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

项目概要 监测多发性硬化症 (MS) 患者的炎症对于预测和优化治疗至关重要 治疗。在当前的临床实践中，炎症是根据急性炎症中钆（Gd）的积累来推断的。 血脑屏障被破坏的病变。然而，大量且持久的小胶质细胞 完整血脑屏障后面发生的已形成病变中的炎症无法用 常规 MRI。 在本提案中，我们将通过探索定量磁化率绘图的能力来解决这一未满足的需求 （QSM）量化白质病变中的小胶质细胞激活。 QSM 是一种后处理工具，可提取 组织磁化率来自梯度回波 (GRE) 数据，因此对铁高度敏感。一个引人注目的 MS 病灶和病灶周边长期激活的小胶质细胞的特征是铁含量高， 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，可以通过 QSM 准确检测。我们进一步假设 富马酸二甲酯 (Tecfidera®) 是 FDA 批准的多发性硬化症治疗药物，可防止小胶质细胞吸收铁， MS 患者慢性病变中并发的组织损伤。 我们将通过多管齐下的方法检验我们的假设，确认铁的积累与 在培养的人类小胶质细胞和人类多发性硬化症尸检组织中具有促炎性、细胞毒性表型 富马酸二甲酯 (Tecfidera®) 可减少培养的小胶质细胞中的铁吸收和促炎性极化。 此外，我们将结合多发性硬化症尸检组织的成像及其组织病理学分析来证实 QSM 检测铁阳性小胶质细胞的准确性。我们最终将进行一项临床研究来测试 Tecfidera® 防止铁积累（从而促进促炎性小胶质细胞激活）的能力以及 MS 患者白质病变中伴随的组织损伤。 总之，我们正在对多发性硬化症患者的一种新的病理机制进行表征、量化和靶向治疗， 小胶质细胞持续促炎激活，可能导致神经退行性变和疾病 严重程度。 QSM 可以很容易地在临床实践中实施，并可能成为一种常规 MRI 技术来帮助 针对常规 MRI 表现稳定但病变负担较高的患者的治疗决策 小胶质细胞激活。

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.