White matter microstructure and its relation to longitudinal measures of depressive symptoms in mid-late life

Background: Studies of white matter microstructure in depression typically show alterations in depressed individuals, but they are frequently limited by small sample sizes and the absence of longitudinal measures of depressive symptoms. Depressive symptoms are however dynamic and understanding the neurobiology of different trajectories could have important clinical implications. Methods: We examined associations between current and longitudinal measures of depressive symptoms and white matter microstructure (Fractional Anisotropy: FA; Mean Diffusivity: MD) in the UK Biobank Imaging study. Depressive symptoms were assessed on 2-4 occasions over 5.9 to 10.7 years (on N=18,959 individuals on at least two occasions, N=4,444 on four occasions) from which we derived four measures of depressive symptomatology: (i) cross-sectional measure at the time of scan, and three longitudinal measures, (ii) trajectory (iii) mean and (iv) intra-subject variance over time. Results: Decreased white matter microstructure in the anterior thalamic radiation demonstrated significant associations across all four measures of depressive symptoms (MD: β=0.020 to 0.029, pcorr<0.030). The greatest effect sizes were seen between white matter microstructure and longitudinal progression (MD: β=0.030 to 0.040, pcorr<0.049). Cross-sectional symptom severity was particularly associated with decreased white matter integrity in association fibers and thalamic radiations (MD: β=0.015 to 0.039, pcorr<0.041). While greater mean and within-subject variance were mainly associated with decreased white matter microstructure within projection fibers (MD: β=0.019 to 0.029, pcorr<0.044). Conclusions: These findings indicate shared and differential neurobiological associations with severity, course and intra-subject variability of depressive symptoms. This enriches our understanding of the neurobiology underlying dynamic features of the disorder.