Background: Despite approximately 55.9 million annual mild traumatic brain injuries (mTBIs) worldwide, the accurate diagnosis of mTBI continues to challenge clinicians due to symptom ambiguity, reliance on subjective report and presentation variability. Non-invasive fluid biomarkers of mTBI offer a biological measure to diagnose and monitor mTBI without the need for blood draws or neuroimaging. The objective of this study is to systematically review the utility of such biomarkers to diagnose mTBI and predict disease progression.

Methods: A systematic review performed in PubMed, Scopus, Cochrane and Web of Science followed by a manual search of references without a specified timeframe. Search strings were generated and run (27 June 2022) by a research librarian. Studies were included if they: (1) included human mTBI subjects, (2) assessed utility of a non-invasive biomarker and (3) published in English. Exclusion criteria were (1) non-mTBI subjects, (2) mTBI not assessed separately from moderate/severe TBI, (3) required intracranial haemorrhage or (4) solely assesses genetic susceptibility to mTBI.

Results: A total of 29 studies from 27 subject populations (1268 mTBI subjects) passed the inclusion and exclusion criteria. Twelve biomarkers were studied. Salivary RNAs, including microRNA, were assessed in 11 studies. Cortisol and melatonin were assessed in four and three studies, respectively. Eight salivary and two urinary biomarkers contained diagnostic or disease monitoring capability.

Discussion: This systematic review identified several salivary and urinary biomarkers that demonstrate the potential to be used as a diagnostic, prognostic and monitoring tool for mTBI. Further research should examine miRNA-based models for diagnostic and predictive utility in patients with mTBI.

Prospero registration number: CRD42022329293.