The impact of white matter hyperintensities on the structural connectome in late-life depression: Relationship to executive functions

Background: White matter hyperintensities (WMH) represent ischemic white matter damage in late-life depression (LLD) and are associated with cognitive control dysfunction. Understanding the impact of WMH on the structural connectivity of gray matter and the cognitive control correlates of WMH-related structural dysconnectivity can provide insight into the pathophysiology of LLD.Methods: We compared WMH burden and performance on clinical measures of cognitive control in patients with LLD (N = 44) and a control group of non-depressed older adults (N = 59). We used the Network Modification (NeMo) Tool to investigate the impact of WMH on structural dysconnectivity in specific gray matter regions, and how such connectivity was related to cognitive control functions.Results: Compared to the control group, LLD participants had greater WMH burden, poorer performance on Trail Making Test (TMT) A & B, and greater self-reported dysexecutive behavior on the Frosntal Systems Behavior Scale-Executive Function subscale (FrSBe-EF). Within the LLD group, disrupted connectivity in the left supramarginal gyrus, paracentral lobule, thalamus, and pallidum was associated with psychomotor slowing (TMT-A). Altered connectivity in the left supramarginal gyrus, paracentral lobule, precentral gyrus, postcentral gyrus, thalamus, and pallidum was associated with poor attentional set-shifting (TMT-B). A follow-up analysis that isolated set-shifting ability (TMT-B/A ratio) confirmed the association with dysconnectivity in the bilateral paracentral lobule, right thalamus, left precentral gyrus, postcentral gyrus, and pallidum; additionally, it revealed associations with dysconnectivity in the right posterior cingulate, and left anterior cingulate, middle frontal cortex, and putamen.Conclusions: In LLD, WMH are associated with region-specific disruptions in cortical and subcortical gray matter areas involved in attentional aspects of cognitive control systems and sensorimotor processing, which in turn are associated with slower processing speed, and reduced attentional set-shifting.