Physical exercise can improve cognitive dysfunction. Its specific mechanism remains unknown. Recent studies have indicated that elevating or peripherally overexpressing brain-derived neurotrophic factors (BDNF) improve cognitive impairment.
Objective:
This meta-analysis aimed to investigate whether physical exercise improves cognitive performance in patients with cognitive dysfunction, such as mild cognitive impairment (MCI) or Alzheimer’s disease (AD), by increasing peripheral BDNF.
Methods:
PubMed, Embase, Cochrane Library, and Web of Science were searched up to June 2020 for studies that assayed the changes in peripheral BDNF levels in MCI and AD patients after exercise training.
Results:
Peripheral BDNF levels were significantly elevated after a single exercise session (SMD = 0.469, 95% CI: 0.150–0.787, P = 0.004) or regular exercise interventions (SMD = 0.418, 95% CI: 0.105–0.731, P = 0.009). Subgroup analysis showed that only regular aerobic exercise interventions (SMD = 0.543, 95% CI: 0.038–1.049, P = 0.035) and intervention duration of 16 weeks or greater (SMD = 0.443, 95% CI: 0.154 –0.733, P = 0.003) significantly increased peripheral BDNF levels. Only plasma BDNF levels (SMD = 0.365, 95% CI:0.066–0.664, P = 0.017) were significantly increased after exercise interventions.
Conclusions:
Acute and chronic physical exercises may improve cognitive impairment by increasing peripheral BDNF levels. Aerobic exercises and a longer duration of exercising increased BDNF levels. These findings also suggest that BDNF may be a suitable biomarker for evaluating the effect of exercise in patients with cognitive impairment, such as AD or MCI.
Allard,J. S., Ntekim,O., Johnson,S. P., Ngwa,J. S., Bond,V., Pinder,D., Gillum,R. F., Fungwe,T. V., Kwagyan,J., & Obisesan,T. O. (2017). APOEɛ4 impacts up-regulation of brain-derived neurotrophic factor after a six-month stretch and aerobic exercise intervention in mild cognitively impaired elderly African Americans: A pilot study. Experimental Gerontology, 87(Pt A), 129–136. https://doi.org/10.1016/j.exger.2016.11.001
2.
Anderson-Hanley,C., Arciero,P. J., Brickman,A. M., Nimon,J. P., Okuma,N., Westen,S. C., Merz,M. E., Pence,B. D., Woods,J. A., Kramer,A. F., & Zimmerman,E. A. (2012). Exergaming and older adult cognition: a cluster randomized clinical trial. American Journal of Preventive Medicine, 42(2), 109–119. https://doi.org/10.1016/j.amepre.2011.10.016
3.
Armijo-Olivo,S., Saltaji,H., da Costa,B. R., Fuentes,J., Ha,C., & Cummings,G. G. (2015). What is the influence of randomisation sequence generation and allocation concealment on treatment effects of physical therapy trials? A meta-epidemiological study. BMJ Open, 5(9), e008562. https://doi.org/10.1136/bmjopen-2015-008562
4.
Baker,L. D., Frank,L. L., Foster-Schubert,K., Green,P. S., Wilkinson,C. W., McTiernan,A., Plymate,S. R., Fishel,M. A., Watson,G. S., Cholerton,B. A., Duncan,G. E., Mehta,P. D., & Craft,S. (2010). Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Archives of Neurology, 67(1), 71–79. https://doi.org/10.1001/archneurol.2009.307
5.
Berchtold,N. C., Chinn,G., Chou,M., Kesslak,J. P., & Cotman,C. W. (2005). Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus. Neuroscience, 133(3), 853–861. https://doi.org/10.1016/j.neuroscience.2005.03.026
6.
Borenstein,M., Hedges,L. V., Higgins,J. P., & Rothstein,H. R. (2010). A basic introduction to fixed-effect and random-effects models for meta-analysis. Research Synthesis Methods, 1(2), 97–111. https://doi.org/10.1002/jrsm.12
7.
Boström,P., Wu,J., Jedrychowski,M. P., Korde,A., Ye,L., Lo,J. C., Rasbach,K. A., Boström,E. A., Choi,J. H., Long,J. Z., Kajimura,S., Zingaretti,M. C., Vind,B. F., Tu,H., Cinti,S., Højlund,K., Gygi,S. P., & Spiegelman,B. M. (2012). A PGC-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature, 481(7382), 463–468. https://doi.org/10.1038/nature10777
8.
