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

项目总结 监测多发性硬化症(MS)患者的炎症反应对于预测和优化预后至关重要 治疗。在目前的临床实践中，炎症是从急性白血病患者体内Gd的蓄积推断出来的。 血脑屏障被破坏的病变。然而，大量持久的小胶质细胞 发生在完整的血脑屏障后面的已建立的病变中的炎症不能通过 常规核磁共振检查。 在这项提案中，我们将通过探索定量磁化率图谱的能力来解决这一未得到满足的需求 (QSM)对白质病变中的小胶质细胞激活进行量化。QSM是一种后处理工具，可提取 从梯度回波(GRE)数据中提取组织的磁化率，因此对铁高度敏感。惊人的一击 多发性硬化症病变内慢性激活的小胶质细胞的特征，病变周长是其高铁含量， 这可以通过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，QSM可以准确地检测到。我们进一步假设 富马酸二甲酯(Tecfidera®)是FDA批准的MS治疗方法，可防止小胶质细胞和 多发性硬化症患者慢性皮损中的并发组织损害。 我们将用多管齐下的方法检验我们的假设，确认铁的积累与 在培养的人小胶质细胞和人多发性硬化症尸检组织中具有促炎和细胞毒性表型 富马酸二甲酯(Tecfidera®)可减少培养的小胶质细胞的铁摄取和促炎极化。 此外，我们将结合多发性硬化症尸检组织的成像和组织病理学分析来确定 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，在该研究中我们将测试 Tecfidera®防止铁堆积(从而促进炎症的小胶质细胞激活)的能力以及 多发性硬化症患者脑白质损害伴发组织损害。 综上所述，我们正在对MS患者的一种新的病理机制进行表征、量化和靶向， 持续的小胶质细胞前炎症激活，这可能导致神经变性和疾病 严肃性。QSM易于在临床实践中实施，并可能成为一种常规的MRI技术 常规MRI显示稳定但皮损负担高的患者的治疗决定 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.