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模式（PET和MRI）的独特优势。 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 用于促进髓鞘恢复和减少随后的神经变性。 导致MS组织损伤的机制知之甚少，然而氧化损伤的来源，如 先天免疫应答和铁释放被认为有助于髓磷脂损伤、限制髓磷脂修复和 最终导致轴突不稳定通过靶向CNS途径的治疗进行干预，以调节免疫， 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可能性。我们的初步数据表明，PET PK 11195是m/M激活的一种量度，在急性MS中钆（Gd）增强时较高 病变，并迅速下降，在接下来的几个月，而病变的磁化率，如测量 定量易感性绘图（QSM），是敏感的铁，显着增加，在几个月后， Gd增强的分辨率。因此，这项拟议的研究是为了进一步描述这些生物 机制，并证实了我们的假设，急性病变与高先天免疫活性 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这个假设 瞄准目的1：病变铁标测和更高特异性的PET配体（DPA 713）将应用于纵向 急性MS病变的研究，并将确定铁释放和M/M激活的关系，以及 通过MRI测量髓鞘水含量，确定其与随后病变髓鞘含量的相关性 (MWC)显像然后我们假设，慢性MS病变中残留的病变铁和髓鞘丢失将导致MS的严重性。 导致随后神经元变性。我们建议在第二个目标中检验这一假设。目标2： 将MWC/QSM应用于一个明确定义的MS患者队列，我们将测量其残留的 铁和髓磷脂损失在慢性MS病变中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， 使用MRI来识别将从治疗干预中获益的患者， 中枢神经系统炎症，促进髓鞘恢复和减少残疾。

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.