- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04944251
Regular Exercise Improves Physical Capacity and Promotes Neurotrophins in Patients With Multiple Sclerosis
Exercise in Persons With Multiple Sclerosis
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.
Study Overview
Status
Intervention / Treatment
Detailed Description
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.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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Bornova
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Izmir, Bornova, Turkey, 35100
- Ege University
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: aerobic exercise group
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
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the third month, for 30 minutes or 1 hour, 3 days a week
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Experimental: strength exercise group
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.
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the third month, for 30 minutes or 1 hour, 3 days a week
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No Intervention: control group
The patients who didn't want to exercise were included in the control group.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Aerobic capacity assessment after exercise intervention
Time Frame: Each participant's progress will be tested at the beginning and end of the 12-week training period.
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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.
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Strength assessment after exercise intervention
Time Frame: Each participant's progress will be tested at the beginning and end of the 12-week training period.
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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.
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Each participant's progress will be tested at the beginning and end of the 12-week training period.
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plasma neurotrophin values (pg/ml)
Time Frame: Each participant's progress will be tested at the beginning and end of the 12-week training period.
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Plasma NGF and NT-3 levels were measured with an ELISA kit.
Plasma neurotrophin values increased in exercise groups.
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Each participant's progress will be tested at the beginning and end of the 12-week training period.
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Mehmet ACIK, Dr, Ege University
- Study Director: Seckin Senisik, Ass. Prof., Ege University
- Study Director: Nur Yuceyar, Professor, Ege University
Publications and helpful links
General Publications
- KARVONEN MJ, KENTALA E, MUSTALA O. The effects of training on heart rate; a longitudinal study. Ann Med Exp Biol Fenn. 1957;35(3):307-15. No abstract available.
- Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002 Jun;25(6):295-301. doi: 10.1016/s0166-2236(02)02143-4.
- Dalgas U, Stenager E, Jakobsen J, Petersen T, Hansen HJ, Knudsen C, Overgaard K, Ingemann-Hansen T. Fatigue, mood and quality of life improve in MS patients after progressive resistance training. Mult Scler. 2010 Apr;16(4):480-90. doi: 10.1177/1352458509360040. Epub 2010 Mar 1.
- Bamer AM, Johnson KL, Amtmann D, Kraft GH. Prevalence of sleep problems in individuals with multiple sclerosis. Mult Scler. 2008 Sep;14(8):1127-30. doi: 10.1177/1352458508092807. Epub 2008 Jul 16.
- Lassmann H. Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis. Front Immunol. 2019 Jan 10;9:3116. doi: 10.3389/fimmu.2018.03116. eCollection 2018.
- Oh J, Vidal-Jordana A, Montalban X. Multiple sclerosis: clinical aspects. Curr Opin Neurol. 2018 Dec;31(6):752-759. doi: 10.1097/WCO.0000000000000622.
- Mazumder R, Murchison C, Bourdette D, Cameron M. Falls in people with multiple sclerosis compared with falls in healthy controls. PLoS One. 2014 Sep 25;9(9):e107620. doi: 10.1371/journal.pone.0107620. eCollection 2014.
- Benedict RH, Wahlig E, Bakshi R, Fishman I, Munschauer F, Zivadinov R, Weinstock-Guttman B. Predicting quality of life in multiple sclerosis: accounting for physical disability, fatigue, cognition, mood disorder, personality, and behavior change. J Neurol Sci. 2005 Apr 15;231(1-2):29-34. doi: 10.1016/j.jns.2004.12.009. Epub 2005 Jan 26.
- Jorgensen M, Dalgas U, Wens I, Hvid LG. Muscle strength and power in persons with multiple sclerosis - A systematic review and meta-analysis. J Neurol Sci. 2017 May 15;376:225-241. doi: 10.1016/j.jns.2017.03.022. Epub 2017 Mar 18.
- Phillips C, Baktir MA, Srivatsan M, Salehi A. Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling. Front Cell Neurosci. 2014 Jun 20;8:170. doi: 10.3389/fncel.2014.00170. eCollection 2014.
