NeuroExercise: The Effect of a 12-Month Exercise Intervention on Cognition in Mild Cognitive Impairment-A Multicenter Randomized Controlled Trial

Tim Stuckenschneider, Marit L Sanders, Kate E Devenney, Justine A Aaronson, Vera Abeln, Jurgen A H R Claassen, Emer Guinan, Brian Lawlor, Romain Meeusen, Christian Montag, Marcel G M Olde Rikkert, M Cristina Polidori, Martin Reuter, Ralf-Joachim Schulz, Tobias Vogt, Bernd Weber, Roy P C Kessels, Stefan Schneider, Tim Stuckenschneider, Marit L Sanders, Kate E Devenney, Justine A Aaronson, Vera Abeln, Jurgen A H R Claassen, Emer Guinan, Brian Lawlor, Romain Meeusen, Christian Montag, Marcel G M Olde Rikkert, M Cristina Polidori, Martin Reuter, Ralf-Joachim Schulz, Tobias Vogt, Bernd Weber, Roy P C Kessels, Stefan Schneider

Abstract

Exercise intervention studies in mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease (AD), have demonstrated inconsistent yet promising results. Addressing the limitations of previous studies, this trial investigated the effects of a 12-month structured exercise program on the progression of MCI. The NeuroExercise study is a multicenter randomized controlled trial across three European countries (Ireland, Netherlands, Germany). Hundred and eighty-three individuals with amnestic MCI were included and were randomized to a 12-month exercise intervention (3 units of 45 min) of either aerobic exercise (AE; n = 60), stretching and toning exercise (ST; n = 65) or to a non-exercise control group (CG; n = 58). The primary outcome, cognitive performance, was determined by an extensive neuropsychological test battery. For the primary complete case (CC) analyses, between-group differences were analyzed with analysis of covariance under two conditions: (1) the exercise group (EG = combined AE and ST groups) compared to the CG and (2) AE compared to ST. Primary analysis of the full cohort (n = 166, 71.5 years; 51.8% females) revealed no between-group differences in composite cognitive score [mean difference (95% CI)], 0.12 [(-0.03, 0.27), p = 0.13] or in any cognitive domain or quality of life. VO2 peak was significantly higher in the EG compared to the CG after 12 months [-1.76 (-3.39, -0.10), p = 0.04]. Comparing the two intervention groups revealed a higher VO2peak level in the aerobic exercise compared to the stretching and toning group, but no differences for the other outcomes. A 12-month exercise intervention did not change cognitive performance in individuals with amnestic MCI in comparison to a non-exercise CG. An intervention effect on physical fitness was found, which may be an important moderator for long term disease progression and warrants long-term follow-up investigations. Clinical Trial Registration: https://ichgcp.net/clinical-trials-registry/NCT02913053, identifier: NCT02913053.

Keywords: Alzheimer's disease; aerobic exercise; cognition; non-pharmacological treatment; quality of life.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Stuckenschneider, Sanders, Devenney, Aaronson, Abeln, Claassen, Guinan, Lawlor, Meeusen, Montag, Olde Rikkert, Polidori, Reuter, Schulz, Vogt, Weber, Kessels and Schneider.

Figures

Figure 1
Figure 1
Trial profile.
Figure 2
Figure 2
Results of the primary outcome: (A) composite cognitive score for complete case (CC) analysis; (B) results of VO2peak for complete case analysis. Boxplots of mean z-scores and 95% CI of EG: Exercise group (AE and ST together). CG, control group; AE, aerobic exercise and ST, stretching and toning exercise. No differences in the comparison between T2 results of the groups for cognition. *significant difference EG vs. CG and AE vs. ST, p < 0.05 for VO2peak.
Figure 3
Figure 3
Cognition (A) = Mean difference of cognitive composite score between T2 and T0; Quality of Life (B) = mean difference of DemQOL total score between T2 and T0; VO2peak (C) = mean difference of VO2peak (ml/kg/min) between T2 and T0 divided by participation and center (NPP, not per protocol; PP, per protocol; CG, control group; IRE, Ireland, NL, Netherlands; GER, Germany; DemQOL, Health-Related Quality of Life for People with Dementia Questionnaire).

