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: 10417053
• 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 2022-12-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417053
• 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; diagnostic strategy; 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负价和正价退变的影响 电路元素，以及这些效应如何与特定的神经精神症状(NPS)相关联，在 阿尔茨海默病及相关痴呆患者(ADRD)。目前的药物治疗方法 ADRD中的NPS是在50年前开发的，通常无效，并可能产生严重的不良反应 包括增加的死亡率。NPS的神经解剖学治疗，如TMS、DBS和TDC是 很有希望，但它们的发展受到了阻碍，因为我们缺乏对机械和 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)，以确定因素结构 ADRD中的NPS，以更好地理解负面变化(例如恐惧、痛苦、 和焦虑)和积极的(例如奖励行为)配价系统和特定的NP 不同的神经退行性疾病。相同的NPS(例如，冷漠)出现在许多ADRD诊断中， 需要一种跨诊断方法来确定NPS的常见神经生物学信息机制 所有的诊断。我们将研究40名阿尔茨海默病(AD)患者，20名行为变异者 额颞叶痴呆(BvFTD)，亨廷顿病(HD)20例，语义变异原发性痴呆20例 进行性失语(SvPPA)。我们选择这些障碍是因为它们针对特定的RDoC阴性和 正价回路元件包括前额叶皮质(PFC)、背侧纹状体和前颞叶 叶状叶。第一种假说认为，腹内侧核(Vm)PFC在负价和非负价中起核心作用。 VmPFC的退化将与RDoC范型上的低负价、低 内化精神症状(包括焦虑和抑郁)，以及冷漠的NPS。我们也 假设调制vmPFC的负价电路元件的退化，包括 背侧PFC、背侧纹状体和前颞叶将与高负值和 内化精神科NPS。腹侧前额叶和背侧纹状体参与目标定向学习和 将学习从目标导向系统转移到习惯系统。我们假设腹侧PFC的退变 将与从RDoC正价范式的反馈中学习的缺陷和 重复行为的NPS和背侧纹状体变性并有惩罚学习障碍 VS奖励和习惯学习以及重复思想的NPS。这些调查可能第一次， 利用RDoC范式从神经退行性变更好地理解人类NPS的发展 过程，RDoC配价范式的具体缺陷，神经解剖学发现，NPS。这些 研究具有临床意义，因为它们将提高我们对机械和神经支配的知识-- NPS的解剖学基础，用于ADRD基于神经解剖学的新NPS治疗的临床试验。