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，是 年轻人的残疾。多发性硬化症的主要特征是不受控制的免疫反应，促使 脱髓鞘，导致认知障碍不断恶化，最终导致死亡。 一旦临床诊断为多发性硬化症，就需要进行大量的临床评估和磁共振成像(MRI)检查 以评估症状和/或病变的存在。即便如此，对结果的预测和治疗的选择 对每个病人来说都是一个挑战。鉴于炎症在多发性硬化症中的作用，一种可以检测到 免疫反应可以改善患者管理和随后的个体化治疗方法。 在MS病变中，单核巨噬细胞(MPS，巨噬细胞/小胶质细胞)是最丰富的免疫细胞 并导致脱髓鞘和细胞死亡。有趣的是，为了维持高扩散速度，这些国会议员 从静止状态切换到促炎(M1极化)激活状态，并显示乳酸增加 产生与增加的丙酮酸脱氢酶激酶1(PDK1)有关。在缓解期间或在应对 在治疗过程中，激活的MPS转变为神经保护性(M2)表型，参与髓鞘再生。 值得注意的是，M2 MPS表现出分泌高水平精氨酸酶的独特代谢特征 这通过耗尽精氨酸池来抑制T细胞的功能。 这项研究的目标是检验假设，即MPS的激活和M1/M2状态可以在 超极化~(13)C磁共振波谱成像(HP~(13)C-MRSI)在活体多发性硬化病变中的应用 代谢成像可以改善对MS进展和治疗反应的评估。我们的目标是： 目的1.验证幽门螺杆菌丙酮酸~(13)C磁共振波谱作为监测MS患者活化MPS的影像方法 活体损伤。HP[1-13C]丙酮酸的13C MRSI是最成熟和临床可翻译的探针，将是 用于通过增加HP乳酸产量来检测PDK1+/激活的MPS 临床前多发性硬化症模型。将与已建立的MRI方法进行比较以评估敏感性， 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的潜力。 目的2.用超极化的活体~(13)C磁共振成像检测多发性硬化病变的神经保护性M2-MPS 精氨酸。我们将优化精氨酸酶的底物幽门螺杆菌-13C-精氨酸的~(13)C磁共振成像，使之成为非侵入性的 并通过检测临床前MS模型中的HP尿素，在体内特异性地检测精氨酸酶+/M2 MPS。 还将与核磁共振或S进行比较，以评估该方法诊断准确率的提高。 目的3.评价体内MR代谢成像监测治疗反应的价值。我们将结合13C HP[1-13C]丙酮酸和HP-13C-精氨酸的磁共振成像和使用这种多探针代谢成像 监测两种临床前多发性硬化症模型对临床相关治疗的反应的方法。与 将进行磁共振成像/S方法，以评估每种方法提高的监测准确性。

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.