References

    1. Aadahl M., Jorgensen T. (2003). Validation of a new self-report instrument for measuring physical activity. Med. Sci. Sports Exerc. 35, 1196–1202. 10.1249/01.MSS.0000074446.02192.14
    1. Albert M. S., DeKosky S. T., Dickson D., Dubois B., Feldman H. H., Fox N. C., et al. . (2011). The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 7, 270–279. 10.1016/j.jalz.2011.03.008
    1. Altman D. G., Dore C. J. (1990). Randomisation and baseline comparisons in clinical trials. Lancet 335, 149–153. 10.1016/0140-6736(90)90014-V
    1. Astrand P. O., Ryhming I. (1954). A nomogram for calculation of aerobic capacity (physical fitness) from pulse rate during submaximal work. J. Appl. Physiol. 7, 218–221. 10.1152/jappl.1954.7.2.218
    1. Borg G. (1998). Borg's Perceived Exertion and Pain Scales. Champaign: Human Kinetics.
    1. Bosma H., van Boxtel M. P., Ponds R. W., Jelicic M., Houx P., Metsemakers J., et al. . (2002). Engaged lifestyle and cognitive function in middle and old-aged, non-demented persons: a reciprocal association? Z. Gerontol. Geriatr. 35, 575–581. 10.1007/s00391-002-0080-y
    1. Brodaty H., Breteler M. M., Dekosky S. T., Dorenlot P., Fratiglioni L., Hock C., et al. . (2011). The world of dementia beyond 2020. J. Am. Geriatr. Soc. 59, 923–927. 10.1111/j.1532-5415.2011.03365.x
    1. Choi J., Lee M., Lee J. K., Kang D., Choi J. Y. (2017). Correlates associated with participation in physical activity among adults: a systematic review of reviews and update. BMC Public Health 17:356. 10.1186/s12889-017-4255-2
    1. Devenney K. E., Sanders M. L., Lawlor B., Olde Rikkert M. G. M., Schneider S., NeuroExercise Study G. (2017). The effects of an extensive exercise programme on the progression of mild cognitive impairment (MCI): study protocol for a randomised controlled trial. BMC Geriatr. 17:75 10.1186/s12877-017-0457-9
    1. Ding K., Tarumi T., Zhu D. C., Tseng B. Y., Thomas B. P., Turner M., et al. . (2018). Cardiorespiratory fitness and white matter neuronal fiber integrity in mild cognitive impairment. J. Alzheimers Dis. 61, 729–739. 10.3233/JAD-170415
    1. Dougherty R. J., Schultz S. A., Boots E. A., Ellingson L. D., Meyer J. D., Van Riper S., et al. . (2017). Relationships between cardiorespiratory fitness, hippocampal volume, and episodic memory in a population at risk for Alzheimer's disease. Brain Behav. 7:e00625. 10.1002/brb3.625
    1. Edvardsen E., Hansen B. H., Holme I. M., Dyrstad S. M., Anderssen S. A. (2013). Reference values for cardiorespiratory response and fitness on the treadmill in a 20- to 85-year-old population. Chest 144, 241–248. 10.1378/chest.12-1458
    1. Fletcher G. F., Balady G. J., Amsterdam E. A., Chaitman B., Eckel R., Fleg J., et al. . (2001). Exercise standards for testing and training: a statement for healthcare professionals from the American Heart Association. Circulation 104, 1694–1740. 10.1161/hc3901.095960
    1. Fratiglioni L., Wang H. X., Ericsson K., Maytan M., Winblad B. (2000). Influence of social network on occurrence of dementia: a community-based longitudinal study. Lancet 355, 1315–1319. 10.1016/S0140-6736(00)02113-9
    1. Ganguli M., Snitz B. E., Saxton J. A., Chang C. C., Lee C. W., Vander Bilt J., et al. . (2011). Outcomes of mild cognitive impairment by definition: a population study. Arch. Neurol. 68, 761–767. 10.1001/archneurol.2011.101
    1. Gillman M. W., Hammond R. A. (2016). Precision treatment and precision prevention: integrating “below and above the skin.” JAMA Pediatr. 170, 9–10. 10.1001/jamapediatrics.2015.2786
