Connectomic imaging in familial and sporadic frontotemporal degeneration

家族性和散发性额颞叶变性的连接组学成像

• 批准号: 9110441
• 负责人: MARIA LUISA GORNO TEMPINI
• 金额: $ 125.32万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110441
• 关键词: Address; Affect; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Animals; Autopsy; Biological Markers; Brain region; C9ORF72; California; Cells; Clinic; Clinical; Clinical Data; Cost Savings; DNA-Binding Proteins; Data; Data Set; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Frontotemporal Lobar Degenerations; Functional Magnetic Resonance Imaging; Funding; Genetic; Graph; Histopathology; Human; Image; Individual; Language; Life; Link; Longevity; Magnetic Resonance Imaging; Medical Genetics; Modeling; Motor; Multimodal Imaging; Mutation; Nerve Degeneration; Neuroanatomy; Neurobiology; Neurodegenerative Disorders; Pathology; Pathway interactions; Patients; Pattern; Pennsylvania; Phenotype; Primary Progressive Aphasia; Procedures; Progressive Supranuclear Palsy; Protocols documentation; Public Health; Quality Control; Registries; Rest; Role; Sampling; San Francisco; Semantics; Site; Spin Labels; Staging; Testing; Time; Twin Studies; United States National Institutes of Health; Universities; Variant; White Matter Disease; accurate diagnosis; autosomal dominant mutation; base; cohort; connectome; cost effective; data acquisition; data sharing; endophenotype; frontotemporal degeneration; gray matter; in vivo; mutation carrier; pre-clinical; prion-like; public health relevance; response; screening; social cognition; tau Proteins; theories; tool; treatment trial; white matter

 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.

 描述（适用提供）：神经退行性疾病是一个主要的公共卫生问题。额颞变性（FTD）是一种影响灰质（GM）和白质（WM）并引起网络障碍的临床神经退行性疾病。 FTD是一个出色的模型，用于直接想象神经退行性的神经生物学，因为相关病理学涉及每个患者的单蛋白蛋白质病 - 额叶lobar变性（FTLD）是由于TAU（FTLD-TAU）或43KD（FTLD-TAU）的TAU（FTLD-TAU）引起的。我们提出了一种连接方法，以识别体内FTLD-TAU和FTLD-TDP。这是及时的，这是因为发现了疾病调整剂，并且需要在治疗试验期间对精确的Anthermotem诊断，生物标志物进行衡量的需求，以及即使在临床前阶段，也可以阐明疾病进展的机制。大约25％的病例患有家族性FTD（FFTD），这是由于一小撮突变引起了其中一种病理。其余75％的病例具有零星的FTD（SFTD），没有用于FTLD-TAU或FTLD-TDP病理学的确定生物标志物。初步数据表明，WM疾病的GM疾病和扩散MRI（DMRI）的多模式结构MRI（SMRI）可以鉴定FTLD-TAU和FTLD-TDP中的脆弱网络。我们提出了一个五个站点的财团，包括梅奥诊所，MGH/哈佛大学，西北大学，加利福尼亚大学旧金山大学和宾夕法尼亚大学，以获取FTD的HCP成像。这将与两个由NIH资助的生物标志物注册机构链接，并且这种联系将可节省大量成本。我们提出了三个具体目标。在01年，AIM 1将对SMRI，DMRI，BOLD BOLD MRI（RS-FMRI），基于任务的功能MRI（TFMRI）和动脉旋转标签（ASL）实施并验证人类连接项目（HCP）寿命方案。我们将获取初始数据，与HCP之间的数据协调，实施质量控制程序，使用HCP和本地开发的管道优化分析，并实施数据共享过程。在02年，AIM 2将研究与FTLD-TAU或FTLD-TDP相关的症状和症状FFTD，并评估与FTLD-TAU或FTLD-TDP高度相关的特定表型中的SFTD。连接成像将与获取临床，遗传和生物流体数据的NIH资助的注册表进行集成。基于组织病理学显示，与FTLD-TDP相比，FTLD-TAU中的WM疾病更大，我们期望先进的HCP成像在症状的多模态成像中显示出部分不同的模式，以及在03-04的症状图像中以及曾在03-04年中，AIM 3 Will Will Will Will Will Will Will Will Will Will Will Will tergutical Data获得了对疾病的竞争，以评估疾病的竞争性，并在Persympts中传播症状和症状。与动物研究一致，我们期望图理论和多模式网络分析将显示疾病在当地传播到相邻的大脑区域，从而影响FTLD-TAU或FTLD-TDP中的不同网络。