Vascular Disease Risk Factors and MS Progression: A Study of Brain Metabolism

血管疾病危险因素和多发性硬化症进展：脑代谢研究

• 批准号: 10304842
• 负责人: VIJAYSHREE YADAV
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304842
• 关键词: Address; Affect; American; Antiinflammatory Effect; Atrophic; Blood Volume; Blood flow; Brain; Caring; Cerebrovascular Circulation; Cerebrum; Chronic; Clinical; Clinical Trials; Controlled Study; Data; Development; Diabetes Mellitus; Diagnosis; Diet; Disease; Disease Progression; Dose; Enrollment; Gait; Goals; Health Sciences; Heart Diseases; Hyperlipidemia; Hypertension; Image; Imaging Device; Impairment; Inflammatory; Intervention; Intervention Studies; Life Style; Magnetic Resonance Imaging; Measurement; Measures; Metabolism; Mitochondria; Modification; Multiple Sclerosis; Nerve Degeneration; Neuraxis; Neurologic; Oregon; Pathogenesis; Patients; Perfusion; Peripheral Vascular Diseases; Phosphorus; Play; Prevention; Progressive Disease; Quality of life; Registries; Research; Research Design; Research Methodology; Research Proposals; Respondent; Risk; Risk Factors; Role; Site; Surveys; System; Techniques; Time; United States; Universities; Vascular Diseases; Veterans; Walking; aged; arm; base; brain metabolism; cerebral atrophy; cohort; design; disability; disability risk; disorder risk; effectiveness evaluation; gray matter; hypercholesterolemia; imaging study; improved; inorganic phosphate; magnetic resonance spectroscopic imaging; mitochondrial dysfunction; multiple sclerosis treatment; novel; public health relevance; response; treatment program; vascular risk factor

 DESCRIPTION: Recent studies suggest that presence of vascular disease risk factors (VDRF) such as diabetes, hypertension, hyperlipidemia, peripheral vascular disease and heart disease can significantly increase the risk of disability progression in multiple sclerosis (MS). There appears to be a dose-response relationship between VDRF and MS disability with the presence of a single VDRF increasing the risk of early gait disability by 51% and the presence of 2 of these conditions increasing the risk to 228%. Among Veterans, VDRF are highly prevalent. In the last two years, among the 19,282 Veterans with MS who received care within the VA system, ~9300 had hyperlipidemia, ~9200 suffered from hypertension and ~3500 had diabetes mellitus. Approximately 5900 MS Veterans had both hypertension and hyperlipidemia. Increasingly, evidence indicates mitochondrial dysfunction and resultant deficiencies in ATP and other high energy phosphorus metabolites contribute to neurodegeneration in MS. Our collaborator Dr. William Rooney at the Oregon Health & Science University Advanced Imaging Research Center has developed techniques to measure high energy phosphorus (HEP) metabolites and cerebral blood flow using a 7 Tesla (T) magnetic resonance imaging (MRI) instrument and demonstrated that people with MS have gray matter deficiencies in HEP metabolites as well as cerebral blood flow abnormalities. The purpose of this research is to determine if VDRF are associated with increased abnormalities in cerebral blood flow and metabolism in people with MS as assessed with high-field brain MRI and if these abnormalities contribute to brain atrophy and clinical disease progression in MS. The overriding hypothesis of this project is that vascular risk factors in MS increase the rate of disease progression and do so by decreasing gray matter metabolism and blood flow and worsening brain atrophy. To address this hypothesis the following aims will be achieved: Specific Aim 1: Using matched cohorts, determine whether Veterans with MS with VDRF in comparison with those without VDRF have decreased cerebral blood flow and volume detected by MRI and high energy phosphate metabolites in cerebral gray matter assessed by 31P magnetic resonance spectroscopic imaging (MRSI). Specific Aim 2: Determine if brain atrophy progresses faster in Veterans with MS and VDRF than those without VDRF and whether 31P MRSI and cerebral blood flow deficits are associated with an increased rate of brain atrophy. Specific Aim 3: Determine if clinical impairment, disability and quality of life deteriorates faster in Veterans with MS and VDRF than those without VDRF and whether 31P MRSI and cerebral blood flow deficits are associated with an increased rate of disease progression. Research Design and Methods: We propose a longitudinal, quantitative MRI study using 31P MRSI assessing mitochondrial function and perfusion measurements to quantify blood volume and flow to investigate whether MS Veterans with VDRF in comparison with those without VDRF have reduced cerebral blood flow and volume, reduced high energy phosphorus metabolites, and accelerated brain atrophy, clinical impairment and disability. This will be a 3-year long controlled study with a single-site, mixed design (cross sectional and longitudinal) with two arms. MRI data will be collected at baseline, 12, 24 and 36 months. We will enroll a total of 60 MS subjects with goal to have 30 subjects in each arm: 1) MS subjects with VDRF; 2) MS subjects without VDRF. MS Subjects aged 40-65 years will be included and may or may not be on disease modifying therapy. The results of these studies will provide the basis for designing a clinical trial to study if interventions aimed at improving VDRF can reduce the risk of disease progression among MS Veterans.

