Aerobic Exercise and Brain Health in Multiple Sclerosis

Study Overview
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Brief Summary
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The purpose of the project is to investigate how aerobic exercise affects brain volume, specific brain regions, neurotrophins and cognition in patients with multiple sclerosis. The study will be a single blinded randomized controlled trial with a 6 months intervention. It is hypothesized that aerobic exercise can slow down brain atrophy, increase the size of hippocampus, upregulate the secretion of neurotrophins and improve cognitive performance in people with multiple sclerosis.

Detailed Description
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Multiple Sclerosis (MS) is a physically and cognitively disabling, chronic autoimmune disease of unknown etiology. It is the most common neurological disease affecting young adults in Western countries. According to the Danish MS Registry the prevalence has increased markedly over the last 40 years for particularly women, and today there are approximately 14.000 patients with MS (PwMS) in Denmark. The pathological hallmark of MS is sclerotic plaque. Plaques in the central nervous system (CNS) can be detected in vivo using magnetic resonance imaging (MRI). Both the accumulation of lesions and the accelerated whole-brain atrophy correlate with the progressing physical and cognitive disabilities that clinically characterize PwMS. The disease causes damage of both white and grey matter in the CNS, leading to whole brain atrophy and topographically specific atrophy within the hippocampus and the frontal and temporal cortices. The degradation of the CNS manifests as cognitive and physical disability. Cognitive impairment is estimated to affect up to 65% of PwMS, making it one of the most common and disabling symptoms of MS. Medical therapies for cognitive impairment in MS have so far proved ineffective. Collectively, the prevalence, impact and missing treatments highlight the importance of alternative approaches towards preservation of cognitive function. Despite equivocal findings, aerobic exercise represents a promising approach towards preservation or even expansion of hippocampal volume and cognitive functioning in MS. No longitudinal randomized controlled trial (RCT) study has so far applied the MRI technique when evaluating the potential neuro-protective effect of exercise on brain structure and function in MS. Also, given the scarcity of effective treatments for cognitive impairment in MS, a longitudinal exercise intervention evaluating the potential effect of aerobic exercise on cognition is urgently needed in MS. The purpose of the present project is to investigate how aerobic exercise affects brain volume, specific brain regions, neurotrophins and cognition in PwMS. It is hypothesized that aerobic exercise can slow down brain atrophy, increase the size of hippocampus, upregulate the secretion of neurotrophins and improve cognitive performance in people with MS. The study will be a single blinded RCT. The exercise intervention will contain 6 months of aerobic training (bicycling, rowing and cross trainer) performed two times a week at moderate to high intensity and under supervision. The control group will be living as usual and will be offered the same exercise intervention after a 6 month period. A total of approximately 85 PwMS will be expected to be enrolled. The primary outcome of the study will be brain atrophy determined by MRI. The current interdisciplinary project aims to document and understand the possible neuro-protective effects of exercise in MS. This would be of high relevance to PwMS (and other neurological pathologies). From a societal perspective it would help optimize MS rehabilitation and subsequently reduce MS related costs due to disability. In case of positive findings, this would provide the first convincing human evidence of a disease modifying effect of exercise in MS.

Official Title
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Effects of Aerobic Exercise on Brain Health in People With Multiple Sclerosis

Conditions
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Multiple Sclerosis, Brain Atrophy, Cognitive Impairment

Intervention / Treatment
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* Other: Aerobic exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed consent Definite MS diagnosis Be clarified with the diagnosis and treatment Expectedly able to carry out the aerobic training / test Expanded Disability Status Scale (EDSS) score ≤6.0 Must be able to transport themselves to and from training sessions Exclusion Criteria: Dementia, alcohol abuse or pacemaker Medical comorbidity such as cardiovascular, respiratory, orthopedic or metabolic disorders or other concurrent diseases causing disability and hindering participation in the intervention Disease relapse in a 8 week period prior to study start Pregnancy Metallic implants hindering the MRI scans. Expected training attendance below 85%

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aerobic exercise<br>Aerobic exercise two times per week for 24 weeks. | Other: Aerobic exercise<br> <br> |
| No Intervention: Habitual lifestyle<br>Habitual lifestyle the first 24 weeks. Will be offered the same exercise intervention after 24 weeks. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage brain volume change |  | 0, 24 and 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognition measured by the Brief Repeatable Battery of Neuropsychological Tests |  | 0, 24 and 48 weeks | 
| Blood samples: Cytokines and neurotrophins | brain derived neurotrophic factor and key cytokines | 0, 24 and 48 weeks | 
| VO2max |  | 0, 24 and 48 weeks | 
| Regional volume change changes (e.g. hippocampus, thalamus) |  | 0, 24 and 48 weeks | 
| Modified Fatigue Impact Scale | Lower score is better. Range 0-84 | 0, 24 and 48 weeks | 
| Fatigue Severity Scale | Lower score is better. Range 9-63. | 0, 24 and 48 weeks | 
| Major Depression Inventory | Lower score is better. Range 0-50 | 0, 24 and 48 weeks | 
| Short Form 36 | Higher score is better. Each item is scored on a 0 to 100 range. | 0, 24 and 48 weeks | 
| Multiple Sclerosis Impact Scale 29 | Converted to a 0-100 scale where 100 indicates greater impact of disease on daily function | 0, 24 and 48 weeks | 
| 6-min walk test | Walk as far as possible in 6 minutes. Higher is better. | 0, 24 and 48 weeks | 
| Six Spot Step Test | Complete the task as fast as possible. Faster is better. | 0, 24 and 48 weeks |