impacts (p = 0.0157), and 1.9 × greater risk-weighted exposure (p = 0.0175) than their physically matched controls. This finding provides further evidence that head impact data need to be considered at the individual level and that cohort wide assessments may be of little value in the context of concussion. Published version

ObjectiveWe compared data from the National Collegiate Athletic Association (NCAA) Concussion Study (1999–2001) and the NCAA-Department of Defense Concussion Assessment, Research and Education (CARE) Consortium (2014–2017) to examine how clinical management, return to play (RTP) and risk of repeat concussion in collegiate football players have changed over the past 15 years.MethodsWe analysed data on reported duration of symptoms, symptom-free waiting period (SFWP), RTP and occurrence of within-season repeat concussion in collegiate football players with diagnosed concussion from the NCAA Study (n=184) and CARE (n=701).ResultsCARE athletes had significantly longer symptom duration (CARE median=5.92 days, IQR=3.02–9.98 days; NCAA median=2.00 days, IQR=1.00–4.00 days), SFWP (CARE median=6.00 days, IQR=3.49–9.00 days; NCAA median=0.98 days, IQR=0.00–4.00 days) and RTP (CARE median=12.23 days, IQR=8.04–18.92 days; NCAA median=3.00 days, IQR=1.00–8.00 days) than NCAA Study athletes (all pConclusionOur findings indicate that concussion in collegiate football is managed more conservatively than 15 years ago. These changes in clinical management appear to have reduced the risk of repetitive concussion during the critical period of cerebral vulnerability after sport-related concussion (SRC). These data support international guidelines recommending additional time for brain recovery before athletes RTP after SRC.

Background The long-term effects of concussions have led to concerns regarding former professional American football players’ post-career transitions. This cross-sectional study examines post-career transition experiences of former players retiring due to brain-health concerns. Methods Former players (n=1,784), recruited via National Football League (NFL) and Players’ Association contact lists, completed an online/paper questionnaire. Variables included: demographics, playing history, retirement reasons (pre-specified options), and factors helping/hindering post-career transitions (open-ended). We calculated descriptives for study variables from players reporting retirement due to brain-health concerns. Using template analysis, we coded open-ended responses to identify factors helping/hindering post-career transitions. Results Overall, 211 (11.8%) former players retired due to brain-health concerns (mean age=50.9±18.1, mean years played professionally=6.9±3.3). Alongside brain-health, other retirement reasons included: concerns about long-term physical health (n=155), mental health (n=121), and chronic pain (n=120). Factors helping post-career transitions were problem-focused (e.g., future planning, advice from older players, saving money) and emotionally-focused (e.g., faith/religion, spousal support, health provider/therapist care). Hindering factors were personal (e.g., ongoing musculoskeletal injury/pain issues, mental health concerns, poor health insurance, lacking transition plans, losing former schedule/routine), interpersonal (e.g. lacking support/empathy, being asked why they need to still work), and organizational (e.g., poor post-career transition support). These themes were also present among former players not reporting retirement due to brain-health concerns. Conclusion Numerous post-career transition issues concern former players. Multidimensional interventions that mitigate cognitive challenges, chronic pain, and occupational stressors may help optimize post-career transition coping strategies. Learning Outcomes Describe the post-career transition experiences of former players retiring from brain-health concerns.

OBJECTIVE To test sleep quality as one mechanistic pathway through which repeated concussion increases risk of depression later in life among former contact sport athletes. SETTING Multicenter study enrolled former American collegiate football players from 16 different National Collegiate Athletic Association member institutions. PARTICIPANTS Fifty-eight former American collegiate football players approximately 15 years following sport discontinuation. DESIGN Participants completed in-person evaluations including comprehensive semistructured interviews with detailed concussion history and sport history, as well as self-reported measures of depression symptom severity (Beck Depression Inventory-II) and sleep quality (Pittsburgh Sleep Quality Index). Years of football participation were included as a covariate. Mediation modeling examined the degree to which sleep quality accounted for the association between repeated concussion and depression symptoms. RESULTS Within the mediation model, concussion history significantly predicted sleep quality (B = 1.03; 95% CI, 0.37 to 1.65; P = .002) and sleep quality significantly predicted depressive symptom severity (controlling for the effects of concussion history; B = 0.15; 95% CI, 0.06 to 0.24; P = .001). The association between prior concussion and depressive symptom severity was fully mediated by sleep quality. With inclusion of the indirect effects, concussion history did not predict depressive symptom severity (direct effect: B = 0.14; 95% CI, -0.09 to 0.41; P = .249; indirect effect: 0.15; 95% CI, 0.03 to 0.29; P = .016). CONCLUSIONS Current findings raise the possibility that the greater risk of depression reported in those with a history of mTBI/concussion is mediated by sleep quality, a common sequela of mTBI. These findings highlight potential opportunities for prophylactic sleep-related intervention among individuals with multiple prior concussions to mitigate the risk of depression.

