MECHANISMS OF NEURODEGENERATION AND STRATEGIES FOR NEUROPROTECTION IN MS

多发性硬化症的神经变性机制和神经保护策略

• 批准号: 7602577
• 负责人: PETER A CALABRESI
• 金额: $ 3.45万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7602577
• 关键词: 3-Dimensional; Acute; Area; Atrophic; Axon; Biological Markers; Chronic; Clinical; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Computer software; Demyelinations; Diffusion Magnetic Resonance Imaging; Disease; Distal; Distant; Enhancing Lesion; Fiber; Funding; Gadolinium; Goals; Grant; Image; Individual; Inflammation; Inflammatory; Injury; Institution; Lesion; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Mediating; Molecular; Multiple Sclerosis; Myelin; Nerve Degeneration; Outcome Measure; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phase II/III Trial; Protons; Research; Research Personnel; Resources; Site; Source; Specificity; Staging; Surrogate Markers; Testing; Thinking; Time; Translating; United States National Institutes of Health; Wallerian Degeneration; bench to bedside; brain tissue; density; disability; improved; interest; neuroprotection; reconstruction; repaired; white matter

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A fundamental objective in multiple sclerosis (MS) research is to elucidate the cellular and molecular pathways that are involved in mediating permanent disability. Clinical, radiographic, and pathological studies suggest that disability can ensue both from acute clinical exacerbations and during the chronic progressive stages of the disease. The underlying hypothesis in our research is that permanent disability in MS, regardless of the stage of the disease, is a result of damage to the axon. Herein, we plan to define the cellular and molecular mechanisms of axonal injury in MS, develop imaging biomarkers of disability, and thereby test rational neuroprotective and neuroreparative strategies. A major goal in translating neuroprotective and neuroreparative strategies for MS from the bench to the bedside is to develop surrogate measures of myelin and axon integrity that can be used in phase II clinical trials to screen for preliminary efficacy. The utility of gadolinium-enhancing lesions as a surrogate marker of inflammation in phase II/ III trials of immunomodulatory drugs is now well accepted. Nonetheless, even in the absence of apparent inflammation, clinical disability progresses. This is thought to occur as a result of axon degeneration mediated by numerous downstream factors. Radiological studies have demonstrated evidence of distant Wallerian degeneration and atrophy that ensue months to years after active inflammatory demyelination. The correlation between disability and conventional measures such as T1 volume (post-gadolinium), T2 volume, and atrophy or T1 black holes is only modest (correlation coefficients between 0.3 and 0.6 in a variety of studies), presumably because all of these measures lack specificity for permanent brain tissue pathology. Recent advances in magnetic resonance imaging (MRI) such as magnetization transfer imaging (MTI), proton magnetic resonance spectroscopy (1H-MRS), and diffusion tensor imaging (DTI) offer promise as more sensitive and specific measures of underlying structural pathology. There is a great need to develop and optimize these measures so as to be able to non-invasively quantify the extent of demyelination and axon degeneration in MS patients. We will focus on developing DTI and MTI to allow quantitative measurement of pathology along white-matter tracts, which can then be used as outcome measures for clinical trials of potential neuroprotective and neuroreparative agents. DTI gives information on the directionality and integrity of white-matter tracts, containing both axonal and myelin information. MTI has been shown to be associated with both axon density and myelin integrity, and therefore may be relevant to tracking local and distant changes in axons that pass through areas of damaged myelin, as well as a measure of myelin repair. Fiber-tracking software allows the 3 dimensional reconstruction of specific pathways distal and proximal to a region of interest (ROI) or between two or more ROIs. In this way, multiple types of quantitative information can then be acquired both locally and at distant sites from an acute inflammatory lesion. Moreover, we can interrogate the reconstructed pathways to measure changes over time in an individual patient. Since all of the MR images are coregistered we can compare DTI and MTI tract specific information, which may improve our ability to discern different pathologies along the trajectories.

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