1,546
Views
0
CrossRef citations to date
0
Altmetric
Geriatrics

Brain-Derived neurotrophic factor and inflammatory biomarkers are unaffected by acute and chronic intermittent hypoxic-hyperoxic exposure in geriatric patients: a randomized controlled trial

ORCID Icon, , ORCID Icon, ORCID Icon, ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon show all
Article: 2304650 | Received 11 Jul 2023, Accepted 24 Nov 2023, Published online: 22 Jan 2024

References

  • Harada CN, Natelson Love MC, Triebel KL. Normal cognitive aging. Clin Geriatr Med. 2013;29(4):1–17. doi:10.1016/j.cger.2013.07.002.
  • Raz N, Rodrigue KM, Head D, et al. Differential aging of the medial temporal lobe: a study of a five-year change. Neurology. 2004;62(3):433–438. doi:10.1212/01.wnl.0000106466.09835.46.
  • Fjell AM, Walhovd KB. Structural brain changes in aging: courses, causes and cognitive consequences. Rev Neurosci. 2010;21(3):187–221. doi:10.1515/revneuro.2010.21.3.187.
  • Oschwald J, Guye S, Liem F, et al. Brain structure and cognitive ability in healthy aging: a review on longitudinal correlated change. Rev Neurosci. 2019;31(1):1–57. doi:10.1515/revneuro-2018-0096.
  • O’Shea A, Cohen RA, Porges EC, et al. Cognitive aging and the hippocampus in older adults. Front Aging Neurosci. 2016;8:298. doi:10.3389/fnagi.2016.00298.
  • Madden DJ, Spaniol J, Costello MC, et al. Cerebral white matter integrity mediates adult age differences in cognitive performance. J Cogn Neurosci. 2009;21(2):289–302. doi:10.1162/jocn.2009.21047.
  • Tartaglia MC, Rosen HJ, Miller BL. Neuroimaging in dementia. Neurotherapeutics. 2011;8(1):82–92. doi:10.1007/s13311-010-0012-2.
  • Colcombe SJ, Erickson KI, Scalf PE, et al. Aerobic exercise training increases brain volume in aging humans. J Gerontol A Biol Sci Med Sci. 2006;61(11):1166–1170. doi:10.1093/gerona/61.11.1166.
  • Wood KN, Nikolov R, Shoemaker JK. Impact of long-term endurance training vs. Guideline-based physical activity on brain structure in healthy aging. Front Aging Neurosci. 2016;8:155. doi:10.3389/fnagi.2016.00155.
  • Jonasson LS, Nyberg L, Kramer AF, et al. Aerobic exercise intervention, cognitive performance, and brain structure: results from the physical influences on brain in aging (PHIBRA) study. Front Aging Neurosci. 2016;8:336. doi:10.3389/fnagi.2016.00336.
  • Herold F, Törpel A, Schega L, et al. Functional and/or structural brain changes in response to resistance exercises and resistance training lead to cognitive improvements - a systematic review. Eur Rev Aging Phys Act. 2019;16(1):10. doi:10.1186/s11556-019-0217-2.
  • Stillman CM, Cohen J, Lehman ME, et al. Mediators of physical activity on neurocognitive function: a review at multiple levels of analysis. Front Hum Neurosci. 2016;10:626. doi:10.3389/fnhum.2016.00626.
  • Stimpson NJ, Davison G, Javadi A-H. Joggin’ the noggin: towards a physiological understanding of exercise-induced cognitive benefits. Neurosci Biobehav Rev. 2018;88:177–186. doi:10.1016/j.neubiorev.2018.03.018.
  • Brigadski T, Leßmann V. BDNF: a regulator of learning and memory processes with clinical potential. e-Neuroforum. 2014;5(1):1–11. doi:10.1007/s13295-014-0053-9.
  • Eggert S, Kins S, Endres K, et al. Brothers in arms: proBDNF/BDNF and sAPPα/Aβ-signaling and their common interplay with ADAM10, TrkB, p75NTR, sortilin, and sorLA in the progression of alzheimer’s disease. Biol Chem. 2022;403(1):43–71. doi:10.1515/hsz-2021-0330.
  • Edelmann E, Lessmann V, Brigadski T. Pre- and postsynaptic twists in BDNF secretion and action in synaptic plasticity. Neuropharmacology. 2014;76 Pt C:610–627. doi:10.1016/j.neuropharm.2013.05.043.
  • Brigadski T, Leßmann V. The physiology of regulated BDNF release. Cell Tissue Res. 2020;382(1):15–45. doi:10.1007/s00441-020-03253-2.
  • Leal G, Afonso PM, Salazar IL, et al. Regulation of hippocampal synaptic plasticity by BDNF. Brain Res. 2015;1621:82–101. doi:10.1016/j.brainres.2014.10.019.
  • Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci. 2001;24(1):677–736. doi:10.1146/annurev.neuro.24.1.677.
  • Park H, Poo M. Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci. 2013;14(1):7–23. doi:10.1038/nrn3379.
  • Yamada K, Nabeshima T. Brain-derived neurotrophic factor/TrkB signaling in memory processes. J Pharmacol Sci. 2003;91(4):267–270. doi:10.1254/jphs.91.267.
  • Edelmann E, Cepeda-Prado E, Franck M, et al. Theta burst firing recruits BDNF release and signaling in postsynaptic CA1 neurons in Spike-Timing-dependent LTP. Neuron. 2015;86(4):1041–1054. doi:10.1016/j.neuron.2015.04.007.
  • Das K, Chao S, White L, et al. Differential patterns of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 mRNA and protein levels in developing regions of rat brain. Neuroscience. 2001;103(3):739–761. doi:10.1016/S0306-4522(01)00011-2.
  • Conner JM, Lauterborn JC, Yan Q, et al. Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. J Neurosci. 1997;17(7):2295–2313. doi:10.1523/JNEUROSCI.17-07-02295.1997.
  • Webster MJ, Herman MM, Kleinman JE, et al. BDNF and trkB mRNA expression in the hippocampus and temporal cortex during the human lifespan. Gene Expr Patterns. 2006;6(8):941–951. doi:10.1016/j.modgep.2006.03.009.
  • Rasmussen P, Brassard P, Adser H, et al. Evidence for a release of brain-derived neurotrophic factor from the brain during exercise. Exp Physiol. 2009;94(10):1062–1069. doi:10.1113/expphysiol.2009.048512.
  • Klein AB, Williamson R, Santini MA, et al. Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int J Neuropsychopharmacol. 2011;14(3):347–353. doi:10.1017/S1461145710000738.
  • Pan W, Banks WA, Fasold MB, et al. Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology. 1998;37(12):1553–1561. doi:10.1016/S0028-3908(98)00141-5.
  • Hwang J, Brothers RM, Castelli DM, et al. Acute high-intensity exercise-induced cognitive enhancement and brain-derived neurotrophic factor in young, healthy adults. Neurosci Lett. 2016;630:247–253. doi:10.1016/j.neulet.2016.07.033.
  • Griffin ÉW, Mullally S, Foley C, et al. Aerobic exercise improves hippocampal function and increases BDNF in the serum of young adult males. Physiol Behav. 2011;104(5):934–941. doi:10.1016/j.physbeh.2011.06.005.
  • Erickson KI, Miller DL, Roecklein KA. The aging hippocampus: interactions between exercise, depression, and BDNF. Neuroscientist. 2012;18(1):82–97. doi:10.1177/1073858410397054.
  • Miranda M, Morici JF, Zanoni MB, et al. Brain-Derived neurotrophic factor: a key molecule for memory in the healthy and the pathological brain. Front Cell Neurosci. 2019;13:363. doi:10.3389/fncel.2019.00363.
  • Erickson KI, Prakash RS, Voss MW, et al. Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume. J Neurosci. 2010;30(15):5368–5375. doi:10.1523/JNEUROSCI.6251-09.2010.
  • Coelho FM, Pereira DS, Lustosa LP, et al. Physical therapy intervention (PTI) increases plasma brain-derived neurotrophic factor (BDNF) levels in non-frail and pre-frail elderly women. Arch Gerontol Geriatr. 2012;54(3):415–420. doi:10.1016/j.archger.2011.05.014.
  • Roh E, Hwang SY, Song E, et al. Association of plasma brain-derived neurotrophic factor levels and frailty in community-dwelling older adults. Sci Rep. 2022;12(1):18605. doi:10.1038/s41598-022-19706-3.
  • Laske C, Stransky E, Leyhe T, et al. BDNF serum and CSF concentrations in alzheimer’s disease, normal pressure hydrocephalus and healthy controls. J Psychiatr Res. 2007;41(5):387–394. doi:10.1016/j.jpsychires.2006.01.014.
  • Du Y, Wu H-T, Qin X-Y, et al. Postmortem brain, cerebrospinal fluid, and blood neurotrophic factor levels in alzheimer’s disease: a systematic review and Meta-Analysis. J Mol Neurosci. 2018;65(3):289–300. doi:10.1007/s12031-018-1100-8.
  • Ng TKS, Ho CSH, Tam WWS, et al. Decreased serum brain-derived neurotrophic factor (BDNF) levels in patients with alzheimer’s disease (AD): a systematic review and Meta-Analysis. Int J Mol Sci. 2019;20(2):257. doi:10.3390/ijms20020257.
