Brain Oxygen Metabolism and Hemodynamic Impairment in Multiple Sclerosis

多发性硬化症的脑氧代谢和血流动力学损伤

• 批准号: 8675294
• 负责人: Yulin Ge
• 金额: $ 53.29万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8675294
• 关键词: ATP Synthesis Pathway; Address; Affect; Age; Binding; Biochemical; Biological Markers; Blood; Blood Vessels; Blood flow; Brain; Breathing; Carbon Dioxide; Cells; Central Nervous System Diseases; Cerebrum; Chronic; Clinical; Complex; Consumption; Control Groups; Core-Binding Factor; Coupling; Data; Demyelinating Diseases; Diet; Diffuse; Disease; Disease Progression; Enhancing Lesion; Evaluation; Failure; Functional disorder; Future; Goals; Health; Hypoxia; Image; Impaired cognition; Impairment; Inflammatory; Ingestion; Injury; Intake; Lesion; Life; Link; Magnetic Resonance Imaging; Measurement; Measures; Mediator of activation protein; Metabolic; Metabolism; Mitochondria; Modeling; Multiple Sclerosis; Nature; Nerve Degeneration; Neurocognitive; Neurologic; Neuronal Dysfunction; Neurons; Neuropsychological Tests; Nitrates; Nitric Oxide; Nitric Oxide Pathway; Nitrites; Outcome; Oxygen; Oxygen Consumption; Pathogenesis; Pathology; Patients; Phase; Physiology; Play; Predictive Value; Production; Regulation; Relapse; Relapsing-Remitting Multiple Sclerosis; Relative (related person); Relaxation; Rest; Risk; Role; Secondary Progressive Multiple Sclerosis; Secondary to; Staging; Techniques; Time; Tissues; Vascular Smooth Muscle; Vascular blood supply; Work; base; blood oxygen level dependent; brain tissue; cerebrovascular; design; dietary nitrate; disability; follow-up; healthy volunteer; hemodynamics; human subject; in vivo; indexing; middle age; mitochondrial dysfunction; neuroinflammation; novel therapeutics; progressive neurodegeneration; public health relevance; relating to nervous system; respiratory; response; sex; treatment strategy; uptake; vascular endothelial dysfunction; vascular inflammation

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.

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，也是青壮年人非创伤性残疾的最常见原因之一。然而，其标志之一是进行性神经变性，它在神经残疾的进展中发挥着关键作用。人们对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/轴突损伤中发挥关键作用。此外，NO 是神经血管耦合的强介质，负责在短暂的神经激活过程中增加血液供应。在多发性硬化症中，紧张性高NO水平（即使在休息时）可能会随着时间的推移使血管平滑肌变得不敏感，从而导致血管舒张能力或脑血管反应性（CVR）下降，并且当神经元执行艰巨的任务时血液供应有限。该提案的总体目标是检测和表征早期多发性硬化症中耗氧量和血管反应性的异常，并使用几种先进的代谢/血管 MRI 技术识别处于危险中的组织。其中包括最近开发的用于评估全局脑氧代谢率 (CMRO2) 的 T2 松弛下自旋标记 (TRUST) 和使用 CO2 吸入测量 CVR 的患者舒适血氧水平依赖 (BOLD) 范例。我们将量化早期复发缓解型 (RR) MS 和随后的继发进展型 (SP) MS 晚期患者的 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化的关键因素。我们还假设 CMRO2 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果的客观标志物。具体目标如下： 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 患者的整体 CMRO2 异常； 2. 通过吸入5%CO2和BOLD成像测量CVR，以阐明MS患者脑血管功能障碍的性质； 3. 测量膳食硝酸盐摄入量低和高（对应于较高的 NO 水平）的健康对照组之间的 CVR 和 CMRO2 变化； 4. 确定早期 RRMS 患者 CMRO2 和 CVR 的纵向变化及其与 5 年期间影像和临床结果的关系。健康相关性：通过提供体内 MRI 证实我们的工作假设，该应用可能会对我们了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）以及未来新型治疗策略的设计产生深远的影响。