Neuromodulatory system abnormalities in late life depression: Associations with mood, cognition, and motor frailty

Major Depressive Disorder in older adults, or Late life depression (LLD), is characterized by mood symptoms and is also often further complicated by motor frailty and cognitive dysfunction. Additionally, LLD is also one of the strongest identified risk factors for accelerated cognitive and functional decline. The factors contributing to motor frailty and cognitive dysfunction in LLD are currently poorly understood which prevents the early identification of individuals most at risk for poor outcomes. The combination of mood, frailty, and cognitive disturbances in LLD implicates dysfunction within specific networks of monoamine- and cholinergic brainstem and basal forebrain nuclei that together make up the neuromodulatory system. The widespread subcortical and cortical projections of the neuromodulatory system control the brain’s activity state and thus behavioral responses to incoming internal and external information. Of note, neuromodulatory system abnormalities are often already present in the preclinical or very early stages of other neurodegenerative diseases before higher order cortical and subcortical structures become affected. These abnormalities therefore have the potential not only to become an early marker of LLD but also risk for poor outcomes. However, the neuromodulatory system is a compex structure made up of densely packed and often not well-delineated fiber tracts and small nuclei that are not discernible on conventional structural 3T MR and thus is understudies in LLD. New multi-contrast based segmentation approach imaging processing methods have developed to address this challenge. The goal of this project is to evaluate the association of depression severity, cognition, and motor frailty with specific components of the neuromodulatory system and to demonstrate that structural and functional abnormalities within this system are more strongly linked to baseline severity and longitudinal progression of these symptoms than abnormalities within their higher cortical and subcortical target structures. Specifically, it will be demonstrated that: 1) Structural and functional abnormalities within the dopaminergic and serotoninergic brainstem and forebrain nuclei will be more strongly associated with depression severity than their cortical and subcortical projection areas, 2) Abnormalities within the noradrenergic locus coeruleus as well as the brainstem and forebrain nuclei connected to it will be more strongly associated with cognition than those within their cortical and subcortical projection areas, and 3) Abnormalities within the brainstem and forebrain motor system will be more strongly associated with motor frailty in LDD than abnormalities within the higher motor centers. This goal will be accomplished in a longitudinal study over 24 months with 100 LLD and 50 age and gender matched non-depressed participants (ND). All participants will undergo a standardized evaluation of mood, cognition, and frailty and structural and functional imaging at 3T at baseline. Longitudinal evaluations will include depression assessments at six month intervals and cognition and frailty assessments will be conducted annually (months 12 and 24).