Influence of different rehabilitative aerobic exercise programs on (anti-) inflammatory immune signalling, cognitive and functional capacity in persons with MS - study protocol of a randomized controlled trial

Niklas Joisten, Annette Rademacher, Wilhelm Bloch, Alexander Schenk, Max Oberste, Ulrik Dalgas, Dawn Langdon, Daniel Caminada, Mette-Triin Purde, Roman Gonzenbach, Jan Kool, Philipp Zimmer, Jens Bansi, Niklas Joisten, Annette Rademacher, Wilhelm Bloch, Alexander Schenk, Max Oberste, Ulrik Dalgas, Dawn Langdon, Daniel Caminada, Mette-Triin Purde, Roman Gonzenbach, Jan Kool, Philipp Zimmer, Jens Bansi

Abstract

Background: Studies have shown positive effects of therapeutic exercise on motor- and cognitive function as well as on psychosocial outcomes in persons with multiple sclerosis (MS). A reduction of inflammatory stress through physical exercise has been suspected as one key mechanism, mediating the positive effects of exercise in the context of MS. The primary objective of this trial is to investigate the acute and chronic effects of different exercise modalities on (anti-)inflammatory immune signalling as well as on cognitive and functional capacity in persons with MS.

Methods: A two armed single-blind randomized controlled design will investigate 72 persons with relapsing remitting or secondary progressive MS (EDSS 3.0-6.0), during 3 weeks of inpatient rehabilitation. Participants will be randomized into either a high-intensity interval training (HIIT) or a moderate continuous training group; the latter represents the local standard therapy (ST). Both groups will exercise 3x per week. The HIIT group will perform 5 × 1.5-min high-intensive exercise bouts at 95-100% of their maximum heart rate (HRmax) followed by active breaks of unloaded pedalling (60% HRmax) for 2 min. In contrast, the ST group will exercise for 24 min continuously at 65% of HRmax. The proportion of circulating regulatory T-cells will be measured as primary outcome. Secondary outcomes comprise numbers and proportions of further immune cells including Th17-cells, soluble factors ((anti-) inflammatory cytokines, tryptophan metabolites), endurance capacity, cognitive performance, processing skills for activities of daily living, fatigue, depression and healthcare-related quality of life. Outcomes will be assessed before (T0) and after (T3) the 3-week exercise intervention program. Blood samples of T0 will be taken immediately before the first exercise session. Additionally, blood samples for the soluble factors will be collected immediately after (T1) and three hours (T2) after the first exercise session of each group.

Discussion: This study will be the first to investigate both acute and chronic effects of aerobic exercise on immune function and disease associated biomarkers in persons with MS. Combining biological analyses with cognitive and functional capacity assessments may contribute to a better understanding of responses to rehabilitative training, needed to improve exercise recommendations for persons with MS.

Trial registration: This trial was prospectively registered at ClinicalTrials.gov ( NCT03652519 ; 29 August 2018).

Keywords: Cognition; Exercise; High-intensity interval exercise; Immune signalling; Inflammation; Kynurenine pathway; Multiple sclerosis; Rehabilitation.

Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the Swiss Ethics Committee “Ostschweiz” (EKOS) on research involving humans (EKOS18/96; Project ID: 2018–01378). Prior to study participation, a written consent form will be signed by each participant.

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Experimental design of the planned study. Baseline assessments will be conducted before the first training session (T0) and will be used as baseline value for both acute and chronic exercise training effects. Measurement time points T1 (immediately after first training session) and T2 (3 h after first training session) are implemented to examine the acute effects of each exercise modality on soluble factors. All assessments will be repeated 48 h after the last exercise session (T3) to investigate effects of chronic training following the 3-week exercise intervention
Fig. 2
Fig. 2
Spirit diagram depicting the schedule of enrolment, interventions and assessments. T0 = baseline assessment before the first exercise session; T1 = immediately after the first exercise session; T2 = three hours after the first exercise session; T3 = 48 h after the last exercise session. * Cardiorespiratory fitness and fatigue score are used as stratification factor and will be assessed before allocation

