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 enrolling pediatric patients aged 11-20 years within 10 days of a diagnosed concussion and uninjured healthy controls. Concussion subtypes, including anxiety/mood, cognitive, headache/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) and coefficients of variability (CVs) identified elevated biomarkers in pediatric concussion subtypes.

A total of 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 for anxiety/mood (FC = 3.3; CV = 13%); hypoxia-induced factor alpha 1, neurofilament light, and c-Fos immediate early transcription factor for cognitive (FCs = 7.9, 3.0, 2.9; CVs = 18%, 22%, 18%); and B-type natriuretic peptide and Toll-like receptor 2 for headache/migraine (FCs = 2.0, 2.2; CVs = 9%, 14%). Neuropathy target esterase 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.