Brown,B. M., Peiffer,J. J., & Martins,R. N. (2013). Multiple effects of physical activity on molecular and cognitive signs of brain aging: can exercise slow neurodegeneration and delay Alzheimer’s disease?Molecular Psychiatry, 18(8), 864–874. https://doi.org/10.1038/mp.2012.162
9.
Cassilhas,R. C., Lee,K. S., Fernandes,J., Oliveira,M. G., Tufik,S., Meeusen,R., & de Mello,M. T. (2012). Spatial memory is improved by aerobic and resistance exercise through divergent molecular mechanisms. Neuroscience, 202, 309–317. https://doi.org/10.1016/j.neuroscience.2011.11.029
10.
Coelho,F. G., Vital,T. M., Stein,A. M., Arantes,F. J., Rueda,A. V., Camarini,R., Teodorov,E., & Santos-Galduróz,R. F. (2014). Acute aerobic exercise increases brain-derived neurotrophic factor levels in elderly with Alzheimer’s disease. Journal of Alzheimer’s Disease: JAD, 39(2), 401–408. https://doi.org/10.3233/JAD-131073
11.
da Costa Daniele,T. M., de Bruin,P., de Matos,R. S., de Bruin,G. S., Maia Chaves,C.Junior, & de Bruin, V. (2020). Exercise effects on brain and behavior in healthy mice, Alzheimer’s disease and Parkinson’s disease model-A systematic review and meta-analysis. Behavioural Brain Research, 383, 112488. https://doi.org/10.1016/j.bbr.2020.112488
12.
Damirchi,A., Hosseini,F., & Babaei,P. (2018). Mental Training Enhances Cognitive Function and BDNF More Than Either Physical or Combined Training in Elderly Women With MCI: A Small-Scale Study. American Journal of Alzheimer’s Disease and Other Dementias, 33(1), 20–29. https://doi.org/10.1177/1533317517727068
13.
Devenney,K. E., Guinan,E. M., Kelly,Á. M., Mota,B. C., Walsh,C., Olde Rikkert,M., Schneider,S., & Lawlor,B. (2019). Acute high-intensity aerobic exercise affects brain-derived neurotrophic factor in mild cognitive impairment: a randomised controlled study. BMJ Open Sport & Exercise Medicine, 5(1), e000499. https://doi.org/10.1136/bmjsem-2018-000499
14.
Dinoff,A., Herrmann,N., Swardfager,W., & Lanctôt,K. L. (2017). The effect of acute exercise on blood concentrations of brain-derived neurotrophic factor in healthy adults: a meta-analysis. The European Journal of Neuroscience, 46(1), 1635–1646. https://doi.org/10.1111/ejn.13603
15.
Dinoff,A., Herrmann,N., Swardfager,W., Liu,C. S., Sherman,C., Chan,S., & Lanctôt,K. L. (2016). The Effect of Exercise Training on Resting Concentrations of Peripheral Brain-Derived Neurotrophic Factor (BDNF): A Meta-Analysis. PloS one, 11(9), e0163037. https://doi.org/10.1371/journal.pone.0163037
16.
Egan,M. F., Kojima,M., Callicott,J. H., Goldberg,T. E., Kolachana,B. S., Bertolino,A., Zaitsev,E., Gold,B., Goldman,D., Dean,M., Lu,B., & Weinberger,D. R. (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112(2), 257–269. https://doi.org/10.1016/s0092-8674(03)00035-7
17.
Enette,L., Vogel,T., Merle,S., Valard-Guiguet,A. G., Ozier-Lafontaine,N., Neviere,R., Leuly-Joncart,C., Fanon,J. L., & Lang,P. O. (2020). Effect of 9 weeks continuous vs. interval aerobic training on plasma BDNF levels, aerobic fitness, cognitive capacity and quality of life among seniors with mild to moderate Alzheimer’s disease: a randomized controlled trial. European Review of Aging and Physical Activity: Official Journal of the European Group for Research into Elderly and Physical Activity, 17, 2. https://doi.org/10.1186/s11556-019-0234-1
18.
Erickson,K. I., Voss,M. W., Prakash,R. S., Basak,C., Szabo,A., Chaddock,L., Kim,J. S., Heo,S., Alves,H., White,S. M., Wojcicki,T. R., Mailey,E., Vieira,V. J., Martin,S. A., Pence,B. D., Woods,J. A., McAuley,E., & Kramer,A. F. (2011). Exercise training increases size of hippocampus and improves memory. Proceedings of the National Academy of Sciences of the United States of America, 108(7), 3017–3022. https://doi.org/10.1073/pnas.1015950108
19.
