Abstract
Background: Long-term effects of mild traumatic brain injury (mTBI) resemble brain aging changes (i.e., microstructure integrity loss), which implies an accelerated age-associated process. This study aimed to develop a quantifiable neuroimaging marker to characterize the brain-aging process accelerated by mTBI from acute to chronic phases. Methods: A brain-age prediction model was defined using relevance vector regression (RVR) in 523 healthy individuals, based on fractional anisotropy metrics from diffusion-tensor imaging. The model was adopted to estimate brain-predicted age difference (brain-PAD = predicted brain age - chronological age) in 116 acute mTBI patients and 63 healthy controls (HCs). Fifty patients were followed up 6~12 month post-injury to evaluate the longitudinal changes in brain-PAD. Another mTBI group containing 70 acute patients were included as a replicated cohort. We investigated whether brain-PAD was greater in patients with elderly age, post-concussion complaints, and risky apolipoprotein E (APOE) genotype, and whether it had the potential to predict neuropsychological outcomes for information processing speed (IPS). Between-group and longitudinal comparison in brain-PAD was conducted with analysis of covariance and linear mixed-effects model, respectively. The correlation between brain-PAD and continuous variables was analyzed with Spearman rank-order correlation.Results: The RVR brain-age prediction model predicted brain age accurately (r = 0.96, R2 = 0.93). The brain age of mTBI patients was estimated to be "older" in the acute phase, with mean brain-PAD of 2.59 (± 5.97) years compared with HCs (0.12 ± 3.19 years) (P < 0.05) and replicated in another mTBI cohort (brain-PAD: 3.26 ± 4.55 years). The increased brain age in mTBI kept stable at 6-12 month post-injury (2.50 ± 4.54 years). Patients with older age or severer post-concussion complaints obtained greater brain-PAD (P < 0.001, P = 0.024), while patients with APOE ε4 didn’t obtain greater brain-PAD than those without. Additionally, brain-PAD in the acute phase predicted patients’ IPS profile at 6~12 month follow-up (rho = -0.36, P = 0.01). Conclusion: Mild TBI, even a single one, accelerates the brain-aging process. The brain-PAD can be considered as a quantitative neuroimaging marker to evaluate the susceptibility to neurodegeneration or other age-associated conditions following mTBI. Trial registration: NCT02868684.