Background Cerebrovascular disease is regarded as a potential cause of late-life depression. Yet, evidence for associations of neuroimaging markers of vascular brain disease with depressive symptoms is inconclusive. We examined the associations of neuroimaging markers and depressive symptoms in a large population-based study of middle-aged and elderly persons over time. Methods A total of 4943 participants (mean age = 64.6 ± 11.1 years, 55.7% women) from the Rotterdam Study were included. At baseline, total brain volume, gray matter volume, white matter volume, white matter hyperintensities volume, cortical infarcts, lacunar infarcts, microbleeds, white matter fractional anisotropy, and mean diffusivity (MD) were measured with a brain MRI (1.5T). Depressive symptoms were assessed twice with the Center for Epidemiologic Studies Depression scale (median follow-up time: 5.5 years, IQR = 0.9). To assess temporal associations of neuroimaging markers and depressive symptoms, linear mixed models were used. Results A smaller total brain volume (β = −0.107, 95% CI −0.192 to −0.022), larger white matter hyperintensities volume (β = 0.047, 95% CI 0.010–0.084), presence of cortical infarcts (β = 0.194, 95% CI 0.047–0.341), and higher MD levels (β = 0.060, 95% CI 0.022–0.098) were cross-sectionally associated with more depressive symptoms. Longitudinal analyses showed that small total brain volume (β = −0.091, 95% CI −0.167 to −0.015) and presence of cortical infarcts (β = 0.168, 95% CI 0.022–0.314) were associated with increasing depressive symptoms over time. After stratification on age, effect sizes were more pronounced at older ages. Conclusions Neuroimaging markers of white matter microstructural damage were associated with depressive symptoms longitudinally in this study of middle-aged and elderly persons. These associations were more pronounced at older ages, providing evidence for the role of white matter structure in late-life depressive symptomatology.

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