Characterizing axonal damage in multiple sclerosis using TractCaliber MRI

使用 TractCaliber MRI 表征多发性硬化症的轴突损伤

• 批准号: 9086637
• 负责人: Susie Yi Huang
• 金额: $ 19.24万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9086637
• 关键词: Address; Advisory Committees; Autopsy; Award; Axon; Biological; Boston; Brain; Caliber; Central Nervous System Degenerative Diseases; Clinic; Clinical; Clinical Trials; Corpus Callosum; Corticospinal Tracts; Demyelinating Diseases; Demyelinations; Development; Development Plans; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Education; Educational workshop; Fostering; Funding; Future; Goals; Grant; Health; Histopathology; Human; Image; Imaging Techniques; Imaging technology; Impaired cognition; Inflammatory; Injury; Institution; Lead; Lesion; Life; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Mentors; Modeling; Multiple Sclerosis; Multiple Sclerosis Lesions; Neurologic; Outcome; Outcome Measure; Pathogenesis; Pathologic; Pathology; Patient Care; Patients; Physically Handicapped; Positioning Attribute; Preparation; Recruitment Activity; Research; Research Personnel; Research Proposals; Resources; Severities; Specificity; Techniques; Time; Tissue Banking; Tissue Banks; Tissue Sample; Training; Translating; Translations; Treatment Effectiveness; Universities; Validation; Weight; Work; axon injury; bioimaging; brain tissue; career development; cognitive function; connectome; density; design; disability; imaging biomarker; imaging modality; improved; in vivo imaging; insight; multiple sclerosis patient; nervous system disorder; neuroimaging; non-invasive imaging; novel; patient population; prevent; programs; progressive neurodegeneration; public health relevance; research clinical testing; response; technology development; white matter; young adult

 DESCRIPTION (provided by applicant): In this application, I propose a project of technology development, validation, and translation aimed at providing a better imaging marker of axonal damage in patients with multiple sclerosis (MS). This award will provide protected research time and training in preparation for independent R01 funding. Multiple sclerosis is the leading non-traumatic cause of disability in young adults. Axonal damage is considered the pathologic substrate underlying clinical disability in MS but currently lacks a reliable imaging biomarker. Advanced diffusion MRI techniques with microstructural specificity for axon diameter and density offer the potential to improve the understanding of axonal damage in MS. The goal of the proposed research is to develop, validate and translate a new diffusion MRI method called Tract Caliber MRI to provide more direct and accurate measures of axonal damage in people with MS than existing MRI techniques. I will optimize the Tract Caliber technique to measure axon diameter and density within lesions and normal-appearing white matter in people with MS compared to healthy controls. The Tract Caliber measurements will then be validated against axon diameter and density measurements from histopathology performed on ex vivo brain tissue obtained at autopsy from MS patients. Once validated, Tract Caliber measurements of axon diameter and density in the corpus callosum and corticospinal tracts will be correlated with physical disability and cognitive dysfunction in MS patients compared to conventional MRI, magnetization transfer imaging, and diffusion tensor imaging in order to address the clinical utility of these different imaging techniques in tracking disease progression. This research proposal will enable me to achieve my short-term goal of becoming an independent investigator in translational neuroimaging. My ultimate goal is to lead an independently-funded research program in the development and clinical translation of novel imaging biomarkers for improving the care of patients with neurological diseases such as MS. To facilitate my progression to a position of independence, I have designed with my mentors a career development plan involving tailored didactic coursework, workshops, seminars, and hands-on training that will provide me with formal education in histopathological validation, disease pathogenesis, and clinical evaluation of patients with MS. The primary mentor for this project is Dr. Lawrence Wald, an expert in developing advanced diffusion MRI technology to solve specific biological and clinical problems. Dr. Howard Weiner will serve as the secondary mentor, lending his renowned expertise in MS. In addition, I will work with a team of collaborators/consultants from MGH (Dr. Bruce Fischl, Dr. Eric Klawiter), Boston University (Dr. Kathleen Rockland), and the Cleveland Clinic (Dr. Bruce Trapp), who will provide additional expertise and guidance as part of my scientific advisory committee. This research will be performed at the Martinos Center for Biomedical Imaging, a world-leading institution for translational neuroimaging and the study of the brain in health and disease. The project will greatly benefit from the unique resources of the Martinos Center, including the one-of-a-kind 3 Tesla Human Connectome MRI scanner equipped with ultra-high gradient strengths ideal for probing axonal microstructure. We will recruit patients with MS from the large patient population served by the MGH Multiple Sclerosis Clinic and Partners MS Center for the development and translational aims of this project and obtain fixed brain tissue samples from the MS tissue bank established at the Cleveland Clinic for the validation aim. This collaborative framework will help me foster relationships with leading experts in MS and will increase the impact and visibility of my research.

