Abstract
There is potential scientific and clinical value in validation of objective biomarkers for sport-related concussion (SRC). To investigate the association of acute-phase blood biomarker levels with SRC in collegiate athletes. 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. 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. 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). 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.
Highlights
During the past decade, several candidate biomarkers have emerged as potential diagnostic markers of traumatic brain injury (TBI).[1,2,3,4] Biomarkers have provided insight into the underlying pathophysiological mechanisms of TBI, the mechanisms and dynamic course of neuronal, axonal, and astroglial damage that result from TBI.[5]An estimated 90% of brain injuries are classified as mild TBI
Athletes with concussion had significant elevation in glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), and tau levels at the acute postinjury time point compared with preseason baseline
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; the acute postinjury area under the curve for all 4 biomarkers combined was 0.72
Summary
Several candidate biomarkers have emerged as potential diagnostic markers of traumatic brain injury (TBI).[1,2,3,4] Biomarkers have provided insight into the underlying pathophysiological mechanisms of TBI, the mechanisms and dynamic course of neuronal, axonal, and astroglial damage that result from TBI.[5]An estimated 90% of brain injuries are classified as mild TBI. Previous studies[8,9,10] have reported high sensitivity and negative predictive value of UCH-L1, GFAP, NF-L, and tau biomarkers to predict intracranial injury present on acute-phase head computed tomography. Within the spectrum of TBI, SRC reflects the most subtle and mild form of mild TBI; diagnosing SRC is often challenging because of the need to rely on subjective selfreported symptoms that are not specific to mild TBI and the limited diagnostic utility of common clinical tests.[11] As in the broader mild TBI spectrum, diagnostic biomarkers have potential to objectively assess SRC presence and severity and to monitor recovery while advancing our understanding of the underlying pathophysiological mechanisms of concussion. A previous systematic review[12] found several studies that reported alterations in various biomarkers during the acute phase after SRC, but the strength and generalizability of their findings are limited by small sample sizes, varied methods, and other factors. That review[12] concluded that there was early, but still limited, evidence that biomarkers have significant promise as research tools for studying SRC but require larger-scale validation to determine their ultimate clinical utility
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