Dopaminergic Dysfunction in Late-Life Depression

Overview

Late-Life Depression (LLD), or depression in older adults, often presents with motivational deficits, deficits in performance in cognitive domains including processing speed and executive dysfunction, and mobility impairments. This triad of findings implicate dopaminergic dysfunction as a core pathophysiologic feature in depression, and may contribute to cognitive decline and motor disability. Normal aging results in brain-wide dopamine declines, decreased D1/D2 receptor density, and loss of dopamine transporters. Although brain changes associated with depression and aging converge on dopamine circuits, the specific disturbances in LLD and how responsive the system is to modulation remain unclear. In this study, investigators are testing integrative model that aging, in concert with pro-inflammatory shifts, decreases dopamine signaling. These signally changes affects behaviors supported by these circuits, in the context of age-associated cortical atrophy and ischemic microvascular changes, resulting in variable LLD phenotypes. Investigators propose a primary pathway where dopaminergic dysfunction in depressed elders contributes to slowed processing speed and mobility impairments that increase the effort cost associated with voluntary behavior. The central hypothesis of this study is that late-life depression is characterized by dysfunction in the dopamine system and, by enhancing dopamine functioning in the brain. By improving cognitive and motor slowing, administration of carbidopa/levodopa (L-DOPA) will improve depressive symptoms.

Late Life Depression (LLD) is a prevalent, disabling, and at times lethal condition for which currently available treatments are often ineffective. No prior study has comprehensively examined dopamine-dependent behaviors (i.e., reward processing, cognition, motor function) in LLD, and none has integrated positron emission tomography (PET), multimodal magnetic resonance imaging (MRI), neuropsychological evaluation, and mobility assessments. Should cognitive and motor slowing result in altered effort-based decision making as researchers hypothesize, treatment development may shift from addressing mood and hedonic responses toward facilitating cognition and movement, reducing the effort cost of voluntary behavior, and promoting behavioral activation. This study, across collaborative sites, will enroll 100 evaluable elderly depressed outpatients who enter baseline study procedures and who exhibit evidence of dopaminergic dysfunction, characterized as either slowed processing speed or slowed gait speed. To disentangle depression effects from age-related changes, 70 never-depressed elders also will complete baseline evaluation. To achieve this goal, at Vanderbilt University Medical Center (VUMC) the investigators will enroll 80 depressed elders and 50 never-depressed elders who complete baseline study procedures. The University of Pittsburgh Medical Center will enroll an additional 20 depressed elders and 20 never-depressed elders who complete baseline study procedures. Assessments include PET imaging of receptor density, neuromelanin-sensitive MRI (NM-MRI) measurement of nigrostriatal status, task-based MRI focused on effort-based decision making and reward processing, and comprehensive psychiatric, neurocognitive, and physical performance evaluation. Depressed participants then will be randomized to levodopa (L-DOPA) or placebo for 3 weeks, followed by repeat multimodal MRI and cognitive/behavioral assessments. In a cross-over phase, participants will receive the opposite intervention for an additional 3 weeks followed by clinical and cognitive assessments only. This mechanistic probe allows the investigators to examine the contributions and interrelationships of dopamine-dependent processes in LLD and evaluate the responsivity of dopamine systems in LLD to pharmacological stimulation. AIM 1: To characterize dopaminergic dysfunction in LLD at molecular, circuit, and behavioral levels. Hyp 1: Compared to age- and gender-matched controls on baseline functional MRI (fMRI), LLD participants will be less willing to expend effort for rewards and exhibit lower prefrontal cortex and striatal activation on the Effort Expenditure for Rewards Task (EEfRT). Hyp 2: Across all participants, lower striatal \[18F\]-FDOPA relative influx rate, lower midbrain \& striatal \[18F\]-fallypride binding, and lower NM-MRI signal in the substantia nigra, pars compacta will predict lower performance across RDoC domains: Positive Valence (impaired willingness to expend effort, decreased neural activations on the EEfRT), Cognitive (slowed processing speed and executive dysfunction), and Sensorimotor (slowed gait speed). Hyp 3: Across all participants, slowed processing and gait speed likewise will predict lower willingness to expend effort on the EEfRT. AIM 2: To examine responsivity of dopamine circuits in LLD to stimulation with L-DOPA. Hyp 1: Compared to placebo, L-DOPA will result in greater normalization of neural activations and improved behavioral performance in Positive Valence, Cognitive, and Sensorimotor domains. Hyp 2: Baseline PET and NM-MRI measures will moderate L-DOPA effects. The greatest improvements will be observed in those with the lowest baseline \[18F\]-FDOPA relative influx rate, \[18F\]-fallypride binding, and NM-MRI signal. Exploratory Aims: 1) To investigate associations of baseline proinflammatory markers with dopaminergic function across molecular, circuit, cognitive and behavioral levels of analysis. 2) To evaluate the durability of L-DOPA effects on RDoC domains in the crossover phase.