Demographic and clinical characteristics of mTBI patients and HCs
Demographic and clinical information for test sets are reported in Table 2. The mTBI cohort included 116 acute patients (58 males, aged 39.7 ± 11.9 years, education: 7.9 ± 3.9 years; first-visit post-injury: 3.5 ± 3.4 days). There were 8 patients had the retrospective baseline health conditions in (i.e., hyperglycaemia, hypertension, and hyperlipidemia). Sixty-four patients consented to join in the follow-up investigations and 50 of them (78.1%) were finally followed 6-12 month post-injury (216.2 ± 117.8 days). Sixty-three HCs were enrolled (31 males, aged 36.7 ± 12.4 years, education: 10.9 ± 6.6 years). Patients showed worse performance on IPS tests than HCs (TMT_A: W = 2124, P < 0.001, rrb = 0.41; DSCT: W = 5224.5, P < 0.001, rrb = 0.45).
Chronological age predicted by FA values
The RVR model could accurately predict the individual chronological age for both the training set and the HC test set. For the training set, age was accurately predicted by FA values (r = 0.96, R2 = 0.93, MAE = 3.74, RMSE = 5.03). The mean PAD for the training group was -0.18 (± 5.03) years. For HC test set, brain age was also accurately predicted (r = 0.97, R2 = 0.94, MAE = 2.57, RMSE = 3.16), and the mean PAD was 0.12 (± 3.19) years (details in eResults of Supplemental Materials).
MTBI patients had increased brain age
The predicted brain age significantly correlated with chronological age in both HCs (R2 = 0.93, P < 0.001) and mTBIs (R2 = 0.87, P < 0.001) (Fig. 3A). MTBI patients had older predicted-brain age than their chronological age in acute phase (PAD = 2.59 ± 5.97 years; W = 4854, P < 0.001, rrb = 0.431), which was replicated in an independent mTBI cohort (PAD = 3.26 ± 4.55 years; W = 2158, P < 0.001, rrb = 0.737). Acute mTBI patients had higher brain-PAD scores (2.59 ± 5.97 years) than that of HCs (0.12 ± 3.19 years) (F1, 173 = 7.23, P = 0.008, partial η2 = 0.041; Fig. 3B).
In order to avoid the educational level and baseline health conditions of patients being confounding factors, we performed additional analysis. The educational years in the mTBI cohort were lower than that of HCs (P < 0.001). Therefore, we randomly selected a subgroup of mTBI patients (N = 108) and HCs (N = 47), who were matched with age, gender and education level, and then compared the difference in brain-PAD scores between groups. Acute mTBI patients still held higher brain-PAD scores (2.68 ± 5.99 years) than HC group (0.31 ± 3.27 years) (F1, 173 = 6.60, P = 0.011, partial η2 = 0.042). Additionally, the correlation analysis showed no statistically significant correlation between brain-PAD and years of education in mTBI patients (rho = -0.137, P = 0.143). Considering that baseline health conditions might affect the brain-PAD, we examine the differences between the subgroup of mTBI patients with a history of hyperglycaemia, hypertension, or/and hyperlipidemia (N = 8) and a matched group of patients who were randomly selected from whom without (N = 8). The result showed there was no statistical difference (W = 34, P = 0.88) in acute brain-PAD between two group patients. Those results showed the educational years and baseline health conditions of patients had no effects on PAD in the present study. Therefore, all 116 patients were included in the following analysis.
MTBI patients held relatively stable brain-PAD (2.50 ± 4.54 years) at 6~12 month follow-up derived from acute injury. The longitudinal comparison in brain-PAD between two phase showed no statistical differences (F1, 112 = 0.436, P = 0.51; Fig. 3C). In addition, brain-PAD scores were not associated with post-injury days in both acute and chronic phases (acute phase: rho = -0.045, P = 0.634; chronic phase: rho = -0.015, P = 0.920). Moreover, brain-PAD derived from the acute phase was inversely related to the IPS performance in both acute phase (rho = -0.294, P = 0.001; Fig. 4A) and 6-12 month follow-up (rho = -0.356, P = 0.011; Fig. 4B).
Neurodegeneration-vulnerable tracts associated with brain-PAD scores
The rho between brain-PAD and FA value of WMTs involved in model training (N = 33) was calculated to evaluate the related WMTs contributing to the increased brain age. The FA value in 16 WMTs presented significantly correlated to the brain-PAD scores in the acute phase. They were mainly located in the commissural, association, and projection fibers (rho: -0.305 ~ -0.473, P < 0.05 after family-wise error (FWE) correction for multiple comparisons) (Table 3), primarily including the corpus callosum, fornix, corona radiate and superior longitudinal fasciculus. In the chronic phase, the FA value in the body of fornix was still significantly related to the brain-PAD at follow-up 6~12 months (rho = -0.434, P < 0.05, after FWE correction for multiple comparisons) (Table 3).
Factors affecting on brain-PAD scores
The patients’ chronological age at mTBI occurring affected their PAD derived from acute phase (F2, 111 = 10.05, P < 0.001, partial η2 = 0.15), after adjusting for sex and education (Table 4). Brain-PAD scores in the elderly patients (N = 27, 6.74 ± 5.61 years) were higher than the middle-aged (N = 57, 1.98 ± 5.44 years) and youth patients (N = 32, 0.18 ± 5.66 years) (multiple comparisons for Bonferroni correction, P < 0.05) (Fig. 5A). The PCS severity post-injury also affected the PAD in acute phase (F1, 111 = 5.26, P = 0.02, partial η2 = 0.05), after adjusting for sex, education and age. Patients with PCS complaints (i.e., PCS+) had higher brain-PAD scores (N = 91, 3.21 ± 5.44 years) than that of PCS- group (N = 25, 0.34 ± 5.50 years) (Fig. 5B) (Table 4).
The anterograde amnesia (AA) and APOE genotypes did not affect PAD in acute phase (AA: F1,111 = 0.86, P = 0.35; APOE: F1, 111 = 0.46, P = 0.49), after adjusting for sex, education and age. Differences in PAD between of AA+ subgroup (N = 15, 3.84 ± 5.57 years) and AA- subgroup (N = 101, 2.41 ± 5.52 years) was not statistically significant (Table 4). There were also no significant differences in PAD between APOE ε4+ (N = 17, 3.75 ± 6.31 years) and APOE ε4- subgroups (N = 64, 2.57 ± 6.24 years) (Table 4).