Retinal microvasculature as a predictor of neurodegeneration in multiple sclerosis

视网膜微血管作为多发性硬化症神经变性的预测因子

• 批准号: 10680414
• 负责人: Elizabeth Silbermann
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680414
• 关键词: Acceleration; Accounting; Acute; Address; Affect; Age; Angiography; Anti-Inflammatory Agents; Atrophic; Biological Markers; Blood Vessels; Brain; Brain imaging; Caring; Cell Death; Central Nervous System; Cerebrovascular system; Cerebrum; Cholesterol; Chronic; Chronic Disease; Clinic; Clinical; Cross-Sectional Studies; Data; Dedications; Demyelinations; Deterioration; Disease; Disease Progression; Drops; Early Intervention; Early identification; Education; Enrollment; FDA approved; Gait; Gender; Goals; Healthcare Systems; Hyperlipidemia; Hypertension; Hypoxia; Image; Impairment; Inflammation; Inflammatory; Intervention Trial; K-Series Research Career Programs; Leadership; Light; Magnetic Resonance Imaging; Measures; Methods; Microvascular Dysfunction; Mission; Modeling; Multiple Sclerosis; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Obesity; Observational Study; Optical Coherence Tomography; Outcome; Outpatients; Participant; Pathology; Patient Outcomes Assessments; Patient Participation; Patients; Performance; Persons; Play; Positioning Attribute; Procedures; Progressive Disease; Prospective, cohort study; Quality of life; Questionnaires; Rehabilitation therapy; Reporting; Reproducibility; Research; Retina; Risk Factors; Role; Scanning; Spinal Cord; Statistical Data Interpretation; Structure; Swelling; System; Techniques; Technology; Testing; Thinness; Time; Training; Training Programs; Translating; United States; United States National Institutes of Health; Upper Extremity; Vascular Diseases; Veterans; Visual; Walking; aged; arterial spin labeling; brain magnetic resonance imaging; career; cerebral atrophy; cerebral hypoperfusion; clinical care; clinical examination; cognitive performance; cohort; comorbidity; density; disability; experience; gray matter; health related quality of life; improved; longitudinal analysis; military veteran; multiple sclerosis patient; multiple sclerosis treatment; neuron loss; neuroprotection; primary outcome; progressive neurodegeneration; rehabilitation research; retina blood vessel structure; retinal imaging; secondary analysis; skills; standard measure; therapy development; trial design; white matter

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.

目的：多发性硬化症（MS）是一种慢性炎症和神经退行性疾病， 在美国有100万人。目前，没有FDA批准的治疗方法可以直接解决 神经变性及其相关的临床损伤。全身性血管疾病合并症，包括 高血压、高脂血症和肥胖独立地恶化了MS相关行走限制。此外，MS 病理学显示中枢神经系统（CNS）中的微血管功能障碍。我们的工作模式是 CNS血管功能障碍加速神经退行性变，从而限制活动和健康相关的 生活质量本研究的目的是量化MS患者的CNS血管病变， 视网膜中的微血管变化作为识别神经变性的可治疗修饰剂的第一步。 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变化 血管造影（OCTA），在MS患者中将与患者报告的和客观的测量相关， 神经变性长期的目标是使用OCTA作为血管功能障碍的替代品， 神经保护疗法 计划：这是一项观察性研究。研究程序包括一组标准的神经和视觉检查。 评估受试者功能的临床检查、评估受试者生活质量的问卷和OCTA， 通过视网膜评估CNS血管系统。 方法：这项为期2年的前瞻性队列研究采用横断面和纵向分析， 血管合并症对视网膜血管密度的影响，通过OCTA测定，作为衡量 神经元结构和功能的完整性。将在基线和2年时收集研究MRI数据。我们将 入组44例受试者（占纵向目标脱落的25%），目标为34例MS受试者， 无血管合并症（分别为V+、V-）。来自另外22名健康对照的数据已经 已收集并将纳入分析。受试者年龄为30-70岁，将按年龄匹配， 性别和疾病修饰疗法的使用。主要结果是比较视网膜血管密度， V+和V-退伍军人通过横截面分析（具体目标1）。我们还将探讨视网膜血管 与V-退伍军人相比，V+中密度与脑萎缩率增加相关（具体目标2）。 重要的是，我们还将确定V+与V-患者的临床损害和生活质量恶化是否更快 具体目标3（Specific Aim 3） 与退伍军人事务部使命的相关性：拟议的研究将对我们的退伍军人群体产生深远的影响： 在VA系统内接受MS护理的28，000名退伍军人中，大约50%至少有一个 血管疾病合并症。由于这些合并症中的许多是可改变的， 功能障碍为早期干预提供了一个机会窗口，以优化活动，参与和 健康相关的生活质量。VA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MS的退伍军人提供护理。另外，我们是世界上仅有的 弗吉尼亚州内的国家MS卓越中心（MSCoe West）。有了这个名称，我们有一个特殊的 致力于为临床护理，教育和高质量的合作研究制定标准， 患有多发性硬化症的退伍军人。使用通过两个VA MSCoe协调的VA MS诊所网络，研究结果来自 这项研究可以转化为改善所有退伍军人与MS的护理。通过这一经验，我也将 获得必要的技能，在视觉效果，统计分析，试验设计，和团队领导，让我 成为康复研究的国家领导者，并最终提高退伍军人的生活质量 女士