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、验证和翻译项目，旨在为多发性硬化症（MS）患者的轴突损伤提供更好的成像标记物。该奖项将提供受保护的研究时间和培训，为独立的R 01资金做准备。 多发性硬化症是年轻人残疾的主要非创伤性原因。轴突损伤被认为是MS临床残疾的病理基础，但目前缺乏可靠的成像生物标志物。先进的扩散磁共振成像技术与轴突直径和密度的微观结构特异性提供了潜在的，以提高对MS轴突损伤的理解。拟议的研究的目标是开发，验证和翻译一种新的扩散磁共振成像方法称为道口径MRI提供更直接，更准确的措施，轴突损伤的人与MS比现有的MRI技术。我将优化Tract Caliber技术，以测量MS患者与健康对照组相比病变和正常白色物质内轴突直径和密度。然后，将根据在MS患者尸检时获得的离体脑组织上进行的组织病理学的轴突直径和密度测量值来验证Tract Caliber测量值。一旦验证，与常规MRI、磁化传递成像和扩散张量成像相比，胼胝体和皮质脊髓束中轴突直径和密度的Tract Caliber测量将与MS患者的身体残疾和认知功能障碍相关，以解决这些不同成像技术在跟踪疾病进展中的临床效用。 这项研究计划将使我能够实现我的短期目标，成为一个独立的研究人员在翻译神经影像学。我的最终目标是领导一个独立资助的研究计划，开发和临床翻译新的成像生物标志物，以改善神经系统疾病患者的护理，如MS为了促进我的发展到独立的位置，我与我的导师设计了一个职业发展计划，包括量身定制的教学课程，研讨会，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MS患者的临床评估方面的正规教育。该项目的主要导师是Lawrence Wald博士，在开发先进的扩散磁共振成像技术，以解决特定的生物和临床问题的专家。霍华德韦纳博士将担任第二导师，提供他在MS方面的著名专业知识。此外，我将与来自MGH（布鲁斯菲舍尔博士，埃里克克拉维特博士），波士顿大学（凯瑟琳罗克兰博士）和克利夫兰诊所（布鲁斯特拉普博士）的合作者/顾问团队合作，他们将作为我的科学咨询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Martinos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和大脑健康与疾病研究机构。该项目将极大地受益于Martinos中心的独特资源，包括独一无二的3特斯拉人类连接组MRI扫描仪，该扫描仪配备了超高梯度强度，非常适合探测轴突微结构。我们将从MGH多发性硬化症诊所和合作伙伴MS中心服务的大量患者人群中招募MS患者，以实现本项目的开发和转化目标，并从克利夫兰诊所建立的MS组织库中获得固定脑组织样本，以实现验证目标。这个合作框架将帮助我培养与领导者的关系。 这将增加我的研究的影响力和知名度。