    1. Glass S., Dwyer G. B., American College of Sports Medicine (2007). ACSM's Metabolic Calculations Handbook. Philadelphia, PA: Lippincott Williams and Wilkins.
    1. Gomes-Osman J., Cabral D. F., Morris T. P., McInerney K., Cahalin L. P., Rundek T., et al. (2018). Exercise for cognitive brain health in aging: a systematic review for an evaluation of dose. Neurol. Clin. Pract. 8, 257–265. 10.1212/CPJ.0000000000000460
    1. Hendriks M., Bouman Z., Kessels R., Aldenkamp A. (2014). Wechsler Memory Scale-Dutch Edition (WMS-IV-NL). Amsterdam: Pearson Assessment.
    1. Hotting K., Roder B. (2013). Beneficial effects of physical exercise on neuroplasticity and cognition. Neurosci. Biobehav. Rev. 37, 2243–2257. 10.1016/j.neubiorev.2013.04.005
    1. Knopman D. S., Petersen R. C. (2014). Mild cognitive impairment and mild dementia: a clinical perspective. Mayo Clin. Proc. 89, 1452–1459. 10.1016/j.mayocp.2014.06.019
    1. Lezak M. D. (2004). Neuropsychological Assessment. New York, NY: Oxford University Press.
    1. Lim Y. Y., Snyder P. J., Pietrzak R. H., Ukiqi A., Villemagne V. L., Ames D., et al. . (2016). Sensitivity of composite scores to amyloid burden in preclinical Alzheimer's disease: introducing the Z-scores of attention, verbal fluency, and episodic memory for nondemented older adults composite score. Alzheimers Dement (Amst). 2, 19–26. 10.1016/j.dadm.2015.11.003
    1. Maruff P., Collie A., Darby D., Weaver-Cargin J., Masters C., Currie J. (2004). Subtle memory decline over 12 months in mild cognitive impairment. Dement. Geriatr. Cogn. Disord. 18, 342–348. 10.1159/000080229
    1. Mavros Y., Gates N., Wilson G. C., Jain N., Meiklejohn J., Brodaty H., et al. . (2017). Mediation of cognitive function improvements by strength gains after resistance training in older adults with mild cognitive impairment: outcomes of the study of mental and resistance training. J. Am. Geriatr. Soc. 65, 550–559. 10.1111/jgs.14542
    1. McKhann G. M., Knopman D. S., Chertkow H., Hyman B. T., Jack C. R., Jr., et al. (2011). The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 7, 263–269. 10.1016/j.jalz.2011.03.005
    1. Mhaolain A. M., Gallagher D., Crosby L., Ryan D., Lacey L., Coen R. F., et al. . (2012). Frailty and quality of life for people with Alzheimer's dementia and mild cognitive impairment. Am. J. Alzheimers Dis. Other Demen. 27, 48–54. 10.1177/1533317511435661
    1. Moher D., Hopewell S., Schulz K. F., Montori V., Gotzsche P. C., Devereaux P. J., et al. . (2010). CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. J. Clin. Epidemiol. 63, e1–37. 10.1016/j.jclinepi.2010.03.004
    1. Muller J., Chan K., Myers J. N. (2017). Association between exercise capacity and late onset of dementia, Alzheimer disease, and cognitive impairment. Mayo Clin. Proc. 92, 211–217. 10.1016/j.mayocp.2016.10.020
    1. Nagamatsu L. S., Handy T. C., Hsu C. L., Voss M., Liu-Ambrose T. (2012). Resistance training promotes cognitive and functional brain plasticity in seniors with probable mild cognitive impairment. Arch. Intern. Med. 172, 666–668. 10.1001/archinternmed.2012.379
    1. Nascimento C. M., Pereira J. R., de Andrade L. P., Garuffi M., Talib L. L., Forlenza O. V., et al. . (2014). Physical exercise in MCI elderly promotes reduction of pro-inflammatory cytokines and improvements on cognition and BDNF peripheral levels. Curr. Alzheimer Res. 11, 799–805. 10.2174/156720501108140910122849
    1. Ngandu T., Lehtisalo J., Solomon A., Levalahti E., Ahtiluoto S., Antikainen R., et al. . (2015). A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet 385, 2255–2263. 10.1016/S0140-6736(15)60461-5
