BACKGROUND: The natural history of mild traumatic brain injury (TBI) or concussion remains poorly defined and no objective biomarker of physiological recovery exists for clinical use. The National Collegiate Athletic Association (NCAA) and the US Department of Defense (DoD) established the Concussion Assessment, Research and Education (CARE) Consortium to study the natural history of clinical and neurobiological recovery after concussion in the service of improved injury prevention, safety and medical care for student-athletes and military personnel. OBJECTIVES: The objectives of this paper were to (i) describe the background and driving rationale for the CARE Consortium; (ii) outline the infrastructure of the Consortium policies, procedures, and governance; (iii) describe the longitudinal 6-month clinical and neurobiological study methodology; and (iv) characterize special considerations in the design and implementation of a multicenter trial. METHODS: Beginning Fall 2014, CARE Consortium institutions have recruited and enrolled 23,533 student-athletes and military service academy students (approximately 90% of eligible student-athletes and cadets; 64.6% male, 35.4% female). A total of 1174 concussions have been diagnosed in participating subjects, with both concussion and baseline cases deposited in the Federal Interagency Traumatic Brain Injury Research (FITBIR) database. CONCLUSIONS: Challenges have included coordinating regulatory issues across civilian and military institutions, operationalizing study procedures, neuroimaging protocol harmonization across sites and platforms, construction and maintenance of a relational database, and data quality and integrity monitoring. The NCAA-DoD CARE Consortium represents a comprehensive investigation of concussion in student-athletes and military service academy students. The richly characterized study sample and multidimensional approach provide an opportunity to advance the field of concussion science, not only among student athletes but in all populations at risk for mild TBI.
IMPORTANCE: Concussions are a common occurrence in young athletes. Hypobaric hypoxemia, such as that experienced during airplane travel, can potentially cause alterations to cerebral blood flow and increased neuroinflammatory response. It remains unknown whether flying early after a concussion may influence the clinical course of injury. OBJECTIVE: To determine whether there is an association between concussion recovery and airplane travel in collegiate athletes and military cadets. DESIGN, SETTING, AND PARTICIPANTS: This cohort study was conducted by the National Collegiate Athletic Association and US Department of Defense Concussion Assessment, Research, and Education Consortium from August 3, 2014, to September 13, 2018. Participant groups were categorized by those who flew within 72 hours of injury and those who did not fly. All participants included in the final analyses had complete data of interest and only 1 injury during the study. Data analysis was performed from September 2018 to March 2020. MAIN OUTCOMES AND MEASURES: Recovery outcome measures were defined as time (in days) from injury to return to activity, school, and baseline symptoms. Symptom and headache severity scores were derived from the Sports Concussion Assessment Tool—Third Edition. Scores for both groups were taken at baseline and a median of 2 days after injury. RESULTS: A total of 92 participants who flew (mean [SD] age, 19.1 [1.2] years; 55 male [59.8%]) and 1383 participants who did not fly (mean [SD] age, 18.9 [1.3] years; 809 male [58.5%]) were included in the analysis of symptom recovery outcomes (analysis 1). Similarly, 100 participants who flew (mean [SD] age, 19.2 [1.2] years; 63 male [63.0%]) and 1577 participants who did not fly (mean [SD] age, 18.9 [1.3] years; 916 male [58.1%]) were included in the analysis of symptom severity outcomes (analysis 2). No significant group differences were found regarding recovery outcome measures. Likewise, there were no group differences in symptom (estimated mean difference, 0.029; 95% CI, ...
Importance: Concussions are a common occurrence in young athletes. Hypobaric hypoxemia, such as that experienced during airplane travel, can potentially cause alterations to cerebral blood flow and increased neuroinflammatory response. It remains unknown whether flying early after a concussion may influence the clinical course of injury. Objective: To determine whether there is an association between concussion recovery and airplane travel in collegiate athletes and military cadets. Design, Setting, and Participants: This cohort study was conducted by the National Collegiate Athletic Association and US Department of Defense Concussion Assessment, Research, and Education Consortium from August 3, 2014, to September 13, 2018. Participant groups were categorized by those who flew within 72 hours of injury and those who did not fly. All participants included in the final analyses had complete data of interest and only 1 injury during the study. Data analysis was performed from September 2018 to March 2020. Main Outcomes and Measures: Recovery outcome measures were defined as time (in days) from injury to return to activity, school, and baseline symptoms. Symptom and headache severity scores were derived from the Sports Concussion Assessment Tool-Third Edition. Scores for both groups were taken at baseline and a median of 2 days after injury. Results: A total of 92 participants who flew (mean [SD] age, 19.1 [1.2] years; 55 male [59.8%]) and 1383 participants who did not fly (mean [SD] age, 18.9 [1.3] years; 809 male [58.5%]) were included in the analysis of symptom recovery outcomes (analysis 1). Similarly, 100 participants who flew (mean [SD] age, 19.2 [1.2] years; 63 male [63.0%]) and 1577 participants who did not fly (mean [SD] age, 18.9 [1.3] years; 916 male [58.1%]) were included in the analysis of symptom severity outcomes (analysis 2). No significant group differences were found regarding recovery outcome measures. Likewise, there were no group differences in symptom (estimated mean difference, 0.029; 95% CI, -0.083 to 0.144; P = .67) or headache (estimated mean difference, -0.007; 95% CI, -0.094 to 0.081; P = .91) severity scores. Conclusions and Relevance: Airplane travel early after concussion was not associated with recovery or severity of concussion symptoms. These findings may help guide future recommendations on flight travel after concussion in athletes.