References

    1. Motl RW, Sandroff BM, Kwakkel G, Dalgas U, Feinstein A, Heesen C, et al. Exercise in patients with multiple sclerosis. Lancet Neurol. 2017;16:848–856. doi: 10.1016/S1474-4422(17)30281-8.
    1. Dalgas U. Exercise therapy in multiple sclerosis and its effects on function and the brain. Neurodegener Dis Manag. 2017;7:35–40. doi: 10.2217/nmt-2017-0040.
    1. Kjølhede T, Siemonsen S, Wenzel D, Stellmann J-P, Ringgaard S, Pedersen BG, et al. Can resistance training impact MRI outcomes in relapsing-remitting multiple sclerosis? Mult Scler. 2017:1352458517722645. 10.1177/1352458517722645.
    1. Dalgas U, Stenager E. Exercise and disease progression in multiple sclerosis: can exercise slow down the progression of multiple sclerosis? Ther Adv Neurol Disord. 2012;5:81–95. doi: 10.1177/1756285611430719.
    1. Rossi S, Furlan R, de CV, Musella A, Lo Giudice T, Mataluni G, et al. Exercise attenuates the clinical, synaptic and dendritic abnormalities of experimental autoimmune encephalomyelitis. Neurobiol Dis. 2009;36:51–59. doi: 10.1016/j.nbd.2009.06.013.
    1. Sorensen TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VA, et al. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest. 1999;103:807–815. doi: 10.1172/JCI5150.
    1. Grigoriadis N, van Pesch V. A basic overview of multiple sclerosis immunopathology. Eur J Neurol. 2015;22(Suppl 2):3–13. doi: 10.1111/ene.12798.
    1. Mathur N, Pedersen BK. Exercise as a mean to control low-grade systemic inflammation. Mediat Inflamm. 2008;2008:109502. doi: 10.1155/2008/109502.
    1. Deckx N, Wens I, Nuyts AH, Hens N, Winter BY d, Koppen G, et al. 12 weeks of combined endurance and resistance training reduces innate markers of inflammation in a randomized controlled clinical trial in patients with multiple sclerosis. Mediat Inflamm. 2016;2016:6789276. doi: 10.1155/2016/6789276..
    1. Mokhtarzade M, Ranjbar R, Majdinasab N, Patel D, Molanouri Shamsi M. Effect of aerobic interval training on serum IL-10, TNFalpha, and adipokines levels in women with multiple sclerosis: possible relations with fatigue and quality of life. Endocrine. 2017;57:262–271. doi: 10.1007/s12020-017-1337-y.
    1. Zimmer P, Bloch W, Schenk A, Oberste M, Riedel S, Kool J, et al. High-intensity interval exercise improves cognitive performance and reduces matrix metalloproteinases-2 serum levels in persons with multiple sclerosis: a randomized controlled trial. Mult Scler. 2017:1352458517728342. 10.1177/1352458517728342.
    1. Fakhoury M. Role of immunity and inflammation in the pathophysiology of neurodegenerative diseases. Neurodegener Dis. 2015;15:63–69. doi: 10.1159/000369933.
    1. Pedersen BK, Saltin B. Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand J Med Sci Sports. 2015;25(Suppl 3):1–72. doi: 10.1111/sms.12581.
    1. Racette BA, Gross A, Vouri SM, Camacho-Soto A, Willis AW, Searles Nielsen S. Immunosuppressants and risk of Parkinson disease. Ann Clin Transl Neurol. 2018;5:870–875. doi: 10.1002/acn3.580.
    1. Hanken K, Eling P, Hildebrandt H. The representation of inflammatory signals in the brain – a model for subjective fatigue in multiple sclerosis. Front Neurol. 2014. 10.3389/fneur.2014.00264.
    1. Choi J, Joseph L, Pilote L. Obesity and C-reactive protein in various populations: a systematic review and meta-analysis. Obes Rev. 2013;14:232–244. doi: 10.1111/obr.12003.