Farias,S. T., Mungas,D., Reed,B. R., Harvey,D., & DeCarli,C. (2009). Progression of mild cognitive impairment to dementia in clinic- vs community-based cohorts. Archives of Neurology, 66(9), 1151–1157. https://doi.org/10.1001/archneurol.2009.106
20.
Franzmeier,N., Ren,J., Damm,A., Monté-Rubio,G., Boada,M., Ruiz,A., Ramirez,A., Jessen,F., Düzel,E., Rodríguez Gómez,O., Benzinger,T., Goate,A., Karch,C. M., Fagan,A. M., McDade,E., Buerger,K., Levin,J., Duering,M., Dichgans,M., Suárez-Calvet,M.,... Ewers,M. (2021). The BDNFVal66MetSNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease. Molecular Psychiatry, 26(2), 614–628. https://doi.org/10.1038/s41380-019-0404-6
21.
Fungwe,T. V., Ngwa,J. S., Ntekim,O. E., Allard,J. S., Nadarajah,S., Wolday,S., Ogunlana,O. O., Johnson,S. P., Hughes,K., Larbi,D., Gillum,R. F., & Obisesan,T. O. (2019). Exercise Training Induced Changes In Nuclear Magnetic Resonance-Measured Lipid Particles In Mild Cognitively Impaired Elderly African American Volunteers: A Pilot Study. Clinical Interventions in Aging, 14, 2115–2123. https://doi.org/10.2147/CIA.S195878
22.
Gomez-Pinilla,F., Zhuang,Y., Feng,J., Ying,Z., & Fan,G. (2011). Exercise impacts brain-derived neurotrophic factor plasticity by engaging mechanisms of epigenetic regulation. The European Journal of Neuroscience, 33(3), 383–390. https://doi.org/10.1111/j.1460-9568.2010.07508.x
23.
Hamer,M., & Chida,Y. (2009). Physical activity and risk of neurodegenerative disease: a systematic review of prospective evidence. Psychological Medicine, 39(1), 3–11. https://doi.org/10.1017/S0033291708003681
24.
Jerónimo-Santos,A., Vaz,S. H., Parreira,S., Rapaz-Lérias,S., Caetano,A. P., Buée-Scherrer,V., Castrén,E., Valente,C. A., Blum,D., Sebastião,A. M., & Diógenes,M. J. (2015). Dysregulation of TrkB Receptors and BDNF Function by Amyloid-β Peptide is Mediated by Calpain. Cerebral cortex (New York, N.Y. : 1991), 25(9), 3107–3121. https://doi.org/10.1093/cercor/bhu105
25.
Kim,H. J., Lee,S. Y., Lee,H. G., Cho,Y. H., & Ko,E. M. (2018). Effects of a Single-Session Cognitive Enhancement Fitness Program on Serum Brain-Derived Neurotrophic Factor Levels and Cognitive Function in Middle-Aged Women. Journal of Sports Science & Medicine, 17(1), 110–116.
26.
Kohanpour,M. A., Peeri,M., & Azarbayjani,M. A. (2017). The effects of aerobic exercise with lavender essence use on cognitive state and serum brain-derived neurotrophic factor levels in elderly with mild cognitive impairment. Journal of HerbMed Pharmacology, 6(2), 80–84.
27.
Lourenco,M. V., Frozza,R. L., de Freitas,G. B., Zhang,H., Kincheski,G. C., Ribeiro,F. C., Gonçalves,R. A., Clarke,J. R., Beckman,D., Staniszewski,A., Berman,H., Guerra,L. A., Forny-Germano,L., Meier,S., Wilcock,D. M., de Souza,J. M., Alves-Leon,S., Prado,V. F., Prado,M., Abisambra,J. F.,... De Felice, F. G. (2019). Exercise-linked FNDC/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nature Medicine, 25(1), 165–175. https://doi.org/10.1038/s41591-018-0275-4
28.
Nascimento,C. M., Pereira,J. R., de Andrade,L. P., Garuffi,M., Talib,L. L., Forlenza,O. V., Cancela,J. M., Cominetti,M. R., & Stella,F. (2014). Physical exercise in MCI elderly promotes reduction of pro-inflammatory cytokines and improvements on cognition and BDNF peripheral levels. Current Alzheimer Research, 11(8), 799–805. https://doi.org/10.2174/156720501108140910122849
29.