    1. Ohman H., Savikko N., Strandberg T. E., Pitkala K. H. (2014). Effect of physical exercise on cognitive performance in older adults with mild cognitive impairment or dementia: a systematic review. Dement. Geriatr. Cogn. Disord. 38, 347–365. 10.1159/000365388
    1. Perkins J. M., Multhaup K. S., Perkins H. W., Barton C. (2008). Self-efficacy and participation in physical and social activity among older adults in Spain and the United States. Gerontologist 48, 51–58. 10.1093/geront/48.1.51
    1. Petersen R. C. (2004). Mild cognitive impairment as a diagnostic entity. J. Intern. Med. 256, 183–194. 10.1111/j.1365-2796.2004.01388.x
    1. Petersen R. C., Caracciolo B., Brayne C., Gauthier S., Jelic V., Fratiglioni L. (2014). Mild cognitive impairment: a concept in evolution. J. Intern. Med. 275, 214–228. 10.1111/joim.12190
    1. Petersen R. C., Lopez O., Armstrong M. J., Getchius T. S. D., Ganguli M., Gloss D., et al. (2018). Practice guideline update summary: mild cognitive impairment: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology. Neurology 90, 126–135. 10.1212/WNL.0000000000004826
    1. Prince M. W., Wimo A., Guerchet M., Ali G., Wu Y., Prina M. (eds.). (2015). The Global Impact of Dementia: An Analysis of Prevalence Incidence, Cost and Trends. London: Alzheimer's Disease International (ADI).
    1. Randolph C., Tierney M. C., Mohr E., Chase T. N. (1998). The repeatable battery for the assessment of neuropsychological status (RBANS): preliminary clinical validity. J. Clin. Exp. Neuropsychol. 20, 310–319. 10.1076/jcen.20.3.310.823
    1. Roberts R. O., Knopman D. S., Mielke M. M., Cha R. H., Pankratz V. S., Christianson T. J., et al. . (2014). Higher risk of progression to dementia in mild cognitive impairment cases who revert to normal. Neurology 82, 317–325. 10.1212/WNL.0000000000000055
    1. Sanders M. L., Stuckenschneider T., Devenney K. E., Lawlor B., Schneider S., Olde Rikkert M. G. M., et al. . (2018). Real world recruiting of older subjects with mild cognitive impairment for exercise trials: community readiness is pivotal. J. Alzheimers Dis. 62, 579–581. 10.3233/JAD-171083
    1. Schultz S. A., Boots E. A., Darst B. F., Zetterberg H., Blennow K., Edwards D. F., et al. . (2017). Cardiorespiratory fitness alters the influence of a polygenic risk score on biomarkers of AD. Neurology 88, 1650–1658. 10.1212/WNL.0000000000003862
    1. Snapinn S. M., Jiang Q. (2007). Responder analyses and the assessment of a clinically relevant treatment effect. Trials 8:31. 10.1186/1745-6215-8-31
    1. Song D., Yu D. S. F., Li P. W. C., Lei Y. (2018). The effectiveness of physical exercise on cognitive and psychological outcomes in individuals with mild cognitive impairment: a systematic review and meta-analysis. Int. J. Nurs. Stud. 79, 155–164. 10.1016/j.ijnurstu.2018.01.002
    1. Sperling R. A., Aisen P. S., Beckett L. A., Bennett D. A., Craft S., Fagan A. M., et al. . (2011). Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 7, 280–292. 10.1016/j.jalz.2011.03.003
    1. Stuckenschneider T., Askew C. D., Rudiger S., Polidori M. C., Abeln V., Vogt T., et al. . (2018). Cardiorespiratory fitness and cognitive function are positively related among participants with mild and subjective cognitive impairment. J. Alzheimers Dis. 62, 1865–1875. 10.3233/JAD-170996
    1. Stuckenschneider T., Rudiger S., Abeln V., Askew C. D., Wollseiffen P., Schneider S., et al. (2019). Rating of perceived exertion—a valid method for monitoring light to vigorous exercise intensity in individuals with subjective and mild cognitive impairment? Eur. J. Sport Sci. 20, 261–268. 10.1080/17461391.2019.1629632