BACKGROUND: Timely removal from activity after concussion symptoms remains problematic despite heightened awareness. Previous studies indicated potential adverse effects of continuing to participate in physical activity immediately after sustaining a concussion. HYPOTHESIS/PURPOSE: The purpose was to determine the effect of timing of removal from play after concussion on clinical outcomes. It was hypothesized that immediate removal from activity after sport-related concussion (SRC) would be associated with less time missed from sport, a shorter symptomatic period, and better outcomes on acute clinical measures. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Data were reported from the National Collegiate Athletic Association and Department of Defense Grand Alliance: Concussion Awareness, Research, and Education (CARE) Consortium. Participants with 506 diagnosed SRCs from 18 sports and 25 institutions and military service academies were analyzed and classified as either immediate removal from activity (I-RFA) or delayed removal from activity (D-RFA). Outcomes of interest included time missed from sport attributed to their SRC, symptom duration, and clinical assessment scores. RESULTS: There were 322 participants (63.6%) characterized as D-RFA. I-RFA status was associated with significantly less time missed from sport (R(2) change = .022–.024, P < .001 to P = .001) and shorter symptom duration (R(2) change = .044–.046, P < .001 [all imputations]) while controlling for other SRC recovery modifiers. These athletes missed approximately 3 fewer days from sport participation. I-RFA athletes had significantly less severe acute SRC symptoms and were at lower risk of recovery taking ≥14 days (relative risk = .614, P < .001, small-medium effect size) and ≥21 days (relative risk = .534, P = .010, small effect size). CONCLUSION: I-RFA is a protective factor associated with less severe acute symptoms and shorter recovery after SRC. Conveying this message to athletes, coaches, and others involved in the ...
Discussions surrounding concussion have made their way into the public sphere over the previous decade with media attention and coverage of the injury fueling public debate. These conversations have devolved into discussions on banning contact and collision sports and raised legal questions surrounding injury management. Questions raised about concussion eclipse what science can answer, but the University of Michigan Injury Center (MI, USA) hosted a Concussion Summit in September 2015 as a means to condense, solidify and disseminate what is currently known on the topic. Areas for discussion included concussion incidence and prevention, diagnosis and management, legislation and education, legal and social aspects and future directions. A summary of those presentations are included within.
Despite the significant impact that concussion has on military service members, significant gaps remain in our understanding of the optimal diagnostic, management, and return to activity/duty criteria to mitigate the consequences of concussion. In response to these significant knowledge gaps, the US Department of Defense (DoD) and the National Collegiate Athletic Association (NCAA) partnered to form the NCAA-DoD Grand Alliance in 2014. The NCAA-DoD CARE Consortium was established with the aim of creating a national multisite research network to study the clinical and neurobiological natural history of concussion in NCAA athletes and military Service Academy cadets and midshipmen. In addition to the data collected for the larger CARE Consortium effort, the service academies have pursued military-specific lines of research relevant to operational and medical readiness associated with concussion. The purpose of this article is to describe the structure of the NCAA-DoD Grand Alliance efforts at the service academies, as well as discuss military-specific research objectives and provide an overview of progress to date. A secondary objective is to discuss the challenges associated with conducting large-scale studies in the Service Academy environment and highlight future directions for concussion research endeavors across the CARE Service Academy sites.
