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

项目摘要 冷漠是许多阿尔茨海默氏症患者中最常见和最令人丧失能力的行为症状 疾病及相关疾病(ADRD)，包括行为变异型额颞部变性(BvFTD)。 冷漠表现为目标导向行为(GDB)的减少，并存在计划不善、计划不善、 即使是最简单的自我照顾活动，动机和能力也会导致残疾，并极大地 生活质量下降。因此，冷漠是一个糟糕的预后指标，对临床下降有深远的影响。 在日常的病人功能活动中。最近的研究表明，冷漠与精神分裂有关 GDB中的障碍--启蒙、计划和动机--表明冷漠是一种异质性综合症 有着不同的潜在机制。此外，这些在功能上不可关联的gdb进程映射到 不同的和分布的大脑区域。虽然以前的成像工作主要集中在 确定与冷漠有关的单个大脑区域的结构磁共振相关，这项研究的总体目标是 建议调查bvFTD中潜在的GDB受损的大规模功能网络--那里是冷漠 非常普遍。在我们以前工作的基础上，这里提出的框架将捕捉到复杂的 GDB受损的协会涵盖了冷漠的各个领域，并将检查 大规模内在网络的崩溃会导致冷漠的临床症状。在目标1中，我们将研究 GDB中明显的损害如何影响日常功能的纵向临床下降率 活动。在目标2中，我们将使用静息状态功能磁共振来识别GDB受损和 大规模神经认知网络的崩溃。在目标3中，我们将研究如何更改 随着时间的推移，功能网络连接会导致GDB组件的下降，我们将评估如何 GDB潜在的退化网络在日常功能活动中调节临床衰退的速度。这 一项提案解决了一个严重未得到满足的需要，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。鉴于其有效性有限， 痴呆症冷漠的药物治疗，这项翻译工作对指导未来的临床是必要的 对这种衰弱综合症的试验。

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.