    1. Bharath LP, Ip BC, Nikolajczyk BS. Adaptive immunity and metabolic health: harmony becomes dissonant in obesity and aging. Compr Physiol. 2017;7:1307–1337. doi: 10.1002/cphy.c160042.
    1. Weinhold M, Shimabukuro-Vornhagen A, Franke A, Theurich S, Wahl P, Hallek M, et al. Physical exercise modulates the homeostasis of human regulatory T cells. J Allergy Clin Immunol. 2016;137:1607–1610.e8. doi: 10.1016/j.jaci.2015.10.035.
    1. Fallarino F, Grohmann U, Puccetti P. Indoleamine 2,3-dioxygenase: from catalyst to signaling function. Eur J Immunol. 2012;42:1932–1937. doi: 10.1002/eji.201242572.
    1. Cervenka I, Agudelo LZ, Ruas JL. Kynurenines: Tryptophan's metabolites in exercise, inflammation, and mental health. Science. 2017. 10.1126/science.aaf9794.
    1. Tremblay MS, Copeland JL, van Helder W. Effect of training status and exercise mode on endogenous steroid hormones in men. J Appl Physiol. 2004;96:531–539. doi: 10.1152/japplphysiol.00656.2003.
    1. AA-B B. Tryptophan availability for kynurenine pathway metabolism across the life span: control mechanisms and focus on aging, exercise, diet and nutritional supplements. Neuropharmacology. 2017;112:248–263. doi: 10.1016/j.neuropharm.2015.11.015.
    1. Schrocksnadel K, Wirleitner B, Winkler C, Fuchs D. Monitoring tryptophan metabolism in chronic immune activation. Clin Chim Acta. 2006;364:82–90. doi: 10.1016/j.cca.2005.06.013.
    1. Platten M, von Knebel Doeberitz N, Oezen I, Wick W, Ochs K. Cancer immunotherapy by targeting IDO1/TDO and their downstream effectors. Front Immunol. 2014;5:673. doi: 10.3389/fimmu.2014.00673.
    1. Maddison DC, Giorgini F. The kynurenine pathway and neurodegenerative disease. Semin Cell Dev Biol. 2015;40:134–141. doi: 10.1016/j.semcdb.2015.03.002.
    1. Lovelace MD, Varney B, Sundaram G, Franco NF, Ng ML, Pai S, et al. Current evidence for a role of the kynurenine pathway of tryptophan metabolism in multiple sclerosis. Front Immunol. 2016. 10.3389/fimmu.2016.00246.
    1. Fujigaki H, Yamamoto Y, Saito K. L-tryptophan-kynurenine pathway enzymes are therapeutic target for neuropsychiatric diseases: focus on cell type differences. Neuropharmacology. 2017;112:264–274. doi: 10.1016/j.neuropharm.2016.01.011.
    1. Agudelo LZ, Femenía T, Orhan F, Porsmyr-Palmertz M, Goiny M, Martinez-Redondo V, et al. Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell. 2014;159:33–45. doi: 10.1016/j.cell.2014.07.051.
    1. Pocivavsek A, Wu H-Q, Potter MC, Elmer GI, Pellicciari R, Schwarcz R. Fluctuations in endogenous kynurenic acid control hippocampal glutamate and memory. Neuropsychopharmacology. 2011;36:2357–2367. doi: 10.1038/npp.2011.127.
    1. Stone TW, Darlington LG. The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders. Br J Pharmacol. 2013;169:1211–1227. doi: 10.1111/bph.12230.
    1. Lindberg RL, de GCJ, Montagne L, Freitag P, van der Valk P, Kappos L, Leppert D. The expression profile of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in lesions and normal appearing white matter of multiple sclerosis. Brain. 2001;124:1743–1753. doi: 10.1093/brain/124.9.1743.
    1. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292–302. doi: 10.1002/ana.22366.
    1. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS) Neurology. 1983;33:1444–1452. doi: 10.1212/WNL.33.11.1444.
