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Detection, characterization and treatment of chronic microglial inflammation in established MS lesions

已确定的多发性硬化症病变中慢性小胶质细胞炎症的检测、表征和治疗

基本信息

批准号：
10245035
负责人：
David Pitt
金额：
$ 34.66万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10245035
关键词：
Acute Address Anti-Inflammatory Agents Area Autopsy Biological Markers Blood - brain barrier anatomy Brain Brain imaging Cell Culture Techniques Chronic Clinical Research Clinical Trials Data Deposition Detection Diffusion Magnetic Resonance Imaging Enhancing Lesion Excision FDA approved Fumarates Gadolinium Generations Histologic Human Image Imaging Techniques Immunohistochemistry Inflammation Inflammatory Interferon-beta Iron Lesion Magnetic Resonance Imaging Magnetism Maps Measures Methods Microglia Monitor Multiple Sclerosis Multiple Sclerosis Lesions Myelin Nerve Degeneration Neuraxis Pathologic Pathology Patient Care Patients Phenotype Predisposition Prevention Recombinant interferon beta-1b Relaxation Research Severity of illness Stains Testing Time Tissue Extracts Tissue Stains Tissues Work avonex base brain tissue clinical care clinical practice cytotoxic data acquisition density human imaging imaging modality improved induced pluripotent stem cell iron metabolism macrophage multiple sclerosis patient multiple sclerosis treatment neurotoxic novel preconditioning prevent prognostic tissue injury tool treatment group treatment optimization uptake white matter

项目摘要

PROJECT SUMMARY It is critical to monitor inflammation in multiple sclerosis (MS) patients for prognostication and optimization of treatment. In current clinical practice, inflammation is inferred from accumulation of gadolinium (Gd) in acute lesions where the blood brain barrier is disrupted. However, the substantial and long-lasting microglial inflammation in established lesions occurring behind an intact blood brain barrier cannot be detected with conventional MRI. In this proposal we will address this unmet need by exploring the ability of quantitative susceptibility mapping (QSM) to quantify microglial activation in white matter lesions. QSM is a post-processing tool that extracts tissue magnetic susceptibility from gradient echo (GRE) data and is thus highly sensitive to iron. A striking feature of chronically activated microglia within MS lesions and the lesion perimeter is their high iron content, which can be detected by QSM. We hypothesize that iron is a sensitive biomarker for chronic, neurotoxic microglial activation in MS lesions and can be accurately detected with QSM. We further hypothesize that dimethyl fumarate (Tecfidera®), a FDA-approved MS treatment, prevents iron uptake by microglia and concurrent tissue damage in chronic lesions in MS patients. We will test our hypotheses in a multipronged approach, by confirming that accumulation of iron is associated with a proinflammatory, cytotoxic phenotype in cultured human microglia and in human MS autopsy tissue and that dimethyl fumarate (Tecfidera®) reduces iron uptake and proinflammatory polarization in cultured microglia. Moreover, we will combine imaging of MS autopsy tissue with its histopathological analysis to confirm the accuracy of QSM in detecting iron-positive microglia. We will finally conduct a clinical study in which we test the ability of Tecfidera® to prevent iron accumulation (and thus proinflammatory microglial activation) and concomitant tissue damage in white matter lesions of MS patients. In summary, we are characterizing, quantifying and targeting in MS patients a novel pathomechanisms, persistent proinflammatory activation of microglia, which may contribute to neurodegeneration and disease severity. QSM can be easily implemented in clinical practice and may become a routine MRI technique to aid treatment decisions for patients that appear stable on conventional MRI but contain a high burden of lesional microglial activation.

项目总结