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

• 批准号: 9981449
• 负责人: David Pitt
• 金额: $ 9.42万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/9981449
• 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

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.

项目摘要 监测多发性硬化症（MS）患者的注射以提示和优化 治疗。在目前的临床实践中，急性中的gadolinium（GD）的积累推断出炎症 血脑屏障破坏的病变。但是，实质而持久的小胶质细胞 无法检测到完整血脑屏障后发生的已建立病变的炎症 常规MRI。 在此提案中，我们将通过探索定量敏感性映射的能力来满足这种未满足的需求 （QSM）量化白质病变中的小胶质细胞激活。 QSM是提取的后处理工具 梯度回波（GRE）数据的组织磁敏感性，因此对铁高度敏感。一个醒目的人 MS病变内长期活化的小胶质细胞和病变周长的特征是它们的高铁含量， 可以通过QSM检测到。我们假设铁是慢性神经毒性的敏感生物标志物 MS病变中的小胶质细胞激活，可以用QSM准确检测到。我们进一步假设 FDA批准的MS处理，富马酸二甲基（Tecfidera®）可防止小胶质细胞的铁吸收和 MS患者的慢性病变的同时组织损伤。 我们将通过确认铁的积累是相关的，以多收益的方法来检验我们的假设 培养的人类小胶质细胞和人类MS尸检组织中的促炎性，细胞毒性表型和 富马酸二甲基二甲基（Tecfidera®）减少了培养的小胶质细胞中铁的摄取和促炎极化。 此外，我们将将MS尸检组织的成像与其组织病理学分析相结合，以确认 QSM检测铁阳性小胶质细胞的精度​​。我们最终将进行一项临床研究，进行测试 Tecfidera®防止铁积累（从而促炎的小胶质细胞激活）和 MS患者的白质病变中伴随的组织损伤。 总而言之，我们在MS患者中表征，量化和靶向一种新型的病理机理， 小胶质细胞的持续性促炎激活，这可能有助于神经退行性和疾病 严重程度。 QSM可以轻松在临床实践中实施，并可能成为常规的MRI技术来帮助 在常规MRI上看起来稳定但含有高烧伤的患者的治疗决定 小胶质激活。