  • Kim BY, Lee SH, Graham PL, et al. Peripheral brain-derived neurotrophic factor levels in alzheimer’s disease and mild cognitive impairment: a comprehensive systematic review and meta-analysis. Mol Neurobiol. 2017;54(9):7297–7311. doi:10.1007/s12035-016-0192-9.
  • Karege F, Perret G, Bondolfi G, et al. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res. 2002;109(2):143–148. doi:10.1016/s0165-1781(02)00005-7.
  • Ryou M-G, Chen X, Cai M, et al. Intermittent hypoxia training prevents deficient learning-memory behavior in mice modeling alzheimer’s disease: a pilot study. Front Aging Neurosci. 2021;13:674688. doi:10.3389/fnagi.2021.674688.
  • Vermehren-Schmaedick A, Jenkins VK, Knopp SJ, et al. Acute intermittent hypoxia-induced expression of brain-derived neurotrophic factor is disrupted in the brainstem of methyl-CpG-binding protein 2 null mice. Neuroscience. 2012;206:1–6. doi:10.1016/j.neuroscience.2012.01.017.
  • Satriotomo I, Nichols NL, Dale EA, et al. Repetitive acute intermittent hypoxia increases growth/neurotrophic factor expression in non-respiratory motor neurons. Neuroscience. 2016;322:479–488. doi:10.1016/j.neuroscience.2016.02.060.
  • Wang H, Ward N, Boswell M, et al. Secretion of brain-derived neurotrophic factor from brain microvascular endothelial cells. Eur J Neurosci. 2006;23(6):1665–1670. doi:10.1111/j.1460-9568.2006.04682.x.
  • Schega L, Peter B, Brigadski T, et al. Effect of intermittent normobaric hypoxia on aerobic capacity and cognitive function in older people. J Sci Med Sport. 2016;19(11):941–945. doi:10.1016/j.jsams.2016.02.012.
  • Schega L, Peter B, Törpel A, et al. Effects of intermittent hypoxia on cognitive performance and quality of life in elderly adults: a pilot study. Gerontology. 2013;59(4):316–323. doi:10.1159/000350927.
  • Wang H, Shi X, Schenck H, et al. Intermittent hypoxia training for treating mild cognitive impairment: a pilot study. Am J Alzheimers Dis Other Demen. 2020;35:1533317519896725. doi:10.1177/1533317519896725.
  • Burtscher J, Mallet RT, Burtscher M, et al. Hypoxia and brain aging: neurodegeneration or neuroprotection? Ageing Res Rev. 2021;68:101343. doi:10.1016/j.arr.2021.101343.
  • Rybnikova EA, Nalivaeva NN, Zenko MY, et al. Intermittent hypoxic training as an effective tool for increasing the adaptive potential, endurance and working capacity of the brain. Front Neurosci. 2022;16:941740. doi:10.3389/fnins.2022.941740.
  • Hickey MM, Simon MC. Regulation of angiogenesis by hypoxia and hypoxia-inducible factors. In:: Elsevier; 2006. p. 217–257. doi:10.1016/S0070-2153(06)76007-0.
  • Katayama K, Fujita O, Iemitsu M, et al. The effect of acute exercise in hypoxia on flow-mediated vasodilation. Eur J Appl Physiol. 2013;113(2):349–357. doi:10.1007/s00421-012-2442-5.
  • Muangritdech N, Hamlin MJ, Sawanyawisuth K, et al. Hypoxic training improves blood pressure, nitric oxide and hypoxia-inducible factor-1 alpha in hypertensive patients. Eur J Appl Physiol. 2020;120(8):1815–1826. doi:10.1007/s00421-020-04410-9.
  • Chen C, Pore N, Behrooz A, et al. Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J Biol Chem. 2001;276(12):9519–9525. doi:10.1074/jbc.M010144200.
  • Soo J, Raman A, Lawler NG, et al. The role of exercise and hypoxia on glucose transport and regulation. Eur J Appl Physiol. 2023;123(6):1147–1165. doi:10.1007/s00421-023-05135-1.
  • Manukhina EB, Downey HF, Shi X, et al. Intermittent hypoxia training protects cerebrovascular function in alzheimer’s disease. Exp Biol Med (Maywood). 2016;241(12):1351–1363. doi:10.1177/1535370216649060.
  • Smith KA, Waypa GB, Schumacker PT. Redox signaling during hypoxia in mammalian cells. Redox Biol. 2017;13:228–234. doi:10.1016/j.redox.2017.05.020.
  • Sies H, Jones DP. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol. 2020;21(7):363–383. doi:10.1038/s41580-020-0230-3.
  • Törpel A, Peter B, Hamacher D, et al. Dose-response relationship of intermittent normobaric hypoxia to stimulate erythropoietin in the context of health promotion in young and old people. Eur J Appl Physiol. 2019;119(5):1065–1074. doi:10.1007/s00421-019-04096-8.
