Abstract
Mild traumatic brain injury (mTBI) accounts for around 80–90% of TBI cases, is increasing in incidence, and represents a major public health concern. Despite its high incidence, mTBI lacks reliable molecular biomarkers for diagnosis or prognosis. Metabolomics, the profiling of small-molecule metabolites (≤1 kDa), has emerged as a promising approach to characterize acute neurometabolic perturbations in mTBI and identify candidate biomarkers. However, metabolomic changes in mTBI have not yet been comprehensively characterized. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines, we conducted a scoping review of studies from 2010 to 2025 on acute-phase (24–72 h post-injury) serum/plasma metabolomics in adult mTBI (Glasgow Coma Scale 13–15). Systematic searches of PubMed, Scopus, and Embase identified 11 eligible studies. Seven metabolites were consistently reported as altered in ≥2 studies: glucose and the ketone body 3-hydroxybutyrate were elevated in mTBI, whereas five amino acids (valine, isoleucine, glycine, methionine, and tryptophan) were decreased. Pathway analysis revealed branched-chain amino acid biosynthesis as the most enriched pathway, while one-carbon folate-mediated metabolism and energy metabolism were also implicated. Preliminary evidence indicates that acute mTBI also perturbs lipid metabolism, with increases in phospholipid breakdown products and sphingomyelins, reflecting membrane disruption and altered energy utilization. This metabolic signature aligns with known acute mTBI pathophysiology, including hypermetabolism, excitotoxicity, and neuroinflammation, and may reflect compensatory responses to increased energy demand and oxidative stress. These changes show promise as candidate biomarkers and therapeutic targets but require validation in larger cohorts to establish their utility in mTBI diagnosis, prognosis, and management.