Importance Validation of protein biomarkers for concussion diagnosis and management in military combative training is important, as these injuries occur outside of traditional health care settings and are generally difficult to diagnose. Objective To investigate acute blood protein levels in military cadets after combative training-associated concussions. Design, Setting, and Participants This multicenter prospective case-control study was part of a larger cohort study conducted by the National Collegiate Athletic Association and the US Department of Defense Concussion Assessment Research and Education (CARE) Consortium from February 20, 2015, to May 31, 2018. The study was performed among cadets from 2 CARE Consortium Advanced Research Core sites: the US Military Academy at West Point and the US Air Force Academy. Cadets who incurred concussions during combative training (concussion group) were compared with cadets who participated in the same combative training exercises but did not incur concussions (contact-control group). Clinical measures and blood sample collection occurred at baseline, the acute postinjury point (

Objectives:Years of sport participation (YoP) is conventionally used to estimate cumulative repetitive head impacts (RHI) experienced by contact sport athletes. The relationship of this measure to other estimates of head impact exposure and the potential associations of these measures with neurobehavioral functioning are unknown. We investigated the association between YoP and the Head Impact Exposure Estimate (HIEE), and whether associations between the two estimates of exposure and neurobehavioral functioning varied.Methods:Former American football players (N = 58; age = 37.9 ± 1.5 years) completed in-person evaluations approximately 15 years following sport discontinuation. Assessments consisted of neuropsychological assessment and structured interviews of head impact history (i.e., HIEE). General linear models were fit to test the association between YoP and the HIEE, and their associations with neurobehavioral outcomes.Results:YoP was weakly correlated with the HIEE, p = .005, R2 = .13. Higher YoP was associated with worse performance on the Symbol Digit Modalities Test, p = .004, R2 = .14, and Trail Making Test-B, p = .001, R2 = .18. The HIEE was associated with worse performance on the Delayed Recall trial of the Hopkins Verbal Learning Test-Revised, p = .020, R2 = .09, self-reported cognitive difficulties (Neuro-QoL Cognitive Function), p = .011, R2 = .10, psychological distress (Brief Symptom Inventory-18), p = .018, R2 = .10, and behavioral regulation (Behavior Rating Inventory of Executive Function for Adults), p = .017, R2 = .10.Conclusions:YoP was marginally associated with the HIEE, a comprehensive estimate of head impacts sustained over a career. Associations between each exposure estimate and neurobehavioral functioning outcomes differed. Findings have meaningful implications for efforts to accurately quantify the risk of adverse long-term neurobehavioral outcomes potentially associated with RHI.

ObjectivesTo examine the relationships among self-reported sport-related concussion (SRC) history and current health-promoting behaviours (exercise frequency, diet quality and sleep duration) with self-reported measures of brain health (cognitive function, symptoms of depression and anxiety and emotional–behavioural dyscontrol) in former NFL players.MethodsIn this cross-sectional study, a questionnaire was sent to former NFL players. Respondents reported SRC history (categorical: 0; 1–2; 3–5; 6–9; 10+ concussions), number of moderate-to-vigorous aerobic and resistance exercise sessions per week, diet quality (Rapid Eating Assessment for Participants—Shortened) and average nightly sleep duration. Outcomes were Patient-Reported Outcomes Measurement Information System Cognitive Function, Depression, and Anxiety, and Neuro-QoL Emotional-Behavioral Dyscontrol domain T-scores. Multivariable linear regression models were fit for each outcome with SRC history, exercise frequency, diet quality and sleep duration as explanatory variables alongside select covariates.ResultsMultivariable regression models (n=1784) explained approximately 33%–38% of the variance in each outcome. For all outcomes, SRC history (0.144≤|β|≤0.217) was associated with poorer functioning, while exercise frequency (0.064≤|β|≤0.088) and diet quality (0.057≤|β|≤0.086) were associated with better functioning. Sleeping under 6 hours per night (0.061≤|β|≤0.093) was associated with worse depressive symptoms, anxiety and emotional–behavioural dyscontrol.ConclusionSeveral variables appear to be associated with mood and perceived cognitive function in former NFL players. SRC history is non-modifiable in former athletes; however, the effects of increasing postplaying career exercise frequency, making dietary improvements, and obtaining adequate sleep represent important potential opportunities for preventative and therapeutic interventions.

