Gene Expression Alterations in Peripheral Blood Following Sport-Related Concussion in a Prospective Cohort of Collegiate Athletes: A Concussion Assessment, Research and Education (CARE) Consortium Study.

BACKGROUND: Molecular-based approaches to understanding concussion pathophysiology provide complex biological information that can advance concussion research and identify potential diagnostic and/or prognostic biomarkers of injury. OBJECTIVE: The aim of this study was to identify gene expression changes in peripheral blood that are initiated following concussion and are relevant to concussion response and recovery. METHODS: We analyzed whole blood transcriptomes in a large cohort of concussed and control collegiate athletes who were participating in the multicenter prospective cohort Concussion Assessment, Research, and Education (CARE) Consortium study. Blood samples were collected from collegiate athletes at preseason (baseline), within 6 h of concussion injury, and at four additional prescribed time points spanning 24 h to 6 months post-injury. RNA sequencing was performed on samples from 230 concussed, 130 contact control, and 102 non-contact control athletes. Differential gene expression and deconvolution analysis were performed at each time point relative to baseline. RESULTS: Cytokine and immune response signaling pathways were activated immediately after concussion, but at later time points these pathways appeared to be suppressed relative to the contact control group. We also found that the proportion of neutrophils increased and natural killer cells decreased in the blood following concussion. CONCLUSIONS: Transcriptome signatures in the blood reflect the known pathophysiology of concussion and may be useful for defining the immediate biological response and the time course for recovery. In addition, the identified immune response pathways and changes in immune cell type proportions following a concussion may inform future treatment strategies.

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.

Longitudinal white-matter abnormalities in sports-related concussion: A diffusion MRI study.

OBJECTIVE: To study longitudinal recovery trajectories of white matter after sports-related concussion (SRC) by performing diffusion tensor imaging (DTI) on collegiate athletes who sustained SRC. METHODS: Collegiate 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. RESULTS: In 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. CONCLUSIONS: Changes 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.

Head Impact Exposure in College Football after a Reduction in Preseason Practices.

INTRODUCTION: Regulatory efforts toward reducing concussion risk have begun to focus on decreasing the number of head impacts (i.e., head impact burden) sustained by athletes in contact sports. To that end, in 2018, the NCAA decreased the number of preseason on-field team activities for Division I teams from 29 to 25. The objective of the current study was to quantify changes in practice schedule and head impact exposure between the 2017 and 2018 football preseasons. METHODS: Athletes from five NCAA Division I football teams (n = 426) were consented and enrolled. RESULTS: On average, athletes participated in 10% fewer contact practices in 2018. However, the effect of this ruling on preseason head impact burden was mixed. Across all athletes, the total preseason head impact burden was essentially the same from 2017 to 2018. However, this study revealed significant team-by-team differences in preseason head impact burden, with one team demonstrating a 35% increase in the average number of recorded head impacts from 2017 to 2018, despite a modest decrease in the number of contact practices. Other teams had similar or decreased head impact burden. CONCLUSIONS: Team-based differences in total preseason head impact burden were attributable to changes in daily practice schedule, with longer practice durations and more intense contact practice sessions contributing to increases in daily head impact exposure that, in turn, led to greater preseason head impact burden. Results of this study have highlighted the difficulty in decreasing contact sport head impact exposure through rule changes targeted at limiting on-field team activities. Future efforts aimed specifically at contact practice duration, daily head impact exposure, or limiting time in specific drills may be more effective at reducing total preseason head impact burden.

Repetitive Head Impact Exposure in College Football Following an NCAA Rule Change to Eliminate Two-A-Day Preseason Practices: A Study from the NCAA-DoD CARE Consortium.

Repetitive head impact exposure sustained by athletes of contact sports has been hypothesized to be a mechanism for concussion and a possible explanation for the high degree of variability in sport-related concussion biomechanics. In an attempt to limit repetitive head impact exposure during the football preseason, the NCAA eliminated two-a-day practices in 2017, while maintaining the total number of team practice sessions. The objective of this study was to quantify head impact exposure during the preseason and regular season in Division I college football athletes to determine whether the 2017 NCAA ruling decreased head impact exposure. 342 unique athletes from five NCAA Division I Football Bowl Subdivision (FBS) programs were consented and enrolled. Head impacts were recorded using the Head Impact Telemetry (HIT) System during the entire fall preseasons and regular seasons in 2016 and 2017. Despite the elimination of two-a-day practices, the number of preseason contact days increased in 2017, with an increase in average hourly impact exposure (i.e., contact intensity), resulting in a significant increase in total head impact burden (+ 26%) for the 2017 preseason. This finding would indicate that the 2017 NCAA ruling was not effective at reducing the head impact burden during the football preseason. Additionally, athletes sustained a significantly higher number of recorded head impacts per week (+ 40%) during the preseason than the regular season, implicating the preseason as a time of elevated repetitive head impact burden. With increased recognition of a possible association between repetitive head impact exposure and concussion, increased preseason exposure may predispose certain athletes to a higher risk of concussion during the preseason and regular season. Accordingly, efforts at reducing concussion incidence in contact sports should include a reduction in overall head impact exposure.