Nascimento,C. M., Pereira,J. R., Pires de Andrade,L., Garuffi,M., Ayan,C., Kerr,D. S., Talib,L. L., Cominetti,M. R., & Stella,F. (2015). Physical exercise improves peripheral BDNF levels and cognitive functions in mild cognitive impairment elderly with different bdnf Val66Met genotypes. Journal of Alzheimer’s Disease: JAD, 43(1), 81–91. https://doi.org/10.3233/JAD-140576
30.
Ng,T., Ho,C., Tam,W., Kua,E. H., & Ho,R. C. (2019). Decreased Serum Brain-Derived Neurotrophic Factor (BDNF) Levels in Patients with Alzheimer’s Disease (AD): A Systematic Review and Meta-Analysis. International Journal of Molecular Sciences, 20(2), 257. https://doi.org/10.3390/ijms20020257
31.
Northey,J. M., Cherbuin,N., Pumpa,K. L., Smee,D. J., & Rattray,B. (2018). Exercise interventions for cognitive function in adults older than 50: a systematic review with meta-analysis. British Journal of Sports Medicine, 52(3), 154–160. https://doi.org/10.1136/bjsports-2016-096587
32.
PedersenB. K. (2019). Physical activity and muscle-brain crosstalk. Nature reviews. Endocrinology, 15(7), 383–392. https://doi.org/10.1038/s41574-019-0174-x
Stillman,C. M., Weinstein,A. M., Marsland,A. L., Gianaros,P. J., & Erickson,K. I. (2017). Body-Brain Connections: The Effects of Obesity and Behavioral Interventions on Neurocognitive Aging. Frontiers in Aging Neuroscience, 9, 115. https://doi.org/10.3389/fnagi.2017.00115
35.
Ströhle,A., Schmidt,D. K., Schultz,F., Fricke,N., Staden,T., Hellweg,R., Priller,J., Rapp,M. A., & Rieckmann,N. (2015). Drug and Exercise Treatment of Alzheimer Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis of Effects on Cognition in Randomized Controlled Trials. The American Journal of Geriatric Psychiatry: Official Journal of the American Association for Geriatric Psychiatry, 23(12), 1234–1249. https://doi.org/10.1016/j.jagp.2015.07.007
36.
Sungkarat,S., Boripuntakul,S., Kumfu,S., Lord,S. R., & Chattipakorn,N. (2018). Tai Chi Improves Cognition and Plasma BDNF in Older Adults With Mild Cognitive Impairment: A Randomized Controlled Trial. Neurorehabilitation and Neural Repair, 32(2), 142–149. https://doi.org/10.1177/1545968317753682
37.
Suzuki,T., Shimada,H., Makizako,H., Doi,T., Yoshida,D., Ito,K., Shimokata,H., Washimi,Y., Endo,H., & Kato,T. (2013). A randomized controlled trial of multicomponent exercise in older adults with mild cognitive impairment. PloS one, 8(4), e61483. https://doi.org/10.1371/journal.pone.0061483
38.
Tsai,C. L., Pai,M. C., Ukropec,J., & Ukropcová,B. (2019). Distinctive Effects of Aerobic and Resistance Exercise Modes on Neurocognitive and Biochemical Changes in Individuals with Mild Cognitive Impairment. Current Alzheimer Research, 16(4), 316–332. https://doi.org/10.2174/1567205016666190228125429
39.
Tsai,C. L., Ukropec,J., Ukropcová,B., & Pai,M. C. (2017). An acute bout of aerobic or strength exercise specifically modifies circulating exerkine levels and neurocognitive functions in elderly individuals with mild cognitive impairment. NeuroImage Clinical, 17, 272–284. https://doi.org/10.1016/j.nicl.2017.10.028
40.
Venezia,A. C., Quinlan,E., & Roth,S. M. (2017). A single bout of exercise increases hippocampal Bdnf: influence of chronic exercise and noradrenaline. Genes, brain, and behavior, 16(8), 800–811. https://doi.org/10.1111/gbb.12394
41.
Wan,X., Wang,W., Liu,J., & Tong,T. (2014). Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Medical Research Methodology, 14, 135. https://doi.org/10.1186/1471-2288-14-135
42.
Weinstein,G., Beiser,A. S., Choi,S. H., Preis,S. R., Chen,T. C., Vorgas,D., Au,R., Pikula,A., Wolf,P. A., DeStefano,A. L., Vasan,R. S., & Seshadri,S. (2014). Serum brain-derived neurotrophic factor and the risk for dementia: the Framingham Heart Study. JAMAneurology, 71(1), 55–61. https://doi.org/10.1001/jamaneurol.2013.4781