Identifying the associations between head impact biomechanics and clinical recovery may inform better head impact monitoring procedures and identify athletes who may benefit from early treatments aimed to enhance recovery. The purpose of this study was to test whether head injury biomechanics are associated with clinical recovery of symptom severity, balance, and mental status, as well as symptom resolution time (SRT) and return-to-participation (RTP) time. We studied 45 college American football players (n = 51 concussions) who sustained an incident concussion while participating in a multi-site study. Player race/ethnicity, prior concussion, medical history, position, body mass index, event type, and impact location were covariates in our multivariable analyses. Multivariable negative binomial regression models analyzed associations between our study outcomes and (1) injury-causing linear and rotational head impact severity, (2) season repetitive head impact exposure (RHIE), and (3) injury day RHIE. Median SRT was 6.1 days (IQR 5.8 days, n = 45) and median RTP time was 12.3 days (IQR 7.8 days, n = 36) across our study sample. RTP time was 86% (Ratio 1.86, 95% CI [1.05, 3.28]) longer in athletes with a concussion history. Offensive players had SRTs 49% shorter than defensive players (Ratio 0.51, 95% CI [0.29, 0.92]). Per-unit increases in season RHIE were associated with 22% longer SRT (Ratio 1.22, 95% CI [1.09, 1.36]) but 28% shorter RTP time (Ratio 0.72, 95% CI [0.56, 0.93]). No other head injury biomechanics predicted injury recovery.

Key Points Question Are plasma biomarkers associated with a return-to-sport period of less than 14 days vs 14 days or more in male and female collegiate athletes following a sport-related concussion? Findings This diagnostic study, which included 127 collegiate athletes who had sustained a sports-related concussion, found that higher total tau concentrations 24 to 48 hours after injury and at the time of symptom resolution as well as lower glial fibrillary acidic protein levels acutely postinjury were associated with return-to-sport decisions. Meaning In this study, total tau and glial fibrillary acidic protein levels were associated with return to sport in male and female collegiate athletes following a sports-related concussion., This diagnostic study examines whether plasma biomarkers can differentiate collegiate athletes who return to sport in less than 14 days vs 14 days or more following a sports-related concussion., Importance Identifying plasma biomarkers associated with the amount of time an athlete may need before they return to sport (RTS) following a sport-related concussion (SRC) is important because it may help to improve the health and safety of athletes. Objective To examine whether plasma biomarkers can differentiate collegiate athletes who RTS in less than 14 days or 14 days or more following SRC. Design, Setting, and Participants This multicenter prospective diagnostic study, conducted by the National Collegiate Athletics Association–Department of Defense Concussion Assessment, Research, and Education Consortium, included 127 male and female athletes who had sustained an SRC while enrolled at 6 Concussion Assessment, Research, and Education Consortium Advanced Research Core sites as well as 2 partial–Advanced Research Core military service academies. Data were collected between February 2015 and May 2018. Athletes with SRC completed clinical testing and blood collection at preseason (baseline), postinjury (0-21 hours), 24 to 48 hours postinjury, time of symptom resolution, and 7 days after unrestricted RTS. Main Outcomes and Measures A total of 3 plasma biomarkers (ie, total tau protein, glial fibrillary acidic protein [GFAP], and neurofilament light chain protein [Nf-L]) were measured using an ultrasensitive single molecule array technology and were included in the final analysis. RTS was examined between athletes who took less than 14 days vs those who took 14 days or more to RTS following SRC. Linear mixed models were used to identify significant interactions between period by RTS group. Area under the receiver operating characteristic curve analyses were conducted to examine whether these plasma biomarkers could discriminate between RTS groups. Results The 127 participants had a mean (SD) age of 18.9 (1.3) years, and 97 (76.4%) were men; 65 (51.2%) took less than 14 days to RTS, and 62 (48.8%) took 14 days or more to RTS. Linear mixed models identified significant associations for both mean (SE) plasma total tau (24-48 hours postinjury

