White matter and subcortical MRI markers of subsequent cognitive decline in late-life depression: A two-stage study

Background Late-life depression (LLD) is associated with increased risk of cognitive decline and dementia, yet clinically relevant neuroimaging markers of short-term cognitive decline remain uncertain. Methods We conducted a two-stage study. In the Shanghai Action to Prevent the Elderly from Dementia (SHAPE) cohort, baseline MRI was compared among 40 LLD participants with stable cognition (LLDcs), 38 LLD participants with cognitive decline over two years (LLDcd), and 47 healthy controls. Measures included peak width of skeletonized mean diffusivity (PSMD), global and tract-specific difference in distribution function based on mean diffusivity (DDF MD ), grey-matter measures, and regional diffusion tensor image analysis along the perivascular space (ALPS) indices. Within-group partial correlations between MRI measures and cognitive performance were also examined. Candidate markers were then evaluated in the Sydney Memory and Ageing Study (MAS) LLD sample (21 LLDcs, 16 LLDcd) using SHAPE-trained single-marker Firth logistic models applied without refitting. Results In SHAPE, LLDcd showed greater white-matter microstructural burden than LLDcs and controls, including higher PSMD, lower global and tract-specific DDF MD , alongside smaller left nucleus accumbens (L_NAcc) volume. Within LLDcd, poorer white-matter integrity was associated with worse orientation and other cognitive domains. In MAS, global DDF MD and L_NAcc volume were the two markers whose discrimination of LLDcd survived correction for multiple comparisons. Conclusions White-matter microstructural burden and smaller L_NAcc volume may help characterize LLD patients at higher near-term risk of cognitive decline. These findings warrant evaluation in larger longitudinal LLD cohorts.