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.

这项研究的目的是确定RDOC负和正价变性的影响 电路元素，以及这些影响与特定的神经精神症状（NP）如何相关 阿尔茨海默氏病和相关痴呆症（ADRD）的人。当前的药物治疗 ADRD中的NP是50年前开发的，通常是效率低下的，可能会产生严重的不利影响 包括增加死亡率。基于神经解剖学的治疗方法，例如NP的TMS，DB和TDC是 很有希望，但是由于我们对机械性和 ADRD中NP的神经解剖基础。拟议的项目将利用NIH支持的资源， 包括RDOC项目和我们的实验室中的一个项目（R01AG062268），以确定因素结构 ADRD中的NP，以更好地了解负面变化之间的联系（例如恐惧，痛苦， 和动画）和积极的（例如奖励行为）价系统和特定的NP 不同的神经退行性疾病。相同的NP（例如，冷漠）发生在许多ADRD诊断中， 需要采用反诊断方法来识别NP的常见神经生物学知识的机制 跨诊断。我们将研究40名患有阿尔茨海默氏病（AD）的参与者，有行为变化的参与者 额颞痴呆（BVFTD），20种亨廷顿氏病（HD）和20个具有语义变化的原发性 渐进失语（SVPPA）。我们选择了这些疾病，因为它们针对特定的RDOC负面和 正价电路元件，包括前额叶皮层（PFC），背纹状体和前临时 爱。第一个假设是腹侧（VM）PFC在负价和 VMPFC的退化将与RDOC范式的低负价相关，低。 精神病症状（包括焦虑和抑郁症）和冷漠的NP。我们也是 假设调节VMPFC的负价电路元件的变性，包括 背侧PFC，背纹状体和前临时爱情将与高负相关和 互化的精神病学NP。腹侧PFC和背纹状体参与目标指导的学习和 将学习从目标定向转移到习惯系统。我们假设腹侧PFC的变性 将与从RDOC正价范式的反馈中学习以及与 重复行为的NPS和背纹状体的退化，并从惩罚中学习的定义 与奖励和习惯学习以及重复思想的NP。这些调查可能是第一次 利用RDOC范式更好地了解神经退行性的人类NP的发展 在RDOC价范式中的特定定义，即神经解剖学发现的过程。这些 调查在临床上是相关的，因为它们将提高我们对机械和神经虫的了解 NP的tomical基础用于ADRD中NP的新型神经解剖治疗的临床试验。