Despite the significant impact that concussion has on military service members, significant gaps remain in our understanding of the optimal diagnostic, management, and return to activity/duty criteria to mitigate the consequences of concussion. In response to these significant knowledge gaps, the US Department of Defense (DoD) and the National Collegiate Athletic Association (NCAA) partnered to form the NCAA-DoD Grand Alliance in 2014. The NCAA-DoD CARE Consortium was established with the aim of creating a national multisite research network to study the clinical and neurobiological natural history of concussion in NCAA athletes and military Service Academy cadets and midshipmen. In addition to the data collected for the larger CARE Consortium effort, the service academies have pursued military-specific lines of research relevant to operational and medical readiness associated with concussion. The purpose of this article is to describe the structure of the NCAA-DoD Grand Alliance efforts at the service academies, as well as discuss military-specific research objectives and provide an overview of progress to date. A secondary objective is to discuss the challenges associated with conducting large-scale studies in the Service Academy environment and highlight future directions for concussion research endeavors across the CARE Service Academy sites.
Introduction The prevalence and possible long-term consequences of concussion remain an increasing concern to the U.S. military, particularly as it pertains to maintaining a medically ready force. Baseline testing is being used both in the civilian and military domains to assess concussion injury and recovery. Accurate interpretation of these baseline assessments requires one to consider other influencing factors not related to concussion. To date, there is limited understanding, especially within the military, of what factors influence normative test performance. Given the significant physical and mental demands placed on service academy members (SAM), and their relatively high risk for concussion, it is important to describe demographics and normative profile of SAMs. Furthermore, the absence of available baseline normative data on female and non-varsity SAMs makes interpretation of post-injury assessments challenging. Understanding how individuals perform at baseline, given their unique individual characteristics (e.g., concussion history, sex, competition level), will inform post-concussion assessment and management. Thus, the primary aim of this manuscript is to characterize the SAM population and determine normative values on a concussion baseline testing battery. Materials and Methods All data were collected as part of the Concussion Assessment, Research and Education (CARE) Consortium. The baseline test battery included a post-concussion symptom checklist (Sport Concussion Assessment Tool (SCAT), psychological health screening inventory (Brief Symptom Inventory (BSI-18) and neurocognitive evaluation (ImPACT), Balance Error Scoring System (BESS), and Standardized Assessment of Concussion (SAC). Linear regression models were used to examine differences across sexes, competition levels, and varsity contact levels while controlling for academy, freshman status, race, and previous concussion. Zero inflated negative binomial models estimated symptom scores due to the high frequency of zero scores. Results Significant, but small, sex effects were observed on the ImPACT visual memory task. While, females performed worse than males (p < 0.0001, pη2 = 0.01), these differences were small and not larger than the effects of the covariates. A similar pattern was observed for competition level on the SAC. There was a small, but significant difference across competition level. SAMs participating in varsity athletics did significantly worse on the SAC compared to SAMs participating in club or intramural athletics (all p's < 0.001, η2 = 0.01). When examining symptom reporting, males were more than two times as likely to report zero symptoms on the SCAT or BSI-18. Intramural SAMs had the highest number of symptoms and severity compared to varsity SAMs (p < 0.0001, Cohen's d < 0.2). Contact level was not associated with SCAT or BSI-18 symptoms among varsity SAMs. Notably, the significant differences across competition level on SCAT and BSI-18 were sub-clinical and had small effect sizes. Conclusion The current analyses provide the first baseline concussion battery normative data among SAMs. While statistically significant differences may be observed on baseline tests, the effect sizes for competition and contact levels are very small, indicating that differences are likely not clinically meaningful at baseline. Identifying baseline differences and significant covariates is important for future concussion-related analyses to inform concussion evaluations for all athlete levels.
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 ...