    1. Suzuki T., Shimada H., Makizako H., Doi T., Yoshida D., Ito K., et al. . (2013). A randomized controlled trial of multicomponent exercise in older adults with mild cognitive impairment. PLoS ONE 8:e61483. 10.1371/journal.pone.0061483
    1. Suzuki T., Shimada H., Makizako H., Doi T., Yoshida D., Tsutsumimoto K., et al. . (2012). Effects of multicomponent exercise on cognitive function in older adults with amnestic mild cognitive impairment: a randomized controlled trial. BMC Neurol. 12:128. 10.1186/1471-2377-12-128
    1. Tari A. R., Nauman J., Zisko N., Skjellegrind H. K., Bosnes I., Bergh S., et al. . (2019). Temporal changes in cardiorespiratory fitness and risk of dementia incidence and mortality: a population-based prospective cohort study. Lancet Public Health 4, e565–e574. 10.1016/S2468-2667(19)30183-5
    1. Tarumi T., Rossetti H., Thomas B. P., Harris T., Tseng B. Y., Turner M., et al. . (2019). Exercise training in amnestic mild cognitive impairment: a one-year randomized controlled trial. J. Alzheimers Dis. 71, 421–433. 10.3233/JAD-181175
    1. Tarumi T., Thomas B. P., Tseng B. Y., Wang C., Womack K. B., Hynan L., et al. . (2020). Cerebral white matter integrity in amnestic mild cognitive impairment: a 1-year randomized controlled trial of aerobic exercise training. J. Alzheimers Dis. 73, 489–501. 10.3233/JAD-190875
    1. Thomas B. P., Tarumi T., Sheng M., Tseng B., Womack K. B., Cullum C. M., et al. . (2020). Brain perfusion change in patients with mild cognitive impairment after 12 months of aerobic exercise training. J. Alzheimers Dis. 75, 617–631. 10.3233/JAD-190977
    1. Van Breukelen G. J. (2006). ANCOVA versus change from baseline: more power in randomized studies, more bias in nonrandomized studies [corrected]. J. Clin. Epidemiol. 59, 920–925. 10.1016/j.jclinepi.2006.02.007
    1. Vickland V., McDonnell G., Werner J., Draper B., Low L. F., Brodaty H. (2010). A computer model of dementia prevalence in Australia: foreseeing outcomes of delaying dementia onset, slowing disease progression, and eradicating dementia types. Dement. Geriatr. Cogn. Disord. 29, 123–130. 10.1159/000272436
    1. Wang C., Yu J. T., Wang H. F., Tan C. C., Meng X. F., Tan L. (2014). Non-pharmacological interventions for patients with mild cognitive impairment: a meta-analysis of randomized controlled trials of cognition-based and exercise interventions. J. Alzheimers Dis. 42, 663–678. 10.3233/JAD-140660
    1. Wechsler D. (2008). Wechsler Adult Intelligence Scale-Fourth. San Antonio, TX: The Psychological Corporation Google Scholar; 10.1037/t15169-000
    1. Winblad B., Palmer K., Kivipelto M., Jelic V., Fratiglioni L., Wahlund L. O., et al. . (2004). Mild cognitive impairment—beyond controversies, towardz a consensus: report of the International Working Group on Mild Cognitive Impairment. J. Intern. Med. 256, 240–246. 10.1111/j.1365-2796.2004.01380.x
    1. Young J., Angevaren M., Rusted J., Tabet N. (2015). Aerobic exercise to improve cognitive function in older people without known ognitive impairment. Cochrane Database Syst. Rev. 4:CD005381 10.1002/14651858.CD005381.pub4
    1. Zheng G., Xia R., Zhou W., Tao J., Chen L. (2016). Aerobic exercise ameliorates cognitive function in older adults with mild cognitive impairment: a systematic review and meta-analysis of randomised controlled trials. Br. J. Sports Med. 50, 1443–1450. 10.1136/bjsports-2015-095699

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