Using RDoC Negative and Positive Valence Paradigms to Investigate the Mechanisms of Neuropsychiatric Symptoms (NPS) in Alzheimer's Disease and Related Dementias

使用 RDoC 负价和正价范式研究阿尔茨海默病和相关痴呆症中神经精神症状 (NPS) 的机制

• 批准号: 10166948
• 负责人: Edward D Huey
• 金额: $ 40.5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10166948
• 关键词: Adverse effects; Alzheimer' s Disease; Alzheimer' s disease related dementia; Anatomy; Animal Experimentation; Animals; Anterior; Anxiety; Behavior; Behavioral; Behavioral Paradigm; Brain; Caring; Cessation of life; Clinical; Clinical Trials; Corpus striatum structure; DNA; DSM-V; Data; Deep Brain Stimulation; Development; Diagnosis; Diagnostic; Disease; Dorsal; Elements; Emotional; Feedback; Fright; Functional Magnetic Resonance Imaging; Goals; Habits; Human; Huntington Disease; Impairment; Interview; Investigation; Knowledge; Laboratories; Learning; Link; Literature; Magnetic Resonance Imaging; Measures; Mental Depression; Modality; Negative Valence; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Pain; Participant; Patients; Persons; Pharmaceutical Preparations; Pharmacological Treatment; Play; Positive Valence; Prefrontal Cortex; Preparation; Primary Progressive Aphasia; Process; Psychological Transfer; Public Health; Punishment; Research; Research Domain Criteria; Resources; Rest; Rewards; Role; Sampling; Semantics; Signal Transduction; Structure; Symptoms; System; Temporal Lobe; Testing; Thinking; Time; Transcranial magnetic stimulation; United States National Institutes of Health; Variant; base; behavioral variant frontotemporal dementia; clinical investigation; clinically relevant; common symptom; cost; habit learning; improved; mortality; neuropsychiatric symptom; novel; psychiatric symptom; repetitive behavior; response; therapy development

The goal of this study is to determine the effects of degeneration of RDoC Negative and Positive Valence Circuit Elements, and how these effects are associated with specific Neuropsychiatric Symptoms (NPS), in persons with Alzheimer’s disease and related dementias (ADRD). Current pharmacological treatments for NPS in ADRD were developed 50 years ago, are often inefficacious, and can have serious adverse effects including increased mortality. Neuroanatomically-based treatments such as TMS, DBS, and tDCS for NPS are promising, but their development has been hampered by our lack of knowledge about the mechanistic and neuroanatomical bases of NPS in ADRD. The proposed project will leverage NIH-supported resources, including the RDoC Project and a project in our laboratory (R01AG062268) to determine the factor structure of NPS in ADRD, to better understand the connections between changes in the Negative (for example fear, pain, and anxiety) and Positive (for example rewarding behaviors) Valence Systems and specific NPS across different neurodegenerative disorders. The same NPS (e.g., apathy) occur across many ADRD diagnoses, necessitating a trans-diagnostic approach to identify common neurobiologically-informed mechanisms of NPS across diagnoses. We will study 40 participants with Alzheimer’s disease (AD), 20 with behavioral-variant Frontotemporal dementia (bvFTD), 20 with Huntington’s disease (HD), and 20 with semantic-variant Primary Progressive Aphasia (svPPA). We have chosen these disorders as they target specific RDoC Negative and Positive Valence Circuit Elements including the prefrontal cortex (PFC), dorsal striatum, and anterior temporal lobes. The first hypothesis is that the ventromedial (vm)PFC plays a central role in Negative Valence and degeneration of the vmPFC will be associated with low Negative Valence on RDoC Paradigms, low Internalizing psychiatric symptoms (including anxiety and depression), and the NPS of apathy. We also hypothesize that degeneration of Negative Valence Circuit Elements that modulate the vmPFC, including the dorsal PFC, dorsal striatum, and anterior temporal lobes, will be associated with high Negative Valence and Internalizing psychiatric NPS. The ventral PFC and dorsal striatum are involved in goal-directed learning and transferring learning from goal-directed to habit systems. We hypothesize that degeneration of the ventral PFC will be associated with deficits in learning from feedback on RDoC Positive Valence Paradigms and with the NPS of repetitive behaviors, and degeneration of the dorsal striatum with deficits in learning from punishment vs. reward and habit learning and the NPS of repetitive thoughts. These investigations could, for the first time, utilize RDoC Paradigms to better understand the development of NPS in humans from neurodegenerative processes, to specific deficits in RDoC Valence Paradigms, to neuroanatomical findings, to NPS. These investigations are clinically relevant as they will improve our knowledge of the mechanistic and neuroana- tomical bases of NPS for use in clinical trials of novel neuroanatomically-based treatments for NPS in ADRD.

本研究的目的是确定 RDoC 负价和正价变性的影响 电路元件，以及这些影响如何与特定的神经精神症状 (NPS) 相关，在 患有阿尔茨海默病和相关痴呆症（ADRD）的人。目前的药物治疗 ADRD 中的 NPS 是 50 年前开发的，通常无效，并且可能产生严重的副作用 包括死亡率增加。基于神经解剖学的治疗方法，例如针对 NPS 的 TMS、DBS 和 tDCS 前景广阔，但由于我们缺乏对其机械和原理的了解，它们的发展受到了阻碍。 ADRD 中 NPS 的神经解剖学基础。拟议的项目将利用 NIH 支持的资源， 包括RDoC项目和我们实验室的一个项目（R01AG062268），以确定因子结构 ADRD 中的 NPS，以更好地理解负面变化（例如恐惧、疼痛、 和焦虑）和积极（例如奖励行为）效价系统和特定的NPS 不同的神经退行性疾病。许多 ADRD 诊断中都会出现相同的 NPS（例如冷漠）， 需要采用跨诊断方法来识别 NPS 的常见神经生物学机制 跨诊断。我们将研究 40 名患有阿尔茨海默病 (AD) 的参与者，其中 20 名患有行为变异 额颞叶痴呆 (bvFTD)、20 名患有亨廷顿病 (HD) 和 20 名患有语义变异原发性痴呆 进行性失语症（svPPA）。我们选择这些疾病是因为它们针对特定的 RDoC 阴性和 正价电路元件，包括前额皮质 (PFC)、背侧纹状体和前颞叶 叶。第一个假设是腹内侧 (vm)PFC 在负价和 vmPFC 的退化将与 RDoC 范式上的低负价相关，低 内化精神症状（包括焦虑和抑郁）和冷漠的 NPS。我们也 假设调节 vmPFC 的负价电路元件退化，包括 背侧 PFC、背侧纹状体和前颞叶，将与高负价相关 内化精神科 NPS。腹侧 PFC 和背侧纹状体参与目标导向的学习和 将学习从目标导向转向习惯系统。我们假设腹侧 PFC 退化 将与从 RDoC 正价范式的反馈中学习的缺陷以及 重复行为的 NPS 和背侧纹状体退化，从惩罚中学习存在缺陷 与奖励和习惯学习以及重复想法的 NPS 相比。这些调查首次可以 利用 RDoC 范式更好地了解人类神经退行性疾病中 NPS 的发展 过程、RDoC 价范式中的特定缺陷、神经解剖学发现、NPS。这些 研究具有临床相关性，因为它们将提高我们对机制和神经分析的了解 NPS 的组织学基础，用于针对 ADRD 中 NPS 的新型神经解剖学治疗的临床试验。