Extracellular vesicle-associated cytokines in sport-related concussion

Growing evidence suggests that sport-related concussion results in a robust inflammatory response that can be measured in serum or plasma and is predictive of symptom recovery. Recently, extracellular vesicles (EV) derived from serum or plasma have emerged as a promising source of biomarkers for neurological disorders like concussion because they may better reflect central immunological activity. However, the association of acute concussion with EV-associated cytokines has not yet been systematically studied in humans. We tested the hypothesis that EV-associated cytokines are elevated acutely and predictive of symptom duration following concussion in a cohort of high-school and collegiate football players. Players were enrolled and provided serum samples at a preseason baseline visit (N = 857). An additional blood draw was obtained in players that subsequently suffered a concussion (N = 23) within 6-hours post-injury and in matched, uninjured players (N = 44). Concentrations of Interleukin-6 (IL-6), IL-1β, IL-1 receptor antagonist (IL-1RA), IL-10, and tumor necrosis factor were measured in EV and EV-depleted serum samples. EV-associated IL-6 was significantly elevated post-injury relative to baseline levels and controls (ps < 0.01). In EV-depleted samples, IL-1RA was significantly elevated post-injury relative to baseline levels and controls (ps < 0.01). Time-to-event analyses showed that post-injury EV-associated IL-6 levels were positively associated with the number of days that injured athletes reported symptoms (p < 0.05). These results highlight the potential of EV-associated cytokines as biomarkers of concussion.