 描述： 最近的研究表明，血管疾病危险因素（VDRF）的存在，例如糖尿病，高血压，高脂血症，周围血管疾病和心脏病可以显着增加多发性硬化症（MS）残疾进展的风险。 VDRF和MS残疾之间似乎存在剂量反应关系，而单个VDRF的存在增加了早期满足残疾的风险，其中2种疾病的存在将风险增加到228％。在退伍军人中，VDRF非常普遍。在过去的两年中，在有MS的19,282名退伍军人中，在VA系统内接受了护理，〜9300患有高脂血症，约9200人患有高血压，〜3500例患有糖尿病。大约5900毫秒的退伍军人同时患有高血压和高脂血症。越来越多的证据表明，ATP和其他高能磷代谢物的线粒体功能障碍和导致的缺陷有助于MS的神经变性。我们的合作者威廉·鲁尼（William Rooney）博士在俄勒冈州健康与科学大学高级成像研究中心开发了使用7 Tesla（T）磁共振成像（MRI）仪器来测量高能量磷（HEP）代谢物和脑血流量的技术，并证明患有MS的人在HEP代理中具有灰质的人缺乏。这项研究的目的是确定VDRF是否与使用高场脑MRI评估的MS患者的脑血流和代谢异常有关，以及这些异常是否有助于MS的脑萎缩和临床疾病进展。该项目的重要假设是，MS中的血管危险因素会增加疾病进展的速度，并通过减少灰质代谢和血流以及令人担忧的脑萎缩来做到这一点。为了解决这一假设，将实现以下目的：具体目标1：使用匹配的队列，确定与没有VDRF的MS的退伍军人是否与没有VDRF的老兵相比是否降低了MRI和高能磷酸代谢物在由31p磁共振光谱图像中评估的大​​脑灰质物中检测到的脑血流和体积。具体目标2：确定MS和VDRF的退伍军人的脑萎缩是否比没有VDRF的退伍军人更快，以及31p MRSI和脑血流量是否与脑萎缩率提高有关。具体目标3：确定MS和VDRF退伍军人的临床障碍，残疾和生活质量是否比没有VDRF的退伍军人更快，以及31p MRSI和脑血流量是否与疾病进展的增加有关。研究设计和方法：我们提出了一项使用31p MRSI评估线粒体功能和灌注测量的纵向定量MRI研究，以量化血液体积和流量，以调查与没有VDRF的VDRF的MS退伍军人相比，与大脑血流相比是否减少了能量磷酸化的高磷酸化和加速型的精神磷酸化，并降低了高能量磷酸化的脑磷酸化。这将是一项为期3年的对照研究 两臂。 MRI数据将在基线12、24和36个月收集。我们将总共招募60毫秒的受试者，目标有30个受试者：1）具有VDRF的MS受试者； 2）无VDRF的MS受试者。将包括40-65岁的MS受试者，可能会或可能不接受疾病的治疗。这些研究的结果将为设计临床试验的设计提供基础，以研究旨在改善VDRF的干预措施可以降低MS退伍军人的疾病进展风险。