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

项目摘要：越来越多的证据表明，多巴胺在多种疾病中起着关键作用 RDOC域，特别是正价系统、认知系统和感觉运动系统。在……里面 晚年抑郁(LLD)，所有这些系统的功能障碍都很常见，预示着不良结局，以及 表现为动力和努力不足、执行功能障碍和步态障碍。在研究的同时 多巴胺在早中期抑郁症中的作用主要集中在奖赏处理上，它们往往排除了 认知和感觉运动领域与老年人相关，尽管公认的多巴胺下降 在正常衰老的情况下工作。哥伦比亚大学与哥伦比亚大学合作的R01计划的目标 大学/纽约州精神病研究所和范德比尔特大学医学中心将：1)描述 跨多个RDoC域的LLD的多巴胺能功能障碍(正价系统，认知 系统和感应运动系统)在多个分析级别(细胞[PET]、电路[MRI]和行为 /自我报告)；和2)检查多巴胺相关回路和行为对刺激的响应性 左旋多巴(L-多巴)。在试点数据的支持下，这个项目建立在我们过去工作的基础上，证明了 多巴胺功能随着年龄的增长而下降，多巴胺能功能障碍导致行为障碍 正价系统、认知系统和感觉运动系统的度量以及L-DOPA 管理可提高这些系统中的性能。这一系列研究的长期目标是 确定多巴胺能功能障碍如何影响LLD的临床表现，反应如何 行为症状是对多巴胺功能的调节，并为未来识别新的靶点 干预措施。我们的方法是招募60名精神健康的老年人(每个站点30名)和120名抑郁症患者 老年人(每个部位60人)表现出可能的多巴胺能功能障碍，特征是处理速度减慢 加速或减慢步态速度。参与者将接受彻底的临床特征和完整的PET 神经黑素敏感型核磁共振成像测量多巴胺合成和多巴胺受体可用性 测量长期黑质纹状体多巴胺传递，任务阳性磁共振侧重于努力型 决策和奖励处理，全面的神经认知评估，体能表现 炎症标志物的评估和测量。为了评估多巴胺系统对 调制后，抑郁症受试者将被随机服用L多巴或安慰剂3周，然后重复 多模式核磁共振和认知/行为评估。使用交叉设计，参与者将获得 相反的干预再进行3周，之后只进行临床和认知评估。这 这项提议意义重大，具有创新性，因为之前发表的研究报告都没有全面研究过 LLD中的多巴胺依赖行为。这将为专注于促进认知的治疗方法提供信息 和运动，降低自愿行为的努力成本，促进行为激活。

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.