Context: Little research has examined health-related quality of life in former National Football League (NFL) players. Objective: Examine the association of musculoskeletal injury history and current self-reported physical and mental health in former NFL players. Setting: Cross-sectional questionnaire. Patients or Other Participants: Historical cohort of 2,103 former NFL players that played at least one season between 1940 and 2001. Intervention: Players were grouped by self-reported professional career musculoskeletal injury history and whether injuries affected current health: (1) no musculoskeletal injury history; (2) musculoskeletal injury history, currently affected by injuries; and (3) musculoskeletal injury history, not currently affected by injuries. Main Outcome Measure: The Short Form 36 Measurement Model for Functional Assessment of Health and Well-Being (SF-36) yielded physical and mental health composite scores (PCS and MCS, respectively); higher scores indicated better health. Multivariable linear regression computed mean differences (MD) among injury groups. Covariates included demographics, playing history characteristics, surgical intervention for musculoskeletal injuries, and whether injury resulted in premature end to career. MD with 95% CI excluding 0.00 were deemed significant. Results: Overall, 90.3% reported at least one musculoskeletal injury during their professional football careers, of which 74.8% reported being affected by their injuries at time of survey completion. Adjusting for covariates, mean PCS in the “injury and affected” group was lower than the “no injury” (MD = −3.2; 95% CI: −4.8, −1.7) and “injury and not affected” groups (MD = −4.3; 95% CI: −5.4, −3.3); mean MCS did not differ. Conclusion: Many players reported musculoskeletal injuries, highlighting the need for developing and evaluating injury management interventions.

Background: Organizations recommend that athletes should be asymptomatic or symptom-limited before initiating a graduated return-to-play (GRTP) protocol after sports-related concussion, although asymptomatic or symptom-limited is not well-defined. Hypotheses: (1) There will be a range (ie, beyond zero as indicator of “symptom-free”) in symptom severity endorsement when athletes are deemed ready to initiate a GRTP protocol. (2) Baseline symptom severity scores and demographic/preinjury medical history factors influence symptom severity scores at the commencement of the GRTP protocol. (3) Greater symptom severity scores at GRTP protocol initiation will result in longer protocol duration. (4) Symptom severity scores will not differ between those who did and did not sustain a repeat injury within 90 days of their initial injury. Study Design: Cohort study; Level of evidence, 2. Methods: Across 30 universities, athletes (N = 1531) completed assessments at baseline and before beginning the GRTP protocol, as determined by local medical staff. Symptom severity scores were recorded with the symptom checklist of the Sport Concussion Assessment Tool–3rd Edition. Nonparametric comparisons were used to examine the effect of medical, demographic, and injury factors on symptom endorsement at GRTP protocol initiation, as well as differences in symptom severity scores between those who did and did not sustain a repeat injury within 90 days. A Cox regression was used to examine the association between symptom severity scores at GRTP protocol initiation and protocol duration. Results: Symptom severity scores at the time when the GRTP protocol was initiated were as follows: 0 to 5 (n = 1378; 90.0%), 6 to 10 (n = 76; 5.0%), 11 to 20 (n = 42; 3.0%), and ≥21 (n = 35; 2.0%). Demographic (sex and age), medical (psychiatric disorders, attention-deficit/hyperactivity disorder, learning disorder), and other factors (baseline symptom endorsement and sleep) were significantly associated with higher symptom severity scores at the GRTP initiation ( P < .05). The 4 GRTP initiation time point symptom severity score groups did not significantly differ in total time to unrestricted RTP, χ2(3) = 1.4; P = .73. When days until the initiation of the GRTP protocol was included as a covariate, symptom severity scores between 11 and 20 ( P = .02; hazard ratio = 1.44; 95% CI, 1.06-1.96) and ≥21 ( P < .001; hazard ratio = 1.88; 95% CI, 1.34-2.63) were significantly associated with a longer GRTP protocol duration as compared with symptom severity scores between 0 and 5. Symptom severity scores at GRTP initiation did not significantly differ between those who sustained a repeat injury within 90 days and those who did not ( U = 29,893.5; P = .75). Conclusion: A range of symptom severity endorsement was observed at GRTP protocol initiation, with higher endorsement among those with higher baseline symptom endorsement and select demographic and medical history factors. Findings suggest that initiation of a GRTP protocol before an absolute absence of all symptoms is not associated with longer progression of the GRTP protocol, although symptom severity scores >10 were associated with longer duration of a GRTP protocol. Results can be utilized to guide clinicians toward optimal GRTP initiation (ie, balancing active recovery with avoidance of premature return to activity).