BACKGROUND: Concussion, or mild traumatic brain injury, is a major public health concern affecting 42 million individuals globally each year. However, little is known regarding concussion risk factors across all concussion settings as most concussion research has focused on only sport-related or military-related concussive injuries. METHODS: The current study is part of the Concussion, Assessment, Research, and Education (CARE) Consortium, a multi-site investigation on the natural history of concussion. Cadets at three participating service academies completed annual baseline assessments, which included demographics, medical history, and concussion history, along with the Sport Concussion Assessment Tool (SCAT) symptom checklist and Brief Symptom Inventory (BSI-18). Clinical and research staff recorded the date and injury setting at time of concussion. Generalized mixed models estimated concussion risk with service academy as a random effect. Since concussion was a rare event, the odds ratios were assumed to approximate relative risk. RESULTS: Beginning in 2014, 10,604 (n = 2421, 22.83% female) cadets enrolled over 3 years. A total of 738 (6.96%) cadets experienced a concussion, 301 (2.84%) concussed cadets were female. Female sex and previous concussion were the most consistent estimators of concussion risk across all concussion settings. Compared to males, females had 2.02 (95% CI: 1.70-2.40) times the risk of a concussion regardless of injury setting, and greater relative risk when the concussion occurred during sport (Odds Ratio (OR): 1.38 95% CI: 1.07-1.78). Previous concussion was associated with 1.98 (95% CI: 1.65-2.37) times increased risk for any incident concussion, and the magnitude was relatively stable across all concussion settings (OR: 1.73 to 2.01). Freshman status was also associated with increased overall concussion risk, but was driven by increased risk for academy training-related concussions (OR: 8.17 95% CI: 5.87-11.37). Medical history of headaches in the past 3 months, diagnosed ADD/ADHD, and BSI-18 Somatization symptoms increased overall concussion risk. CONCLUSIONS: Various demographic and medical history factors are associated with increased concussion risk. While certain factors (e.g. sex and previous concussion) are consistently associated with increased concussion risk, regardless of concussion injury setting, other factors significantly influence concussion risk within specific injury settings. Further research is required to determine whether these risk factors may aid in concussion risk reduction or prevention.
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, <14 days RTS vs ≥14 days RTS: −0.65 [0.12] pg/mL vs −0.14 [0.14] pg/mL; P = .008) and GFAP (postinjury, 14 days RTS vs ≥14 days RTS: 4.72 [0.12] pg/mL vs 4.39 [0.11] pg/mL; P = .04). Total tau at the time of symptom resolution had acceptable discrimination power (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.63-0.86; P < .001). We also examined a combined plasma biomarker panel that incorporated Nf-L, GFAP, and total tau at each period to discriminate RTS groups. Although the analyses did reach significance at each time period when combined, results indicated that they were poor at distinguishing the groups (area under the receiver operating characteristic curve, <0.7). Conclusions and Relevance: The findings of this study suggest that measures of total tau and GFAP may identify athletes who will require more time to RTS. However, further research is needed to improve our ability to determine recovery following an SRC. ; This publication was made possible with support from the Grand Alliance Concussion Assessment, Research, and Education (CARE) Consortium, funded, in part by the NCAA and the Department of Defense. The US Army Medical Research Acquisition Activity, 820 Chandler St, Ft Detrick, MD 21702, 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.
CONTEXT: Assessments of the duration of concussion recovery have primarily been limited to sport-related concussions and male contact sports. Furthermore, whereas durations of symptoms and return-to-activity (RTA) protocols encompass total recovery, the trajectory of each duration has not been examined separately. OBJECTIVE: To identify individual (eg, demographics, medical history), initial concussion injury (eg, symptoms), and external (eg, site) factors associated with symptom duration and RTA-protocol duration after concussion. DESIGN: Cohort study. SETTING: Three US military service academies. PATIENTS OR OTHER PARTICIPANTS: A total of 10 604 cadets at participating US military service academies enrolled in the study and completed a baseline evaluation and up to 5 postinjury evaluations. A total of 726 cadets (451 men, 275 women) sustained concussions during the study period. MAIN OUTCOME MEASURE(S): Number of days from injury (1) until the participant became asymptomatic and (2) to complete the RTA protocol. RESULTS: Varsity athlete cadets took less time than nonvarsity cadets to become asymptomatic (hazard ratio [HR] = 1.75, 95% confidence interval = 1.38, 2.23). Cadets who reported less symptom severity on the Sport Concussion Assessment Tool, third edition (SCAT3), within 48 hours of concussion had 1.45 to 3.77 times shorter symptom-recovery durations than those with more symptom severity. Similar to symptom duration, varsity status was associated with a shorter RTA-protocol duration (HR = 1.74, 95% confidence interval = 1.34, 2.25), and less symptom severity on the SCAT3 was associated with a shorter RTA-protocol duration (HR range = 1.31 to 1.47). The academy that the cadet attended was associated with the RTA-protocol duration (P < .05). CONCLUSIONS: The initial total number of symptoms reported and varsity athlete status were strongly associated with symptom and RTA-protocol durations. These findings suggested that external (varsity status and academy) and injury (symptom burden) factors ...
