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.