Dopaminergic Dysfunction in Late-Life Depression

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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 integ...

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 at Vanderbilt University Medical Center (VUMC) will enroll 60 evaluable elderly depressed outpatients with evidence of dopaminergic dysfunction, characterized as either slowed processing speed or slowed gait speed. To disentangle depression effects from age-related changes, 30 never-depressed elders also will complete baseline evaluation. 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 us to examine the contributions and interrelationships of dopamine-dependent processes in LLD and evaluate the responsivity of dopamine systems in LLD to pharmacological stimulation. To maximize ability to detect drug effects, researchers will combine data gathered at VUMC with data gathered in a comparable sample enrolled at Columbia University. The sample enrolled at Columbia University will complete overlapping but not identical baseline assessments, including different PET imaging. Columbia University will complete a similar crossover trial of L-DOPA. 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 midbrain & striatal [18F]-fallypride binding, and lower NM-MRI signal in the substantia nigra, pars compacta will predict lower performance across cognitive 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]-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 cognitive domains in the crossover phase.

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