Question Is sport-related concussion associated with levels of traumatic brain injury biomarkers in collegiate athletes? Findings In this case-control study of 504 collegiate athletes with concussion, contact sport control athletes, and non-contact sport athletes, the athletes with concussion had significant elevations in multiple traumatic brain injury biomarkers compared with preseason baseline and with 2 groups of control athletes without concussion during the acute postinjury period. Meaning These results suggest that blood biomarkers can be used as research tools to inform the underlying pathophysiological mechanism of concussion and provide additional support for future studies to optimize and validate biomarkers for potential clinical use in sport-related concussion. This case-control study examines the association between sport-related concussion and levels of traumatic brain injury biomarkers in collegiate athletes. Importance There is potential scientific and clinical value in validation of objective biomarkers for sport-related concussion (SRC). Objective To investigate the association of acute-phase blood biomarker levels with SRC in collegiate athletes. Design, Setting, and Participants This multicenter, prospective, case-control study was conducted by the National Collegiate Athletic Association (NCAA) and the US Department of Defense Concussion Assessment, Research, and Education (CARE) Consortium from February 20, 2015, to May 31, 2018, at 6 CARE Advanced Research Core sites. A total of 504 collegiate athletes with concussion, contact sport control athletes, and non-contact sport control athletes completed clinical testing and blood collection at preseason baseline, the acute postinjury period, 24 to 48 hours after injury, the point of reporting being asymptomatic, and 7 days after return to play. Data analysis was conducted from March 1 to November 30, 2019. Main Outcomes and Measures Glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament light chain, and tau were quantified using the Quanterix Simoa multiplex assay. Clinical outcome measures included the Sport Concussion Assessment Tool-Third Edition (SCAT-3) symptom evaluation, Standardized Assessment of Concussion, Balance Error Scoring System, and Brief Symptom Inventory 18. Results A total of 264 athletes with concussion (mean [SD] age, 19.08 [1.24] years; 211 [79.9%] male), 138 contact sport controls (mean [SD] age, 19.03 [1.27] years; 107 [77.5%] male), and 102 non-contact sport controls (mean [SD] age, 19.39 [1.25] years; 82 [80.4%] male) were included in the study. Athletes with concussion had significant elevation in GFAP (mean difference, 0.430 pg/mL; 95% CI, 0.339-0.521 pg/mL; P < .001), UCH-L1 (mean difference, 0.449 pg/mL; 95% CI, 0.167-0.732 pg/mL; P < .001), and tau levels (mean difference, 0.221 pg/mL; 95% CI, 0.046-0.396 pg/mL; P = .004) at the acute postinjury time point compared with preseason baseline. Longitudinally, a significant interaction (group x visit) was found for GFAP (F-7,F-1507.36 = 16.18, P < .001), UCH-L1 (F-7,F-1153.09 = 5.71, P < .001), and tau (F-7,F-1480.55 = 6.81, P < .001); the interaction for neurofilament light chain was not significant (F-7,F-1506.90 = 1.33, P = .23). The area under the curve for the combination of GFAP and UCH-L1 in differentiating athletes with concussion from contact sport controls at the acute postinjury period was 0.71 (95% CI, 0.64-0.78; P < .001); the acute postinjury area under the curve for all 4 biomarkers combined was 0.72 (95% CI, 0.65-0.79; P < .001). Beyond SCAT-3 symptom score, GFAP at the acute postinjury time point was associated with the classification of athletes with concussion from contact controls (beta = 12.298; 95% CI, 2.776-54.481; P = .001) and non-contact sport controls (beta = 5.438; 95% CI, 1.676-17.645; P = .005). Athletes with concussion with loss of consciousness or posttraumatic amnesia had significantly higher levels of GFAP than athletes with concussion with neither loss of consciousness nor posttraumatic amnesia at the acute postinjury time point (mean difference, 0.583 pg/mL; 95% CI, 0.369-0.797 pg/mL; P < .001). Conclusions and Relevance The results suggest that blood biomarkers can be used as research tools to inform the underlying pathophysiological mechanism of concussion and provide additional support for future studies to optimize and validate biomarkers for potential clinical use in SRC. Grand Alliance Concussion Assessment, Research, and Education (CARE) Consortium - NCAA; DODUnited States Department of Defense; Office of the Assistant Secretary of Defense for Health Affairs through the Psychological Health and Traumatic Brain Injury Program [W81XWH-14-2-0151] This work received support from the Grand Alliance Concussion Assessment, Research, and Education (CARE) Consortium funded in part by the NCAA and the DOD andwas supported by award W81XWH-14-2-0151 from the Office of the Assistant Secretary of Defense for Health Affairs through the Psychological Health and Traumatic Brain Injury Program.

