Regular Exercise Improves Physical Capacity and Promotes Neurotrophins in Patients With Multiple Sclerosis

Study Overview
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Brief Summary
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ABSTRACT Objective: The investigators aimed to determine the effect of regular exercise on aerobic capacity, strength values, and plasma levels of nerve growth factor (NGF) and Neurotrophin-3 (NT-3) in patients with multiple sclerosis (MS), and investigate its effects on MS symptoms including cognitive impairment, fatigue, balance disorders and quality of life. Methods: Forty-three relapsing-remitting MS (RRMS) patients with an EDSS score of 4 or less participated in the study. Participants were divided into 3 groups as aerobic exercise, strength exercise and control groups. The patients in the exercise groups had exercise programs 3 days a week, for 3 months. Aerobic capacity (maximum VO2 value), strength measurements and balance tests were done, and NGF and NT-3 plasma levels were analyzed in all participants at the beginning and end of the study. MSQoL54 quality of life, fatigue impact scale (FIS), Pittsburgh Sleep Quality Index (PSQI) and BICAMS scale were applied to evaluate cognitive functions.

Detailed Description
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INTRODUCTION Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder characterized by inflammation, demyelination, axonal damage and gliosis, particularly affecting white matter, and also gray matter 1. It is the most common disorder of the central nervous system (CNS) that causes neurological disability in young adults. Various degrees of physical and cognitive impairments are seen starting in the early period, and particularly in the progressive course of the disease 2. Physical inactivity may lead to progressive muscle atrophy in MS patients due to insufficient neural stimulation to the muscles 6. In MS patients, maximal oxygen consumption (VO2 max), which is a marker of cardiorespiratory fitness and functional performance, has been shown to decrease 7. All of these conditions may lead to worsening of MS symptoms and fatigue, which may result in a vicious cycle and cause reduced physical activity and an impairment in quality of life. Exercise has numerous neurobiological effects, including anatomical and physiological changes in the brains of healthy and unhealthy individuals 8. Exercise provides comprehensive alterations in cerebrovascular structures such as blood flow, nutrient delivery, development of angiogenesis and regeneration of blood vessels 9. These alterations facilitate neurogenesis, increase synaptic plasticity, and ultimately may improve brain health and MS-related symptoms 9. Neurotrophins (NT) are growth factors that provide the survival and hypertrophy of neurons, as well as neurogenesis and synaptic plasticity 10. They are synthesized by a number of cell types including peripheral nervous system neurons, peripheral tissues, and particularly in the CNS 11,12. It is believed that exercise activates molecules and cellular cascades that support and maintain brain plasticity, facilitates neurogenesis, and thus may be effective in neurodegenerative processes and cognitive disorders 13. In this study, the investigators aimed to investigate the effect of regular exercise on aerobic capacity and strength values, and to determine whether exercise contributes to the improvement of cognitive, balance, and sleep disorders and fatigue, and quality of life in MS patients. The investigators also investigated post-exercise changes in the plasma levels of neurotrophins, nerve growth factor (NGF) and neurotrophin-3 (NT-3), which are important biomarkers in neural regeneration and re-myelination. MATERIAL AND METHODS Study design A total of 53 relapsing remitting form MS (RRMS) patients between the ages of 18-55 years, diagnosed with definite MS according to 2017 McDonald criteria, and followed up in Ege University MS and Demyelinating Diseases Unit, without an MS attack in the last 3 months, had an EDSS score ≤ 4 that did not change with symptomatic or immunomodulatory treatments within 6 months were included in this prospective randomized controlled study. The procedures and possible side effects (such as exercise-related injuries and having an MS attack) were explained in detail to each participant candidate, and the Informed Consent Form was signed by the volunteers. Ege University Clinical Research Ethics Committee approved the study protocol (date: Apr 03, 2019, decree no: 19-4T/43). The patients who participated in the study and wished to be included in the exercise group were randomly allocated to the aerobic exercise and strength exercise groups. The patients who didn't want to exercise were included in the control group. Four patients in the aerobic group and 6 patients in the strength group could not complete the study due to reasons such as knee pain (1), not attending exercise sessions regularly (8), and not attending control measurements (1). Exercise Procedures: The patients in the exercise groups carried out tailor-made exercise programs, under the supervision of a faculty member of the Faculty of Sports Sciences. It was paid attention to keep the temperature of the exercise room at 20°C. The control patients did not participate in any exercise or physical activity program. In the first month, the patients in the aerobic group started to exercise at a heart rate corresponding to 60% of the maximal VO2, by adjusting the pedal resistance of the exercise bike, consistent with the Karvonen formula. This was followed by exercise cycling at a heart rate corresponding to 70% of maximal VO2 in the second month, and 80% of maximal VO2 in the third month, for 30 minutes, 3 days a week (Figure 1) 14. The patients included in the strength exercise group performed weight training exercises involving 10 large muscle groups (leg press, chest press, leg curl, lateral pull down, leg extension, dumbbell lateral raise, calf press, upright row, sit up, quadruped arm opposite leg raise), 3 days a week; including 1 set of 12-15 repetitions in the first month, 2 sets of 12-15 repetitions in the second month, and 3 sets of 12-15 repetitions in the third month. Participants' working weights were set as 60% of the maximum weight they could lift.

