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: 9238376
• 负责人: Virginia Emily Sturm
• 金额: $ 60.66万
• 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 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238376
• 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; Biological Neural Networks; 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; Modality; Modeling; Monitor; Mutation; Neurodegenerative Disorders; Neuronal Dysfunction; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Physiology; Recruitment Activity; 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; mutation carrier; network dysfunction; neural circuit; neuroimaging; novel; novel therapeutics; pre-clinical; psychiatric symptom; 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，其特征是进行性下降。 社交行为、情感和语言。在行为变体FTD(BvFTD)中，最常见的FTD亚型， 情绪障碍和同理心是由于情绪回路退化而出现的显著特征。 虽然bvFTD开始于额岛和前扣带回皮质，但大脑中已知在 内脏运动情绪生成和自主神经整合是情绪系统功能障碍的最早迹象 都是未知的。大约40%的FTD病例是遗传的，原因是C9ORF72、GRN和 MAPT。基因阳性突变携带者为FTD的早期情绪改变提供了一种新的途径，因为 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。 出现症状的早期临床阶段。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。建议数 研究将有助于表征临床前情绪缺陷及其潜在的回路，并确定 这些赤字是否是FTD下降的早期指标。解剖学上的特定标记可以用来 在无症状或轻度的临床试验中监测症状进展或跟踪疾病相关功能障碍 有症状的个体。这一建议综合了自主神经系统反应性的实验室测量。 以及面部表情和多模式神经成像技术，以确定情绪系统是如何变化的 FTD的早期阶段。我们将研究100名无症状基因阳性的受试者(50名C9ORF72+，30名GRN+和 20例MAPT阳性)，50例健康对照(年龄匹配，基因阴性的家庭成员)，40例bvFTD患者，以及 在两次年度研究访问中，40名年龄匹配的健康对照组。受试者将接受实验室检测 除了临床检查和结构和功能连接磁共振外的情绪 成像。这一建议的中心假设是情绪、生理和行为的客观衡量标准 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 临床前和症状早期的FTD。我们将解决三个主要目标。在目标1中，我们将分离 早期FTD中情绪障碍的领域，并确定特定的情绪障碍如何与 行为和情感症状。在目标2中，我们将描述识别出的潜在神经回路 BvFTD和临床前FTD中的情绪障碍。在目标3中，我们将确定跟踪的实验室措施 在FTD早期，情绪网络随着时间的推移而下降。该项目有可能推动当前型号的 FTD和其他具有相似情绪的临床障碍患者情绪障碍的生物学基础 有症状，但没有明显的脑部损害。