Emotion network dysfunction and decline in early frontotemporal dementia

早期额颞叶痴呆的情绪网络功能障碍和衰退

• 批准号: 10063463
• 负责人: Virginia Emily Sturm
• 金额: $ 63.36万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063463
• 关键词: Address; Affective; Affective Symptoms; Age; Amygdaloid structure; Anatomy; Animal Model; Anterior; Arousal; Atrophic; Autonomic nervous system; Behavior; Behavioral; Behavioral Symptoms; Biological Markers; Biological Models; Brain; Brain region; C9ORF72; Clinical; Clinical Trials; Collaborations; Communities; Cues; Data; Development; Diagnosis; Disease; Disease model; Emotional; Emotions; Empathy; Evaluation; Exhibits; Facial Expression; Family member; Fostering; Frontotemporal Dementia; Functional disorder; Generations; Genes; Genetic; Genotype; Grant; Homeostasis; Human; Hypothalamic structure; Impairment; Individual; Investigation; Laboratories; Language; Left; Lesion; Magnetic Resonance Imaging; Measures; Modeling; Monitor; Mutation; Neurodegenerative Disorders; Neuronal Dysfunction; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Physiology; Reporting; Research; Rest; Role; Social Behavior; Stimulus; Structure; Symptoms; System; Techniques; Testing; Time; Visit; behavioral variant frontotemporal dementia; cingulate cortex; drug development; emotional symptom; experience; follow up assessment; gray matter; improved; informant; midbrain central gray substance; multimodality; mutation carrier; network dysfunction; neural circuit; neural network; neuroimaging; non-invasive system; novel; novel therapeutics; pre-clinical; psychiatric symptom; recruit; social engagement; support network; treatment trial

ABSTRACT Frontotemporal dementia (FTD) is a neurodegenerative disease that is characterized by progressive decline in social behavior, emotion, and language. In behavioral variant FTD (bvFTD), the most common FTD subtype, impairment in emotion and empathy are hallmark features that arise due to degeneration of emotion circuits. Although bvFTD begins in frontoinsula and anterior cingulate cortex, brain regions with known roles in visceromotor emotion generation and autonomic integration, the earliest signs of emotion system dysfunction are unknown. Approximately 40% of FTD cases are genetic and due to mutations in C9ORF72, GRN, and MAPT. Gene-positive mutation carriers offer a novel inroad into early emotion alterations in FTD because these individuals can be identified, studied, and followed during the asymptomatic, preclinical phase of disease and in the early symptomatic clinical phase. Changes in emotion physiology and behavior may occur early in the disease, reflect decline in emotion-relevant brain networks, and relate to affective symptoms. The proposed studies will help to characterize preclinical emotion deficits and their underlying circuitry and to determine whether these deficits are early indicators of decline in FTD. Anatomically-specific markers could be used to monitor symptom progression or to track disease-related dysfunction in clinical trials of asymptomatic or mildly symptomatic individuals. This proposal integrates laboratory measures of autonomic nervous system reactivity and facial expression with multi-modal neuroimaging techniques to identify how emotion systems change in the earliest stages of FTD. We will study 100 asymptomatic gene-positive subjects (50 C9ORF72+, 30 GRN+, and 20 MAPT+), 50 healthy controls (age-matched, gene-negative family members), 40 patients with bvFTD, and 40 older age-matched healthy controls at two annual research visits. Subjects will undergo laboratory testing of emotion in addition to a clinical work-up and structural and functional connectivity magnetic resonance imaging. The central hypothesis of this proposal is that objective measures of emotion physiology and behavior are direct readouts of vulnerable brain systems that can be measured noninvasively and track progression in the in preclinical and early symptomatic phase of FTD. We will address three key aims. In Aim 1, we will isolate the domains of emotional dysfunction in early FTD and determine how specific emotional deficits relate to behavioral and affective symptoms. In Aim 2, we will delineate the neural circuitry underlying identified emotional deficits in bvFTD and preclinical FTD. In Aim 3, we will identify laboratory measures that track emotion network decline over time in early FTD. This project has the potential to advance current models of the biological basis of emotion dysfunction in FTD and other clinical disorders that have similar emotional symptoms but lack obvious brain lesions.

摘要 额颞叶痴呆（FTD）是一种神经退行性疾病，其特征在于脑内神经元的功能进行性下降。 社会行为、情感和语言。在行为变异FTD（bvFTD）中，最常见的FTD亚型， 情感和移情的损伤是由于情感回路退化而出现的标志性特征。 虽然bvFTD开始于额叶皮层和前扣带皮层，但已知作用于 内脏情绪产生和自主神经整合，情绪系统功能障碍的最早迹象 是未知的。大约40%的FTD病例是遗传性的，是由于C9ORF72、GRN和 地图。基因阳性突变携带者为FTD的早期情绪改变提供了新的途径， 这些个体可以在疾病的无症状、临床前阶段被识别、研究和跟踪 和早期症状性临床阶段。情绪生理和行为的变化可能发生在早期， 这种疾病反映了与情绪相关的大脑网络的衰退，并与情感症状有关。拟议 研究将有助于描述临床前情绪缺陷及其潜在电路，并确定 这些缺陷是否是FTD下降的早期指标。解剖学特异性标记可用于 监测症状进展或跟踪无症状或轻度的临床试验中的疾病相关功能障碍 有症状的人该建议整合了自主神经系统反应性的实验室测量 和面部表情的多模态神经成像技术，以确定如何情绪系统的变化， FTD的早期阶段。我们将研究100例无症状基因阳性受试者（50例C9ORF72+，30例GRN+， 20例MAPT+）、50例健康对照（年龄匹配、基因阴性家族成员）、40例bvFTD患者和 在两次年度研究访问中，40名年龄匹配的老年健康对照者。受试者将接受以下实验室检查： 情绪除了临床检查和结构和功能连接磁共振 显像这一建议的核心假设是，情绪生理和行为的客观测量 是脆弱的大脑系统的直接读数，可以非侵入性地测量并跟踪进展， FTD的临床前和早期症状阶段。我们将实现三个关键目标。在目标1中，我们将隔离 早期FTD中情绪功能障碍的领域，并确定具体的情绪缺陷如何与 行为和情感症状。在目标2中，我们将描绘出识别出的神经回路。 bvFTD和临床前FTD的情绪缺陷。在目标3中，我们将确定跟踪 在早期FTD中，情绪网络随时间推移而下降。该项目有可能推进目前的模式， FTD和其他具有类似情绪障碍的临床疾病中情绪功能障碍的生物学基础 症状，但没有明显的脑部病变。