  • Wojan F, Stray-Gundersen S, Nagel MJ, et al. Short exposure to intermittent hypoxia increases erythropoietin levels in healthy individuals. J Appl Physiol (1985). 2021;130(6):1955–1960. doi:10.1152/japplphysiol.00941.2020.
  • Knaupp W, Khilnani S, Sherwood J, et al. Erythropoietin response to acute normobaric hypoxia in humans. J. Appl. Physiol. 1992;73:937–840.
  • Beckman B, Silberstein P, Aldoss IT. Erythropoiesis. In: Enna SJ, Bylund DB, editors. xPharm: the comprehensive pharmacology reference. Elsevier; 2010. p. 1–4. doi:10.1016/B978-008055232-3.60269-7.
  • Rey F, Balsari A, Giallongo T, et al. Erythropoietin as a neuroprotective molecule: an overview of its therapeutic potential in neurodegenerative diseases. ASN Neuro. 2019;11:1759091419871420. doi:10.1177/1759091419871420.
  • Mallet RT, Burtscher J, Manukhina EB, et al. Hypoxic–hyperoxic conditioning and dementia. In: Martin CR, Preedy VR, editors. Diagnosis and management in dementia. Elsevier; 2020. p. 745–760. doi:10.1016/B978-0-12-815854-8.00047-1.
  • Furman D, Campisi J, Verdin E, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019;25(12):1822–1832. doi:10.1038/s41591-019-0675-0.
  • Kiers D, Wielockx B, Peters E, et al. Short-Term hypoxia dampens inflammation in vivo via enhanced adenosine release and adenosine 2B receptor stimulation. EBioMedicine. 2018;33:144–156. doi:10.1016/j.ebiom.2018.06.021.
  • Glazachev O. Optimization of clinical application of interval hypoxic training. Biomed Eng. 2013;47(3):134–137. doi:10.1007/s10527-013-9352-7.
  • Sazontova TG, Bolotova AV, Bedareva IV, et al. Adaptation to intermittent hypoxia/hyperoxia enhances efficiency of exercise training. In: xi L, Serebrovskaya TV, editors. Intermittent hypoxia and human diseases. London: springer London; 2012. p. 191–205. doi:10.1007/978-1-4471-2906-6_16.
  • Behrendt T, Bielitzki R, Behrens M, et al. Effects of intermittent hypoxia-hyperoxia on performance- and Health-Related outcomes in humans: a systematic review. Sports Med Open. 2022;8(1):70. doi:10.1186/s40798-022-00450-x.
  • Bayer U, Likar R, Pinter G, et al. Intermittent hypoxic-hyperoxic training on cognitive performance in geriatric patients. Alzheimers Dement (N Y). 2017;3(1):114–122. doi:10.1016/j.trci.2017.01.002.
  • Behrendt T, Bielitzki R, Behrens M, et al. Effects of intermittent hypoxia-hyperoxia exposure prior to aerobic cycling exercise on physical and cognitive performance in geriatric patients—a randomized controlled trial. Front Physiol. 2022;13:899096. doi:10.3389/fphys.2022.899096.
  • Serebrovska ZO, Serebrovska TV, Kholin VA, et al. Intermittent hypoxia-hyperoxia training improves cognitive function and decreases circulating biomarkers of alzheimer’s disease in patients with mild cognitive impairment: a pilot study. Int J Mol Sci. 2019;20(21):5405. doi:10.3390/ijms20215405.
  • Behrendt T, Altorjay A-C, Bielitzki R, et al. Influence of acute and chronic intermittent hypoxic-hyperoxic exposure prior to aerobic exercise on cardiovascular risk factors in geriatric patients—a randomized controlled trial. Front Physiol. 2022;13:1043536. doi:10.3389/fphys.2022.1043536.
  • Deutsche Gesellschaft für Geriatrie e. V. (DGG). Deutsche Gesellschaft für Geriatire (DGG). https://www.dggeriatrie.de/.
  • Holthoff VA, Marschner K, Scharf M, et al. Effects of physical activity training in patients with alzheimer’s dementia: results of a pilot RCT study. PLoS One. 2015;10(4):e0121478. doi:10.1371/journal.pone.0121478.
  • Soo J, Girard O, Ihsan M, et al. The use of the SpO2 to FiO2 ratio to individualize the hypoxic doxe in sport science, exercise, and health settings. Front Physiol. 2020;11:570472. doi:10.3389/fphys.2020.570472.
  • Izquierdo M, Merchant RA, Morley JE, et al. International exercise recommendations in older adults (ICFSR): expert consensus guidelines. J Nutr Health Aging. 2021;25(7):824–853. doi:10.1007/s12603-021-1665-8.
