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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的额颞叶痴呆 (FTD) 是一种神经退行性疾病，其特征是智力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，情绪和同理心受损是由于情绪回路退化而出现的标志性特征。尽管 bvFTD 始于额岛叶和前扣带皮层，但具有已知作用的大脑区域内脏运动情绪的产生和自主神经整合，情绪系统功能障碍的最早迹象未知。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 早期情绪改变提供了新的途径，因为在疾病的无症状临床前阶段可以识别、研究和跟踪这些个体并处于早期症状临床阶段。情绪生理和行为的变化可能在早期就发生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。拟议的研究将有助于表征临床前情绪缺陷及其潜在回路，并确定这些赤字是否是 FTD 下降的早期指标。解剖学特异性标记可用于在无症状或轻度症状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。该提案整合了自主神经系统反应性的实验室测量和面部表情与多模式神经成像技术来识别情绪系统如何变化 FTD 的最早阶段。我们将研究 100 名无症状基因阳性受试者（50 名 C9ORF72+、30 名 GRN+ 和 20 MAPT+）、50 名健康对照（年龄匹配、基因阴性的家庭成员）、40 名 bvFTD 患者，以及每年两次的研究访问中，有 40 名年龄匹配的老年健康对照者。受试者将接受实验室测试除了临床检查以及结构和功能连接磁共振之外，还包括情绪成像。该提案的中心假设是情绪生理学和行为的客观测量是脆弱大脑系统的直接读数，可以无创地测量并跟踪进展 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，并确定特定情绪缺陷如何与其相关行为和情感症状。在目标 2 中，我们将描绘所识别的潜在神经回路 bvFTD 和临床前 FTD 中的情绪缺陷。在目标 3 中，我们将确定追踪的实验室措施在早期 FTD 中，情绪网络随着时间的推移而下降。该项目有潜力推进当前的模型 FTD 和其他具有类似情绪的临床疾病中情绪功能障碍的生物学基础有症状但缺乏明显的脑部病变。