Potential salivary protein biomarkers for the identification of mild traumatic brain injury: A systematic review

Uncovering objective biomarkers of mild traumatic brain injury (mTBI) may lead to earlier and more accurate identification of this injury, improved prognostic assessment and earlier targeted treatments. Emerging evidence highlights the potential of salivary biomarkers, particularly proteins, as a noninvasive, inexpensive and objective method for diagnosing mTBI, due to their presence in saliva following blood-brain barrier disruption; however, consensus on their utility remains limited. Our aim was to explore the diagnostic potential of salivary protein biomarkers in the identification of mTBI. A comprehensive search was conducted from April to September 2024 across the PubMed, Embase and Google Scholar databases. Original observational studies examining the diagnostic utility of salivary protein biomarkers for mTBI in human populations were included. Seven (1.7%) studies out of 411 identified reports met the inclusion criteria. A total of 49 salivary proteins demonstrated significant differential expression. Subgroup analysis based on the mechanism of injury (sports-related and non-sports-related) identified 4 overlapping proteins: ALOX5, ITGB2, ADRB2, and HRH1. ALOX5 and ITGB2 were significantly upregulated in both subgroups, while ADRB2 and HRH1 were downregulated in sports-related cases and upregulated in non-sports-related cases, which may reflect differential expression related to the region of impact and progression of injury pathophysiology. These findings suggest that salivary proteins such as ALOX5, ITGB2, ADRB2, and HRH1 may serve as promising noninvasive biomarkers for the diagnosis of mTBI. Their involvement in key processes in mTBI pathology supports further investigation in larger, rigorously designed clinical studies to validate their diagnostic utility.