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Identifying mechanisms of tissue injury in MS lesions: a multi-modality imaging approach

识别多发性硬化症病变组织损伤的机制：多模态成像方法

基本信息

批准号：
10251158
负责人：
Susan A Gauthier
金额：
$ 42.01万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10251158
关键词：
Acute Axon Biological Brain Chronic Clinical Cognitive Data Demyelinations Disease Progression Enhancing Lesion Event Gadolinium Goals Image Imaging Device Immune Immunotherapy Inflammation Inflammatory Innate Immune Response Intervention Iron Knowledge Lesion Ligands Link Longitudinal Studies Macrophage Activation Magnetic Resonance Imaging Magnetism Maps Measurement Measures Microglia Modeling Motion Multimodal Imaging Multiple Sclerosis Multiple Sclerosis Lesions Myelin Nerve Degeneration Neuraxis Outcome Outcomes Research Oxidative Stress Pathologic Pathway interactions Patients Peripheral Positron-Emission Tomography Predisposition Protocols documentation Recovery Reproducibility Research Research Project Grants Residual state Resolution Severities Site Source Specificity Testing Therapeutic Therapeutic Intervention Time Validation Water axon injury base central nervous system demyelinating disorder central nervous system injury chronic demyelination cohort cytotoxic disability experience gray matter imaging approach imaging modality immunoregulation macrophage multiple sclerosis patient neuron loss oxidative damage prevent rate of change remyelination repaired targeted treatment therapeutic evaluation tissue injury treatment strategy uptake white matter

项目摘要

Project Summary/Abstract The overall goal of this proposal is to leverage the distinct advantages of different imaging modalities (PET and MRI) to facilitate the testing of therapeutic strategies aimed at limiting cytotoxic damage and oxidative stress within MS lesions for the promotion of myelin recovery and reduction of subsequent neurodegeneration. Mechanisms leading to tissue injury in MS are poorly understood, however sources of oxidative injury, such as the innate immune response and iron release, are felt to contribute to myelin damage, limited myelin repair and eventual axonal instability. Intervention with treatments targeting CNS pathways for immune modulation and reduction of oxidative damage requires validation of timing and extent of damage; gaining this knowledge provides the potential to intervene and prevent clinical disability. Our preliminary data demonstrates that PET PK11195, a measure of m/M activation, is high at the time of gadolinium (Gd) enhancement in acute MS lesions and quickly decreases in the following months, whereas lesion magnetic susceptibility, as measured by quantitative susceptibility mapping (QSM) and is sensitive to iron, significantly increases in the months after resolution of Gd-enhancement. Accordingly, this proposed research is to further describe these biological mechanisms in early MS lesions and confirm our hypothesis that acute lesions with high innate immune activity and high iron content would result in severe demyelination. We propose to test this hypothesis through our first aim. Aim 1: Lesion iron mapping and a higher specificity PET ligand (DPA713) will be applied to a longitudinal study of acute MS lesions and will define the relationship of iron release and m/M activation as well as determine their association with subsequent lesion myelin content, as measured by MRI myelin water content (MWC) imaging. We then hypothesize that residual lesion iron and myelin loss within chronic MS lesions will lead to subsequent neuronal degeneration. We propose to test this hypothesis in our second aim. Aim 2: To apply MWC/QSM to a well-defined cohort of MS patients for which we will measure the association of residual iron and myelin loss within chronic MS lesions on subsequent global neuronal loss and clinical disability. The overall goal of this proposal is to leverage the distinct advantages of different imaging modalities to facilitate the use of MRI to identify patients that would benefit from a therapeutic intervention targeting the reduction in CNS inflammation for the promotion of myelin recovery and reduction of disability.

项目总结/文摘