Retinal microvasculature as a predictor of neurodegeneration in multiple sclerosis

目的：多发性硬化症(MS)是一种慢性炎症性和神经退行性疾病，几乎影响到 美国有100万人。目前，还没有FDA批准的治疗方法直接解决 神经退行性变及其相关的临床损害。系统性血管疾病合并症，包括 高血压、高脂血症和肥胖独立地加重了MS相关的步行限制。此外，MS 病理显示中枢神经系统(CNS)存在微血管功能障碍。我们的工作模式是 中枢神经系统血管功能障碍会加速神经退变，从而限制活动和与健康相关的 生活质量。本研究的目的是量化MS患者的中枢神经系统血管病变。 视网膜的微血管变化是确定神经退行性变的可治疗修饰物的第一步。 总体研究假设是，通过光学相干断层扫描测量的视网膜微血管改变 多发性硬化症患者的血管造影(OCTA)将与患者报告的和客观的 神经退行性变。长期目标是使用OCTA作为血管功能障碍的替代试验 神经保护性疗法。 计划：这是一项观察性研究。研究程序包括一组标准的神经学和视觉 临床检查评估参与者的功能，问卷评估参与者的生活质量，以及OCTA 通过视网膜评估中枢神经系统的血管形成。 方法：这项为期两年的前瞻性队列研究采用横断面和纵向分析进行比较。 血管并存对视网膜血管密度的影响，由OCTA确定，作为一种测量 神经元结构和功能的完整性。研究的MRI数据将在基线和2年内收集。我们会 招收44名受试者(占纵向目标辍学的25%)，目标是34名MS受试者， 无血管合并症(V+、V-)。来自另外22名健康对照的数据已经 已被收集，并将被纳入分析。受试者的年龄将在30-70岁之间，并将按年龄匹配， 性别，以及疾病修正疗法的使用。主要结果是比较患者的视网膜血管密度 V+和V-退伍军人通过横断面分析(具体目标1)。我们还将探索视网膜血管 与V-退伍军人相比，密度与V+的脑萎缩率增加相关(特定目标2)。 重要的是，我们还将确定V+和V-的临床损害和生活质量是否恶化得更快 退伍军人(具体目标3)。 与退伍军人事务部的使命相关：拟议的研究将对我们的退伍军人群体产生深远影响： 在退伍军人管理局系统内接受多发性硬化症治疗的28,000名退伍军人中，约50%至少有一名 血管疾病共病。由于这些合并症中的许多是可改变的，早期识别血管 功能障碍为早期干预提供了机会之窗，以优化活动、参与和 与健康相关的生活质量。退伍军人管理局波特兰医疗保健系统(VAPORHCS)是我的理想场所 培训计划。我们每年为500多名患有多发性硬化症的退伍军人提供护理。此外，我们是仅有的两个 弗吉尼亚州内的国家MS卓越中心(MSCoE West)。有了这个称号，我们就有了一个特殊的 致力于制定临床护理、教育和高质量协作研究的标准 患有多发性硬化症的退伍军人使用退伍军人管理局诊所网络通过两个退伍军人管理局MSCoE进行协调，结果来自 这项研究可以转化为改善所有有MS的退伍军人的护理。通过这次经历，我也会 获得视觉结果、统计分析、试验设计和团队领导方面的必要技能，以使我 成为全国康复研究的领先者，最终提高退伍军人的生活质量 和梅根女士在一起。

Objectives: Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative illness that affects nearly 1 million people in the United States. Currently, there are no FDA-approved treatments that directly address neurodegeneration and its associated clinical impairment. Systemic vascular disease comorbidities, including hypertension, hyperlipidemia, and obesity, independently worsen MS-related walking limitations. In addition, MS pathology demonstrates microvascular dysfunction in the central nervous system (CNS). Our working model is that CNS vascular dysfunction accelerates neurodegeneration and thus limitations in activity and health-related quality of life. The purpose of this study is to quantify CNS vasculopathy in people with MS through microvascular changes in the retina as a first step to identify treatable modifiers of neurodegeneration. The overall study hypothesis is that retinal microvascular changes, measured by optical coherence tomography angiography (OCTA), in people with MS will correlate with patient-reported and objective measures of neurodegeneration. The long-term goal is to use OCTA as a surrogate of vascular dysfunction in trials of neuroprotective therapies. Plan: This is an observational study. The study procedures include a standard battery of neurologic and visual clinical exams to assess participant function, questionnaires to assess participant quality of life, and OCTA to assess CNS vasculature through the retina. Methods: This 2-year prospective cohort study features cross-sectional and longitudinal analyses to compare the impact of vascular comorbidities on retinal vascular density, determined by OCTA, as a measure of neuronal structural and functional integrity. Study MRI data will be collected at baseline and 2 years. We will enroll 44 subjects (accounting for 25% drop out for longitudinal aims) with a goal of 34 MS subjects with and without vascular comorbidities (V+, V- respectively). Data from an additional 22 healthy controls has already been collected and will be included for analysis. Subjects will be aged 30-70 and will be matched by age, gender, and use of disease modifying therapies. The primary outcome is to compare retinal vascular density in V+ and V- Veterans through cross-sectional analysis (Specific Aim 1). We will also explore if retinal vascular density correlates with increased rate of brain atrophy in V+ compared to V- Veterans (Specific Aim 2). Importantly, we will also determine if clinical impairment and quality of life deteriorates faster in V+ versus V- Veterans (Specific Aim 3). Relevance to VA’s Mission: The proposed study will have a profound impact on our Veteran population: of the 28,000 Veterans receiving care for MS within the VA system, approximately 50% have at least one vascular disease comorbidity. Since many of these comorbidities are modifiable, early identification of vascular dysfunction provides a window of opportunity for early interventions to optimize activity, participation and health-related quality of life. The VA Portland Health Care System (VAPORHCS) is an ideal place for my training program. We provide care for over 500 Veterans with MS annually. Additionally, we are one of only two national MS Centers of Excellence (MSCoE West) within the VA. With this designation, we have a particular dedication to setting the standards for clinical care, education, and high-quality collaborative research for Veterans with MS. Using the network of VA MS Clinics coordinated through the two VA MSCoE, findings from this study can be translated into improved care of all Veterans with MS. Through this experience, I will also gain the necessary skills in visual outcomes, statistical analysis, trial design, and team leadership to allow me to become a national leader in rehabilitation research and to ultimately improve the quality of life of Veterans with MS.