Systolic Blood Pressure Variability and Multiple Sclerosis Disease Progression

Technical Abstract Background: Over 25% of individuals with multiple sclerosis (MS) also suffer from ≥ 1 co-morbid condition.1,2 Those individuals with both MS and comorbid disease, are at an increased risk of delay in diagnosis,3 MS relapse,4 disease progression,3 reduced quality of life,5 and increased socio-economic burdens.2 Among co-morbid diseases, vascular comorbidities and risk factors (e.g. hypertension, hyperlipidemia, obesity, and smoking) are associated with higher disability and patient-reported worsening of symptoms.6,7 Systolic blood pressure variability (SBPv) is emerging as a risk factor for a wide array of health outcomes.8-10 The effects of excessive SBPv have been found to be independent of mean blood pressure and observed for both hypertensive and normotensive persons.11,12 SBPv is linked to cognitive decline and MRI changes in the elderly.13 Within neurology, SBPv is associated with cognitive dysfunction in Parkinson’s disease14 and other conditions. We identified excessive SBPv as a risk factor for self-reported MS disability.15 This novel component of vascular disease merits further study. This proposal directly addresses the Focus Area “Correlates of Disease Activity and Progression in Multiple Sclerosis.” Hypothesis/Objective: Hypothesis 1: Vascular comorbidities are associated with increased disability in MS patients. Hypothesis 2: Excessive SBPv is associated with higher probability of disability progression, independent of comorbid vascular conditions and covariates. Study Question 3: Can optimal treatments to reduce blood pressure and SBPv delay the time to the first negative MS outcome? Specific Aims: Aim 1: Evaluate the impact of vascular comorbidities and related risk factors on MS disability in a dataset of ~1200 subjects from three well-controlled clinical trials with 96-week endpoint. Disability progression will be measured by the Expanded Disability Status Scale (EDSS). Aim 2: Determine if excessive SBPv is associated with clinical or subclinical disease progression from baseline to 96-week endpoint, controlling for obesity and other vascular risk factors. Aim 3: Develop a Markov Decision Process prediction model to determine the impact of vascular co-morbid disease and risk factor management on MS outcomes. Using combined clinical trial data, we will build a 10- year horizon model to determine outcomes in MS patients based on initial health status and treatments for comorbid conditions. We will assess if treatments to manage vascular comorbidities and improve risk factors will delay the time to the first negative MS outcome (EDSS ≥ 7.0). Study Design: This study will utilize data for ~1200 MS subjects from three completed Phase II and III clinical trials, which included longitudinal outcomes assessed every 3 months over two years (96 weeks). These data will include both relapsing and progressive populations and provide an opportunity to study the impact of vascular comorbidities and SBPv across the complete spectrum of MS disease. Impact: The proposed project represents the largest and first longitudinal assessment of vascular comorbidities and related risk factors in MS disease progression. Using novel mathematical modeling, this study will also provide insights into the therapeutic impact of managing these conditions for MS patients. Our work will provide critical and actionable information that has implications for clinical practice in the short term and scientific knowledge base to build on for future improvements in care for individuals living with MS in the long term.