Diagnostic Accuracy of Plasma Biomarkers for Mild Traumatic Brain Injury in Older Adults

Importance: Mild traumatic brain injury (mTBI) is common among older adults but challenging to diagnose due to symptoms that overlap with age-related changes. Blood biomarkers are proposed to complement diagnostic criteria, but older adults are underrepresented in existing studies, leaving performance and thresholds uncertain. Objective: To determine the diagnostic accuracy of 4 plasma biomarkers-glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), brain-derived tau (BD-tau), and neurofilament light (NfL)-for identifying mTBI and to explore the utility of these biomarkers for discriminating clinically ambiguous suspected mTBI in older adults. Design, Setting, and Participants: This cross-sectional study was conducted between June 27, 2024, and August 5, 2025. Participants were individuals 60 years of age or older who visited a tertiary adult trauma center in Melbourne, Australia, within 72 hours of a suspected head injury or community-dwelling volunteers at least 60 years of age with no recent head injury or bodily trauma (controls). Exposure: Clinical diagnosis of mTBI within 72 hours of injury based on 2023 American Congress of Rehabilitation Medicine criteria. Main Outcomes and Measures: Glasgow Coma Scale score, ranging from 3 to 15, with higher values indicating milder injury, collected during enrollment. Diagnostic performance of each plasma biomarker quantified by age- and sex-adjusted area under the (receiver operating characteristic) curve (AAUC). Results: Participants (n = 89) ranged in age from 60.0 to 84.0 years (mean [SD], 70.8 [6.6] years; 48 [54%] male). Among them, 35 were healthy controls, 45 were diagnosed with mTBI, and 9 had suspected mTBI. The majority of the group diagnosed with mTBI presented with a Glasgow Coma Scale score of 15 (n = 34 [76%]). All 4 biomarkers were significantly elevated in participants with diagnosed mTBI vs controls (B = 129.36 [95% CI, 86.66-172.06]; P < .001 for GFAP; B = 5.61 [95% CI, 3.99-7.24]; P < .001 for BD-tau; B = 4.63 [95% CI, 1.53-7.74]; P = .005 for NfL; and B = 16.52 [95% CI, 5.96-27.07]; P < .001 for UCH-L1). GFAP demonstrated excellent diagnostic accuracy (AAUC = 0.93 [95% CI, 0.86-0.98]), and BD-tau showed good accuracy (AAUC = 0.72 [95% CI, 0.54-0.95]). UCH-L1 and NfL showed fair accuracy (AAUC = 0.68 [95% CI, 0.487-0.93] and AAUC = 0.67 [95% CI, 0.54-0.79], respectively). Optimal diagnostic thresholds for biomarkers were age-dependent (eg for GFAP, 94-108 pg/mL at age 60 years to 194-208 pg/mL at age 84 years) and sex-dependent (eg for UCH-L1, approximately 9.6 pg/mL for females and approximately 2.3 pg/mL for males across the age range). The suspected mTBI group had elevated GFAP (B = -87.04 [95% CI, -151.38 to -22.70]; P = .01) and BD-tau (B = -5.59 [95% CI, -8.83 to -2.36]; P = .001) concentrations vs controls, with 6 participants (67%) to 8 participants (89%) exceeding their personalized diagnostic cutoffs, for GFAP and BD-tau, respectively. Conclusions and Relevance: In this cross-sectional study of older adults presenting within 72 hours of injury, the plasma GFAP concentration demonstrated excellent diagnostic accuracy for mTBI. GFAP was elevated in the majority of clinically suspected mTBI cases using age- and sex-adjusted thresholds, supporting its potential to improve diagnostic certainty in mTBI, particularly in diagnostically ambiguous presentations, in older adults.