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

通过神经影像学和电操作研究 ADRD 冷漠的神经解剖学基础

• 批准号: 10656199
• 负责人: Nora Vanegas-Arroyave
• 金额: $ 67.41万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656199
• 关键词: 3-Dimensional; Affect; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Animal Model; Anterior; Apple; Atrophic; Basal Ganglia; Behavior; Behavioral; Brain; Caregiver Burden; Caregivers; Cognitive; Computers; Corpus striatum structure; Decision Making; Deep Brain Stimulation; Dementia; Deterioration; Development; Dimensions; Disease; Dissociation; Dorsal; Electric Stimulation; Electrodes; Emotional; Enrollment; Focused Ultrasound; Frontotemporal Dementia; Goals; Hypersensitivity; Insula of Reil; Intervention; Knowledge; Lesion; Link; Literature; Location; Measures; Mediating; Mediator; Motivation; Nerve Degeneration; Neuroanatomy; Neurobiology; Neurosciences; Operative Surgical Procedures; Parkinson Disease; Participant; Patients; Performance; Pharmaceutical Preparations; Play; Population; Positive Valence; Postoperative Period; Prefrontal Cortex; Public Health; Quality of life; Research; Research Domain Criteria; Rewards; Risk; Role; STN stimulation; Severities; Structure; Structure of subthalamic nucleus; Symptoms; Syndrome; Task Performances; Testing; Time; Ventral Striatum; Viral Vector; Work; cingulate cortex; cognitive process; effective therapy; experience; experimental study; frontal lobe; functional MRI scan; human imaging; information processing; motivated behavior; motor control; motor deficit; neural; neural circuit; neuroimaging; neuropathology; neuropsychiatric symptom; neuropsychiatry; new therapeutic target; recruit; routine care; study population; systems research; white matter

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.

由于治疗方案有限，阿尔茨海默病（AD）患者经常出现的麻木症状，