- Lange-Asschenfeldt C, Kojda G. Alzheimer's disease, cerebrovascular dysfunction and the benefits of exercise: from vessels to neurons. Exp Gerontol. 2008 Jun;43(6):499-504. doi: 10.1016/j.exger.2008.04.002. Epub 2008 Apr 6.
- Vilar M, Mira H. Regulation of Neurogenesis by Neurotrophins during Adulthood: Expected and Unexpected Roles. Front Neurosci. 2016 Feb 9;10:26. doi: 10.3389/fnins.2016.00026. eCollection 2016.
- Riley CP, Cope TC, Buck CR. CNS neurotrophins are biologically active and expressed by multiple cell types. J Mol Histol. 2004 Nov;35(8-9):771-83. doi: 10.1007/s10735-004-0778-9.
- Yamamoto M, Sobue G, Yamamoto K, Terao S, Mitsuma T. Expression of mRNAs for neurotrophic factors (NGF, BDNF, NT-3, and GDNF) and their receptors (p75NGFR, trkA, trkB, and trkC) in the adult human peripheral nervous system and nonneural tissues. Neurochem Res. 1996 Aug;21(8):929-38. doi: 10.1007/BF02532343.
- Langeskov-Christensen M, Heine M, Kwakkel G, Dalgas U. Aerobic capacity in persons with multiple sclerosis: a systematic review and meta-analysis. Sports Med. 2015 Jun;45(6):905-23. doi: 10.1007/s40279-015-0307-x.
- Langeskov-Christensen M, Langeskov-Christensen D, Overgaard K, Moller AB, Dalgas U. Validity and reliability of VO(2)-max measurements in persons with multiple sclerosis. J Neurol Sci. 2014 Jul 15;342(1-2):79-87. doi: 10.1016/j.jns.2014.04.028. Epub 2014 Apr 27.
- ASTRAND PO, RYHMING I. A nomogram for calculation of aerobic capacity (physical fitness) from pulse rate during sub-maximal work. J Appl Physiol. 1954 Sep;7(2):218-21. doi: 10.1152/jappl.1954.7.2.218. No abstract available.
- Lippi G, Mattiuzzi C, Sanchis-Gomar F. Updated overview on interplay between physical exercise, neurotrophins, and cognitive function in humans. J Sport Health Sci. 2020 Jan;9(1):74-81. doi: 10.1016/j.jshs.2019.07.012. Epub 2019 Sep 6.
- Ernfors P, Lee KF, Kucera J, Jaenisch R. Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents. Cell. 1994 May 20;77(4):503-12. doi: 10.1016/0092-8674(94)90213-5.
- Dominguez-Sanchez MA, Bustos-Cruz RH, Velasco-Orjuela GP, Quintero AP, Tordecilla-Sanders A, Correa-Bautista JE, Triana-Reina HR, Garcia-Hermoso A, Gonzalez-Ruiz K, Pena-Guzman CA, Hernandez E, Pena-Ibagon JC, Tellez-T LA, Izquierdo M, Ramirez-Velez R. Acute Effects of High Intensity, Resistance, or Combined Protocol on the Increase of Level of Neurotrophic Factors in Physically Inactive Overweight Adults: The BrainFit Study. Front Physiol. 2018 Jun 27;9:741. doi: 10.3389/fphys.2018.00741. eCollection 2018.
- Manni L, Rocco ML, Bianchi P, Soligo M, Guaragna M, Barbaro SP, Aloe L. Nerve growth factor: basic studies and possible therapeutic applications. Growth Factors. 2013 Aug;31(4):115-22. doi: 10.3109/08977194.2013.804073. Epub 2013 Jun 19.
- Briken S, Gold SM, Patra S, Vettorazzi E, Harbs D, Tallner A, Ketels G, Schulz KH, Heesen C. Effects of exercise on fitness and cognition in progressive MS: a randomized, controlled pilot trial. Mult Scler. 2014 Mar;20(3):382-90. doi: 10.1177/1352458513507358. Epub 2013 Oct 24.
