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

由于治疗选择有限，阿尔茨海默病（AD）患者经常出现冷漠症状， 相关性痴呆（ADRD）和帕金森病（PD），显著影响患者的生活质量， 照顾者尽管对额叶皮层和皮层的重要作用有着很好的理解， 在冷漠综合征和目标导向行为（GDB）的皮层下结构上， 从神经退化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，站在发展神经生物学靶向的道路上， 针对痴呆症患者的这种神经精神问题的治疗方法。虽然我们的长期目标是发展 有效治疗ADRD和PD中的冷漠，本申请的总体目标是（i）测试是否 局灶性神经变性导致ADRD和PD冷漠的影响可以通过以下差异来解释： 奖励和努力的敏感性-认知过程的组成部分，以GDB，和（ii）在PD参与者提到，接受 脑深部电刺激手术（DBS），谁是众所周知的，后来发展的冷漠率高，直接测试是否 刺激丘脑底核（subthalamic nucleus，ENA）和相连的额叶-皮层下回路， GDB的即时变化。中心假设是，无论原发性神经病理或位置如何， 沿着神经回路，既有萎缩，观察到结构和功能连接的变化， 沿着额前-基底神经节网络的刺激，直接改变GDB并表现为冷漠。两 提出了独立的目标：目标1。合并所有三个研究人群（PD n=100，FTD n=50， AD n=100），评估奖励和努力敏感性的独立影响，作为一个机械的联系， 基底神经节-额叶网络的神经变性和冷漠的特定维度的发展，通过 确定冷漠的三个维度中的每一个的神经解剖学基础（A），通过以下方式测量 维度冷漠量表（DAS），提供三个冷漠维度的子评分，以及（B）奖励和 来自Apple Gather任务（AGt）的努力敏感度，以及（C）评估奖励和努力敏感度作为解释 神经影像学指标和冷漠维度的介质。AGt是一台30分钟的计算机， 基于努力的决策模式，其中奖励与努力相权衡。与RDoC一致 在这个框架中，AGt允许通过将GDB的组件与不同的 神经解剖学基质在目标2中，对于PD-DBS参与者，确定是否对 GDB直接改变了奖励和努力信息处理，从而改变了GDB。为了证明因果关系 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 在三个时间点评估他们在AGt上的表现：（i）基线和术后6个月（ii）DBS- 总的来说，这项研究将确定新的干预措施（即病毒感染）的切实治疗靶点。 向量，聚焦超声），因此，使临床医生能够管理痴呆症相关条件下的冷漠。

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.