Vascular Mechanisms, Functional Outcomes, & Exercise Among Persons With Multiple Sclerosis With Hypertension

Functionally, the disease pathophysiology of multiple sclerosis (MS) brings about a number of consequences, including cognitive dysfunction and mobility disability, which are two of the most prevalent outcomes of MS. Cognitive impairments typically occur in domains of mental processing speed and working memory and is present in 40-70% of patients with MS based on neuropsychological testing. Cognitive impairment compromises quality of life, activities of daily living, employment, and independent living in persons with MS, and co-occurs with decrements in physical abilities. Mobility disability presents as slowed walking speed and reduced walking endurance and presents in nearly 75% of persons with MS population. Cognitive dysfunction and mobility disability might be worsened through the presence of co-morbid conditions that are manageable through life-style behaviors in MS.

Hypertension is the most prevalent cardiovascular comorbidity in MS and is 25% more common in MS than the general population. Yet, there is truly a dearth of research investigating the unique and understudied population of hypertensives with MS. Importantly, hypertension produces vascular changes causing increased blood pressure (BP) pulsatility. The increased pulsatility has been associated with detrimental changes in the brain in the general population and persons with MS. The investigators have shown that BP pulsatility is inversely associated with mobility in people with MS, and that elevated BP is associated with worse cognition in MS. This suggests that mitigating hypertension and decreasing BP pulsatility through lifestyle behaviors may represent important mechanistic pathways for exerting functional adaptations in cognition and mobility for people with MS.

Physical activity and exercise training are effective approaches for improving vascular hemodynamics and BP in the general population of person with hypertension. The investigators have shown that endothelial function and arterial stiffness, which are two important mechanisms related to hypertension, are associated with physical activity in people with MS. The investigators have further shown that exercise training improves endothelial function, mobility, and cognitive function in people with MS. This suggests that exercise training may improve cognition and mobility through vascular outcomes in persons with MS who have hypertension.

The existing studies that improve cardiovascular fitness, cognitive function, and mobility in persons with MS have been center-based, directly supervised, and prescreened participants for the absence of risk factors for cardiovascular disease (CVD). This severely limits the scalability and reach of exercise interventions for managing the functional consequences of MS, and no exercise studies, to date, have targeted persons with MS who are hypertensive, thus, it is unknown if the results will transfer or work better in this group who are higher risk of CVD-related outcomes. Based on our previous randomized controlled trial (RCT) funded by the National Multiple Sclerosis Society (Grant RG4702A), The investigators are the first to successfully demonstrate that a 12-week home-based aerobic exercise intervention, coupled with internet-based monitoring and behavioral coaching, is safe and feasible among persons with MS and yielded improvements in aerobic fitness, vascular function, and mobility. However, our RCT was conducted in volunteers with MS who were prescreened for CVD risk factors (i.e., excluded persons with CVD-related comorbidities), but serves as a precursor for conducting a similar RCT in persons with cardiovascular comorbidities, such as hypertension. The proposed study aims to address this important gap and underrepresented population.

Our long-term goal involves establishing the scientific basis of home-based exercise training as a therapeutic approach for optimizing functional recovery and quality of life in persons with MS. The objective of this application will follow a RCT design and will evaluate if home-based exercise training can elicit improvements in mechanisms of hemodynamic control related to hypertension and yield clinical benefits for cognition and mobility among persons with MS who have hypertension. This would be the first of its kind RCT ever conducted in persons with MS.

Our central hypothesis is that aerobic exercise training will positively impact cognition and mobility disability (two primary outcomes) and that it will also improve cardiovascular-specific mechanisms of hypertension (secondary outcomes). Exercise training improves hypertension, and hypertension is negatively associated with cognition and mobility in older adults and persons with Alzheimer's disease. The investigators believe that a well-designed aerobic exercise training stimulus is likely to improve hypertension-related mechanisms, which will positively impact cognition and mobility disability in persons with MS, thus improving functional recovery. This central hypothesis will be addressed by pursuing two main specific aims and one exploratory specific aim via a 12-week home-based aerobic exercise training program among persons with MS who have hypertension compared with an attention-control program:

1. Specific Aim 1 is to determine if the intervention improves functional outcomes related to cognition, specifically information processing speed, and mobility in hypertensives with MS. Our working hypothesis is that 12 weeks of aerobic exercise training will improve information processing speed (symbol digits modality test (SDMT) and California Verbal Learning Test-II (CVLT-II)) and attenuate mobility disability (e.g., timed 25-foot walk), which are important markers of functional outcomes. 2. Specific Aim 2 will determine if vascular function and BP improve with exercise training compared with control. Our working hypothesis is that 12 weeks of aerobic exercise training will reduce BP and pulsatility, while also improving vascular-specific mechanisms related to hypertension (e.g., endothelial function and arterial stiffness). 3. Specific Aim 3 is exploratory and will determine if the change in BP and vascular function can account for the change in cognition and/or mobility following exercise training. Our exploratory hypothesis is that changes in vascular function and BP will be associated with changes in cognition and walking mobility.

• Blood pressure [Time frame: Baseline, pre-intervention/oscillometry, applanation tonometry; Within 5 days after completion of training intervention/oscillometry, applanation tonometry]
• Flow-mediated dilation [Time frame: Baseline, pre-intervention/ultrasonography; Within 5 days after completion of training intervention/ultrasonography]
• Forearm blood flow [Time frame: Baseline, pre-intervention/ strain-gauge plethysmography; Within 5 days after completion of training intervention/strain-gauge plethysmography]
• Cardiorespiratory fitness [Time frame: Baseline, pre-intervention/indirect calorimetry; Within 5 days after completion of training intervention/indirect calorimetry]