MR metabolic Imaging of Multiple Sclerosis

摘要 多发性硬化症（MS）是一种多方面的神经系统疾病，也是多发性硬化症最常见的原因之一。 年轻人的残疾MS的主要标志是不受控制的免疫反应， 脱髓鞘，导致持续恶化的认知障碍，并最终导致死亡。 在MS的临床诊断后，需要进行大量的临床评估和MR成像（MRI）检查 以评估症状和/或病变的存在。即便如此，预测结果和治疗选择 这对每一位患者来说都是一个挑战。鉴于炎症在多发性硬化症中的作用，一种可以检测的成像方法 免疫应答可以改善患者管理和随后的个体化治疗方法。 在MS病变中，单核吞噬细胞（MP，巨噬细胞/小胶质细胞）是最丰富的免疫细胞。 细胞，并驱动脱髓鞘和细胞死亡。有趣的是，为了维持高增殖率，这些MP 从静止状态转换为促炎（M1极化）激活状态，并显示乳酸增加 与丙酮酸脱氢酶激酶1（PDK 1）增加相关的生产。缓解期间或针对 在治疗中，活化的MP转变为神经保护性（M2）表型并参与髓鞘再生。 值得注意的是，M2 MP呈现出分泌高水平的胰蛋白酶（一种酶）的独特代谢特征。 通过消耗精氨酸库来抑制T细胞功能。 本研究的目的是检验MPs激活和M1/M2状态可以在 使用超极化13 C MR光谱成像（HP 13 C MRSI）在体内观察MS病变， 代谢成像可以改善MS进展和治疗反应的评估。我们的目标是： 目标1。HP丙酮酸盐的13 C MRSI作为监测MS中活化MP的成像方法 体内病变。HP [1- 13 C]丙酮酸盐的13 C MRSI是最成熟和临床上可翻译的探针， 用于检测PDK 1 +/激活的MP，通过增加HP乳酸盐的产生，在两个充分表征的 临床前MS模型。将与已建立的MRI方法进行比较，以评估灵敏度， 该方法的特异性和诊断准确性，以及其监测疾病进展的改进潜力。 目标二。使用超极化的体内13 C MRSI检测MS损伤中的神经保护性M2 MP 精氨酸。我们将优化HP胍基-13 C-精氨酸的13 C MRSI，使其无创性 并通过检测临床前MS模型中的HP尿素来特异性地检测体内HP酶+/M2 MP。 还将与MRI/S进行比较，以评估该方法的诊断准确性提高。 目标3。评价体内MR代谢成像以监测对治疗的反应。我们将联合收割机13 C HP [1- 13 C]丙酮酸和HP胍基-13 C-精氨酸的MRSI，并使用该多探针代谢成像 在两种临床前MS模型中监测对临床相关治疗的反应的方法。相比 将进行MRI/S方法，以评估每种方法的监测准确性改善。

ABSTRACT Multiple sclerosis (MS) is a multifaceted neurological disease and one of the most common causes of disability in young adults. The major hallmark of MS is an uncontrolled immune response that drives demyelination, resulting in continuously worsening cognitive impairments, and eventually leading to death. Upon clinical diagnosis of MS, numerous clinical evaluations and MR Imaging (MRI) sessions are required to assess symptoms and/or presence of lesions. Even then, prediction of outcome and choice of treatment remain a challenge for each patient. Given the role of inflammation in MS, an imaging method that could detect immune response could improve patient management and subsequent individualized therapeutic approaches. In MS lesions, mononuclear phagocytes (MPs, macrophages/microglia) are the most abundant immune cells, and drive demyelination and cell death. Interestingly, to sustain high proliferation rates, these MPs have switched from quiescent to pro-inflammatory (M1-polarized) activated state and show increased lactate production linked to increased pyruvate dehydrogenase kinase 1 (PDK1). During remissions or in response to therapies, activated MPs switch to a neuroprotective (M2) phenotype and participate in remyelination. Remarkably, M2 MPs present the unique metabolic feature of excreting high levels of arginase, an enzyme that inhibits T cells function through depletion of the arginine pool. The goal of this study is to test the hypothesis that MPs activation and M1/M2 status can be detected in MS lesions in vivo using hyperpolarized 13C MR Spectroscopic Imaging (HP 13C MRSI) and that such metabolic imaging can improve evaluation of MS progression and treatment response. Our Aims are: Aim 1. Validate 13C MRSI of HP pyruvate as an imaging method to monitor activated MPs in MS lesions in vivo. 13C MRSI of HP [1-13C] pyruvate, the most established and clinically translatable probe, will be used to detect PDK1+/activated MPs through increased HP lactate production in two well-characterized preclinical MS models. Comparison with established MRI methods will be performed to assess the sensitivity, specificity and diagnostic accuracy of the method, and its improved potential to monitor disease progression. Aim 2. Detect neuroprotective M2 MPs in MS lesions using in vivo 13C MRSI of hyperpolarized arginine. We will optimize 13C MRSI of HP guanidino-13C-arginine, the substrate of arginase, to non-invasively and specifically detect arginase+/M2 MPs in vivo through detection of HP urea in preclinical MS models. Comparison to MRI/S will also be performed to assess the improved diagnostic accuracy of this approach. Aim 3. Evaluate in vivo MR metabolic imaging to monitor response to therapies. We will combine 13C MRSI of HP [1-13C] pyruvate and HP guanidino-13C-arginine and use this multiprobe metabolic imaging approach to monitor response to clinically relevant therapies in two preclinical MS models. Comparison to MRI/S methods will be conducted to assess the improved monitoring accuracy of each method.