Brain Structural Connectivity in Late-Life Major Depressive Disorder

Disrupted brain connectivity might explain both the pathogenesis and consequences of late-life major depressive disorder (LLD). However, it remains difficult to ascertain whether and how specific circuits are affected. We reviewed literature regarding brain connectivity in LLD, and we specifically focused on the role of structural pathology. LLD is associated with greater levels of cerebrovascular disease, and greater levels of cerebrovascular disease are associated with both depression development and treatment nonresponsiveness. Cerebrovascular disease is most often measured as white matter hyperintensity (WMH) burden, and histopathology studies suggest that WMHs reflect myelin damage and fluid accumulation (among other underlying pathology). WMHs appear as confluent caps around the ventricles (periventricular), as well as isolated lesions in the deep white matter. The underlying tissue damage and implications for brain connectivity may differ by WMH location or severity. WMHs are associated with lower white matter microstructural integrity (measured with diffusion tensor imaging) and altered brain function (measured with functional magnetic resonance imaging). LLD is also associated with lower white matter microstructural integrity and gray matter volume, which may also alter the network properties and function of the brain. Damage to brain structure (reflected by WMH, reduced white-matter microstructural integrity, and atrophy) may affect brain function and is therefore a likely pathophysiological mechanism of LLD. Additional research is needed to fully characterize the developmental course and pathology underlying these imaging markers and to understand how structural damage explains the various clinical manifestations of LLD.