Investigating neuroanatomical underpinnings of apathy in ADRD through neuroimaging and electrical manipulation

通过神经影像学和电操作研究 ADRD 冷漠的神经解剖学基础

基本信息

批准号：
10438901
负责人：
Nora Vanegas-Arroyave
金额：
$ 62.07万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10438901
关键词：
3-Dimensional Affect Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Animal Model Anterior Apple Atrophic Basal Ganglia Behavior Behavioral Brain Caregiver Burden Caregivers Cognitive Computers Corpus striatum structure Decision Making Deep Brain Stimulation Dementia Deterioration Development Dimensions Disease Dorsal Electric Stimulation Electrodes Emotional Enrollment Focused Ultrasound Frontotemporal Dementia Goals Hypersensitivity Insula of Reil Intervention Knowledge Lesion Link Literature Location Measures Mediating Mediator of activation protein Motivation Nerve Degeneration Neurobiology Neurosciences Operative Surgical Procedures Parkinson Disease Participant Patients Performance Pharmaceutical Preparations Play Population Positive Valence Postoperative Period Prefrontal Cortex Public Health Quality of life Research Research Domain Criteria Rewards Risk Role STN stimulation Severities Structure Structure of subthalamic nucleus Symptoms Syndrome Task Performances Testing Time Ventral Striatum Viral Vector Work base cingulate cortex cognitive process effective therapy experience experimental study functional MRI scan human imaging information processing motivated behavior motor deficit neural circuit neuroimaging neuropathology neuropsychiatric symptom neuropsychiatry new therapeutic target recruit relating to nervous system routine care study population systems research white matter

项目摘要

With limited treatment options, apathetic symptoms often experienced by patients with Alzheimer's disease (AD), related dementias (ADRD) and Parkinson's Disease (PD), significantly impact the quality of life of patients and caregivers. Despite a well-grounded understanding of the essential roles played by frontal cortical and subcortical structures on the apathy syndrome and on goal-directed behavior (GDB), lingering gaps remain on the causal links from neurodegeneration to the development of apathy. Thus, the fragmented understanding of the cognitive and neuroanatomical basis of apathy, stands on the way of developing neuro-biologically targeted treatments for this debilitating neuropsychiatric issue across dementias. While our long-term goal is to develop an effective treatment for apathy in ADRD and PD, the overall objectives of this application are to (i) test whether the effects of focal neurodegeneration leading to apathy in ADRD and PD can be explained by differences in reward and effort sensitivity - cognitive processes integral to GDB, and (ii) in PD participants referred to receive deep-brain stimulation surgery (DBS), who are known to later develop high rates of apathy, directly test whether stimulation of the subthalamic nucleus (STN) and connected frontal-subcortical circuits, would result in immediate changes in GDB. The central hypothesis is that, regardless of the primary neuropathology or location along the neural circuit, both atrophy, observed as structural and functional connectivity changes, and electrical stimulation along the prefrontal-basal ganglia network, directly alter GDB and manifest as apathy. Two independent aims are proposed: Aim 1. With all three study populations combined (PD n=100, FTD n=50, and AD n=100), evaluate the independent effects of reward and effort sensitivity as a mechanistic link between neurodegeneration of basal ganglia-to-frontal network and the development of specific dimensions of apathy, by identifying the neuroanatomical underpinnings for (A) each of the three dimensions of apathy as measured by Dimensional Apathy Scale (DAS), which provides subscores for three apathy dimensions, and (B) reward and effort sensitivity from the Apple Gather task (AGt), and (C) evaluating reward and effort sensitivity as explanatory mediators for neuroimaging metrics and apathy dimensions. The AGt is a 30-minute computer administered effort-based decision-making paradigm in which rewards are weighed against effort. Consistent with the RDoC framework, the AGt allows a mechanistic approach to apathy by dissociating components of GDB with distinct neuroanatomical substrates. In Aim 2, for PD-DBS participants, determine whether electrical manipulation of the STN directly alters reward and effort information processing and consequently GDB. To demonstrate a causal effect of DBS on changes in motivated behavior in PD participants, while `on' dopaminergic medications, we will assess their performance on AGt at three time points: (i) baseline, and 6-months postoperatively with (ii) DBS- OFF and (iii) DBS-ON. Overall, this study will identify tangible therapeutic targets for novel interventions (i.e viral vectors, focused ultrasound), and thus, enable clinicians to manage apathy in dementia-related conditions.

由于治疗选择有限，阿尔茨海默病 (AD) 患者经常出现精神萎靡的症状，相关痴呆症（ADRD）和帕金森病（PD），显着影响患者的生活质量照顾者。尽管对额叶皮质和皮层下结构对冷漠综合症和目标导向行为（GDB）的影响仍然存在挥之不去的差距神经退行性变与冷漠发展的因果关系。因此，碎片化的理解冷漠的认知和神经解剖学基础，站在发展神经生物学目标的道路上针对痴呆症中这种使人衰弱的神经精神问题的治疗方法。虽然我们的长期目标是发展作为 ADRD 和 PD 冷漠的有效治疗方法，该应用程序的总体目标是 (i) 测试是否局灶性神经变性导致 ADRD 和 PD 中冷漠的影响可以通过奖励和努力敏感性 - GDB 不可或缺的认知过程，以及 (ii) 在 PD 参与者中被称为接收众所周知，深部脑刺激手术（DBS）后来会出现高比例的冷漠，直接测试是否刺激底丘脑核（STN）和连接的额叶皮质下回路，会导致 GDB 立即发生变化。中心假设是，无论原发神经病理学或位置如何沿着神经回路，随着结构和功能连接的变化观察到萎缩，以及电沿前额叶-基底神经节网络的刺激，直接改变 GDB 并表现为冷漠。二提出了独立的目标：目标 1. 将所有三个研究人群相结合（PD n=100，FTD n=50，并且 AD n=100)，评估奖励和努力敏感性的独立影响作为两者之间的机械联系基底神经节到额叶网络的神经变性和冷漠特定维度的发展确定 (A) 冷漠的三个维度中每一个维度的神经解剖学基础维度冷漠量表 (DAS)，提供三个冷漠维度的子分数，以及 (B) 奖励和来自 Apple Gather 任务 (AGt) 的努力敏感性，以及 (C) 评估奖励和努力敏感性作为解释神经影像指标和冷漠维度的中介。 AGt 是由计算机管理的 30 分钟基于努力的决策范式，其中奖励与努力进行权衡。与 RDoC 一致框架中，AGt 通过将 GDB 的组件与不同的组件分离，允许采用一种机械的方法来处理冷漠问题。神经解剖学基质。在目标 2 中，对于 PD-DBS 参与者，确定是否对 STN 直接改变奖励和努力信息处理，从而改变 GDB。为了证明因果关系 DBS 对 PD 参与者动机行为变化的影响，同时“使用”多巴胺能药物，我们将评估他们在三个时间点的 AGt 表现：(i) 基线和术后 6 个月，(ii) DBS- 关和 (iii) DBS-开。总体而言，这项研究将为新的干预措施确定切实的治疗目标（即病毒矢量、聚焦超声），从而使临床医生能够管理痴呆相关疾病中的冷漠情绪。