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.

由于治疗方案有限，阿尔茨海默氏病（AD）患者经常出现冷漠症状相关痴呆症（ADRD）和帕金森氏病（PD）显着影响患者的生活质量和照顾者。尽管对额叶皮质和冷漠综合征和目标指导行为（GDB）的皮质下结构，缠绵的差距仍在从神经变性到冷漠发展的因果关系。因此，对冷漠的认知和神经解剖学基础是开发以神经生物为目标的方式在痴呆症中，这种使人衰弱的神经精神问题的治疗方法。而我们的长期目标是发展在ADRD和PD中对冷漠的有效治疗方法，本应用的总体目标是（i）测试是否是否局灶性神经变性导致ADRD和PD的冷漠的影响可以通过差异来解释奖励和努力敏感性 - GDB不可或缺的认知过程，（ii）在PD参与者中被称为接收深脑刺激手术（DBS），后来众所周知会出现高冷漠的速率，直接测试是否是否刺激丘脑下核（STN）和连接的额叶皮层电路，将导致 GDB的立即变化。中心假设是，无论主要神经病理学或位置如何沿着神经回路，都被视为结构和功能连通性的变化，以及电气沿前额叶神经节网络刺激，直接改变了GDB并表现为冷漠。二提出了独立目的：目标1。所有三个研究人群合并（pd n = 100，ftd n = 50，并且 ad n = 100），评估奖励和努力敏感性的独立效果，作为一种机械联系基底神经节网络的神经变性和漠不关心的特定维度的发展识别（a）的神经解剖学基础，尺寸冷漠量表（DAS），为三个冷漠维度提供亚尺寸，以及（b）奖励和奖励和苹果收集任务（AGT）的努力敏感性，以及（c）评估奖励和努力敏感性作为解释性神经影像学指标和冷漠维度的介体。 AGT是一台30分钟的电脑基于努力的决策范式在其中权衡了奖励与努力。与RDOC一致框架，AGT允许通过分离GDB的组件的机械方法来冷漠神经解剖底物。在AIM 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。展示因果关系 DBS对PD参与者动机行为变化的影响，而“对”多巴胺能药物，我们将评估他们在三个时间点上对AGT的表现：（i）基线和术后6个月，并使用（ii）DBS- OFF和（iii）DBS-ON。总体而言，这项研究将确定新干预措施的切实治疗靶标（即病毒载体，重点超声），因此使临床医生能够在与痴呆有关的疾病中管理冷漠。