Browsing by Author "Pasquina, Paul"
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Item Are EPB41 and alpha-synuclein diagnostic biomarkers of sport-related concussion? Findings from the NCAA and Department of Defense CARE Consortium(Elsevier, 2023) Vorn, Rany; Devoto, Christina; Meier, Timothy B.; Lai, Chen; Yun, Sijung; Broglio, Steven P.; Mithani, Sara; McAllister, Thomas W.; Giza, Christopher C.; Kim, Hyung-Suk; Huber, Daniel; Harezlak, Jaroslaw; Cameron, Kenneth L.; McGinty, Gerald; Jackson, Jonathan; Guskiewicz, Kevin M.; Mihalik, Jason P.; Brooks, Alison; Duma, Stefan; Rowson, Steven; Nelson, Lindsay D.; Pasquina, Paul; McCrea, Michael A.; Gill, Jessica M.; CARE Consortium Investigators; Psychiatry, School of MedicineBackground: Current protein biomarkers are only moderately predictive at identifying individuals with mild traumatic brain injury or concussion. Therefore, more accurate diagnostic markers are needed for sport-related concussion. Methods: This was a multicenter, prospective, case-control study of athletes who provided blood samples and were diagnosed with a concussion or were a matched non-concussed control within the National Collegiate Athletic Association-Department of Defense Concussion Assessment, Research, and Education Consortium conducted between 2015 and 2019. The blood was collected within 48 h of injury to identify protein abnormalities at the acute and subacute timepoints. Athletes with concussion were divided into 6 h post-injury (0-6 h post-injury) and after 6 h post-injury (7-48 h post-injury) groups. We applied a highly multiplexed proteomic technique that used a DNA aptamers assay to target 1305 proteins in plasma samples from athletes with and without sport-related concussion. Results: A total of 140 athletes with concussion (79.3% males; aged 18.71 ± 1.10 years, mean ± SD) and 21 non-concussed athletes (76.2% males; 19.14 ± 1.10 years) were included in this study. We identified 338 plasma proteins that significantly differed in abundance (319 upregulated and 19 downregulated) in concussed athletes compared to non-concussed athletes. The top 20 most differentially abundant proteins discriminated concussed athletes from non-concussed athletes with an area under the curve (AUC) of 0.954 (95% confidence interval: 0.922‒0.986). Specifically, after 6 h of injury, the individual AUC of plasma erythrocyte membrane protein band 4.1 (EPB41) and alpha-synuclein (SNCA) were 0.956 and 0.875, respectively. The combination of EPB41 and SNCA provided the best AUC (1.000), which suggests this combination of candidate plasma biomarkers is the best for diagnosing concussion in athletes after 6 h of injury. Conclusion: Our data suggest that proteomic profiling may provide novel diagnostic protein markers and that a combination of EPB41 and SNCA is the most predictive biomarker of concussion after 6 h of injury.Item Assessment of Blood Biomarker Profile After Acute Concussion During Combative Training Among US Military Cadets(JAMA, 2021-02) Giza, Christopher C.; McCrea, Michael; Huber, Daniel; Cameron, Kenneth L.; Houston, Megan N.; Jackson, Jonathan C.; McGinty, Gerald; Pasquina, Paul; Broglio, Steven P.; Brooks, Alison; DiFiori, John; Duma, Stefan; Harezlak, Jaroslaw; Goldman, Joshua; Guskiewicz, Kevin; McAllister, Thomas W.; McArthur, David; Meier, Timothy B.; Mihalik, Jason P.; Nelson, Lindsay D.; Rowson, Steven; Gill, Jessica; Foroud, Tatiana; Katz, Barry; Saykin, Andrew; Campbell, Darren E.; Svoboda, Steven; Psychiatry, School of MedicineImportance: 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.Item Association between Preseason/Regular Season Head Impact Exposure and Concussion Incidence in NCAA Football(ACSM, 2022-06) Stemper, Brian D.; Harezlak, Jaroslaw; Shah, Alok S.; Rowson, Steven; Mihalik, Jason P.; Riggen, Larry; Duma, Stefan; Pasquina, Paul; Broglio, Steven P.; Mcallister, Thomas W.; Mccrea, Michael A.; CARE Consortium Investigators; Psychiatry, School of MedicinePurpose Contact sport athletes are exposed to a unique environment where they sustain repeated head impacts throughout the season and can sustain hundreds of head impacts over a few months. Accordingly, recent studies outlined the role that head impact exposure (HIE) has in concussion biomechanics and in the development of cognitive and brain-based changes. Those studies focused on time-bound effects by quantifying exposure leading up to the concussion, or cognitive changes after a season in which athletes had high HIE. However, HIE may have a more prolonged effect. This study identified associations between HIE and concussion incidence during different periods of the college football fall season. Methods This study included 1120 athlete seasons from six