Utility of Acute and Subacute Blood Biomarkers to Assist Diagnosis in CT-Negative Isolated Mild Traumatic Brain Injury

BACKGROUND AND OBJECTIVES: Blood biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) have recently been Food and Drug Administration approved as predictors of intracranial lesions on CT after mild traumatic brain injury (mTBI). However, most cases with mTBI are CT negative, and no biomarkers are approved to assist diagnosis in these individuals. In this study, we aimed to determine the optimal combination of blood biomarkers to assist mTBI diagnosis in otherwise healthy adults younger than 50 years presenting to an emergency department within 6 hours of injury. To further understand the utility of biomarkers, we assessed how biological sex, presence or absence of loss of consciousness and/or post-traumatic amnesia (LOC/PTA), and delayed presentation affected classification performance. METHODS: Blood samples, symptom questionnaires, and cognitive tests were prospectively conducted for participants with mTBI recruited from The Alfred Hospital Level 1 Emergency & Trauma Center and uninjured controls. Follow-up testing was conducted at 7 days. Simoa quantified plasma GFAP, UCH-L1, tau, neurofilament light chain (NfL), interleukin (IL)–6, and IL-1β. Area under the receiver operating characteristic (AUC) analysis assessed classification accuracy for diagnosed mTBI, and logistic regression models identified optimal biomarker combinations. RESULTS: Plasma IL-6 (AUC 0.91, 95% CI 0.86–0.96), GFAP (AUC 0.85, 95% CI 0.78–0.93), and UCH-L1 (AUC 0.79, 95% CI 0.70–0.88) best differentiated mTBI (n = 74) from controls (n = 44) acutely (<6 hours), with NfL (AUC 0.81, 95% CI 0.72–0.90) the only marker to have such utility subacutely (7 days). Biomarker performance was similar between sexes and for participants with and without LOC/PTA, with the exception at 7 days, where GFAP and IL-6 retained some utility in female participants (GFAP: AUC 0.71, 95% CI 0.55–0.88; IL-6: AUC 0.71, 95% CI 0.55–0.87) and in those with LOC/PTA (GFAP: AUC 0.73, 95% CI 0.59–0.86; IL-6: AUC 0.71, 95% CI 0.57–0.84). Acute IL-6 (R(2) = 0.50, 95% CI 0.34–0.64) outperformed GFAP and UCH-L1 combined (R(2) = 0.35, 95% CI 0.17–0.50), with the best acute model featuring GFAP and IL-6 (R(2) = 0.54, 95% CI 0.34–0.68). DISCUSSION: These findings indicate that adding IL-6 to a panel of brain-specific proteins such as GFAP and UCH-L1 might assist in the acute diagnosis of mTBI in adults younger than 50 years. Multiple markers had high classification accuracy in participants without LOC/PTA. When compared with the best-performing acute markers, subacute measures of plasma NfL resulted in minimal reduction in classification accuracy. Future studies will investigate the optimal time frame over which plasma IL-6 might assist diagnostic decisions and how extracranial trauma affects utility.