Systematic review and meta-analysis of observational studies evaluating glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCHL1) as blood biomarkers of mild acute traumatic brain injury (mTBI) or sport-related concussion (SRC) in adult subjects

Introduction: Neurotrauma is the leading cause of death in individuals <45 years old. Many of the published articles on UCHL1 and GFAP lack rigorous methods and reporting. Content: Due to the high heterogeneity between studies, we evaluated blood GFAP and UCHL1 levels in the same subjects. We determined the biomarker congruence among areas under the ROC curves (AUCs), sensitivities, specificities, and laboratory values in ng/L to avoid spurious results. The definitive meta-analysis included 1,880 subjects in eight studies. The items with the highest risk of bias were as follows: cut-off not prespecified and case-control design not avoided. The AUC of GFAP was greater than the AUC of UCHL1, with a lower prediction interval (PI) limit of 50.1 % for GFAP and 37.3 % for UCHL1, and a significantly greater percentage of GFAP Sp. The PI of laboratory results for GFAP and UCHL1 were 0.517-7,518 ng/L (diseased), 1.2-255 ng/L (nondiseased), and 3-4,180 vs. 3.2-1,297 ng/L, respectively. Summary: Only the GFAP positive cut-off (255 ng/L) appears to be reliable. The negative COs appear unreliable. Outlook: GFAP needs better standardization. However, the AUCs of the phospho-Tau and phospho-Tau/Tau proteins resulted not significantly lower than AUC of GFAP, but this result needs further verifications.