Brain age gap as a diffusion MRI-based marker of traumatic brain injury-related brain changes and associated outcomes.

Traumatic brain injury is a common neurological disorder and a leading cause of long-term disability, presenting with heterogeneous cognitive, emotional, and functional impairments. A critical clinical challenge is the early identification of patients at risk for persistent symptoms. The Brain Age Gap (BAG), the difference between an individual's predicted brain age from imaging data and their chronological age, has emerged as a potential marker of injury-related brain changes. Here, we aim to evaluate diffusion-MRI-derived BAG for identifying traumatic brain injury patients (Glasgow Coma Scale 13-15) at risk for persistent symptoms. For this, we trained a normative age-prediction model on >13 000 healthy controls, and applied it to traumatic brain injury patients. We associated BAG clinical scores that evaluate processing speed and executive function (Trail Making Test Parts A and B), verbal memory (Rey Auditory Verbal Learning Test), general processing speed (Wechsler Adult Intelligence Scale), post-concussion symptoms (Rivermead Post-Concussion Symptoms Questionnaire), psychological distress (Brief Symptom Inventory-18) and insomnia severity (Insomnia Severity Index). Analyses included: (i) cross-sectional comparisons across three BAG-based subgroups: BAG+, BAGn and BAG-, representing patients with higher, neutral and lower BAGs relative to healthy controls, (ii) longitudinal linear mixed-effects models evaluating BAG measured at 2-week post-injury (BAG