Brain Oxygen Metabolism and Hemodynamic Impairment in Multiple Sclerosis

描述(申请人提供)：多发性硬化症(MS)是一种慢性中枢神经系统(CNS)炎症性疾病，是年轻人和中年人中最常见的非创伤性残疾原因之一。然而，其中一个特征是进行性神经变性，它在神经功能障碍的进展中起着关键作用。关于神经炎症和神经退行性变之间的联系，人们知之甚少。最近的生化研究表明，由于血管炎症导致一氧化氮(NO)的增加，线粒体存在氧代谢缺陷，这可能在神经元/轴突损伤中起着关键作用。此外，NO是神经血管偶联的强大中介，在短暂的神经激活过程中导致血液供应增加。在多发性硬化症中，随着时间的推移，强直的高NO水平(即使在休息时)可能会使血管平滑肌失去敏感性，导致血管扩张能力或脑血管反应性(CVR)下降，当神经元执行苛刻的任务时，血液供应也会受到限制。这项建议的首要目标是检测和描述早期MS的氧耗和血管反应性的异常，并使用几种先进的代谢/血管MRI技术识别危险组织。其中包括最近开发的用于评估全球脑氧代谢率(CMRO2)的T2松弛自旋标记(TRUST)，以及使用二氧化碳吸入来测量CVR的患者舒适的血氧水平依赖(BOLD)范例。我们将量化早期复发缓解(RR)MS和继发进展期(SP)MS患者的CMRO2和CVR异常，这些异常与临床残疾和疾病进展相关。我们假设氧代谢异常与血流调节受损是导致早期退变的关键因素。我们还假设CMRO2和CVR的联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指标。具体目标如下：1.用TRUST MRI评估早期RR和SP患者的CMRO2异常，并与年龄/性别匹配的正常对照组比较；2.用5%CO2吸入和BOLD成像测量CVR，以阐明MS患者脑血管功能障碍的性质；3.测量健康对照组的CVR和CMRO2的变化，在饮食硝酸盐摄入量低和高的两组之间(对应于较高的NO水平)；4.研究早期RRMS患者CMRO2和CVR的纵向变化及其与影像和临床转归的关系。健康相关性：通过提供我们的工作假说的体内MRI确认，这一应用可能会对我们理解多发性硬化症的疾病发病机制和进展(神经功能障碍和认知能力下降)以及未来新的治疗策略的设计产生深远的影响。

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.