Repetitive head hits (RHHs) in sports and military settings are increasingly recognized as a risk factor for adverse neurologic outcomes, but they are not currently tracked. Blood-based biomarkers of concussion have recently been shown to increase after non-concussive RHHs during a single sporting contest, raising the possibility that they could be used in real-time to monitor the brain's early response to repeated asymptomatic head hits. In order to test this hypothesis, we measured GFAP in serum immediately before (T0), immediately after (T1) and 45 minutes (T2) after a single collegiate football game in 30 athletes. GFAP changes were correlated to 3 measures of head impact exposure (number of hits, total linear acceleration, and total rotational acceleration captured by helmet impact sensors) and to changes in brain white matter (WM) integrity, estimated by regional changes in fractional anisotropy (FA) and mean diffusivity (MD) on diffusion tensor imaging from 24 hours before (T-1) to 48 hours after (T3) the game). To account for the potentially confounding effects of physical exertion on GFAP, correlations were adjusted for kilocalories of energy expended during the game measured by wearable body sensors. All 30 participants were male with a mean age of 19.5+1.2 years. No participant had a concussion during the index game. We observed a significant increase in GFAP from T0 to T1 (mean 79.69 vs 91.95 pg/mL, p=0.008) and from T0 to T2 (mean 79.69 vs 99.21 pg/mL, p<0.001). White matter integrity decreased in multiple WM regions but was statistically significant in the right fornix (mean % FA change -1.43, 95% CI:-2.20, -0.66). T0 to T2 increases in GFAP correlated with reduced FA in the left fornix, right fornix, and right medical meniscus, and with increased MD in the right fornix (|r-values| ranged from 0.59-0.61). Adjustment for exertion had minimal effect on these correlations. GFAP changes did not correlate to head hit exposure, but after adjustment for exertion, T0 to T2 increases correlated with all three hit metrics (r-values ranged from 0.69-0.74). Thus, acute elevations in GFAP after a single collegiate football game of RHHs correlated with in-game head hit exposure and with reduced WM integrity 2 days later. These results suggest that GFAP may be a biologically relevant indicator of the brain's early response to RHHs during a single sporting event. Developing tools to measure the neurologic response to RHHs on an individual level has the potential to provide insight into the heterogeneity in adverse outcomes after RHH exposure and for developing effective and personalized countermeasures. Due to small sample size, these findings should be considered preliminary; validation in a larger, independent cohort is necessary.
Keywords: BIOMARKERS; Diffusion Tensor Imaging; GLIA CELL RESPONSE TO INJURY; HEAD TRAUMA; TRAUMATIC BRAIN INJURY.