- Zheng F, Zhou X, Moon C, Wang H. Regulation of brain-derived neurotrophic factor expression in neurons. Int J Physiol Pathophysiol Pharmacol. 2012;4(4):188-200. Epub 2012 Dec 26.
- Leavitt VM, Cirnigliaro C, Cohen A, Farag A, Brooks M, Wecht JM, Wylie GR, Chiaravalloti ND, DeLuca J, Sumowski JF. Aerobic exercise increases hippocampal volume and improves memory in multiple sclerosis: preliminary findings. Neurocase. 2014;20(6):695-7. doi: 10.1080/13554794.2013.841951. Epub 2013 Oct 4.
- Frielingsdorf H, Simpson DR, Thal LJ, Pizzo DP. Nerve growth factor promotes survival of new neurons in the adult hippocampus. Neurobiol Dis. 2007 Apr;26(1):47-55. doi: 10.1016/j.nbd.2006.11.015. Epub 2006 Dec 20.
- Erickson KI, Kramer AF. Aerobic exercise effects on cognitive and neural plasticity in older adults. Br J Sports Med. 2009 Jan;43(1):22-4. doi: 10.1136/bjsm.2008.052498. Epub 2008 Oct 16. No abstract available.
- Paltamaa J, Sjogren T, Peurala SH, Heinonen A. Effects of physiotherapy interventions on balance in multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials. J Rehabil Med. 2012 Oct;44(10):811-23. doi: 10.2340/16501977-1047.
- Cakt BD, Nacir B, Genc H, Saracoglu M, Karagoz A, Erdem HR, Ergun U. Cycling progressive resistance training for people with multiple sclerosis: a randomized controlled study. Am J Phys Med Rehabil. 2010 Jun;89(6):446-57. doi: 10.1097/PHM.0b013e3181d3e71f.
- Sadeghi Bahmani D, Kesselring J, Papadimitriou M, Bansi J, Puhse U, Gerber M, Shaygannejad V, Holsboer-Trachsler E, Brand S. In Patients With Multiple Sclerosis, Both Objective and Subjective Sleep, Depression, Fatigue, and Paresthesia Improved After 3 Weeks of Regular Exercise. Front Psychiatry. 2019 May 3;10:265. doi: 10.3389/fpsyt.2019.00265. eCollection 2019.
- Yang PY, Ho KH, Chen HC, Chien MY. Exercise training improves sleep quality in middle-aged and older adults with sleep problems: a systematic review. J Physiother. 2012;58(3):157-63. doi: 10.1016/S1836-9553(12)70106-6.
- Santos RV, Tufik S, De Mello MT. Exercise, sleep and cytokines: is there a relation? Sleep Med Rev. 2007 Jun;11(3):231-9. doi: 10.1016/j.smrv.2007.03.003.
- Melancon MO, Lorrain D, Dionne IJ. Exercise and sleep in aging: emphasis on serotonin. Pathol Biol (Paris). 2014 Oct;62(5):276-83. doi: 10.1016/j.patbio.2014.07.004. Epub 2014 Aug 4.
- Rooney S, Wood L, Moffat F, Paul L. Is Fatigue Associated With Aerobic Capacity and Muscle Strength in People With Multiple Sclerosis: A Systematic Review and Meta-analysis. Arch Phys Med Rehabil. 2019 Nov;100(11):2193-2204. doi: 10.1016/j.apmr.2019.06.014. Epub 2019 Aug 6.
- Motl RW, Snook EM. Physical activity, self-efficacy, and quality of life in multiple sclerosis. Ann Behav Med. 2008 Feb;35(1):111-5. doi: 10.1007/s12160-007-9006-7. Epub 2008 Feb 12.
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Study record dates
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Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
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First Posted (Actual)
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Last Update Posted (Actual)
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More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 19-4T/43
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
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- STUDY_PROTOCOL
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