    1. Scott NW, McPherson GC, Ramsay CR, Campbell MK. The method of minimization for allocation to clinical trials. A review. Control Clin Trials. 2002;23:662–674. doi: 10.1016/S0197-2456(02)00242-8.
    1. Zimmer P, Baumann FT, Bloch W, Zopf EM, Schulz S, Latsch J, et al. Impact of a half marathon on cellular immune system, pro-inflammatory cytokine levels, and recovery behavior of breast cancer patients in the aftercare compared to healthy controls. Eur J Haematol. 2016;96:152–159. doi: 10.1111/ejh.12561.
    1. Wenning P, Kreutz T, Schmidt A, Opitz D, Graf C, Voss S, et al. Endurance exercise alters cellular immune status and resistin concentrations in men suffering from non-insulin-dependent type 2 diabetes. Exp Clin Endocrinol Diabetes. 2013;121:475–482. doi: 10.1055/s-0033-1343395.
    1. Langdon DW, Amato MP, Boringa J, Brochet B, Foley F, Fredrikson S, et al. Recommendations for a brief international cognitive assessment for multiple sclerosis (BICAMS) Mult Scler. 2012;18:891–898. doi: 10.1177/1352458511431076.
    1. Becker M, Sturm W, Willmes K, Zimmermannn P. Normierungsstudie zur Aufmerksamkeitstestbatterie (TAP) von Zimmermann und Fimm. Z Neuropsychol. 1996:3–15.
    1. Penner I-K, Rausch M, Kappos L, Opwis K, Radü EW. Analysis of impairment related functional architecture in MS patients during performance of different attention tasks. J Neurol. 2003;250:461–472. doi: 10.1007/s00415-003-1025-0.
    1. Littman R, Takács Á. Do all inhibitions act alike? A study of go/no-go and stop-signal paradigms. PLoS One. 2017;12:e0186774. doi: 10.1371/journal.pone.0186774.
    1. Fioravanti AM, Bordignon CM, Pettit SM, Woodhouse LJ, Ansley BJ. Comparing the responsiveness of the assessment of motor and process skills and the functional independence measure. Can J Occup Ther. 2012;79:167–174. doi: 10.2182/cjot.2012.79.3.6.
    1. Bansi J, Bloch W, Gamper U, Kesselring J. Training in MS: influence of two different endurance training protocols (aquatic versus overland) on cytokine and neurotrophin concentrations during three week randomized controlled trial. Mult Scler. 2013;19:613–621. doi: 10.1177/1352458512458605.
    1. Wasserman K. Principles of exercise testing and interpretation: including pathophysiology and clinical applications. 4. Philadelphia: Lippincott Williams & Wilkins; 2005.
    1. Penner IK, Raselli C, Stocklin M, Opwis K, Kappos L, Calabrese P. The fatigue scale for motor and cognitive functions (FSMC): validation of a new instrument to assess multiple sclerosis-related fatigue. Mult Scler. 2009;15:1509–1517. doi: 10.1177/1352458509348519.
    1. Petermann F. Hospital anxiety and depression scale, deutsche version (HADS-D) Z Psychiatr Psychol Psychother. 2011;59:251–253. doi: 10.1024/1661-4747/a000077.
    1. Hays RD, Bjorner JB, Revicki DA, Spritzer KL, Cella D. Development of physical and mental health summary scores from the patient-reported outcomes measurement information system (PROMIS) global items. Qual Life Res. 2009;18:873–880. doi: 10.1007/s11136-009-9496-9.
    1. Faul F, Erdfelder E, Lang A-G, Buchner A. G*power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39:175–191. doi: 10.3758/BF03193146.
    1. Borm GF, Fransen J, Lemmens WAJG. A simple sample size formula for analysis of covariance in randomized clinical trials. J Clin Epidemiol. 2007;60:1234–1238. doi: 10.1016/j.jclinepi.2007.02.006.

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