  • Yang H-C, Lee C-L, Lin R, et al. Effect of biofeedback cycling training on functional recovery and walking ability of lower extremity in patients with stroke. Kaohsiung J Med Sci. 2014;30(1):35–42. doi:10.1016/j.kjms.2013.07.006.
  • Schmider E, Ziegler M, Danay E, et al. Is it really robust? Methodology. 2010;6(4):147–151. doi:10.1027/1614-2241/a000016.
  • Blanca MJ, Alarcón R, Arnau J, et al. Non-normal data: is ANOVA still a valid option? Psicothema. 2017;29(4):552–557. doi:10.7334/psicothema2016.383.
  • Havlicek LL, Peterson NL. Robustness of the T test: a guide for researchers on effect of violations of assumptions. Psychol Rep. 1974;34(3_suppl):1095–1114. doi:10.2466/pr0.1974.34.3c.1095.
  • Pagano RR. Understanding statistics in the behavioral sciences. 9th ed. Belmont: wadsworth Cengage Learning; 2009.
  • Lakens D. Calculating and reporting effect sizes to facilitate cumulative science: a practical primer for t-tests and ANOVAs. Front Psychol. 2013;4:863. doi:10.3389/fpsyg.2013.00863.
  • Abbott EF, Serrano VP, Rethlefsen ML, et al. Trends in P value, confidence interval, and power analysis reporting in health professions education research reports: a systematic appraisal. Acad Med. 2018;93(2):314–323. doi:10.1097/ACM.0000000000001773.
  • Lee DK. Alternatives to P value: confidence interval and effect size. Korean J Anesthesiol. 2016;69(6):555–562. doi:10.4097/kjae.2016.69.6.555.
  • Ranstam J. Why the P-value culture is bad and confidence intervals a better alternative. Osteoarthritis Cartilage. 2012;20(8):805–808. doi:10.1016/j.joca.2012.04.001.
  • Cohen J. Quantitative methods in psychology: a power primer. Psychol Bull. 1992;112(1):155–159. doi:10.1037//0033-2909.112.1.155.
  • Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Routledge; 1988.
  • Tanaka H, Monahan KD, Seals DR. Age-predicted maximal heart rate revisited. J Am Coll Cardiol. 2001;37(1):153–156. doi:10.1016/S0735-1097(00)01054-8.
  • Helan M, Aravamudan B, Hartman WR, et al. BDNF secretion by human pulmonary artery endothelial cells in response to hypoxia. J Mol Cell Cardiol. 2014;68:89–97. doi:10.1016/j.yjmcc.2014.01.006.
  • Ehrenreich H, Gassmann M, Poustka L, et al. Exploiting moderate hypoxia to benefit patients with brain disease: molecular mechanisms and translational research in progress. Neuroprotection. 2023;1(1):9–19. doi:10.1002/nep3.15.
  • Piotrowicz Z, Chalimoniuk M, Płoszczyca K, et al. Exercise-Induced elevated BDNF level does not prevent cognitive impairment due to acute exposure to moderate hypoxia in well-trained athletes. Int J Mol Sci. 2020;21(15):5569. doi:10.3390/ijms21155569.
  • van Cutsem J, Pattyn N, Vissenaeken D, et al. The influence of a mild thermal challenge and severe hypoxia on exercise performance and serum BDNF. Eur J Appl Physiol. 2015;115(10):2135–2148. doi:10.1007/s00421-015-3193-x.
  • Ferris LT, Williams JS, Shen C-L. The effect of acute exercise on serum brain-derived neurotrophic factor levels and cognitive function. Med Sci Sports Exerc. 2007;39(4):728–734. doi:10.1249/mss.0b013e31802f04c7.
  • El Hayek L, Khalifeh M, Zibara V, et al. Lactate mediates the effects of exercise on learning and memory through SIRT1-Dependent activation of hippocampal brain-derived neurotrophic factor (BDNF). J Neurosci. 2019;39(13):2369–2382. doi:10.1523/JNEUROSCI.1661-18.2019.
  • Schiffer T, Schulte S, Sperlich B, et al. Lactate infusion at rest increases BDNF blood concentration in humans. Neurosci Lett. 2011;488(3):234–237. doi:10.1016/j.neulet.2010.11.035.
  • Brooks GA, Osmond AD, Arevalo JA, et al. Lactate as a myokine and exerkine: drivers and signals of physiology and metabolism. J Appl Physiol (1985). 2023;134(3):529–548. doi:10.1152/japplphysiol.00497.2022.
  • Hashimoto T, Tsukamoto H, Takenaka S, et al. Maintained exercise-enhanced brain executive function related to cerebral lactate metabolism in men. Faseb J. 2018;32(3):1417–1427. doi:10.1096/fj.201700381RR.
