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. 2024 Sep 3;7(9):e2431959.
doi: 10.1001/jamanetworkopen.2024.31959.

Plasma Biomarkers of Traumatic Brain Injury in Adolescents With Sport-Related Concussion

Jason B Tabor  1   2   3 , Linden C Penner  1   2   3 , Jean-Michel Galarneau  1 , Nik Josafatow  1   2   3 , Jennifer Cooper  4 , Mohammad Ghodsi  4 , Johnny Huang  4 , Douglas D Fraser  5 , Jonathan Smirl  1   2   3 , Michael J Esser  2   3 , Keith Owen Yeates  2   3   6 , Cheryl L Wellington  4 , Chantel T Debert  1   2   3   7 , Carolyn A Emery  1   2   3   8
Affiliations

Plasma Biomarkers of Traumatic Brain Injury in Adolescents With Sport-Related Concussion

Jason B Tabor et al. JAMA Netw Open. .

Abstract

Importance: Blood-based biomarkers may clarify underlying neuropathology and potentially assist in clinical management of adolescents with sport-related concussion (SRC).

Objective: To investigate the association between SRC and plasma biomarkers in adolescents.

Design, setting, and participants: Prospective cohort study in Canadian sport and clinic settings (Surveillance in High Schools and Community Sport to Reduce Concussions and Their Consequences study; September 2019 to November 2022). Participants were a convenience sample of 849 adolescent (ages 10-18 years) sport participants with blood samples. Data were analyzed from February to September 2023.

Exposures: Blood collection and clinical testing preseason (uninjured) and post-SRC follow-ups (ie, ≤72 hours, 1 week, and biweekly until medical clearance to return to play [RTP]).

Main outcomes and measures: Plasma glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase-L1 (UCH-L1), neurofilament light (NfL), and total tau (t-tau) were assayed. Group-level comparisons of biomarker levels were conducted between uninjured and post-SRC intervals (postinjury day [PID] 0-3, 4-10, 11-28, and >28) considering age and sex as modifiers. Secondary analyses explored associations between biomarker concentrations and clinical outcomes (Sport Concussion Assessment Tool, Fifth Edition [SCAT5] symptom scores and time to RTP).

Results: This study included 1023 plasma specimens from 695 uninjured participants (467 male participants [67.2%]; median [IQR] age, 15.90 [15.13-16.84] years) and 154 participants with concussion (78 male participants [51.0%]; median [IQR] age, 16.12 [15.31-17.11] years). Acute (PID 0-3) differences relative to uninjured levels were found for GFAP (female participants: 17.8% increase; β = 0.164; 95% CI, 0.064 to 0.263; P = .001; male participants: 17.1% increase; β = 0.157; 95% CI, 0.086 to 0.229; P < .001), UCH-L1 (female participants: 43.4% increase; β = 0.361; 95% CI, 0.125 to 0.596; P = .003), NfL (male participants: 19.0% increase; β = 0.174; 95% CI, 0.087 to 0.261; P < .001), and t-tau (female participants: -22.9%; β = -0.260; 95% CI, -0.391 to -0.130; P < .001; male participants: -18.4%; β = -0.203; 95% CI, -0.300 to -0.106; P < .001). Differences were observed for all biomarkers at PID 4 to 10, 11 to 28, and greater than 28 compared with uninjured groups. GFAP, NfL, and t-tau were associated with SCAT5 symptom scores across several PID intervals. Higher GFAP after 28 days post-SRC was associated with earlier clearance to RTP (hazard ratio, 4.78; 95% CI, 1.59 to 14.31; P = .01). Male participants exhibited lower GFAP (-9.7%), but higher UCH-L1 (21.3%) compared with female participants. Age was associated with lower GFAP (-5.4% per year) and t-tau (-5.3% per year).

Conclusions and relevance: In this cohort study of 849 adolescents, plasma biomarkers differed between uninjured participants and those with concussions, supporting their continued use to understand concussion neuropathology. Age and sex are critical considerations as these biomarkers progress toward clinical validation.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Tabor reported receiving doctoral funding from the Canadian Institutes of Health during the conduct of the study. Dr Smirl reported receiving grants from Brain Canada, Branch Out Neurological Foundation, and Natural Sciences and Engineering Research Council of Canada outside the submitted work. Ms Cooper reported receiving an Alzheimer’s Society of Canada doctoral award. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participant Flowchart
PID indicates postinjury day; SRC, sport-related concussion.
Figure 2.
Figure 2.. Mean Natural Log-Transformed Uninjured and Post–Sport-Related Concussion Plasma Biomarker Levels Across Postinjury Time Intervals
Mean natural log-transformed uninjured and post–sport-related concussion plasma biomarker levels across postinjury time intervals for A, GFAP; B, UCH-L1; C, NfL; and D, t-tau separated by sex. Error bars represent SEs. Samples beyond 28 days only consist of participants demonstrating prolonged recovery per Concussion in Sport Group definitions of typical recovery. GFAP indicates glial fibrillary acidic protein; NfL, neurofilament light; t-tau, total tau; UCH-L1, ubiquitin-c-hydrolase-L1.
Figure 3.
Figure 3.. Time to Return to Play (RTP) Clearance by Prolonged Recovery (Postinjury Day >28) Median Biomarker Concentration Produced by Age- and Sex-Adjusted Cox Regression
Time to RTP clearance by prolonged recovery (postinjury day >28) median biomarker concentration produced by age- and sex-adjusted Cox regression. A, GFAP (bottom 50%: 33.23-68.63 pg/mL; top 50%: 70.36-133.41 pg/mL); B, UCH-L1 (bottom 50%: 3.25-25.71 pg/mL; top 50%: 29.76-65.37 pg/mL); C, NfL (bottom 50%: 1.56-4.30 pg/mL; top 50%: 4.37-112.92 pg/mL); D, t-tau (bottom 50%: 0.68-4.51 pg/mL; top 50%: 4.52-13.51 pg/mL). GFAP indicates glial fibrillary acidic protein; HR, hazard ratio; NfL, neurofilament light; t-tau, total tau; UCH-L1, ubiquitin-c-hydrolase-L1.
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