National Collegiate Athletic Association Division I football programs across 5 yr. Athletes were instrumented with the Head Impact Telemetry System to record daily HIE. The analysis quantified associations of preseason/regular season/total season concussion incidence with HIE during those periods. Results Strong associations were identified between HIE and concussion incidence during different periods of the season. Preseason HIE was associated with preseason and total season concussion incidence, and total season HIE was associated with total season concussion incidence. Conclusions These findings demonstrate a prolonged effect of HIE on concussion risk, wherein elevated preseason HIE was associated with higher concussion risk both during the preseason and throughout the entire fall season. This investigation is the first to provide evidence supporting the hypothesis of a relationship between elevated HIE during the college football preseason and a sustained decreased tolerance for concussion throughout that season.Item Association of Blood Biomarkers With Acute Sport-Related Concussion in Collegiate Athletes: Findings From the NCAA and Department of Defense CARE Consortium(JAMA Network, 2020-01-03) McCrea, Michael; Broglio, Steven P.; McAllister, Thomas W.; Gill, Jessica; Giza, Christopher C.; Huber, Daniel L.; Harezlak, Jaroslaw; Cameron, Kenneth L.; Houston, Megan N.; McGinty, Gerald; Jackson, Jonathan C.; Guskiewicz, Kevin; Mihalik, Jason; Brooks, M. Alison; Duma, Stephan; Rowson, Steven; Nelson, Lindsay D.; Pasquina, Paul; Meier, Timothy B.; CARE Consortium Investigators; Foroud, Tatiana; Katz, Barry P.; Saykin, Andrew J.; Campbell, Darren E.; Svoboda, Steven J.; Goldman, Joshua; DiFiori, Jon; Psychiatry, School of MedicineImportance: 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 × visit) was found for GFAP (F7,1507.36 = 16.18, P < .001), UCH-L1 (F7,1153.09 = 5.71, P < .001), and tau (F7,1480.55 = 6.81, P < .001); the interaction for neurofilament light chain was not significant (F7,1506.90 = 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 (β = 12.298; 95% CI, 2.776-54.481; P = .001) and non-contact sport controls (β = 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.Item A cohort study to identify and evaluate concussion risk factors across multiple injury settings: findings from the CARE Consortium(Biomed Central, 2019-01-14) Van Pelt, Kathryn L.; Allred, Dain; Cameron, Kenneth L.; Campbell, Darren E.; D’Lauro, Christopher J.; He, Xuming; Houston, Megan N.; Johnson, Brian R.; Kelly, Tim F.; McGinty, Gerald; Meehan, Sean; O’Donnell, Patrick G.; Peck, Karen Y.; Svoboda, Steven J.; Pasquina, Paul; McAllister, Thomas; McCrea, Michael; Broglio, Steven P.; Medicine, School of MedicineBACKGROUND: 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.Item Concussion-Recovery Trajectories Among Tactical Athletes: Results From the CARE Consortium(Allen Press, 2020-07) Van Pelt, Kathryn L.; Allred, C. Dain; Brodeur, Rachel; Cameron, Kenneth L.; Campbell, Darren E.; D’Lauro, Christopher J.; He, Xuming; Houston, Megan N.; Johnson, Brian R.; Kelly, Tim F.; McGinty, Gerald; Meehan, Sean K.; O’Donnell, Patrick G.; Peck, Karen Y.; Svoboda, Steven J.; Pasquina, Paul; McAllister, Thomas; McCrea, Michael; Broglio, Steven P.; Psychiatry, School of MedicineContext: 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 influenced the time until RTA.Item Descriptive Analysis of a Baseline Concussion Battery Among U.S. Service Academy Members: Results from the Concussion Assessment, Research, and Education (CARE) Consortium(Oxford, 2018-11) O'Connor, Kathryn L.; Allred, C. Dain; Cameron, Kenneth L.; Campbell, Darren E.; D'Lauro, Christopher J.; Houston, Megan N.; Johnson, Brian R.; Kelly, Tim F.; McGinty, Gerald; O'Donnell, Patrick G.; Peck, Karen Y.; Svoboda, Steven J.; Pasquina, Paul; McAllister, Thomas; McCrea, Michael; Broglio, Steven P.; Psychiatry, School of MedicineIntroduction 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.Item Opportunities for Prevention of Concussion and Repetitive Head Impact Exposure in College Football Players: A Concussion Assessment, Research, and Education (CARE) Consortium Study(American Medical Association, 2021) McCrea, Michael A.; Shah, Alok; Duma, Stefan; Rowson, Steven; Harezlak, Jaroslaw; McAllister, Thomas W.; Broglio, Steven P.; Giza, Christopher C.; Goldman, Joshua; Cameron, Kenneth L.; Houston, Megan N.; McGinty, Gerald; Jackson, Jonathan C.; Guskiewicz, Kevin; Mihalik, Jason P.; Brooks, M. Alison; Pasquina, Paul; Stemper, Brian D.; Psychiatry, School of MedicineImportance: Concussion ranks among the most common injuries in football. Beyond the risks of concussion are growing concerns that repetitive head