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

 产品说明： 最近的研究表明，血管疾病危险因素（VDRF），如糖尿病，高血压，高脂血症，外周血管疾病和心脏病的存在可以显着增加多发性硬化症（MS）的残疾进展的风险。VDRF和MS残疾之间似乎存在剂量-反应关系，存在单一VDRF使早期步态残疾的风险增加51%，存在其中2种情况使风险增加至228%。在退伍军人中，VDRF非常普遍。在过去两年中，在VA系统内接受治疗的19，282名MS退伍军人中，约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退伍军人患有高血压和高脂血症。 越来越多的是，有证据表明线粒体功能障碍和由此导致的ATP和其他高能磷代谢物的缺乏导致MS的神经变性。我们的合作者俄勒冈州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（MRI）测量高能磷（HEP）代谢物和脑血流量的技术。仪器，并证明与MS的人有灰质缺乏HEP代谢物以及脑血流异常。 本研究的目的是确定VDRF是否与MS患者的脑血流和代谢异常增加相关，该项目的首要假设是MS中的血管风险因素增加了疾病进展的速率，并且通过减少灰质代谢和减少脑血管病变来实现。血流和脑萎缩恶化为了解决这一假设，将实现以下目标：具体目标1：使用匹配队列，确定与未使用VDRF的MS退伍军人相比，使用VDRF的MS退伍军人是否具有通过MRI检测到的脑血流量和容量减少以及通过31 P磁共振光谱成像（MRSI）评估的脑灰质中的高能磷酸盐代谢物。 具体目标二：确定患有MS和VDRF的退伍军人的脑萎缩进展是否比没有VDRF的退伍军人更快，以及31 P MRSI和脑血流缺损是否与脑萎缩率增加相关。 具体目标3：确定患有MS和VDRF的退伍军人的临床损伤、残疾和生活质量恶化是否比没有VDRF的退伍军人更快，以及31 P MRSI和脑血流缺损是否与疾病进展率增加相关。 研究设计和方法：我们提出了一项纵向定量MRI研究，使用31 P MRSI评估线粒体功能和灌注测量，以量化血容量和血流量，以调查与未使用VDRF的MS退伍军人相比，VDRF是否减少了脑血流量和容量，减少了高能磷代谢物，并加速了脑萎缩，临床损伤和残疾。这将是一项为期3年的对照研究，采用单中心、混合设计（横断面和纵向）， 两个手臂。将在基线、12、24和36个月时收集MRI数据。我们将入组共计60例MS受试者，目标是每组30例受试者：1）合并VDRF的MS受试者; 2）未合并VDRF的MS受试者。将纳入40-65岁的MS受试者，受试者可能正在接受或可能没有接受疾病改善治疗。这些研究的结果将为设计临床试验提供基础，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.