There has been a recent call for longitudinal cohort studies to track the physiological recovery of sport-related concussion (SRC) and its relationship with clinical recovery. Resting-state functional magnetic resonance imaging (rs-fMRI) has shown potential for detecting subtle changes in brain function after SRC. We investigated the effects of SRC on rs-fMRI metrics assessing local connectivity (regional homogeneity; REHO), global connectivity (average nodal strength), and the relative amplitude of slow oscillations of rs-fMRI (fractional amplitude of low-frequency fluctuations; fALFF). Athletes diagnosed with SRC (n = 92) completed visits with neuroimaging at 24–48 h post-injury (24 h), after clearance to begin the return-to-play (RTP) progression (asymptomatic), and 7 days following unrestricted RTP (post-RTP). Non-injured athletes (n = 82) completed visits yoked to the schedule of matched injured athletes and served as controls. Concussed athletes had elevated symptoms, worse neurocognitive performance, greater balance deficits, and elevated psychological symptoms at the 24-h visit relative to controls. These deficits were largely recovered by the asymptomatic visit. Concussed athletes still reported elevated psychological symptoms at the asymptomatic visit relative to controls. Concussed athletes also had elevated REHO in the right middle and superior frontal gyri at the 24-h visit that returned to normal levels by the asymptomatic visit. Additionally, REHO in these regions at 24 h predicted psychological symptoms at the asymptomatic visit in concussed athletes. Current results suggest that SRC is associated with an acute alteration in local connectivity that follows a similar time course as clinical recovery. Our results do not indicate strong evidence that concussion-related alterations in rs-fMRI persist beyond clinical recovery.

ContextAerobic exercise interventions are increasingly being prescribed for concussion rehabilitation, but whether aerobic training protocols influence clinical concussion diagnosis and management assessments is unknown.ObjectiveTo investigate the effects of a brief aerobic exercise intervention on clinical concussion outcomes in healthy, active participants.DesignRandomized controlled clinical trial.SettingLaboratory.Patients or Other ParticipantsHealthy (uninjured) participants (n = 40) who exercised ≥3 times/week.Intervention(s)Participants were randomized into the acute concussion therapy intervention (ACTIVE) training or nontraining group. All participants completed symptom, cognitive, balance, and vision assessments during 2 test sessions approximately 14 days apart. Participants randomized to ACTIVE training completed six 30-minute exercise sessions that progressed from 60% to 80% of individualized maximal oxygen consumption (V˙o2max) across test sessions, while the nontraining group received no intervention.Main Outcome Measure(s)The CNS Vital Signs standardized scores, Vestibular/Ocular Motor Screening near-point convergence distance (cm), and Graded Symptom Checklist, Balance Error Scoring System, and Standardized Assessment of Concussion total scores.ResultsAn interaction effect was found for total symptom score (P = .01); the intervention group had improved symptom scores between sessions (session 1: 5.1 ± 5.8; session 2: 1.9 ± 3.6). Cognitive flexibility, executive functioning, reasoning, and total symptom score outcomes were better but composite memory, verbal memory, and near-point convergence distance scores were worse at the second session (all P values < .05). However, few changes exceeded the 80% reliable change indices calculated for this study, and effect sizes were generally small to negligible.ConclusionsA brief aerobic training protocol had few meaningful effects on clinical concussion assessment in healthy participants, suggesting that current concussion-diagnostic and -assessment tools remain clinically stable in response to aerobic exercise training. This provides normative data for future researchers, who should further evaluate the effect of ACTIVE training on clinical outcomes among concussed populations.Trial Registration NumberClinicalTrials.gov: NCT02872480

