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

点击翻译按钮获取中文摘要

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.