Brain Structural Connectivity in Late-Life Major Depressive Disorder

Abstract

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 responsiveness. Cerebrovascular disease is most often measured as white matter hyperintensity (WMH) burden, and histopathology studies suggest WMH 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 MRI). LLD is also associated with lower white matter microstructural integrity and grey matter loss 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 are therefore likely pathophysiological mechanisms 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 LLD's various clinical manifestations.

Brain Structural Markers and Caregiving Characteristics as Interacting Correlates of Caregiving Strain

“…Nevertheless, our findings (regarding the factors that attenuated the white matter-caregiving strain association) can be interpreted within the context of existing literature and current conceptual frameworks. Depression, a known consequence of strain in caregivers (4, 10), is often conceptualized as a consequence of white matter disease (11-13). Depression symptoms attenuated the association of interest, potentially because depression is an intermediate (mediator) between white matter pathology and caregiving strain, or a downstream consequence of caregiving strain.…”

“…At the core of late-life depression's putative pathophysiological mechanisms is brain structural pathology affecting connectivity (for a recent review, see (11)). In 1997, the ‘vascular depression’ hypothesis was forwarded, positing that cerebrovascular pathology affecting white matter may “predispose, precipitate, or perpetuate a depressive syndrome in many elderly patients” (12).…”

Immunological biomarkers associated with brain structure and executive function in late‐life depression: exploratory pilot study

“…Since LLD is associated with pathology affecting both white and grey matter (Smagula and Aizenstein, 2015), brain structural pathology is likely to be a key driver of LLD’s consequences. Indeed, cerebrovascular disease is well-recognized as a potential contributor to LLD’s consequences (Alexopoulos et al, 1997); for example, evidence shows that LLD patients with a greater burden of cerebrovascular disease (measured by white matter hyperintensities volume (WMH)) are at increased risk for dementia (Steffens et al, 2007) and death (Levy et al, 2003).…”

Altered Connectivity of the Anterior Cingulate and the Posterior Superior Temporal Gyrus in a Longitudinal Study of Later-life Depression

“…Accumulated evidence from structural neuroimaging studies suggests that patients with later-life depression (LLD) show abnormal gray matter (GM) and white matter (WM) brain structures. Patients with LLD have a significantly smaller GM volume in the anterior cingulate cortex (ACC), superior temporal gyrus (STG), middle temporal gyrus, inferior frontal, orbitofrontal cortex, insula, hippocampus, amygdala and putamen than healthy individuals (Andreescu et al, 2008 ; Sexton et al, 2013 ; Du et al, 2014 ; Smagula and Aizenstein, 2016 ). In terms of WM structures, patients with LLD showed abnormal connectivity in the cingulum, uncinate fasciculus (Charlton et al, 2015 ), temporal lobe (Charlton et al, 2015 ), superior longitudinal fasciculus, superior frontal gyrus, corpus callosum (Reppermund et al, 2014 ) and parahippocampal gyrus (Guo et al, 2014 ).…”