Detecting presymptomatic disease in inherited frontotemporal dementia

描述（由申请人提供）：这是加州大学旧金山分校（UCSF）行为神经学家Suzee Lee博士的K23奖申请。李博士在神经退行性疾病的以患者为导向的临床研究方面正在成为一名年轻的研究者。K23奖将为李博士提供必要的支持，以实现以下目标：(1)成为以患者为导向的额颞叶痴呆（FTD）临床研究专家；(2)开展FTD相关症状前基因携带者的临床调查；(3)在临床研究中应用新颖先进的神经影像学技术；(4)发展独立的临床研究事业。为了实现这些目标，李博士组建了一个由两位共同主要导师组成的指导团队。Bruce Miller博士，UCSF记忆与衰老中心（MAC）的临床主任，指导FTD （FTD- ppg）和Hillblom衰老网络研究正常衰老的项目拨款。William Seeley博士是UCSF MAC尸检项目和神经病理学核心的主任，他对神经退行性疾病的选择性易感性进行神经影像学研究，以探索早期疾病的发病机制。指导团队还包括两名合作者：Maria-Luisa Gorno-Tempini博士和John Neuhaus博士，前者是神经学家，主要研究原发性进步性失语症的神经成像，后者是统计学家，研究设计和生物统计分析方面的专家。额颞叶痴呆的早期诊断是出了名的具有挑战性。李博士的研究将集中在检测FTD基因突变的症状前携带者的脆弱大脑网络（目标1和2）。李博士将利用FTD- ppg和Hillblom老化网络的现有基础设施和受试者队列，研究50名FTD先见者未受影响的家庭成员，以确定FTD相关基因对大规模结构和功能连接神经网络改变的影响。这项研究将是一系列调查的第一步，这些调查将有助于从最早阶段开始纵向描述FTD的自然历史，为该领域建立疾病监测策略和未来治疗基因突变携带者的时间点铺平道路。

DESCRIPTION (provided by applicant): This is an application for a K23 award for Dr. Suzee Lee, a behavioral neurologist at the University of California, San Francisco (UCSF). Dr. Lee is establishing herself as a young investigator in patient-oriented clinical research of neurodegenerative disorders. This K23 award will provide Dr. Lee with the support necessary to accomplish the following goals: (1) to become an expert at patient-oriented clinical research in frontotemporal dementia (FTD); (2) to conduct clinical investigations of presymptomatic carriers of genes implicated in FTD; (3) to implement novel and advanced neuroimaging techniques in clinical studies; and (4) to develop an independent clinical research career. To achieve these goals, Dr. Lee has assembled a mentoring team comprised of two co-primary mentors. Dr. Bruce Miller, clinical director of the UCSF Memory and Aging Center (MAC), directs a program project grant on FTD (FTD-PPG) and a Hillblom Aging Network grant to study normal aging. Dr. William Seeley, director the UCSF MAC Autopsy Program and the Neuropathology Core, conducts neuroimaging studies on selective vulnerability in neurodegenerative diseases to explore early-stage disease pathogenesis. The mentoring team also includes two collaborators: Dr. Maria-Luisa Gorno-Tempini, a neurologist who focuses on neuroimaging in primary progressive aphasia and Dr. John Neuhaus, a statistician, who is an expert in study design and biostatistical analysis. Early diagnosis of front temporal dementia is notoriously challenging. Dr. Lee's research will focus on detecting vulnerable brain networks in presymptomatic carriers of FTD gene mutations (Aims 1 and 2). Dr. Lee will use the existing infrastructure and subject cohorts of the FTD-PPG and Hillblom Aging Network to study 50 unaffected family members of probands with FTD to determine the effect of FTD-related genes on alterations in large-scale structural and functional connectivity neural networks. This research will be the first step in a series of investigations that will aid the longitudinal characterization of the natural history of FTD from its earliest stages, paving the way for the field to establish disease monitoring strategies and time points for future treatments in gene mutation carriers. PUBLIC HEALTH RELEVANCE: Improved understanding of when and where in the brain neurodegeneration begins in presymptomatic carriers of front temporal dementia genes are critical to early diagnosis and disease-monitoring. Characterizing the history of front temporal dementia in this way will be crucial for the successful implementation of future treatments of this disease.