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（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) 是一种临床神经退行性疾病，会影响灰质 (GM) 和白质 (WM) 并导致网络障碍。 FTD 是直接对神经变性的神经生物学进行成像的绝佳模型，因为相关的病理学涉及每个患者的单蛋白病 - tau 导致的额颞叶变性 (FTLD) (FTLD-tau) 或 43kD TAR DNA 结合蛋白 (FTLD-TDP)。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，因为疾病缓解剂的发现，以及对准确的生前诊断、治疗试验期间衡量反应的生物标志物以及甚至在临床前阶段阐明疾病进展机制的迫切需求。大约 25% 的病例由于一小部分突变导致其中一种病症而患有家族性 FTD (fFTD)。其余 75% 的病例有散发性 FTD (sFTD)，没有 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。我们提议成立一个由五家机构组成的联盟，包括梅奥诊所、​​麻省总医院/哈佛大学、西北大学、旧金山加利福尼亚大学和宾夕法尼亚大学，以获取 FTD 中的 HCP 成像。这将与美国国立卫生研究院资助的两个生物标志物登记处相关联，这种联系将导致大量成本节省。我们提出三个具体目标。第 01 年，目标 1 将实施并验证 sMRI、dMRI、静息 BOLD MRI (rs-fMRI)、基于任务的功能 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，协调站点之间以及与 HCP 之间的数据，实施质量控制程序，使用 HCP 和本地开发的管道优化分析，并实施数据共享程序。第 02 年，目标 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。连接组学成像将与 NIH 资助的登记处整合，获取临床、遗传和生物流体数据。根据组织病理学显示 FTLD-tau 比 FTLD-TDP 更严重的 WM 疾病，我们预计与 FTLD-TDP 相比，先进的 HCP 成像在有症状以及症状前的家族性和散发性 FTLD-tau 个体的多模态成像中显示出部分不同的模式。在 03-04 年，目标 3 将获取纵向数据，以评估有关症状前和症状 FTD 中疾病传播机制的相互竞争的假设。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邻近的大脑区域，影响 FTLD-tau 或 FTLD-TDP 中的不同网络。