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，是青壮年人群中最常见的非创伤性残疾原因之一。然而，其中一个特点是，在神经功能障碍的进展中起关键作用的进行性神经变性。人们对神经炎症和神经退行性变之间的联系知之甚少。最近的生化研究表明，由于血管炎症导致一氧化氮（NO）增加，线粒体中的氧代谢存在缺陷，这可能在神经元/轴突损伤中起关键作用。此外，一氧化氮是神经血管耦合的强介质，在短暂的神经激活期间负责增加血供。在多发性硬化症中，随着时间的推移，强直性高NO水平的存在（即使在休息期间）也可能使血管平滑肌脱敏，导致血管舒张能力或脑血管反应性（CVR）下降，并在神经元执行高要求任务时限制血液供应。本提案的总体目标是检测和表征早期MS的氧气消耗和血管反应性异常，并使用几种先进的代谢/血管MRI技术识别有风险的组织。其中包括最近开发的用于评估整体脑氧代谢率（cro2）的t2 - relax - underspin - tagging (TRUST)，以及使用CO2吸入测量CVR的患者舒适血氧水平依赖（BOLD）模式。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ccro2和CVR异常。我们假设氧代谢异常与血流调节受损是导致早期变性的关键因素。我们还假设cro2和CVR的联合功能指标有可能成为预测ms神经退行性进展及其临床结局的客观指标。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患者的整体ccro2异常；2. 采用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. 测定饮食中硝酸盐低摄入量组和高摄入量组（对应较高NO水平）健康对照组CVR和ccro2的变化；4. 确定早期RRMS患者cro2和CVR的纵向变化及其与影像学和临床结果的关系。健康相关性：通过提供体内MRI确认我们的工作假设，这一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. PUBLIC HEALTH RELEVANCE: The proposed study will investigate and characterize the oxygen delivery and consumption abnormalities that are tightly linked to vascular endothelial and mitochondrial dysfunction and consequent neuronal/axonal injury using several advanced MRI techniques in early relapsing remitting and advanced secondary progressive multiple sclerosis. We want to address the fundamental question of how these measurements can predict the longitudinal accumulation of neurological disability and neurodegenerative progression or conversion into secondary progressive phase. Potential implications of these data include impact on neuroprotective treatment strategies.