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

项目摘要 监测多发性硬化症（MS）患者的炎症对于确定和优化治疗方案至关重要。 治疗在目前的临床实践中，炎症是从急性炎症中钆（Gd）的积累推断的。 血脑屏障被破坏的病变。然而，大量和持久的小胶质细胞 在完整的血脑屏障后面发生的已建立的病变中的炎症不能用 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)以量化白色病变中的小胶质细胞活化。QSM是一个后处理工具， 根据梯度回波（GRE）数据确定组织磁化率，因此对铁高度敏感。一个引人注目 MS病变和病变周边内慢性激活的小胶质细胞的特征是它们的高铁含量， 这可以通过QSM检测到。我们假设铁是慢性神经毒性， MS病变中的小胶质细胞活化，并且可以用QSM准确检测。我们进一步假设， 富马酸二甲酯（Tecfidera®）是FDA批准的MS治疗药物，可防止小胶质细胞吸收铁， MS患者慢性病变中的并发组织损伤。 我们将以多管齐下的方法验证我们的假设，通过确认铁的积累与 在培养的人小胶质细胞和人MS尸检组织中具有促炎细胞毒性表型， 富马酸二甲酯（Tecfidera®）可降低培养的小胶质细胞的铁摄取和促炎性极化。 此外，我们将把MS尸检组织的联合收割机成像与其组织病理学分析结合起来，以确认 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， Tecfidera®防止铁蓄积（从而防止促炎性小胶质细胞活化）的能力， MS患者白色病变中伴随的组织损伤。 总之，我们正在MS患者中表征、量化和靶向一种新的病理机制， 小胶质细胞的持续促炎性激活，这可能有助于神经变性和疾病 严重性。QSM可以很容易地在临床实践中实现，并可能成为一种常规的MRI技术，以帮助 常规MRI显示稳定但病变负担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.