MRI-derived estimation of biological aging in patients with affective disorders in a 9-year follow-up - a prospective marker of future recurrence

We investigated whether the brain age gap (BAG)-the difference between chronological age and age estimated from structural MRI scans-is associated with long-term disease course in affective disorders, using a prospective nine-year follow-up design. T1-weighted MRI data were collected at two time points (mean interval = 8.98 ± 2.20 years) from patients with Major Depressive Disorder (MDD; N = 32), Bipolar Disorder (BD; N = 6), and healthy controls (HC; N = 37) across two sites. Using a brain age prediction model trained on a sample of over 10,000 subjects of the German National Cohort (GNC), we estimated individual BAG at baseline and follow-up using gray matter segments derived from MRI images. Employing linear-mixed-effects models, we tested main effects of diagnosis and hospitalizations as well as their interaction with time on BAG. In an exploratory analysis, we tested if BAG at baseline was predictive of hospitalizations during the nine-year follow-up using logistic regression and 10-fold nested cross-validation. MDD patients showed significantly higher BAG compared to HC (2.27 ± 5.68 vs. 1.00 ± 5.12 years, d = -0.23), while BAG in BD patients was descriptively elevated (4.71 ± 5.40 years). In the Münster subsample (N = 52), patients with at least one hospitalization had higher BAG than those without (4.16 ± 5.74 vs. 1.65 ± 5.41 years, d = -0.45). No group-by-time interaction was observed. Higher BAG at baseline predicted hospitalization during follow-up (p = 0.035), although cross-validated prediction accuracy (64.3%) did not reach significance (p = 0.071). BAG remained stable over time and was not influenced by future recurrence, supporting its role as a potential trait-like marker of vulnerability to illness recurrence. While exploratory, these findings suggest that BAG may capture individual risk for future hospitalization in affective disorders.