impact exposure (HIE) may increase risk for long-term neurologic health problems in football players. Objective: To investigate the pattern of concussion incidence and HIE across the football season in collegiate football players. Design, setting, and participants: In this observational cohort study conducted from 2015 to 2019 across 6 Division I National Collegiate Athletic Association (NCAA) football programs participating in the Concussion Assessment, Research, and Education (CARE) Consortium, a total of 658 collegiate football players were instrumented with the Head Impact Telemetry (HIT) System (46.5% of 1416 eligible football players enrolled in the CARE Advanced Research Core). Players were prioritized for instrumentation with the HIT System based on their level of participation (ie, starters prioritized over reserves). Exposure: Participation in collegiate football games and practices from 2015 to 2019. Main outcomes and measures: Incidence of diagnosed concussion and HIE from the HIT System. Results: Across 5 seasons, 528 684 head impacts recorded from 658 players (all male, mean age [SD], 19.02 [1.25] years) instrumented with the HIT System during football practices or games met quality standards for analysis. Players sustained a median of 415 (interquartile range [IQR], 190-727) recorded head impacts (ie, impacts) per season. Sixty-eight players sustained a diagnosed concussion. In total, 48.5% of concussions (n = 33) occurred during preseason training, despite preseason representing only 20.8% of the football season (0.059 preseason vs 0.016 regular-season concussions per team per day; mean difference, 0.042; 95% CI, 0.020-0.060; P = .001). Total HIE in the preseason occurred at twice the proportion of the regular season (324.9 vs 162.4 impacts per team per day; mean difference, 162.6; 95% CI, 110.9-214.3; P < .001). Every season, HIE per athlete was highest in August (preseason) (median, 146.0 impacts; IQR, 63.0-247.8) and lowest in November (median, 80.0 impacts; IQR, 35.0-148.0). Over 5 seasons, 72% of concussions (n = 49) (game proportion, 0.28; 95% CI, 0.18-0.40; P < .001) and 66.9% of HIE (262.4 practices vs 137.2 games impacts per player; mean difference, 125.3; 95% CI, 110.0-140.6; P < .001) occurred in practice. Even within the regular season, total HIE in practices (median, 175.0 impacts per player per season; IQR, 76.0-340.5) was 84.2% higher than in games (median, 95.0 impacts per player per season; IQR, 32.0-206.0). Conclusions and relevance: Concussion incidence and HIE among college football players are disproportionately higher in the preseason than regular season, and most concussions and HIE occur during football practices, not games. These data point to a powerful opportunity for policy, education, and other prevention strategies to make the greatest overall reduction in concussion incidence and HIE in college football, particularly during preseason training and football practices throughout the season, without major modification to game play. Strategies to prevent concussion and HIE have important implications to protecting the safety and health of football players at all competitive levels.Item Plasma Biomarker Concentrations Associated With Return to Sport Following Sport-Related Concussion in Collegiate Athletes—A Concussion Assessment, Research, and Education (CARE) Consortium Study(American Medical Association, 2020-08-27) Pattinson, Cassandra L.; Meier, Timothy B.; Guedes, Vivian A.; Lai, Chen; Devoto, Christina; Haight, Thaddeus; Broglio, Steven P.; McAllister, Thomas; Giza, Christopher; Huber, Daniel; Harezlak, Jaroslaw; Cameron, Kenneth; McGinty, Gerald; Jackson, Jonathan; Guskiewicz, Kevin; Mihalik, Jason; Brooks, Alison; Duma, Stefan; Rowson, Steven; Nelson, Lindsay D.; Pasquina, Paul; McCrea, Michael; Gill, Jessica M.; Investigators for the CARE Consortium; Psychiatry, School of MedicineImportance: 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.Item Plasma Biomarker Concentrations Associated With Return to Sport Following Sport-Related Concussion in Collegiate Athletes—A Concussion Assessment, Research, and Education (CARE) Consortium Study(American Medical Association, 2020-08-27) Pattinson, Cassandra L.; Meier, Timothy B.; Guedes, Vivian A.; Lai, Chen; Devoto, Christina; Haight, Thaddeus; Broglio, Steven P.; McAllister, Thomas; Giza, Christopher; Huber, Daniel; Harezlak, Jaroslaw; Cameron, Kenneth; McGinty, Gerald; Jackson, Jonathan; Guskiewicz, Kevin; Mihalik, Jason; Brooks, Alison; Duma, Stefan; Rowson, Steven; Nelson, Lindsay D.; Pasquina, Paul; McCrea, Michael; Gill, Jessica M.; CARE Consortium Investigators; Psychiatry, School of MedicineImportance 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.