Brain Oxygen Metabolism and Hemodynamic Impairment in Multiple Sclerosis

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统（CNS）的慢性炎症性疾病，是青年和中年人非创伤性残疾的最常见原因之一。然而，其中一个标志是进行性神经变性，在神经功能障碍的进展中起着关键作用。神经炎症和神经变性之间的联系知之甚少。最近的生化研究表明，由于血管炎症导致的一氧化氮（NO）增加，线粒体中存在氧代谢缺陷，这可能在神经元/轴突损伤中起关键作用。此外，NO是神经血管耦联的强介质，其负责在短暂神经激活期间增加血液供应。在MS中，当神经元执行要求高的任务时，高浓度NO水平（即使在休息期间）的存在可能随着时间的推移使血管平滑肌脱敏，导致血管舒张能力或脑血管反应性（CVR）降低和血液供应受限。本提案的总体目标是检测和表征早期MS中的耗氧量和血管反应性异常，并使用几种先进的代谢/血管MRI技术识别风险组织。其中包括最近开发的用于评价整体脑氧代谢率（CMRO 2）的T2-松弛-自旋标记（TRUST）和使用CO2吸入测量CVR的患者舒适血氧水平依赖性（BOLD）范例。我们将量化与临床残疾和疾病进展相关的早期复发缓解型（RR）MS和继发性进展型（SP）MS晚期患者的CMRO 2和CVR异常。我们推测氧代谢异常与血流调节受损是导致早期退行性变的关键因素。我们还假设CMRO 2和CVR的组合功能指数有可能成为预测MS神经退行性进展及其临床结局的客观标志物。具体目的如下：1.与年龄/性别匹配的正常对照相比，使用TRUST MRI评估早期RR和SP患者的总体CMRO 2异常; 2.采用5%CO2吸入法和BOLD显像法测定代谢综合征患者的CVR，以探讨代谢综合征患者脑血管功能障碍的本质。测量健康对照组在低和高膳食硝酸盐摄入组（对应于较高的NO水平）之间的CVR和CMRO 2变化; 4.确定早期RRMS患者CMRO 2和CVR的纵向变化及其与5年内影像学和临床结局的关系。健康相关性：通过提供体内MRI证实我们的工作假设，这种应用可能对我们理解MS的疾病发病机制和进展（神经功能障碍和认知能力下降）以及未来设计新的治疗策略产生深远的影响。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) and one of the most common causes of nontraumatic disability among young and middle-aged people. One of the hallmarks, however, is the progressive neurodegeneration that plays a key role in the progression of neurological disabilities. Little is known of the link between neuroinflammation and neurodegeneration. Recent biochemical studies suggested that there is defective oxygen metabolism in mitochondria due to increased nitric oxide (NO) as a result of vascular inflammation, which may play a crucial role in neuronal/axonal injury. In addition, NO is a strong mediator of neurovascular coupling that is responsible for increased blood supply during transient neural activation. In MS, the presence of a tonically high NO level (even during resting) may desensitize the vascular smooth muscle over time with a consequence of decreased vasodilatory capacity or cerebral vascular reactivity (CVR) and limited blood supply when neurons perform a demanding task. The Overarching Goals of this proposal are to detect and characterize abnormalities in oxygen consumption and vascular reactivity in early MS and identify tissues at risk using several advanced metabolic/vascular MRI techniques. These include a recently developed T2-Relaxation-Under-Spin-Tagging (TRUST) for the evaluation of global cerebral metabolic rate of oxygen (CMRO2) and a patient-comfortable blood-oxygen-level-dependent (BOLD) paradigm using CO2 inhalation to measure CVR. We will quantify CMRO2 and CVR abnormalities in patients with early relapsing-remitting (RR) MS and subsequent advanced stage of secondary progressive (SP) MS that are associated with clinical disability and disease progression. We hypothesize that oxygen metabolism abnormality in conjunction with impaired blood flow regulation is a key factor causing early degeneration. We also hypothesize that the combined functional index of CMRO2 and CVR has the potential to be an objective marker to predict neurodegenerative progression and its clinical outcome in MS. The Specific Aims are as follows: 1. To assess global CMRO2 abnormalities using TRUST MRI in patients with early RR and SP patients as compared with age/sex matched normal controls; 2. To measure CVR using inhalation of 5% CO2 and BOLD imaging in order to elucidate the nature of cerebrovascular dysfunction in MS patients; 3. To measure CVR and CMRO2 changes in healthy controls between groups with low and high intake of dietary nitrate (corresponding to higher NO level); 4. To determine longitudinal changes of CMRO2 and CVR in early RRMS patients and their relationship to imaging and clinical outcomes over a 5-year period. Health Relevance: By providing in vivo MRI confirmation of our working hypotheses, this application could have profound consequences for our understanding of disease pathogenesis and progression (neurological disability and cognitive decline) in MS, and for the future design of novel therapeutic strategies.