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

项目摘要/摘要 该提案的总体目标是利用不同成像模式(PET和 磁共振成像)，以便于测试旨在限制细胞毒性损伤和氧化应激的治疗策略 在MS病变内促进髓鞘恢复和减少随后的神经退变。 导致多发性硬化组织损伤的机制尚不清楚，但氧化损伤的来源，如 先天免疫反应和铁的释放，被认为有助于髓鞘损伤，有限的髓鞘修复和 最终的轴突不稳定。针对中枢神经系统通路的免疫调节和干预治疗 减少氧化损伤需要确认损伤的时间和程度；获得这一知识 提供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激活的一个指标，在急性MS患者Gd增强时，PK11195水平较高 病变，并在接下来的几个月里迅速下降，而病变磁化率，通过 定量磁化率图(QSM)和铁敏感，在接下来的几个月里显著增加 Gd增强分辨率。因此，这项拟议的研究旨在进一步描述这些生物学 MS早期病变的机制，并证实了我们的假设，即具有高天然免疫活性的急性病变 铁含量过高会导致严重的脱髓鞘。我们建议通过我们的第一个 瞄准。目的1：病变铁图和更高特异性的PET配体(DPA713)将应用于纵向 对急性多发性硬化症皮损的研究将确定铁释放和m/m激活的关系以及 通过MRI髓鞘水含量测定，确定它们与后续病变髓鞘含量的相关性。 (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丢失将 导致随后的神经元退化。我们建议在我们的第二个目标中检验这一假设。目标2：实现 将MWC/QSM应用于明确定义的多发性硬化症患者队列，我们将测量这些患者的残留量之间的关联 慢性多发性硬化症病变中的铁和髓鞘丢失与随后的全局性神经元丢失和临床残疾有关。这个 这项提议的总体目标是利用不同成像模式的明显优势来促进 使用核磁共振来确定将受益于针对减少 中枢神经系统炎症用于促进髓鞘的恢复和减少残疾。

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.