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: 10824824
• 负责人: Edward D Huey
• 金额: $ 43.9万
• 依托单位: BROWN UNIVERSITY
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10824824
• 关键词: Adverse effects; Alzheimer' s Disease; Alzheimer' s disease patient; 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; Neuroanatomy; Neurobiology; Neurodegenerative Disorders; Pain; Participant; Patients; Persons; Pharmaceutical Preparations; Pharmacological Treatment; Play; Positive Valence; Prefrontal Cortex; Preparation; Primary Progressive Aphasia; Process; 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; transcranial direct current stimulation

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负价和正价的退化效应 电路元素，以及这些影响如何与特定的神经精神症状（NST）， 阿尔茨海默病和相关痴呆症（ADRD）患者。目前的药物治疗 ADRD中的抗抑郁药是50年前开发的，通常无效，并可能产生严重的副作用 包括增加死亡率。基于神经解剖学的治疗，如TMS、DBS和tDCS， 很有希望，但它们的发展受到了我们对机械和 ADRD中的神经解剖学基础。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 在ADRD中，为了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）的配价系统和特定的跨 不同的神经退行性疾病相同的尺寸（例如，冷漠）发生在许多ADRD诊断中， 需要一种跨诊断的方法来确定常见的神经生物学信息的机制， 在诊断中。我们将研究40名阿尔茨海默病（AD）患者，20名行为变异型AD患者， 额颞叶痴呆（bvFTD）、20例亨廷顿病（HD）和20例语义变异型原发性 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， 正价回路元件包括前额叶皮层（PFC）、背侧纹状体和前颞叶 耳垂第一个假设是腹内侧（vm）前额叶皮质在负价中发挥核心作用， vmPFC的退化将与RDoC范式上的低负价相关，低负价 内化精神症状（包括焦虑和抑郁），以及冷漠。我们也 假设调节vmPFC负极电路元件的退化，包括 背侧PFC，背侧纹状体和前颞叶，将与高负价相关， 内化精神疾病。腹侧PFC和背侧纹状体参与目标导向学习， 将学习从目标导向转移到习惯系统。我们假设腹侧前额叶皮层的退化 将与从RDoC正价范式的反馈中学习的缺陷相关， 重复行为的减少，背侧纹状体退化，从惩罚中学习能力不足 vs.奖励和习惯学习以及消除重复性思维。这些调查可能会首次， 利用RDoC范式更好地了解人类神经退行性疾病的发展 过程，RDoC效价范式中的特定缺陷，神经解剖学发现，以神经元。这些 研究是临床相关的，因为它们将提高我们的机械和神经解剖学的知识， 在ADRD中使用基于神经解剖学的新治疗方法的临床试验中使用的神经解剖学基础。

项目成果

Subjective Cognitive Decline Is More Accurate When Metamemory Is Better.

• DOI: 10.3389/fnagi.2022.787552
• 发表时间: 2022
• 期刊: Frontiers in aging neuroscience
• 影响因子: 4.8
• 作者: Chapman S;Joyce JL;Barker MS;Sunderaraman P;Rizer S;Huey ED;Dworkin J;Gu Y;Cosentino S
• 通讯作者: Cosentino S

Multimodal nonlinear correlates of behavioural symptoms in frontotemporal dementia.

额颞叶痴呆行为症状的多模态非线性相关性。

• DOI: 10.21203/rs.3.rs-3271530/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Zamboni,Giovanna;Mattioli,Irene;Arya,Zobair;Tondelli,Manuela;Vinceti,Giulia;Chiari,Annalisa;Jenkinson,Mark;Huey,EdwardD;Grafman,Jordan
• 通讯作者: Grafman,Jordan