Objectives To probe microstructural changes that are associated with subconcussive head impact exposure in deep and cortical gray matter of high school football players over a single season. Methods Players underwent diffusion kurtosis imaging (DKI) and quantitative susceptibility mapping (QSM) scans. Head impact data was recorded. Association between parametric changes and frequency of frontal head impact was assessed. Results In deep gray matter, significant decreases in mean kurtosis (MK) and increases in mean diffusivity (MD) over the season were observed in the thalamus and putamen. Correlations between changes in DKI metrics and frequency of frontal impacts were observed in the putamen and caudate. In cortical gray matter, decreases in MK were observed in regions including the pars triangularis and inferior parietal. In addition, increases in MD were observed in the rostral middle frontal cortices. Negative correlations between MK and frequency of frontal impacts were observed in the posterior part of the brain including the pericalcarine, lingual and middle temporal cortices. Magnetic susceptibility values exhibited no significant difference or correlation, suggesting these diffusion changes common within the group may not be associated with iron-related mechanisms. Conclusion Microstructural alterations over the season and correlations with head impacts were captured by DKI metrics, which suggested that DKI imaging of gray matter may yield valuable biomarkers for evaluating brain injuries associated with subconcussive head impact. Findings of associations between frontal impacts and changes in posterior cortical gray matter also indicated that contrecoup injury rather than coup injury might be the dominant mechanism underlying the observed microstructural alterations. Advances in knowledge Significant microstructural changes, as reflected by DKI metrics, in cortical gray matter such as the rostral middle frontal cortices, and in deep gray matter such as the thalamus were observed in high school football players over the course of a single season without clinically diagnosed concussion. QSM showed no evidence of iron-related changes in the observed subconcussive brain injuries. The detected microstructural changes in cortical and deep gray matter correlated with frequency of subconcussive head impacts. Implications for patient care DKI may yield valuable biomarkers for evaluating the severity of brain injuries associated with subconcussive head impacts in contact sport athletes.

Sport-related concussion (SRC) has become a major health problem, affecting millions of athletes each year. Despite the increasing occurrence and prevalence of SRC, its underlying mechanism and recovery course have yet to be fully elucidated. The National Collegiate Athletic Association–Department of Defense Grand Alliance: Concussion Assessment, Research and Education (CARE) Consortium is a large-scale, multisite study of the natural history of concussion across multiple sports. The Advanced Research Core (ARC) of CARE is focused on the advanced biomarker assessment of a reduced subject cohort. This paper reports findings from two ARC sites to evaluate cerebral blood flow (CBF) changes in acute SRC, as measured using advanced arterial spin labeling (ASL) magnetic resonance imaging (MRI). We compared relative CBF maps assessed in 24 concussed contact sport athletes obtained at 24–48 h after injury to those of a control group of 24 matched contact sport players. Significantly less CBF was detected in several brain regions in concussed athletes, while clinical assessments also indicated clinical symptom and performance impairments in SRC patients. Correlations were found between decreased CBF in acute SRC and clinical assessments, including Balance Error Scoring System total score and Immediate Post-Concussion Assessment and Cognitive Test memory composite and impulse control composite scores, as well as days from injury to asymptomatic. Although using different ASL MRI sequences, our preliminary results from two sites are consistent with previous reports and suggest that advanced ASL MRI methods might be useful for detecting acute neurobiological changes in acute SRC.