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, <14 days RTS vs ≥14 days RTS: −0.65 [0.12] pg/mL vs −0.14 [0.14] pg/mL; P = .008) and GFAP (postinjury, 14 days RTS vs ≥14 days RTS: 4.72 [0.12] pg/mL vs 4.39 [0.11] pg/mL; P = .04). Total tau at the time of symptom resolution had acceptable discrimination power (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.63-0.86; P < .001). We also examined a combined plasma biomarker panel that incorporated Nf-L, GFAP, and total tau at each period to discriminate RTS groups. Although the analyses did reach significance at each time period when combined, results indicated that they were poor at distinguishing the groups (area under the receiver operating characteristic curve, <0.7). Conclusions and Relevance The findings of this study suggest that measures of total tau and GFAP may identify athletes who will require more time to RTS. However, further research is needed to improve our ability to determine recovery following an SRC.
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 (<6 hours), the 24- to 48-hour postinjury point, the asymptomatic postinjury point (defined as the point at which the cadet reported being asymptomatic and began the return-to-activity protocol), and 7 days after return to activity. Biomarker levels and estimated mean differences in biomarker levels were natural log (ln) transformed to decrease the skewness of their distributions. Data were collected from August 1, 2016, to May 31, 2018, and analyses were conducted from March 1, 2019, to January 14, 2020. Exposure Concussion incurred during combative training. Main Outcomes and Measures Proteins examined included glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1, neurofilament light chain, and tau. Quantification was conducted using a multiplex assay (Simoa; Quanterix Corp). Clinical measures included the Sport Concussion Assessment Tool-Third Edition symptom severity evaluation, the Standardized Assessment of Concussion, the Balance Error Scoring System, and the 18-item Brief Symptom Inventory. Results Among 103 military service academy cadets, 67 cadets incurred concussions during combative training, and 36 matched cadets who engaged in the same training exercises did not incur concussions. The mean (SD) age of cadets in the concussion group was 18.6 (1.3) years, and 40 cadets (59.7%) were male. The mean (SD) age of matched cadets in the contact-control group was 19.5 (1.3) years, and 25 cadets (69.4%) were male. Compared with cadets in the contact-control group, those in the concussion group had significant increases in glial fibrillary acidic protein (mean difference in ln values, 0.34; 95% CI, 0.18-0.50; P < .001) and ubiquitin C-terminal hydrolase-L1 (mean difference in ln values, 0.97; 95% CI, 0.44-1.50; P < .001) levels at the acute postinjury point. The glial fibrillary acidic protein level remained high in the concussion group compared with the contact-control group at the 24- to 48-hour postinjury point (mean difference in ln values, 0.22; 95% CI, 0.06-0.38; P = .007) and the asymptomatic postinjury point (mean difference in ln values, 0.21; 95% CI, 0.05-0.36; P = .01). The area under the curve for all biomarkers combined, which was used to differentiate cadets in the concussion and contact-control groups, was 0.80 (95% CI, 0.68-0.93; P < .001) at the acute postinjury point. Conclusions and Relevance This study's findings indicate that blood biomarkers have potential for use as research tools to better understand the pathobiological changes associated with concussion and to assist with injury identification and recovery from combative training-associated concussions among military service academy cadets. These results extend the previous findings of studies of collegiate athletes with sport-associated concussions. ; Grand Alliance Concussion Assessment, Research, and Education Consortium; National Collegiate Athletic Association; US Department of DefenseUnited States Department of Defense; Office of the Assistant Secretary of Defense for Health Affairs [W81XWH-14-2-0151] ; This study was supported by the Grand Alliance Concussion Assessment, Research, and Education Consortium, the National Collegiate Athletic Association, the US Department of Defense, and grant 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.
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, = 14 days RTS: -0.65 [0.12] pg/mL vs -0.14 [0.14] pg/mL; P = .008) and GFAP (postinjury, 14 days RTS vs >= 14 days RTS: 4.72 [0.12] pg/mL vs 4.39 [0.11] pg/mL; P = .04). Total tau at the time of symptom resolution had acceptable discrimination power (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.63-0.86; P < .001). We also examined a combined plasma biomarker panel that incorporated Nf-L, GFAP, and total tau at each period to discriminate RTS groups. Although the analyses did reach significance at each time period when combined, results indicated that they were poor at distinguishing the groups (area under the receiver operating characteristic curve, <0.7). Conclusions and Relevance The findings of this study suggest that measures of total tau and GFAP may identify athletes who will require more time to RTS. However, further research is needed to improve our ability to determine recovery following an SRC. ; Grand Alliance Concussion Assessment, Research, and Education (CARE) Consortium; NCAA; Department of DefenseUnited 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 publication was made possible with support from the Grand Alliance Concussion Assessment, Research, and Education (CARE) Consortium, funded, in part by the NCAA and the Department of Defense. The US Army Medical Research Acquisition Activity, 820 Chandler St, Ft Detrick, MD 21702, 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.
