Browsing by Author "Duma, Stefan"
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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 Diffusion tensor analysis of white matter tracts is prognostic of persisting post-concussion symptoms in collegiate athletes(Elsevier, 2024) Bertò, Giulia; Rooks, Lauren T.; Broglio, Steven P.; McAllister, Thomas A.; McCrea, Michael A.; Pasquina, Paul F.; Giza, Christopher; Brooks, Alison; Mihalik, Jason; Guskiewicz, Kevin; Goldman, Josh; Duma, Stefan; Rowson, Steven; Port, Nicholas L.; Pestilli, Franco; Psychiatry, School of MedicineBackground and objectives: After a concussion diagnosis, the most important issue for patients and loved ones is how long it will take them to recover. The main objective of this study is to develop a prognostic model of concussion recovery. This model would benefit many patients worldwide, allowing for early treatment intervention. Methods: The Concussion Assessment, Research and Education (CARE) consortium study enrolled collegiate athletes from 30 sites (NCAA athletic departments and US Department of Defense service academies), 4 of which participated in the Advanced Research Core, which included diffusion-weighted MRI (dMRI) data collection. We analyzed the dMRI data of 51 injuries of concussed athletes scanned within 48 h of injury. All athletes were cleared to return-to-play by the local medical staff following a standardized, graduated protocol. The primary outcome measure is days to clearance of unrestricted return-to-play. Injuries were divided into early (return-to-play < 28 days) and late (return-to-play >= 28 days) recovery based on the return-to-play clinical records. The late recovery group meets the standard definition of Persisting Post-Concussion Symptoms (PPCS). Data were processed using automated, state-of-the-art, rigorous methods for reproducible data processing using brainlife.io. All processed data derivatives are made available at https://brainlife.io/project/63b2ecb0daffe2c2407ee3c5/dataset. The microstructural properties of 47 major white matter tracts, 5 callosal, 15 subcortical, and 148 cortical structures were mapped. Fractional Anisotropy (FA) and Mean Diffusivity (MD) were estimated for each tract and structure. Correlation analysis and Receiver Operator Characteristic (ROC) analysis were then performed to assess the association between the microstructural properties and return-to-play. Finally, a Logistic Regression binary classifier (LR-BC) was used to classify the injuries between the two recovery groups. Results: The mean FA across all white matter volume was negatively correlated with return-to-play (r = -0.38, p = 0.00001). No significant association between mean MD and return-to-play was found, neither for FA nor MD for any other structure. The mean FA of 47 white matter tracts was negatively correlated with return-to-play (rμ = -0.27; rσ = 0.08; rmin = -0.1; rmax = -0.43). Across all tracts, a large mean ROC Area Under the Curve (AUCFA) of 0.71 ± 0.09 SD was found. The top classification performance of the LR-BC was AUC = 0.90 obtained using the 16 statistically significant white matter tracts. Discussion: Utilizing a free, open-source, and automated cloud-based neuroimaging pipeline and app (https://brainlife.io/docs/tutorial/using-clairvoy/), a prognostic model has been developed, which predicts athletes at risk for slow recovery (PPCS) with an AUC=0.90, balanced accuracy = 0.89, sensitivity = 1.0, and specificity = 0.79. The small number of participants in this study (51 injuries) is a significant limitation and supports the need for future large concussion dMRI studies and focused on recovery.Item Estimated age of first exposure to American football and outcome from concussion(Wolters Kluwer, 2020-11-24) Caccese, Jaclyn B.; Houck, Zac; Kaminski, Thomas W.; Clugston, James R.; Iverson, Grant L.; Bryk, Kelsey N.; Oldham, Jessie R.; Pasquina, Paul F.; Broglio, Steven P.; McAllister, Thomas W.; McCrea, Michael; Reed Hoy, April Marie; Hazzard, Joseph B., Jr.; Kelly, Louise A.; Ortega, Justus D.; Port, Nicholas; Putukian, Margot; Langford, T. Dianne; Giza, Christopher C.; Goldman, Joshua T.; Benjamin, Holly J.; Schmidt, Julianne D.; Feigenbaum, Luis A.; Eckner, James T.; Mihalik, Jason P.; Dysart Miles, Jessica; Anderson, Scott; Master, Christina L.; Collins, Micky W.; Kontos, Anthony P.; Chrisman, Sara P.D.; Brooks, Alison; Jackson, Jonathan C.; McGinty, Gerald; Cameron, Kenneth L.; Susmarski, Adam; O'Donnell, Patrick G.; Duma, Stefan; Rowson, Steve; Miles, Christopher M.; Bullers, Christopher T.; Dykhuizen, Brian H.; Lintner, Laura; Buckley, Thomas A.; Psychiatry, School of MedicineObjective: To examine the association between estimated age at first exposure (eAFE) to American football and clinical measures throughout recovery following concussion. Methods: Participants were recruited across 30 colleges and universities as part of the National Collegiate Athletic Association (NCAA)-Department of Defense Concussion Assessment, Research and Education Consortium. There were 294 NCAA American football players (age 19 ± 1 years) evaluated 24-48 hours following concussion with valid baseline data and 327 (age 19 ± 1 years) evaluated at the time they were asymptomatic with valid baseline data. Participants sustained a medically diagnosed concussion between baseline testing and postconcussion assessments. Outcome measures included the number of days until asymptomatic, Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) composite scores, Balance Error Scoring System (BESS) total score, and Brief Symptom Inventory 18 (BSI-18) subscores. The eAFE was defined as participant's age at