MR Metabolic Imaging of Multiple Sclerosis

摘要 对于多发性硬化症(MS)患者，大量的临床和磁共振成像(MRI) 需要进行会议来评估症状和/或病变的存在。即使到那时，结果预测和 治疗选择是具有挑战性的。为了充分发挥个性化医疗的潜力，特定的生物标记物 需要反射功能(如炎症、氧化还原)来进行全面的表征和表型鉴定。 在这笔赠款最初资助的5年期间，我们已经坚定地确立了超极化(HP)13C 磁共振波谱成像(MRSI)是一种非常有价值的评估MS病变的神经成像方法。我们 我们首次证明了HP[1-13C]丙酮酸的13C MRSI可以检测到HP乳酸到丙酮酸的增加，链接 对于MS小鼠模型中的促炎小胶质细胞/巨噬细胞(MPS)，这一发现在其他研究中得到了进一步证实 模特们。我们还证明了Hp 13C MR可以监测免疫调节治疗的早期反应， 例如富马酸二甲酯(DMF)。此外，我们还发现，由于MPS的表型与反应性水平有关 氧物种(ROS)，HP[1-13C]脱氢抗坏血酸(DHA)，一个氧化还原敏感的HP探针，可以区分 在M1和M2 MPS之间，因此非侵入性地评估这些正交过程。 在这次更新中，我们将在第一个资助期的成功基础上，1/开发改进的HP 13C 代谢成像方法评估多发性硬化和氧化应激的神经炎症和氧化应激 应用HP 13C代谢成像监测MS患者治疗反应的人体研究 具体目标1.提供使用HP的多发性硬化症代谢损害的全面情况[1- 13C]丙酮酸。HP[1-13C]丙酮酸的13C磁共振成像将根据临床现场强度进行优化，以同时检测 氧化代谢和糖酵解代谢分别通过评估重碳酸盐和乳酸盐的动力学，在两个 临床前MS模型，3特斯拉。将进行空间基因组学、免疫染色和生化分析 对配对的体外样本进行研究，以研究驱动HP读数的潜在机制。 特定目的2.用HP g-Gluamyl-[1-Gluamyl]]区分正交的神经炎性过程 13C]甘氨酸。我们将研究g-Glu-[1-13C]Gly作为读数来评估氧化应激的潜力 两个MS型号中的M1/M2状态。为此，HP g-Glu-[1-13C]Gly的13C MRSI将被优化以测量GGT 在3特斯拉的临床前MS模型中通过检测HP[1-13C]甘氨酸的体内活性。人参皂苷的体外分析 组织样本将按照目标1进行，以调查驱动HP读数的潜在机制。 具体目的3.首次使用HP[1-13C]丙酮酸：3A对MS患者进行研究。我们将表演一场 8例RRMS患者对疾病修饰疗法(DMTs)天真的初步研究，以优化HP[1-13C]丙酮酸 在3特斯拉下提高分辨率的MRI参数。3B。然后我们将想象32名RRMS患者天真地接受了DMT 使用3A中定义的参数，在基线以及DMF/MMF治疗1个月和3个月后。联谊会 将评估新的代谢成像标志物和标准临床MRI(T1前/后Gd，T2)之间的关系。

ABSTRACT For people living with multiple sclerosis (MS), numerous clinical and Magnetic Resonance Imaging (MRI) sessions are needed to assess symptoms and/or presence of lesions. Even then, outcome prediction and treatment choice are challenging. To realize the full potential of personalized medicine, specific biomarkers reflecting function (e.g. inflammation, redox) are needed for comprehensive characterization and phenotyping. Over the initially funded 5-year period of this grant, we have firmly established that hyperpolarized (HP) 13C MR Spectroscopic Imaging (MRSI) is a highly valuable neuroimaging method for assessment of MS lesions. We were the first to show that 13C MRSI of HP [1-13C]pyruvate can detect increased HP lactate-to-pyruvate, linked to proinflammatory microglia/macrophages (MPs) in a MS mouse model, a finding further confirmed in other models. We also demonstrated that HP 13C MR could monitor early response to immunomodulatory therapies, e.g. dimethylfumarate (DMF). Additionally, we showed that, as MPs phenotype is linked to levels of Reactive Oxygen Species (ROS), HP [1-13C]dehydroxyascorbic acid (DHA), a redox-sensing HP probe, could differentiate between M1 and M2 MPs, thus non-invasively assessing these orthogonal processes. In this renewal, we will build upon the successes of the first funded period and 1/develop improved HP 13C metabolic imaging approaches to assess neuroinflammation and oxidative stress in MS and 2/conduct the first human study applying HP 13C metabolic imaging to monitor therapy response in people living with MS. Specific Aim 1. Provide a comprehensive picture of metabolic impairment in MS using HP [1- 13C]pyruvate. 13C MRSI of HP [1-13C]pyruvate will be optimized at clinical field strength to simultaneously detect oxidative and glycolytic metabolism through assessment of bicarbonate and lactate kinetics, respectively, in two preclinical MS models at 3 Tesla. Spatial genomics, immunostainings and biochemical assays will be performed on paired ex vivo samples to investigate the underlying mechanisms driving the HP readouts. Specific Aim 2. Differentiate orthogonal neuroinflammatory processes using HP g-Glutamyl-[1- 13C]Glycine. We will investigate the potential of g-Glu-[1-13C]Gly to assess oxidative stress as a read-out of M1/M2 status in two MS models. To do so, 13C MRSI of HP g-Glu-[1-13C]Gly will be optimized to measure GGT activity in vivo through detection of HP [1-13C]Glycine in preclinical MS models at 3 Tesla. Ex vivo analysis of tissue samples will be performed as in Aim 1 to investigate the underlying mechanisms driving the HP readouts. Specific Aim 3. Perform the first study of MS patients using HP [1-13C]pyruvate: 3A. We will perform a pilot study on 8 RRMS patients naïve to disease modifying therapies (DMTs), to optimize HP [1-13C] pyruvate MRI parameters for improved resolution at 3 Tesla. 3B. We will then image 32 RRMS patients naïve to DMTs using parameters defined in 3A, at baseline, and after 1 and 3 months of DMF/MMF therapy. Associations between new metabolic imaging markers and standard clinical MRI (T1 pre/post Gd, T2) will be evaluated.