Identifying mechanisms of tissue injury in MS lesions: a multi-modality imaging approach

项目概要/摘要 该提案的总体目标是利用不同成像方式（PET 和 MRI）以促进旨在限制细胞毒性损伤和氧化应激的治疗策略的测试 在多发性硬化症病变内促进髓磷脂恢复并减少随后的神经变性。 导致多发性硬化症组织损伤的机制尚不清楚，但氧化损伤的来源，例如 先天免疫反应和铁释放被认为会导致髓磷脂损伤、有限的髓磷脂修复和 最终轴突不稳定。针对中枢神经系统途径进行免疫调节和干预治疗 减少氧化损伤需要验证损伤的时间和程度；获得这些知识 提供了干预和预防临床残疾的潜力。我们的初步数据表明 PET PK11195 是 m/M 激活的量度，在急性 MS 中钆 (Gd) 增强时呈高水平 病变并在接下来的几个月内迅速下降，而病变磁化率（通过测量） 定量磁化率图 (QSM) 对铁敏感，在数月后显着增加 Gd增强的分辨率。因此，这项研究旨在进一步描述这些生物 早期多发性硬化症病变的机制，并证实了我们的假设，即具有高先天免疫活性的急性病变 铁含量高会导致严重的脱髓鞘。我们建议通过我们的第一个测试来检验这个假设 目标。目标 1：病变铁图谱和更高特异性 PET 配体 (DPA713) 将应用于纵向 急性多发性硬化症病变的研究，并将定义铁释放和 m/M 激活的关系以及 通过 MRI 髓磷脂水含量测量，确定它们与后续病变髓磷脂含量的关联 （MWC）成像。然后我们假设慢性多发性硬化症病变中残留的病变铁和髓鞘质损失将 导致随后的神经元变性。我们建议在我们的第二个目标中检验这个假设。目标 2： 将 MWC/QSM 应用于明确定义的 MS 患者队列，我们将测量残差的相关性 慢性多发性硬化症病变内的铁和髓磷脂损失对随后的整体神经元损失和临床残疾的影响。的 该提案的总体目标是利用不同成像方式的独特优势来促进 使用 MRI 来识别可从针对减少疾病的治疗干预中受益的患者 中枢神经系统炎症促进髓磷脂恢复和减少残疾。

Project Summary/Abstract The overall goal of this proposal is to leverage the distinct advantages of different imaging modalities (PET and MRI) to facilitate the testing of therapeutic strategies aimed at limiting cytotoxic damage and oxidative stress within MS lesions for the promotion of myelin recovery and reduction of subsequent neurodegeneration. Mechanisms leading to tissue injury in MS are poorly understood, however sources of oxidative injury, such as the innate immune response and iron release, are felt to contribute to myelin damage, limited myelin repair and eventual axonal instability. Intervention with treatments targeting CNS pathways for immune modulation and reduction of oxidative damage requires validation of timing and extent of damage; gaining this knowledge provides the potential to intervene and prevent clinical disability. Our preliminary data demonstrates that PET PK11195, a measure of m/M activation, is high at the time of gadolinium (Gd) enhancement in acute MS lesions and quickly decreases in the following months, whereas lesion magnetic susceptibility, as measured by quantitative susceptibility mapping (QSM) and is sensitive to iron, significantly increases in the months after resolution of Gd-enhancement. Accordingly, this proposed research is to further describe these biological mechanisms in early MS lesions and confirm our hypothesis that acute lesions with high innate immune activity and high iron content would result in severe demyelination. We propose to test this hypothesis through our first aim. Aim 1: Lesion iron mapping and a higher specificity PET ligand (DPA713) will be applied to a longitudinal study of acute MS lesions and will define the relationship of iron release and m/M activation as well as determine their association with subsequent lesion myelin content, as measured by MRI myelin water content (MWC) imaging. We then hypothesize that residual lesion iron and myelin loss within chronic MS lesions will lead to subsequent neuronal degeneration. We propose to test this hypothesis in our second aim. Aim 2: To apply MWC/QSM to a well-defined cohort of MS patients for which we will measure the association of residual iron and myelin loss within chronic MS lesions on subsequent global neuronal loss and clinical disability. The overall goal of this proposal is to leverage the distinct advantages of different imaging modalities to facilitate the use of MRI to identify patients that would benefit from a therapeutic intervention targeting the reduction in CNS inflammation for the promotion of myelin recovery and reduction of disability.