2/2-Dopaminergic Dysfunction in Late-Life Depression (The D3 Study)

晚年抑郁症中的 2/2-多巴胺能障碍（D3 研究）

基本信息

批准号：
10249325
负责人：
Warren D Taylor
金额：
$ 88.63万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10249325
关键词：
Academic Medical Centers Address Age Aging Behavior Behavior assessment Behavioral Behavioral Symptoms Binding Brain Clinical Clinical assessments Cognition Cognitive Cognitive deficits Corpus striatum structure Crossover Design Data Data Set Decision Making Depressed mood Depressive Syndromes Development Dopamine Dopamine D2 Receptor Dopamine Receptor Elderly Enrollment Evaluation Executive Dysfunction Exhibits Expenditure Functional Magnetic Resonance Imaging Functional disorder Future Gait Gait speed Gender Goals Impairment Inflammatory Institutes Intervention Lead Levodopa Magnetic Resonance Imaging Measurement Measures Mental Depression Midbrain structure Modeling Molecular Moods Motivation Motor Movement Neurocognitive Neuropsychology New York Outcome Outpatients Participant Pathway interactions Patient Self-Report Performance Pharmacology Phase Phenotype Physical Function Physical Performance Placebos Positive Valence Positron-Emission Tomography Prefrontal Cortex Process Publishing Randomized Research Research Domain Criteria Rewards Signal Transduction Site Structure Substantia nigra structure System Testing Time Universities Work age effect age related base behavior measurement cerebral atrophy cognitive system cognitive testing cost dopamine system dopamine transporter geriatric depression hedonic improved inflammatory marker innovation middle age multimodality neurochemistry neuromelanin new therapeutic target normal aging novel pars compacta personalized medicine processing speed receptor density relating to nervous system response reward processing sensorimotor system therapy development transmission process willingness young adult

项目摘要

PROJECT SUMMARY: Growing evidence suggests that dopamine contributes to key functions in multiple RDoC domains, specifically Positive Valence Systems, Cognitive Systems, and Sensorimotor Systems. In Late-Life Depression (LLD), dysfunction in all these systems is common, portends poor outcomes, and manifests as deficits in motivation and effort, executive dysfunction, and gait impairment. While studies of dopamine function in early and midlife depression primarily focus on reward processing, they often exclude the cognitive and sensorimotor domains relevant for older adults despite a recognized decline in dopamine function with normal aging. The objectives of this collaborative R01 proposal between Columbia University/New York State Psychiatric Institute and Vanderbilt University Medical Center are to: 1) characterize dopaminergic dysfunction in LLD across multiple RDoC domains (Positive Valence Systems, Cognitive Systems, and Sensorimotor Systems) at several levels of analysis (cellular [PET], circuit [MRI], and behavioral / self-report); and 2) examine the responsivity of dopamine-related circuits and behavior to stimulation with levodopa (L-DOPA). Supported by pilot data, this project builds on our past work demonstrating that dopamine function declines with aging, that dopaminergic dysfunction contributes to deficits in behavioral measures of the Positive Valence Systems, Cognitive Systems, and Sensorimotor Systems, and that L-DOPA administration improves performance in these systems. The long-term goal of this line of research is to determine how dopaminergic dysfunction contributes to clinical presentations of LLD, how responsive behavioral symptoms are to modulation of dopamine function, and to identify novel targets for future interventions. Our approach is to enroll 60 psychiatrically healthy elders (30 per site) and 120 depressed elders (60 per site) exhibiting likely dopaminergic dysfunction, characterized as either slowed processing speed or slowed gait speed. Participants will undergo thorough clinical characterization and complete PET imaging measuring dopamine synthesis and dopamine receptor availability, neuromelanin-sensitive MRI measurement of long-term nigrostriatal dopamine transmission, task positive MRI focused on effort-based decision making and reward processing, a comprehensive neurocognitive evaluation, a physical performance evaluation, and measurement of inflammatory markers. To assess responsivity of the dopamine system to modulation, depressed subjects then will be randomized to L-DOPA or placebo for 3 weeks, followed by repeat multimodal MRI and cognitive/behavioral assessments. Using a cross-over design, participants will receive the opposite intervention for an additional 3 weeks followed by clinical and cognitive assessments only. This proposal is significant and innovative, as no prior published study has comprehensively examined dopamine-dependent behaviors in LLD. This will inform treatment approaches focusing on facilitating cognition and movement, reducing the effort cost of voluntary behavior, and promoting behavioral activation.

项目摘要：越来越多的证据表明多巴胺有助于多重功能 RDOC域，特别是正价系统，认知系统和感觉运动系统。在晚期抑郁症（LLD），所有这些系统的功能障碍都是常见的，预示了不良的结果，并且表现为动机和努力，执行功能障碍和步态障碍的缺陷。同时研究早期和中年抑郁症的多巴胺功能主要集中于奖励处理，他们通常排除尽管多巴胺的认可下降，但与老年人相关的认知和感觉运动领域正常老化的功能。哥伦比亚之间的此协作R01提案的目标大学/纽约州立精神病学研究所和范德比尔特大学医学中心是：1） LLD跨多个RDOC域（正价系统，认知能力，认知）的多巴胺能功能障碍系统和感觉运动系统）在几个级别的分析（细胞[PET]，电路[MRI]和行为方面 /自我报告）； 2）检查与多巴胺相关电路和行为对刺激的响应性左旋多巴（L-DOPA）。在试点数据的支持下，该项目以我们过去的工作为基础，证明了多巴胺功能随着衰老而下降，多巴胺能功能障碍有助于行为不足正价系统，认知系统和感觉运动系统的度量以及L-DOPA 管理改善了这些系统的性能。这一研究的长期目标是确定多巴胺能功能障碍如何促进LLD的临床表现，如何反应行为症状是调节多巴胺功能，并确定未来的新目标干预措施。我们的方法是注册60名精神健康的长老（每个站点30）和120次抑郁症长者（每个站点60）表现出可能多巴胺能功能障碍，特征是加工缓慢速度或步态速度放慢。参与者将进行彻底的临床表征和完整的宠物成像测量多巴胺合成和多巴胺受体的可用性，神经素敏感的MRI 长期长期多巴胺传播的测量，任务为阳性MRI，重点是基于努力的决策和奖励处理，全面的神经认知评估，身体表现评估和炎症标记的测量。评估多巴胺系统对调制，抑郁受试者然后将随机分为L-DOPA或安慰剂，持续3周，然后重复多模式MRI和认知/行为评估。使用跨界设计，参与者将收到相反的干预措施再进行3周，然后进行临床和认知评估。这提案具有重要意义和创新性，因为先前发表的研究尚未全面研究 LLD中的多巴胺依赖性行为。这将为重点促进认知的治疗方法提供信息和运动，减少自愿行为的努力成本，并促进行为激活。