Proteomic Discovery of Noninvasive Biomarkers Associated With Sport-Related Concussions.

Background and Objectives: Sport-related concussions affect millions of individuals across the United States each year and current techniques to diagnose and monitor them rely largely on subjective measures. Our goal was to discover and validate objective, quantifiable non-invasive biomarkers with the potential to be used in sport-related concussion diagnosis. Methods: Urine samples from a convenience series of healthy control collegiate athletes who had not sustained a concussion and athletes who sustained a concussion as diagnosed by a sports medicine physician within seven days were collected prospectively and studied. Participants also completed an instrumented single-task gait analysis as a functional measure. Participants were recruited from a single collegiate athletic program, were ≥18 years old, and were excluded if they had a concomitant injury, active psychiatric conditions or pre-existing neurological disorders. Using Tandem Mass Tags (TMT) mass spectroscopy and enzyme-linked immunosorbent assays (ELISA), urinary biomarkers of concussion were identified and validated. Results: Forty-eight control and 47 concussion age- and sex-matched athletes were included in the study (51.6%F, 48.4%M, average age 19.6y). Participants represented both contact and non-contact sports. All but one of the post-concussion participants reported experiencing symptoms at the time of data collection. Insulin-like growth factor 1 (IGF-1) and IGF binding protein 5 (IGFBP5) were downregulated in the urine of athletes with concussions compared to healthy controls. Multivariable risk algorithms developed to predict the probability of sport-related concussion showed that IGF-1 multiplexed with single-task gait velocity predicts concussion risk across a range of post-injury timepoints (AUC=0.786; 95% CI:0.690-0.884). When IGF-1 and IGFBP5 are multiplexed with single-task gait velocity, they accurately distinguish between healthy controls and concussion at acute timepoints (AUC=0.835, 95% CI:0.701-0·968, p Discussion: These noninvasive biomarkers, discovered in an objective and validated manner, may be useful in diagnosing and monitoring sport-related concussions in both acute phases of injury in addition to several days post-injury. Classification of Evidence: This study provides Class III evidence that urinary IGF-1 and IGFBP5 multiplexed with single-task gait velocity may be useful in diagnosing sport-related concussion. Trial Registration Information: Clinicaltrials.gov identifier NCT02354469, submitted February 2015, first patient enrolled August 2015 (https://clinicaltrials.gov/ct2/show/NCT02354469).