  • Hashimoto T, Tsukamoto H, Ando S, et al. Effect of exercise on brain health: the potential role of lactate as a myokine. Metabolites. 2021;11(12):813. doi:10.3390/metabo11120813.
  • Rojas Vega S, Strüder HK, Vera Wahrmann B, et al. Acute BDNF and cortisol response to low intensity exercise and following ramp incremental exercise to exhaustion in humans. Brain Res. 2006;1121(1):59–65. doi:10.1016/j.brainres.2006.08.105.
  • Hötting K, Schickert N, Kaiser J, et al. The effects of acute physical exercise on memory, peripheral BDNF, and cortisol in young adults. Neural Plast. 2016;2016:6860573–6860512. doi:10.1155/2016/6860573.
  • Navarrete-Opazo A, Mitchell GS. Therapeutic potential of intermittent hypoxia: a matter of dose. Am J Physiol Regul Integr Comp Physiol. 2014;307(10):R1181–97. doi:10.1152/ajpregu.00208.2014.
  • Behrendt T, Kirschnick F, Kröger L, et al. Comparison of the effects of open vs. closed skill exercise on the acute and chronic BDNF, IGF-1 and IL-6 response in older healthy adults. BMC Neurosci. 2021;22(1):71. doi:10.1186/s12868-021-00675-8.
  • Máderová D, Krumpolec P, Slobodová L, et al. Acute and regular exercise distinctly modulate serum, plasma and skeletal muscle BDNF in the elderly. Neuropeptides. 2019;78:101961. doi:10.1016/j.npep.2019.101961.
  • Fernández-Rodríguez R, Álvarez-Bueno C, Martínez-Ortega IA, et al. Immediate effect of high-intensity exercise on brain-derived neurotrophic factor in healthy young adults: a systematic review and meta-analysis. J Sport Health Sci. 2022;11(3):367–375. doi:10.1016/j.jshs.2021.08.004.
  • Dinoff A, Herrmann N, Swardfager W, et al. The effect of acute exercise on blood concentrations of brain-derived neurotrophic factor in healthy adults: a meta-analysis. Eur J Neurosci. 2017;46(1):1635–1646. doi:10.1111/ejn.13603.
  • Coates AM, Joyner MJ, Little JP, et al. A perspective on high-intensity interval training for performance and health. Sports Med. 2023;53(Suppl 1):85–96. doi:10.1007/s40279-023-01938-6.
  • Hubold C, Lang UE, Gehring H, et al. Increased serum brain-derived neurotrophic factor protein upon hypoxia in healthy young men. J Neural Transm (Vienna). 2009;116(10):1221–1225. doi:10.1007/s00702-009-0257-2.
  • Chroboczek M, Kujach S, Łuszczyk M, et al. Acute normobaric hypoxia lowers executive functions among young men despite increase of BDNF concentration. Int J Environ Res Public Health. 2022;19(17):10802. doi:10.3390/ijerph191710802.
  • Li P, Zhang G, You H-Y, et al. Training-dependent cognitive advantage is suppressed at high altitude. Physiol Behav. 2012;106(4):439–445. doi:10.1016/j.physbeh.2012.03.002.
  • Becke A, Müller P, Dordevic M, et al. Daily intermittent normobaric hypoxia over 2 weeks reduces BDNF plasma levels in young adults – a randomized controlled feasibility study. Front Physiol. 2018;9:1337. doi:10.3389/fphys.2018.01337.
  • Wilber RL, Stray-Gundersen J, Levine BD. Effect of hypoxic "dose" on physiological responses and sea-level performance. Med Sci Sports Exerc. 2007;39(9):1590–1599. doi:10.1249/mss.0b013e3180de49bd.
  • Serebrovska T, Serebrovska Z, Egorov E. Fitness and therapeutic potential of intermittent hypoxia training: a matter of dose. Fiziol Zh (1994). 2016;62(3):78–91. doi:10.15407/fz62.03.078.
  • Timon R, González-Custodio A, Vasquez-Bonilla A, et al. Intermittent hypoxia as a therapeutic tool to improve health parameters in older adults. Int J Environ Res Public Health. 2022;19(9):5339. doi:10.3390/ijerph19095339.
  • Burtscher J, Mallet RT, Pialoux V, et al. Adaptive responses to hypoxia and/or hyperoxia in humans. Antioxid Redox Signal. 2022;37(13-15):887–912. doi:10.1089/ars.2021.0280.
  • Hartmann G, Tschöp M, Fischer R, et al. High altitude increases circulating interleukin-6, interleukin-1 receptor antagonist and C-reactive protein. Cytokine. 2000;12(3):246–252. doi:10.1006/cyto.1999.0533.
