Connectomic imaging in familial and sporadic frontotemporal degeneration

 描述（由申请人提供）：神经退行性疾病是一个主要的公共卫生问题。额颞叶变性（FTD）是一种影响灰质（GM）和白色物质（WM）并导致网络障碍的临床神经退行性疾病。FTD是直接成像神经变性神经生物学的极佳模型，因为相关病理学涉及每例患者的单蛋白病-由tau（FTLD-tau）或43 kD TAR DNA结合蛋白（FTLD-TDP）引起的额颞叶变性（FTLD）。我们提出了一种连接组学方法来识别体内FTLD-tau和FTLD-TDP。这是及时的，因为发现了疾病修饰剂，迫切需要准确的生前诊断，生物标志物来衡量治疗试验期间的反应，并阐明疾病进展的机制，即使在临床前阶段。大约25%的病例具有家族性FTD（fFTD），这是由于一小部分突变导致这些病理之一。其余75%的病例有散发性FTD（sFTD），无FTLD-tau或FTLD-TDP病理学的明确生物标志物。初步数据表明，GM疾病的多模态结构MRI（sMRI）和WM疾病的扩散MRI（dMRI）可以识别FTLD-tau和FTLD-TDP中的脆弱网络。我们建议由五个研究中心组成的联盟，包括马约诊所、MGH/哈佛、西北大学、加州大学旧金山分校弗朗西斯科和宾夕法尼亚大学，以获得FTD中的HCP成像。这将与两个NIH资助的生物标志物登记处联系起来，这种联系将节省大量成本。我们提出三个具体目标。在01年，Aim 1将实施和验证用于sMRI、dMRI、静息BOLD MRI（rs-fMRI）、基于任务的功能性MRI（tfMRI）和动脉自旋标记（ASL）的人类连接组项目（HCP）寿命协议。我们将获取初始数据，协调研究中心之间以及与HCP之间的数据，实施质量控制程序，使用HCP和当地开发的管道优化分析，并实施数据共享程序。在第2年，Aim 2将研究与FTLD-tau或FTLD-TDP相关的症状前和症状性fFTD，并评估与FTLD-tau或FTLD-TDP高度相关的特定表型中的sFTD。连接组成像将与NIH资助的登记处集成，这些登记处获取临床，遗传和生物流体数据。基于组织病理学显示FTLD-tau比FTLD-TDP更大的WM疾病，我们预计先进的HCP成像显示与FTLD-TDP相比，家族性和散发性FTLD-tau的症状性以及症状前个体的多模态成像的部分不同模式。在2003 - 2004年，Aim 3将获得纵向数据，以评估症状前和症状性FTD中疾病传播机制的竞争性假设。与动物研究一致，我们预计图论和多模态网络分析将显示疾病局部扩散到相邻的大脑区域，影响FTLD-tau或FTLD-TDP中的不同网络。

 DESCRIPTION (provided by applicant): Neurodegenerative disease is a major public health problem. Frontotemporal degeneration (FTD) is a clinical neurodegenerative condition that affects both gray matter (GM) and white matter (WM) and causes a network disorder. FTD is an excellent model for directly imaging the neurobiology of neurodegeneration because the associated pathology involves a monoproteinopathy in each patient - either frontotemporal lobar degeneration (FTLD) due to tau (FTLD-tau) or to TAR DNA binding protein of 43kD (FTLD-TDP). We propose a connectomic approach to identify FTLD-tau and FTLD-TDP in vivo. This is timely because of the discovery of disease-modifying agents, and pressing needs for accurate antemortem diagnosis, biomarkers to gauge response during treatment trials, and elucidation of mechanisms of disease progression even at the preclinical stage. About 25% of cases have familial FTD (fFTD) due to a small set of mutations causing one of these pathologies. The remaining 75% of cases have sporadic FTD (sFTD) with no definitive biomarkers for FTLD- tau or FTLD-TDP pathology. Preliminary data suggest that multimodal structural MRI (sMRI) of GM disease and diffusion MRI (dMRI) of WM disease can identify vulnerable networks in FTLD-tau and FTLD-TDP. We propose a five-site consortium, including Mayo Clinic, MGH/Harvard, Northwestern University, University of California in San Francisco, and University of Pennsylvania, to acquire HCP imaging in FTD. This will be linked to two NIH-funded biomarker registries, and this linkage will result in substantial cost savings. We propose three Specific Aims. In Year 01, Aim 1 will implement and validate the Human Connectome Project (HCP) Lifespan protocol for sMRI, dMRI, resting BOLD MRI (rs-fMRI), task-based functional MRI (tfMRI) and arterial spin labeling (ASL). We will acquire initial data, harmonize data between sites and with HCP, implement quality control procedures, optimize analyses using HCP and locally-developed pipelines, and implement data sharing procedures. In Year 02, Aim 2 will study presymptomatic and symptomatic fFTD associated with FTLD-tau or FTLD-TDP, and assess sFTD in specific phenotypes highly associated with FTLD-tau or FTLD-TDP. Connectomic imaging will be integrated with NIH-funded registries that acquire clinical, genetic and biofluid data. Based on histopathology showing greater WM disease in FTLD-tau than FTLD-TDP, we expect advanced HCP imaging to show partially distinct patterns in multimodal imaging of symptomatic as well as presymptomatic individuals with familial and sporadic FTLD-tau compared to FTLD-TDP. In Years 03-04, Aim 3 will acquire longitudinal data to assess competing hypotheses about mechanisms of disease spread in presymptomatic and symptomatic FTD. Consistent with animal studies, we expect that graph theoretic and multimodal network analyses will show disease spreading locally to adjacent brain regions, affecting different networks in FTLD-tau or FTLD-TDP.