the time of assessment minus self-reported number of years playing football. Results: In unadjusted regression models, younger eAFE was associated with lower (worse) ImPACT Visual Motor Speed (R 2 = 0.031, p = 0.012) at 24-48 hours following injury and lower (better) BSI-18 Somatization subscores (R 2 = 0.014, p = 0.038) when the athletes were asymptomatic. The effect sizes were very small. The eAFE was not associated with the number of days until asymptomatic, other ImPACT composite scores, BESS total score, or other BSI-18 subscores. Conclusion: Earlier eAFE to American football was not associated with longer symptom recovery, worse balance, worse cognitive performance, or greater psychological distress following concussion. In these NCAA football players, longer duration of exposure to football during childhood and adolescence appears to be unrelated to clinical recovery following concussion.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.Item Plasma phosphorylated tau181 as a biomarker of mild traumatic brain injury: findings from THINC and NCAA-DoD CARE Consortium prospective cohorts(Frontiers Media, 2023-08-17) Devoto, Christina; Vorn, Rany; Mithani, Sara; Meier, Timothy B.; Lai, Chen; Broglio, Steven P.; McAllister, Thomas; Giza, Christopher C.; Huber, Daniel; Harezlak, Jaroslaw; Cameron, Kenneth L.; McGinty, Gerald; Jackson, Jonathan; Guskiewicz, Kevin; Mihalik, Jason P.; Brooks, Alison; Duma, Stefan; Rowson, Steven; Nelson, Lindsay D.; Pasquina, Paul; Turtzo, Christine; Latour, Lawrence; McCrea, Michael A.; Gill, Jessica M.; Psychiatry, School of MedicineObjective: The aim of this study was to investigate phosphorylated tau (p-tau181) protein in plasma in a cohort of mild traumatic brain injury (mTBI) patients and a cohort of concussed athletes. Methods: This pilot study comprised two independent cohorts. The first cohort-part of a Traumatic Head Injury Neuroimaging Classification (THINC) study-with a mean age of 46 years was composed of uninjured controls (UIC, n = 30) and mTBI patients (n = 288) recruited from the emergency department with clinical computed tomography (CT) and research magnetic resonance imaging (MRI) findings. The second cohort-with a mean age of 19 years-comprised 133 collegiate athletes with (n = 112) and without (n = 21) concussions. The participants enrolled in the second cohort were a part of a multicenter, prospective, case-control study conducted by the NCAA-DoD Concussion Assessment, Research and Education (CARE) Consortium at six CARE Advanced Research Core (ARC) sites between 2015 and 2019. Blood was collected within 48 h of injury for both cohorts. Plasma concentration (pg/ml) of p-tau181 was measured using the Single Molecule Array ultrasensitive assay. Results: Concentrations of plasma p-tau181 in both cohorts were significantly elevated compared to controls within 48 h of injury, with the highest concentrations of p-tau181 within 18 h of injury, with an area under the curve (AUC) of 0.690-0.748, respectively, in distinguishing mTBI patients and concussed athletes from controls. Among the mTBI patients, the levels of plasma p-tau181 were significantly higher in patients with positive neuroimaging (either CT+/MRI+, n = 74 or CT-/MRI+, n = 89) compared to mTBI patients with negative neuroimaging (CT-/MRI-, n = 111) findings and UIC (P-values < 0.05). Conclusion: These findings indicate that plasma p-tau181 concentrations likely relate to brain injury, with the highest levels in patients with neuroimaging evidence of injury. Future research is needed to replicate and validate this protein assay's performance as a possible early diagnostic biomarker for mTBI/concussions.Item Proteomic Profiling of Plasma Biomarkers Associated With Return to Sport Following Concussion: Findings From the NCAA and Department of Defense CARE Consortium(Frontiers Media, 2022-07-19) Vorn, Rany; Mithani, Sara; Devoto, Christina; Meier, Timothy B.; Lai, Chen; Yun, Sijung; Broglio, Steven P.; 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.; Psychiatry, School of MedicineObjective: To investigate the plasma proteomic profiling in identifying biomarkers related to return to sport (RTS) following a sport-related concussion (SRC). Methods: This multicenter, prospective, case-control study was part of a larger cohort study conducted by the NCAA-DoD Concussion Assessment, Research, and Education (CARE) Consortium, athletes (n = 140) with blood collected within 48 h of injury and reported day to asymptomatic were included in this study, divided into two groups: (1) recovery <14-days (n = 99) and (2) recovery ≥14-days (n = 41). We applied a highly multiplexed proteomic technique that uses DNA aptamers assay to target 1,305 proteins in plasma samples from concussed athletes with <14-days and ≥14-days. Results: We identified 87 plasma proteins significantly dysregulated (32 upregulated and 55 downregulated) in concussed athletes with recovery ≥14-days relative to recovery <14-days groups. The significantly dysregulated proteins were uploaded to Ingenuity Pathway Analysis (IPA) software for analysis. Pathway analysis showed that significantly dysregulated proteins were associated with STAT3 pathway, regulation of the epithelial mesenchymal transition by growth factors pathway, and acute phase response signaling. Conclusion: Our data showed the feasibility of large-scale plasma proteomic profiling in concussed athletes with a <14-days and ≥ 14-days recovery. These findings provide a possible understanding of the pathophysiological mechanism in neurobiological recovery. Further study is required to determine whether these proteins can aid clinicians in RTS decisions.