Divergent recovery trajectories after mild traumatic brain injury are characterized by distinct acute profiles of neurofilament light, 4R-tau, and white matter diffusivity

OBJECTIVES: Blood-based and diffusion MRI (dMRI) biomarkers of white matter injury after acute mild traumatic brain injury (mTBI) were examined to: (1) distinguish mTBI from healthy controls (HC); (2) quantify inter-modality relationships; (3) identify associations between acute biomarker changes and recovery; (4) evaluate moderating influences of resilience and coping style. METHODS: 36 adults with mTBI (37.6±13.7 years; 37.1% female) and 35 HC participants (34.2 ± 11.9; 47.1% female) underwent baseline testing (≤ 9 days post-mTBI) including: blood-sampling (neurofilament light-chain [NfL], brain-derived tau, glial fibrillary acidic protein, ubiquitin carboxyl terminal hydroxylase-L1, four-repeat tau [4R-tau]), dMRI analysis of 48 white matter tracts, symptom (Post-Concussion Symptom Scale [PCSS]) and psychological questionnaires (Brief Resilience Scale, Utrecht Coping List). Recovery was determined at 3-, 6- and 12-month follow-ups using PCSS scores. Associations were evaluated using correlations, logistic regression, and exploratory moderation analyses. TRIAL REGISTRATION NUMBER: ACTRN12619001226190. RESULTS: 37.1% of participants reported persistent symptoms at 3 months, 42.9% and 28.6% at 6 and 12 months, respectively. NfL and 4R-tau were acutely elevated post-mTBI, alongside widespread increases in radial, mean, and axial diffusivity. Divergent recovery trajectories were defined by distinct baseline biomarker profiles: elevated NfL and mean diffusivity characterized recovered participants, while elevated 4R-tau and radial diffusivity characterized those who remained symptomatic. NfL was associated with recovery at 3 months and 4R-tau with symptomatic status at 12 months. Coping style, not resilience, moderated blood biomarker-outcome relationships. CONCLUSION: Divergent acute profiles of blood biomarkers, white matter diffusivity, and coping style distinguish mTBI recovery trajectories, providing hypothesis-generating support for biologically informed molecular, microstructural, and psychological mTBI phenotypes. TRIAL REGISTRATION NUMBER: ACTRN12619001226190 approved March 2023.