Retinal microvasculature as a predictor of neurodegeneration in multiple sclerosis

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.