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

理解额颞叶退化中冷漠后果和机制的多维方法

• 批准号: 10585053
• 负责人: Lauren M Massimo
• 金额: $ 51.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585053
• 关键词: Address; Admission activity; Affect; Alzheimer' s Disease; Anatomy; Atrophic; Behavior; Behavioral Symptoms; Brain; Brain region; Characteristics; Clinical; Clinical Trials; Cognition; Cognitive; Complex; Degenerative Disorder; Dementia; Disease; Effectiveness; Foundations; Functional Magnetic Resonance Imaging; Future; Goals; Human; Image; Impaired cognition; Impairment; Individual; Investigation; Label; Lead; Magnetic Resonance Imaging; Maps; Mediating; Motivation; Motor; Nerve Degeneration; Neurocognitive; Nursing Homes; Pathway Analysis; Patients; Pharmacological Treatment; Process; Quality of life; Research Design; Rest; Rewards; Role; Self Care; Source; Syndrome; Time; Work; behavioral impairment; behavioral variant frontotemporal dementia; clinical prognosis; cognitive function; disability; effective therapy; efficacious treatment; frontotemporal degeneration; functional decline; insight; mortality risk; motor disorder; neuropsychiatric symptom; novel; patient prognosis; prognostic indicator; relating to nervous system; segregation; targeted treatment

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.

项目摘要 冷漠是在许多阿尔茨海默氏症中共有的行为症状的最常见和残疾 疾病和相关疾病（ADRD），包括行为变异额颞变性（BVFTD）。 冷漠表现为目标指导行为（GDB）的减少，诸如计划差，差的赤字差 动机和无法发起最简单的自我保健活动，有助于残疾，并且很大 减少生活质量。因此，冷相是一个差的预后指标，对临床下降产生了深远的影响 在日常的患者功能活动中。最近的工作表明，冷漠与中断有关 GDB的损害 - 实施，计划和动机 - 探索冷漠是一种异质综合症 具有不同的潜在机制。此外，这些在功能上可解散的GDB过程映射到 独特和分布的大脑区域。虽然以前的成像努力主要集中在 识别涉及冷漠的单个大脑区域的结构MRI相关性，这是总体目标 建议是调查BVFTD中GDB损害的大规模功能网络 - 冷漠是 非常普遍。在我们以前的工作的基础上，这里提出的框架将捕获综合体 GDB受损的关联涵盖了冷漠的各个领域，并将研究 大规模内在网络的崩溃会导致冷漠的临床综合征。在AIM 1中，我们将学习 GDB的不同损害如何导致日常功能的纵向临床下降率 活动。在AIM 2中，我们将使用静止状态fMRI来识别受损GDB和 大规模神经认知网络的崩溃。在AIM 3中，我们将研究如何改变 随着时间的推移，功能网络连接有助于GDB组件的下降，我们将评估如何 GDB的基础网络降低网络介导日常功能活动的临床下降速度。这 提案解决了阐明退化性疾病在损害损害的作用的迫切需求 支持目标指导行为的网络机制。考虑到有限的有效性 对痴呆症冷漠的药理治疗，这项翻译工作对于指导未来的临床是必要的 该衰弱综合征的试验。