Reliable Change of Blood-Based Biomarkers Following Acute Sport-Related Concussion: A CARE Consortium Study

BACKGROUND: Growing evidence supports the potential of blood-based biomarkers for aiding in concussion diagnosis, though most work has focused on biomarker changes at the group level. Here, reliable change indices (RCI) identify individual athletes exhibiting meaningful elevations or decreases in biomarkers from baseline to multiple acute post-concussion timepoints. METHODS: Baseline and post-injury blood (0-12, 12-36, and 36-60 h) was prospectively collected from collegiate athletes in the Concussion Assessment, Research and Education Consortium. Glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCH-L1), tau, neurofilament light (NfL), and phosphorylated-tau181 (p-tau181) were measured in plasma; c-reactive protein (CRP), interleukin (IL)-6, IL-8, IL-10, IL-receptor antagonist (RA), tumor necrosis factor, and vascular endothelial growth factor were measured in serum. Reliable change was calculated by dividing the difference between baseline and post-injury visits by the standard error of the difference from uninjured controls. Athletes with concussion with RCI > 1.65 (upper 5%) were classified as having 'elevated' biomarkers; those RCI < - 1.65 (lower 5%) were classified as 'decreased'. Binomial tests determined if the proportion of athletes with elevated/decreased biomarkers was different than 5%. Fisher's exact tests determined if presence of either loss of consciousness (LOC) and/or post-traumatic amnesia (PTA) impacted proportions of elevated or decreased biomarkers. RESULTS: A total of 521 participants (198 controls, 323 athletes with concussion) were included in this study. A significant proportion of athletes with concussion had elevated GFAP (16.0%), IL-1RA (16.4%), and IL-6 (15.9%) at 0-12 h; a significant proportion had elevated GFAP at 12-36 (19.0%) and 36-60 h (14.6%). Subsets of athletes with concussion had no elevations in any marker at 0-12 (37%), 12-36 (45%), and 36-60-h visits (63%). For decreased biomarkers (RCI < - 1.65), fewer participants with concussion had decreased NfL (0%) and GFAP (0%) at 12-36 h, while a greater proportion had decreased p-tau181, NfL, UCH-L1, tau, IL-1RA, vascular endothelial growth factor (VEGF), and IL-10 at 36-60 h (10.5-21.2%). Presence of LOC and/or PTA was associated with elevated GFAP at 12-36 h (45% versus 15%; p = 0.004). DISCUSSION: Elevations in biomarkers were primarily observed in the early-acute window (0-12 h); with only GFAP showing elevations at later visits and sensitivity to altered consciousness. Only a subset of athletes with concussion had meaningful elevations of any single blood-based biomarker, with elevations seen in single markers rather than a global increase across multiple markers. Any single marker has limited ability to capture the heterogenous physiological response to concussion and ultimately aid in concussion diagnosis.