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: 8439069
• 负责人: Yulin Ge
• 金额: $ 56.89万
• 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/8439069
• 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; relating to nervous system; respiratory; response; sex; treatment strategy; uptake; 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. 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.

描述（由申请人提供）：多发性硬化症（MS）是中枢神经系统（CNS）的慢性炎症性疾病，也是年轻和中年患者中非创伤性残疾的最常见原因之一。然而，标志之一是进行性神经退行性变化，在神经障碍的发展中起着关键作用。神经炎症与神经变性之间的联系知之甚少。最近的生化研究表明，由于血管炎症增加一氧化氮（NO），线粒体中的氧代谢有缺陷，这可能在神经/轴突损伤中起着至关重要的作用。此外，NO是一个强大的神经血管耦合介质，导致瞬时神经激活期间血液供应增加。在MS中，由于血管舒张能力降低或脑血管反应性（CVR）的降低，因此随着时间的推移，具有音调高的NO水平（即使在静止期间）的存在可能会使血管平滑肌脱敏，而当神经元执行苛刻的任务时，血液供应有限。该提案的总体目标是检测和表征早期MS中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技术鉴定有风险的组织。其中包括最近开发的T2 - 释放标签（Trust），用于评估全球脑代谢率（CMRO2）和使用CO2吸入量的CO2量的全球脑代谢率（CMRO2）和患者对患者的血氧级依赖性（BOLD）范式的评估。我们将量化与临床障碍和疾病进展相关的继发性（SP）MS的早期复发（RR）MS患者的CMRO2和CVR异常。我们假设氧代谢异常与血流调节受损相结合是导致早期变性的关键因素。我们还假设CMRO2和CVR的合并功能指数具有预测神经退行性进展及其在MS中其临床结果的客观标记。具体目的如下：1。与年龄/性别匹配的正常对照相比，在早期RR和SP患者的患者中，使用Trust MRI评估全球CMRO2异常； 2。使用5％CO2和粗体成像来测量CVR，以阐明MS患者的脑血管功能障碍的性质； 3。测量饮食中硝酸盐摄入量低和高的组之间健康对照的CVR和CMRO2变化（对应于较高的NO水平）； 4。确定早期RRMS患者中CMRO2和CVR的纵向变化及其在5年内与成像和临床结果的关系。健康相关性：通过提供对我们工作假设的体内MRI确认，该应用可能会对我们在MS中对疾病发病机理和进展（神经残疾和认知下降）的理解以及新型治疗策略的未来设计产生深远的影响。 公共卫生相关性：拟议的研究将调查并表征与血管内皮和线粒体功能障碍密切相关的氧递送和消耗异常，并使用几种早期复发和先进的次要累积性多发性稳态，并使用多种先进的MRI技术进行神经元/轴突损伤。我们想解决这些测量结果如何预测神经残疾和神经退行性进展或转化为次级渐进阶段的纵向积累的基本问题。这些数据的潜在影响包括对神经保护策略的影响。