Factors Affecting Head Impact Exposure in College Football Practices: A Multi-Institutional Study.

Biomechanical data collected from head impacts in football have been used to characterize exposure and predict injury risk. This study sought to specifically quantify the factors that contribute towards player head impact exposure in college football practices. All players included in this study were outfitted with football helmets instrumented with accelerometer arrays (Head Impact Telemetry System). Head impact exposure was defined by the number of head impacts each player experienced in practice, the number of practice head impacts normalized by the number of practice sessions (practice head impact rate), and the 95th percentile linear and rotational resultant head impact accelerations. Practice head impact rate was observed to vary significantly with player position (p < 0.0001; η2 = 0.46), team (p = 0.0016; η2 = 0.03), and the number of game impacts (p < 0.0001; η2 = 0.03), which served as a correlate for player ability. Even after controlling for practice participation, player position, team, and ability, differences between individuals accounted for 48% of the variance in head impact exposure in practice. This work demonstrates the importance of considering head impact exposure on a subject-specific basis rather than estimating head impact exposure from aggregate data.

Comparison of Head Impact Exposure Between Concussed Football Athletes and Matched Controls: Evidence for a Possible Second Mechanism of Sport-Related Concussion.

Studies of football athletes have implicated repetitive head impact exposure in the onset of cognitive and brain structural changes, even in the absence of diagnosed concussion. Those studies imply accumulating damage from successive head impacts reduces tolerance and increases risk for concussion. Support for this premise is that biomechanics of head impacts resulting in concussion are often not remarkable when compared to impacts sustained by athletes without diagnosed concussion. Accordingly, this analysis quantified repetitive head impact exposure in a cohort of 50 concussed NCAA Division I FBS college football athletes compared to controls that were matched for team and position group. The analysis quantified the number of head impacts and risk weighted exposure both on the day of injury and for the season to the date of injury. 43% of concussed athletes had the most severe head impact exposure on the day of injury compared to their matched control group and 46% of concussed athletes had the most severe head impact exposure for the season to the date of injury compared to their matched control group. When accounting for date of injury or season to date of injury, 72% of all concussed athletes had the most or second most severe head impact exposure compared to their matched control group. These trends associating cumulative head impact exposure with concussion onset were stronger for athletes that participated in a greater number of contact activities. For example, 77% of athletes that participated in ten or more days of contact activities had greater head impact exposure than their matched control group. This unique analysis provided further evidence for the role of repetitive head impact exposure as a predisposing factor for the onset of concussion. The clinical implication of these findings supports contemporary trends of limiting head impact exposure for college football athletes during practice activities in an effort to also reduce risk of concussive injury.

Correlation of Concussion Symptom Profile with Head Impact Biomechanics: A Case for Individual-Specific Injury Tolerance.

Concussion is a brain injury induced by biomechanical forces that is broadly defined as a complex pathophysiological process affecting the brain. The intricate link between biomechanical input and concussion injury response is poorly understood. We aimed to test the hypothesis that greater biomechanical forces would result in the presentation of more concussion-related symptoms that would take longer to resolve. The objective of this study was to investigate the relationship between an array of biomechanical parameters measured for concussive impacts and the presentation and resolution of concussion symptoms. A total of 319 collegiate football players from six universities were recruited to participate in this study. Certified athletic trainers and/or team physicians at each site diagnosed and treated concussions sustained by subjects through participation in football. The subjects' helmets were instrumented with accelerometer arrays that measured linear and rotational head accelerations for each impact experienced during games and practices. Correlations between biomechanical measurements associated with concussion symptom presentation and recovery were quantified. A total of 22 subjects collectively sustained 25 concussions, with three subjects sustaining two concussions each. Biomechanical measures associated with injury were not found to be correlated with number of symptoms, Sport Concussion Assessment Tool 3 Symptom Severity Score, or time to symptom resolution. Linear and rotational accelerations associated with injury were not correlated with symptom severity for any of the 22 individual symptoms evaluated. Further, we found no association between impact location and presence of any individual symptom when ignoring severity grade. While concussive impacts did not stand out relative to impacts that did not result in injury, concussive impacts were among the most severe for each individual player. This suggests tolerance to head acceleration might be individual-specific, meaning similar biomechanical inputs can produce different injury presentations between individuals. Future investigations should consider individual-specific analyses of tolerance to head acceleration and injury response.