PET and MRI Evaluation of Cerebral Inflammation and Metabolic Stress in Relapsing Multiple Sclerosis

摘要 多发性硬化症(MS)是一种免疫调节、脱髓鞘和中枢神经系统退行性疾病。 神经系统疾病，是导致年轻人残疾的主要原因。大多数患者从复发开始- 汇款(RRMS)课程。临床复发和新的白质病变形成显著减少 目前的治疗方法。然而，尽管RRMS的治疗明显有效，许多患者最终 发展为进行性多发性硬化症(PMS)，其中残疾累积难以治疗。进展性残疾是 由疾病早期开始的神经退行性变驱动，与复发无关，病情较差。 明白了。神经退行性变的两个潜在因素是亚临床炎症和代谢应激。 临床复发和新的病变形成是由炎性脱髓鞘引起的，但 炎症存在于离散病变的外部。这种炎症与慢性脱髓鞘有关。 以及增加新陈代谢需求。炎症和代谢应激都可能导致神经退化， 要么单独行动，要么联合行动。 这项研究将使用一种新型的正电子发射断层扫描(PET)显像剂，11C-CS1P1，它结合到 鞘氨醇-1-磷酸受体1(S1PR1)作为炎症标志物。S1PR1信令对MS AS至关重要 FDA批准的四种S1P调节剂在减少RRMS复发方面的高效证明。 此外，我们将使用18F-FDG PET的代谢成像和先进的氧气敏感磁感应成像 磁共振成像(MRI)分别测量大脑葡萄糖和氧的利用。这些 将在健康对照参与者的队列中进行测量，RRMS患者将启动 S1P调节药物和RRMS患者开始使用同样有效的非S1P调节药物(B细胞 耗尽疗法)。患者将在开始治疗前和治疗后3个月进行成像。这些数据 将允许测试RRMS中存在亚临床炎症和代谢应激的假设 目前的治疗方法并不能完全缓解这些症状。这项研究将涉及三个具体目标。第一个目标 测试一种假说，即炎症在多发性硬化症病变之外的看似正常的组织中增加 并且通过S1P调制来减少。第二个目标将检查正常人群的新陈代谢需求和压力 MS患者出现脑白质和灰质与对照组比较。前两个目标将进行比较 它们各自的生物标记物在启动S1P模式药物前后。最终目标是调查如何 S1PR1的表达和代谢应激是通过一种有效的但不是S1P调节的治疗来调节的。 这项研究的完成将提供对推动神经退行性变的过程的新理解 多发性硬化症，并导致临床发病率和残疾。

ABSTRACT Multiple sclerosis (MS) is an immune-mediated, demyelinating, and degenerative disease of the central nervous system and is a leading cause of disability in young people. Most patients begin with a relapsing- remitting (RRMS) course. Clinical relapse and new white matter lesion formation is dramatically reduced by current therapies. However, despite evidently efficacious treatment of RRMS, many patients eventually develop progressive MS (PMS) wherein disability accumulates refractory to treatment. Progressive disability is driven by neurodegeneration which begins early in the disease, occurs independent of relapses, and is poorly understood. Two potential contributors to neurodegeneration are subclinical inflammation and metabolic stress. Clinical relapses and new lesion formation are driven by inflammatory demyelination, but additional inflammation is present outside of discrete lesions. This inflammation is associated with chronic demyelination and increased metabolic demand. Both inflammation and metabolic stress may lead to neurodegeneration, either alone or in combination. This study will use a novel positron emission tomography (PET) imaging agent, 11C-CS1P1, which binds to sphingosine-1-phosphate-receptor 1 (S1PR1) as a marker of inflammation. S1PR1 signaling is critical to MS as evidenced by four FDA approved S1P-modulators with high efficacy for reducing relapses in RRMS. Additionally, we will use metabolic imaging with 18F-FDG PET and advanced, oxygen-sensitive magnetic resonance imaging (MRI) to measure cerebral glucose and oxygen utilization, respectively. These measurements will be made in a cohort of heathy control participants, RRMS patients who will be initiating an S1P-modulating drug and RRMS patients initiating a similarly efficacious non-S1P-modulating drug (B-cell depleting therapies). Patients will be imaged prior to and 3-months following initiation of treatment. These data will allow for testing the hypotheses that subclinical inflammation and metabolic stress are present in RRMS and are incompletely mitigated by current treatments. This study will address three Specific Aims. The first aim tests the hypothesis that inflammation is increased outside of MS lesions in seemingly normal appearing tissue and is reduced by S1P-modulation. The second aim will examine the metabolic needs and stress of normal appearing white matter and gray matter in MS patients compared to controls. The first two aims will compare their respective biomarkers pre- vs. post-initiation of an S1P-modualting drug. The final aim investigates how S1PR1 expression and metabolic stress are modulated by an efficacious, but not S1P-modualting therapy. Completion of this study will provide new understanding of processes that drive neurodegeneration in MS and contribute to clinical morbidity and disability.