Age-Specific Clinical Biomarker Ranges in Acute Head Injury, Non-TBI Trauma, and Healthy Control Subjects in the Emergency Department.
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OBJECTIVES: Blood-based biomarkers for traumatic brain injury (TBI) are increasingly integrated into diagnostic algorithms, but their interpretation may be confounded by age-related neurological changes. This study quantified the relative effects of age and TBI on biomarker concentrations to determine whether age-related variation approaches or exceeds that associated with injury. METHODS: Serum biomarkers were analyzed from 762 adults enrolled in the HeadSMART II and HeadSMART Geriatric studies, including healthy controls (n = 88), non-head trauma controls (n = 99), and mild TBI patients (GCS 13-15, n = 575). Participants were categorized by age (18-40, 41-64, 65-74, ≥ 75 years). Six TBI-relevant biomarkers (glial fibrillary acidic protein [GFAP], brain-derived neurotrophic factor [BDNF], neurogranin [NRGN], α-synuclein [SNCA], suppression of tumorigenicity 2 [ST2], and von Willebrand factor [vWF]) were quantified using validated immunoassays (BRAINBox Solutions). Biomarker levels were compared using two-way ANOVA, and the relative effects of age and injury were estimated using Cohen's f. RESULTS: Age significantly influenced several biomarkers. GFAP showed strong age-related increases, with significant elevations across age strata (p < 0.001), exceeding the effect of head injury alone. vWF also increased significantly with age (p < 0.001), while ST2 did not show a main effect of age (p = 0.404), although age interacted with group (p < 0.001). SNCA demonstrated modest age effects (p = 0.001), particularly in older trauma and TBI participants. NRGN showed no significant age-related changes (p = 0.454), and BDNF exhibited age effects within interaction terms (p < 0.001). Overall, age-associated effect sizes for GFAP and vWF were comparable to, or greater than, those of head injury. CONCLUSIONS: Age exerts substantial influence on circulating biomarker concentrations, particularly GFAP and vWF, often rivaling or exceeding TBI-related changes. Diagnostic algorithms that fail to adjust for age may risk misclassification, especially among older adults, underscoring the need for age-normalized biomarker interpretation.