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

 说明： 最近的研究表明，糖尿病、高血压、高脂血症、外周血管疾病和心脏病等血管疾病危险因素(VDRF)的存在会显著增加多发性硬化症(MS)的残疾进展风险。VDRF和MS残疾之间似乎存在剂量-反应关系，单个VDRF的存在使早期步态残疾的风险增加51%，其中两种情况的存在使风险增加到228%。在退伍军人中，VDRF非常普遍。在过去两年中，在退伍军人管理局系统内接受护理的19,282名MS退伍军人中，约有9300人患有高脂血症，约9200人患有高血压，约3500人患有糖尿病。大约5900名MS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，线粒体功能障碍以及由此导致的ATP和其他高能磷代谢产物的缺陷导致多发性硬化症患者的神经变性。我们的合作者俄勒冈健康与科学大学高级成像研究中心的William Rooney博士开发了使用7特斯拉(T)磁共振成像仪测量高能磷(Hep)代谢物和脑血流的技术，并证明MS患者存在HEP代谢物灰质缺乏以及脑血流异常。这项研究的目的是确定VDRF是否与高场脑MRI评估的多发性硬化症患者的脑血流和代谢异常增加有关，以及这些异常是否导致多发性硬化症的脑萎缩和临床疾病进展。该项目的压倒一切的假设是，多发性硬化症的血管风险因素增加了疾病进展的速度，这是通过减少灰质代谢和血流量以及恶化脑萎缩来实现的。为了解决这一假设，将实现以下目标：特定目标1：使用匹配的队列，确定与没有VDRF的退伍军人相比，患有VDRF的退伍军人是否减少了脑血流和容量，并通过31P磁共振波谱成像(MRSI)评估了大脑灰质中的高能磷酸盐代谢产物。具体目标2：确定患有MS和VDRF的退伍军人是否比没有VDRF的退伍军人脑萎缩进展得更快，以及31P磁共振成像和脑血流缺陷是否与脑萎缩的增加有关。具体目标3：确定患有MS和VDRF的退伍军人的临床损害、残疾和生活质量是否比没有VDRF的退伍军人更快恶化，以及31P磁共振成像和脑血流缺陷是否与疾病进展速度增加有关。研究设计和方法：我们提出了一项纵向、定量的MRI研究，使用31P磁共振成像评估线粒体功能和血流灌注测量来量化血液容量和流量，以调查与没有VDRF的MS退伍军人相比，患有VDRF的MS退伍军人是否减少了脑血流和容量，减少了高能磷代谢产物，并加速了脑萎缩、临床损害和残疾。这将是一项为期3年的单点、混合设计(横断面和纵向)的对照研究， 两只胳膊。MRI数据将在基线、12个月、24个月和36个月收集。我们将招收60名MS受试者，目标是每组有30名受试者：1)患有VDRF的MS受试者；2)没有VDRF的MS受试者。40-65岁的多发性硬化症受试者将被包括在内，他们可能正在接受疾病调整治疗，也可能没有。这些研究的结果将为设计一项临床试验提供基础，以研究旨在改善VDRF的干预措施是否可以降低MS退伍军人的疾病进展风险。

 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.