Multidimensional Approaches to Understanding Consequences and Mechanisms of Apathy in Frontotemporal Degeneration

项目摘要 冷漠是最常见的和致残的行为症状共享在许多阿尔茨海默氏症 疾病及相关疾病（ADRD），包括行为变异性额颞叶变性（bvFTD）。 冷漠表现为目标导向行为（GDB）的减少，并伴有计划不周、 即使是最简单的自我护理活动，也会导致残疾， 生活质量下降。因此，冷漠是一个不良的预后指标，对临床下降有深远的影响 患者的日常功能活动。最近的研究表明，冷漠与一种破坏性的行为有关。 GDB的缺陷-启动，计划和动机-表明冷漠是一种异质性综合征 有不同的潜在机制。此外，这些功能上可分离的GDB进程映射到 不同的脑区虽然以前的成像工作主要集中在 识别与冷漠有关的单个大脑区域的结构MRI相关性， 一项研究建议是调查bvFTD中GDB受损的大规模功能网络--冷漠是 非常普遍。基于我们以前的工作，这里提出的框架将捕捉复杂的 GDB受损的协会涵盖了冷漠的各个领域，并将研究 大规模内在网络的崩溃可能导致冷漠的临床综合症。在目标1中，我们将研究 GDB的不同损伤如何导致日常功能的纵向临床下降率 活动在目标2中，我们将使用静息态功能磁共振成像来确定受损的GDB和 大规模神经认知网络的崩溃。在目标3中，我们将研究 随着时间的推移，功能性网络连接导致GDB组件的下降，我们将评估如何 GDB基础网络的退化介导了日常功能活动的临床下降率。这 该提案解决了一个严重未满足的需求，即阐明退行性疾病在损害 支持ADRD中目标导向行为的网络机制。鉴于有效性有限， 药物治疗痴呆症的冷漠，这项翻译工作是必要的，以指导未来的临床 这种衰弱综合症的临床试验

Project Abstract Apathy is the most common and disabling of the behavioral symptoms shared across many Alzheimer's Disease and Related Disorders (ADRDs), including behavioral variant frontotemporal degeneration (bvFTD). Apathy manifests as a decrease in goal-directed behavior (GDB), with deficits such as poor planning, poor motivation and inability to initiate even the simplest self-care activities, contribute to disability and greatly reduced quality of life. Thus, apathy is a poor prognostic indicator, having a profound impact on clinical decline in everyday patient functional activities. Recent work shows that apathy is associated with a disruption in impairments in GDB--initiation, planning and motivation--suggesting that apathy is a heterogenous syndrome with distinct underlying mechanisms. Furthermore, these functionally dissociable GDB processes map onto distinct and distributed brain regions. While previous imaging efforts have predominantly focused on the identification of structural MRI correlates of single brain regions involved in apathy, the overall goal of this proposal is to investigate large-scale functional networks underlying impaired GDB in bvFTD--where apathy is highly prevalent. Building on our previous work, the framework proposed here will capture the complex associations of impaired GDB encompassing the various domains of apathy and will examine the ways the breakdown of large-scale intrinsic networks can lead to the clinical syndrome of apathy. In Aim 1, we will study how distinct impairments in GDB contribute to rate of longitudinal clinical decline in everyday functional activities. In Aim 2, we will use resting-state fMRI to identify relationships between impaired GDB and breakdown of large-scale neurocognitive networks. In Aim 3, we will examine how change in configuration of functional network connectivity over time contributes to decline in components of GDB and we will assess how degrading networks underlying GDB mediate rate of clinical decline in everyday functional activities. This proposal addresses a critically unmet need to elucidate the role of degenerative disease in compromising the network mechanisms that support goal-directed behavior in ADRD. Given the limited effectiveness of pharmacological treatment for apathy in dementia, this translational work is necessary to guide future clinical trials for this debilitating syndrome.