Official Title
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Exercise in Persons With Multiple Sclerosis

Conditions
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Multiple Sclerosis, Exercise Intervention, Neuro-Degenerative Disease

Intervention / Treatment
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* Behavioral: Regular Exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A total of 53 relapsing remitting form MS (RRMS) patients between the ages of 18-55 years, diagnosed with definite MS according to 2017 McDonald criteria, and followed up in Ege University MS and Demyelinating Diseases Unit, without an MS attack in the last 3 months, had an EDSS score ≤ 4 that did not change with symptomatic or immunomodulatory treatments within 6 months were included in this prospective randomized controlled study. Exclusion Criteria: Patients who did not meet the inclusion criteria were excluded from the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized prospective study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: aerobic exercise group<br>the patients in the aerobic group started to exercise at a heart rate corresponding to 60% of the maximal VO2, by adjusting the pedal resistance of the exercise bike, consistent with the Karvonen formula. This was followed by exercise cycling at a heart rate corresponding to 70% of maximal VO2 in the second month, and 80% of maximal VO2 in the third month, for 30 minutes, 3 days a week | Behavioral: Regular Exercise<br>* the third month, for 30 minutes or 1 hour, 3 days a week<br>|
| Experimental: strength exercise group<br>The patients included in the strength exercise group performed weight training exercises involving 10 large muscle groups (leg press, chest press, leg curl, lateral pull down, leg extension, dumbbell lateral raise, calf press, upright row, sit up, quadruped arm opposite leg raise), 3 days a week; including 1 set of 12-15 repetitions in the first month, 2 sets of 12-15 repetitions in the second month, and 3 sets of 12-15 repetitions in the third month (Figure 1). Participants' working weights were set as 60% of the maximum weight they could lift. | Behavioral: Regular Exercise<br>* the third month, for 30 minutes or 1 hour, 3 days a week<br>|
| No Intervention: control group<br>The patients who didn't want to exercise were included in the control group. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Aerobic capacity assessment after exercise intervention | Measurement of Aerobic Capacity: Milliliters were used for the amount of oxygen used, kilograms were used for body weight, and minutes were used for time. the amount of oxygen consumed, weight and time will be combined to report aerobic capacity in ml/kg/min. The unit of aerobic capacity, ml/kg/min, refers to the amount of oxygen the body consumes per kilogram per minute. The indirect Astrand test bicycle test protocol with Lode Corival bicycle ergometer was applied to all patients. The pedal resistance applied in the test and the mean pulse rate were marked in the Astrand normogram, and the aerobic capacities of the patients were calculated. It was observed that aerobic capacity (ml/kg/min) increased in exercise groups after regular exercise. | Each participant's progress will be tested at the beginning and end of the 12-week training period. | 
| Strength assessment after exercise intervention | Strength Measurements: The kilogram-force (kg-f) is a non-standard Gravitational Metric unit of force. The kilogram-force is equal to the magnitude of the force exerted on one kilogram of mass in a 9.80665 m/s2 gravitational field. Kilogram was used for weight. The force is any influence that, when unopposed, will change the motion of an object. Weight and force will be combined to report strength in kg-f. Strength was examined with an isometric hand and backleg dynamometer in all patients. Strength was examined with an isometric hand and backleg dynamometer in all patients. Two measurements were made, at the beginning and at the end of the study. It was observed that strength values increased in exercise groups after regular exercise. | Each participant's progress will be tested at the beginning and end of the 12-week training period. | 
| plasma neurotrophin values (pg/ml) | Plasma NGF and NT-3 levels were measured with an ELISA kit. Plasma neurotrophin values increased in exercise groups. | Each participant's progress will be tested at the beginning and end of the 12-week training period. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple sclerosis, exercise, nerve growth factor, neurotrophin 3, cognition, quality of life