Emotion network dysfunction and decline in early frontotemporal dementia

摘要 额颞性痴呆(FTD)是一种以进行性为特征的神经退行性综合征家族 情绪、社交行为和语言的衰退。FTD的行为变种是临床上最常见的 亚型，以情感、同理心和社会行为缺陷为特征。FTD通常是零星的，但 可由C9orf72、GRN和MAPT的基因突变引起。遗传形式的FTD提供了一个关键的窗口 进入疾病的早期阶段，因为携带基因突变的个体可以被识别、研究和 当他们没有症状和进入疾病的症状阶段时，紧随其后。我们以前的 基于实验室的研究发现，自主神经系统活动、面部表情和 经验发生在FTD的早期，反映了特定大脑网络的功能障碍。解剖学上的特殊情感 生物标志物可用于监测临床试验中的症状进展或治疗反应 无症状或轻微症状的个体，但需要更多可扩展的方法。建议数 该项目将建立在我们之前对无症状和有症状个体的情绪的实验室研究的基础上 使用FTD，将包括对现实世界中的情绪和行为的纵向、多天评估。这些 数据将使我们能够测试我们在实验室中发现的新的情绪生物标记物是否可以 使用远程工具进行跟踪，并将使我们能够在早期确定是否有其他更改区域 之前未被检测到的FTD。这一提议的中心假设是情感是直接的 可用于监测无症状和早期患者进展的脆弱脑系统读数 FTD症状期。我们将对100名突变携带者进行基于实验室的情绪评估 在临床范围内，50名突变的非携带者家族成员对照，50名散发性 行为变异型FTD，以及三次年度研究访问中的50名老年健康对照组，其中包括临床 体检和神经成像。我们还将每年进行五次情绪远程评估，在此期间 我们将测量真实世界的自主生理(使用可穿戴设备)、行为(使用参与者的 照片和自我报告的活动)，以及主观感受(通过经验抽样方法)。我们会 解决三个关键目标。在目标1中，我们将在无症状突变中绘制真实世界的情绪图景 携带者和早期FTD及其与实验室情绪和情感症状测量的相关性。在……里面 目标2，我们将分离情绪中FTD相关异常的神经系统，如在 真实世界和实验室。在目标3中，我们将量化FTD早期的纵向情绪系统衰退。通过 将神经成像技术与实验室和现实世界的情绪测量相结合，这 该项目有可能推进情绪障碍和情绪衰退的生物学基础的现有模型 在FTD早期。

ABSTRACT Frontotemporal dementia (FTD) is a family of neurodegenerative syndromes characterized by progressive decline in emotion, social behavior, and language. The behavioral variant of FTD is the most common clinical subtype and is characterized by deficits in emotion, empathy, and social behavior. FTD is often sporadic but can be caused by genetic mutations in C9orf72, GRN, and MAPT. Genetic forms of FTD offer a critical window into the disease's early stages because individuals with genetic mutations can be identified, studied, and followed when they are asymptomatic and as they enter the symptomatic stage of the disease. Our previous laboratory-based studies have found alterations in autonomic nervous system activity, facial expression, and experience occur early in FTD and reflect dysfunction in specific brain networks. Anatomically specific emotion biomarkers could be used to monitor symptom progression or treatment response in clinical trials of asymptomatic or mildly symptomatic individuals, but more scalable approaches are needed. The proposed project will build on our prior laboratory-based studies of emotion in asymptomatic and symptomatic individuals with FTD and will include longitudinal, multi-day assessments of emotion and behavior in the real world. These data will allow us to test whether novel emotion biomarkers we have discovered in the laboratory can be tracked with remote tools and will enable us to determine whether there are additional areas of change in early FTD that have previously gone undetected. The central hypothesis of this proposal is that emotions are direct readouts of vulnerable brain systems that can be used to monitor progression in the asymptomatic and early symptomatic phase of FTD. We will conduct laboratory-based assessments of emotion in 100 mutation carriers across the clinical spectrum, 50 mutation non-carrier family member controls, 50 people with sporadic behavioral variant FTD, and 50 older healthy controls at three annual research visits that include a clinical work-up and neuroimaging. We will also conduct five biannual remote assessments of emotion during which we will measure real-world autonomic physiology (with wearable devices), behavior (with participants' photographs and self-reported activities), and subjective feelings (with experience sampling methods). We will address three key aims. In Aim 1, we will map the real-world landscape of emotion in asymptomatic mutation carriers and early FTD and its associations with laboratory measures of emotion and affective symptoms. In Aim 2, we will isolate the neural systems underlying FTD-relevant aberrations in emotion as measured in the real world and laboratory. In Aim 3, we will quantify longitudinal emotion system decline in early FTD. By integrating neuroimaging techniques with measures of emotion from the laboratory and the real world, this project has the potential to advance current models of the biological basis of emotion dysfunction and decline in early FTD.