 描述（由申请人提供）：在本申请中，我提出了一个技术开发、验证和转化项目，旨在为多发性硬化症（MS）患者提供更好的轴突损伤成像标记。该奖项将提供受保护的研究时间和培训，为独立 R01 资助做好准备。 多发性硬化症是导致年轻人残疾的主要非创伤性原因。轴突损伤被认为是多发性硬化症临床残疾的病理基础，但目前缺乏可靠的成像生物标志物。先进的扩散 MRI 技术具有轴突直径和密度的微观结构特异性，有可能提高对多发性硬化症轴突损伤的理解。拟议研究的目标是开发、验证和转化一种称为 Tract Calibre MRI 的新扩散 MRI 方法，以提供比现有 MRI 技术更直接、更准确的多发性硬化症患者轴突损伤测量。我将优化 Tract Calibre 技术，以测量多发性硬化症患者与健康对照者病变内的轴突直径和密度以及外观正常的白质。然后，将根据对多发性硬化症患者尸检时获得的离体脑组织进行组织病理学的轴突直径和密度测量来验证 Tract Calibre 测量结果。一旦经过验证，与传统 MRI、磁化转移成像和扩散张量成像相比，Tract Calibre 对胼胝体和皮质脊髓束中轴突直径和密度的测量将与多发性硬化症患者的身体残疾和认知功能障碍相关，以便解决这些不同成像技术在跟踪疾病进展方面的临床效用。 这项研究计划将使我能够实现成为转化神经影像学独立研究者的短期目标。我的最终目标是领导一项独立资助的研究项目，致力于新型成像生物标志物的开发和临床转化，以改善多发性硬化症等神经系统疾病患者的护理。为了促进我走向独立的地位，我与导师一起设计了一份职业发展计划，包括量身定制的教学课程、讲习班、研讨会和实践培训，这将为我提供组织病理学验证、疾病发病机制和多发性硬化症患者临床评估方面的正规教育。该项目的主要导师是 Lawrence Wald 博士，他是开发先进扩散 MRI 技术以解决特定生物和临床问题的专家。 Howard Weiner 博士将担任第二导师，发挥他在多发性硬化症方面的著名专业知识。此外，我还将与来自 MGH（Bruce Fischl 博士、Eric Klawiter 博士）、波士顿大学（Kathleen Rockland 博士）和克利夫兰诊所（Bruce Trapp 博士）的合作者/顾问团队合作，他们将作为我的科学顾问委员会的一部分提供额外的专业知识和指导。 这项研究将在马蒂诺斯生物医学成像中心进行，该中心是世界领先的转化神经成像以及大脑健康和疾病研究机构。该项目将极大受益于马蒂诺斯中心的独特资源，包括独一无二的 3 Tesla 人体连接体 MRI 扫描仪，该扫描仪配备超高梯度强度，非常适合探测轴突微观结构。我们将从 MGH 多发性硬化症诊所和合作伙伴 MS 中心服务的大量 MS 患者中招募 MS 患者，以实现该项目的开发和转化目标，并从克利夫兰诊所建立的 MS 组织库中获取固定脑组织样本，以实现验证目的。这个协作框架将帮助我与领导者建立关系 多发性硬化症领域的专家，将提高我的研究的影响力和知名度。