Associations Between Saliva-Based Biomarkers and Pediatric Concussion Subtypes

To test the hypothesis that specific saliva-based biomarkers are associated with pediatric concussion subtypes.

A cross-sectional, multicenter study was conducted from August 2021 to January 2024, of pediatric patients aged 11-20 years within 10 days of a diagnosed concussion and uninjured, healthy controls. Concussion subtypes, including anxiety/mood, cognitive, migraine, ocular, and vestibular, were blindly adjudicated using previously published common data elements criteria. Participants completed a multidomain, concussion assessment and provided a passive drool saliva sample within 10 days of injury. Digital immunohistochemistry assays measured a panel of 82 stress-response biomarkers in pooled saliva samples representing individual subtypes. Fold change (FC) thresholds (>2-fold) with coefficients of variability (CV) identified elevated biomarkers in pediatric concussion subtypes.

156 participants (mean age=15.3±2.1; 46% female) with concussion and 15 controls were enrolled. Analyses of assays identified 21 biomarkers with ≥2-fold elevation compared with controls in at least 1 concussion subtype. Six of these biomarkers were subtype-specific, including: oxytocin (OXT) for anxiety/mood (FC=3.3; CV=13%); hypoxia-induced factor alpha 1 (HIF1A), neurofilament light (NfL), and c-Fos immediate early transcription factor (c-Fos) for cognitive (FCs=7.9, 3.0, 2.9; CVs=18%, 22%, 18%); and natriuretic peptide B (BNP) and toll-like receptor 2 (TLR2) for headache/migraine (FCs=2.0, 2.2; CVs=9%, 14%). Neuropathy target esterase (NTE) was elevated across subtypes (FCs: 4.0-16.7; CVs: 5-25%).

Results identified an association between saliva-based biomarkers and pediatric concussion subtypes, specifically the anxiety/mood, cognitive, and headache/migraine subtypes. These findings provide preliminary support for using a saliva-based biomarker approach to complement existing multidomain clinical assessments; however, external validation and additional research are needed before clinical implementation.