  • Siervo M, Riley HL, Fernandez BO, et al. Effects of prolonged exposure to hypobaric hypoxia on oxidative stress, inflammation and gluco-insular regulation: the not-so-sweet price for good regulation. PLoS One. 2014;9(4):e94915. doi:10.1371/journal.pone.0094915.
  • Golia MT, Poggini S, Alboni S, et al. Interplay between inflammation and neural plasticity: both immune activation and suppression impair LTP and BDNF expression. Brain Behav Immun. 2019;81:484–494. doi:10.1016/j.bbi.2019.07.003.
  • Rivard A, Berthou-Soulie L, Principe N, et al. Age-dependent defect in vascular endothelial growth factor expression is associated with reduced hypoxia-inducible factor 1 activity. J Biol Chem. 2000;275(38):29643–29647. doi:10.1074/jbc.M001029200.
  • Richalet J-P, Lhuissier FJ. Aging, tolerance to high altitude, and cardiorespiratory response to hypoxia. High Alt Med Biol. 2015;16(2):117–124. doi:10.1089/ham.2015.0030.
  • Wang Y, Lu H, Chen Y, et al. The association of angiotensin-converting enzyme gene insertion/deletion polymorphisms with adaptation to high altitude: a meta-analysis. J Renin Angiotensin Aldosterone Syst. 2016;17(1):1470320315627410. 1470320315627410. doi:10.1177/1470320315627410.
  • Asgarzadeh A, Fouladi N, Asghariazar V, et al. Serum brain-derived neurotrophic factor (BDNF) in COVID-19 patients and its association with the COVID-19 manifestations. J Mol Neurosci. 2022;72(9):1820–1830. doi:10.1007/s12031-022-02039-1.
  • Suwa M, Kishimoto H, Nofuji Y, et al. Serum brain-derived neurotrophic factor level is increased and associated with obesity in newly diagnosed female patients with type 2 diabetes mellitus. Metabolism. 2006;55(7):852–857. doi:10.1016/j.metabol.2006.02.012.
  • Fujimura H, Altar CA, Chen R, et al. Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb Haemost. 2002;87(4):728–734. doi:10.1055/s-0037-1613072.
  • Nakahashi T, Fujimura H, Altar C, et al. Vascular endothelial cells synthesize and secrete brain-derived neurotrophic factor. FEBS Lett. 2000;470(2):113–117. doi:10.1016/S0014-5793(00)01302-8.
  • Matthews VB, Aström M-B, Chan MHS, et al. Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase. Diabetologia. 2009;52(7):1409–1418. doi:10.1007/s00125-009-1364-1.
  • Kerschensteiner M, Gallmeier E, Behrens L, et al. Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J Exp Med. 1999;189(5):865–870. doi:10.1084/jem.189.5.865.
  • Gielen A, Khademi M, Muhallab S, et al. Increased brain-derived neurotrophic factor expression in white blood cells of Relapsing-Remitting multiple sclerosis patients. Scand J Immunol. 2003;57(5):493–497. doi:10.1046/j.1365-3083.2003.01260.x.
  • Tobin B, Costalat G, Renshaw GMC. Intermittent not continuous hypoxia provoked haematological adaptations in healthy seniors: hypoxic pattern may hold the key. Eur J Appl Physiol. 2020;122(2):395–407. doi:10.1007/s00421-020-04310-y.
  • Timon R, Martinez-Guardado I, Brocherie F. Effects of intermittent normobaric hypoxia on Health-Related outcomes in healthy older adults: a systematic review. Sports Med Open. 2023;9(1):19. doi:10.1186/s40798-023-00560-0.
  • Chacaroun S, Borowik A, Doutreleau S, et al. Cardiovascular and metabolic responses to passive hypoxic conditioning in overweight and mildly obese individuals. Am J Physiol Regul Integr Comp Physiol. 2020;319(2):R211–R222. doi:10.1152/ajpregu.00311.2019.
  • Timon R, Martínez-Guardado I, Camacho-Cardeñosa A, et al. Effect of intermittent hypoxic conditioning on inflammatory biomarkers in older adults. Exp Gerontol. 2021;152:111478. doi:10.1016/j.exger.2021.111478.
  • Woods JA, Wilund KR, Martin SA, et al. Exercise, inflammation and aging. Aging Dis. 2012;3(1):130–140.
  • Bautmans I, Salimans L, Njemini R, et al. The effects of exercise interventions on the inflammatory profile of older adults: a systematic review of the recent literature. Exp Gerontol. 2021;146:111236. doi:10.1016/j.exger.2021.111236.
  • Pedersen BK, Fischer CP. Beneficial health effects of exercise–the role of IL-6 as a myokine. Trends Pharmacol Sci. 2007;28(4):152–156. doi:10.1016/j.tips.2007.02.002.
  • Petersen AMW, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol (1985). 2005;98(4):1154–1162. doi:10.1152/japplphysiol.00164.2004.
  • Fischer CP. Interleukin-6 in acute exercise and training: what is the biological relevance? Exerc Immunol Rev. 2006;12:6–33.
  • Marinus N, Hansen D, Feys P, et al. The impact of different types of exercise training on peripheral blood brain-derived neurotrophic factor concentrations in older adults: a Meta-Analysis. Sports Med. 2019;49(10):1529–1546. doi:10.1007/s40279-019-01148-z.
  • Kim J-H, Kim D-Y. Aquarobic exercises improve the serum blood irisin and brain-derived neurotrophic factor levels in elderly women. Exp Gerontol. 2018;104:60–65. doi:10.1016/j.exger.2018.01.024.
  • Pereira DS, Queiroz B D, Miranda AS, et al. Effects of physical exercise on plasma levels of brain-derived neurotrophic factor and depressive symptoms in elderly women–a randomized clinical trial. Arch Phys Med Rehabil. 2013;94(8):1443–1450. doi:10.1016/j.apmr.2013.03.029.
  • Maass A, Düzel S, Brigadski T, et al. Relationships of peripheral IGF-1, VEGF and BDNF levels to exercise-related changes in memory, hippocampal perfusion and volumes in older adults. Neuroimage. 2016;131:142–154. doi:10.1016/j.neuroimage.2015.10.084.
  • Matura S, Fleckenstein J, Deichmann R, et al. Effects of aerobic exercise on brain metabolism and grey matter volume in older adults: results of the randomised controlled SMART trial. Transl Psychiatry. 2017;7(7):e1172–e1172. doi:10.1038/tp.2017.135.
  • Gmiąt A, Jaworska J, Micielska K, et al. Improvement of cognitive functions in response to a regular nordic walking training in elderly women - A change dependent on the training experience. Exp Gerontol. 2018;104:105–112. doi:10.1016/j.exger.2018.02.006.
  • Monteleone P, Tortorella A, Martiadis V, et al. Opposite changes in the serum brain-derived neurotrophic factor in anorexia nervosa and obesity. Psychosom Med. 2004;66(5):744–748. doi:10.1097/01.psy.0000138119.12956.99.
  • Cho H, Kim J, Kim S, et al. The concentrations of serum, plasma and platelet BDNF are all increased by treadmill VO2max performance in healthy college men. Neurosci Lett. 2012;519(1):78–83. doi:10.1016/j.neulet.2012.05.025.
  • Jung SH, Kim J, Davis JM, et al. Association among basal serum BDNF, cardiorespiratory fitness and cardiovascular disease risk factors in untrained healthy korean men. Eur J Appl Physiol. 2011;111(2):303–311. doi:10.1007/s00421-010-1658-5.
  • Nofuji Y, Suwa M, Moriyama Y, et al. Decreased serum brain-derived neurotrophic factor in trained men. Neurosci Lett. 2008;437(1):29–32. doi:10.1016/j.neulet.2008.03.057.
  • Chan KL, Tong KY, Yip SP. Relationship of serum brain-derived neurotrophic factor (BDNF) and health-related lifestyle in healthy human subjects. Neurosci Lett. 2008;447(2-3):124–128. doi:10.1016/j.neulet.2008.10.013.
  • Bouaziz W, Vogel T, Schmitt E, et al. Health benefits of aerobic training programs in adults aged 70 and over: a systematic review. Arch Gerontol Geriatr. 2017;69:110–127. doi:10.1016/j.archger.2016.10.012.
  • Knaepen K, Goekint M, Heymann EM, et al. Neuroplasticity - Exercise-induced response of peripheral brain-derived neurotrophic factor: a systematic review of experimental studies in human subjects.
  • Kim J-M, Stewart R, Bae K-Y, et al. Role of BDNF val66met polymorphism on the association between physical activity and incident dementia. Neurobiol Aging. 2011;32(3):551.e5-12–551.12. doi:10.1016/j.neurobiolaging.2010.01.018.
  • Petryshen TL, Sabeti PC, Aldinger KA, et al. Population genetic study of the brain-derived neurotrophic factor (BDNF) gene. Mol Psychiatry. 2010;15(8):810–815. doi:10.1038/mp.2009.24.
  • Vulturar R, Chiş A, Hambrich M, et al. Allelic distribution of BDNF Val66Met polymorphism in healthy romanian volunteers. Transl Neurosci. 2016;7(1):31–34. doi:10.1515/tnsci-2016-0006.
  • Starkie R, Ostrowski SR, Jauffred S, et al. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. Faseb J. 2003;17(8):884–886. doi:10.1096/fj.02-0670fje.