Beneficial effect of exercise on cognitive function during peripheral arterial disease: potential involvement of myokines and microglial anti-inflammatory phenotype enhancement
Open accessAbstract
Peripheral arterial disease (PAD), leading to intermittent claudication, critical ischemia with rest pain, and/or tissue damage, is a public health issue associated with significant morbidity and mortality. Little is known about the link between PAD, cognitive function, and whether exercise might reduce cognitive dysfunction in PAD patients, as previously observed concerning both quality of life and prognosis. This review highlights the fact that patients suffering from PAD often demonstrate cognitive dysfunction characterized by reduced performance in nonverbal reasoning, reduced verbal fluency, and decreased information processing speed and a greater risk for progression toward dementia. Further, the data presented support that physical exercise, likely through myokine secretion and microglial anti-inflammatory phenotype enhancement, might participate in the cognition protection in common clinical settings.
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Muscle contraction is sensed by the brain, suggesting that peripheral factors induced by exercise may be involved in direct crosstalk between working muscle and brain function.
“The finding that muscle contraction is sensed by the brain suggests that peripheral factors induced by exercise may be involved in direct crosstalk between working muscle and brain function (7, 29, 30, 83) (Fig. 2).”
From Muscle–Organ Crosstalk: The Emerging Roles of Myokines (2020) · cites this paper as [83]
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BackgroundGuillot, M., Charles, A., Chamaraux‐Tran, T., Bouitbir, J., Meyer, A., Zoll, J., Schneider, F., & Gény, B. (2013) · Journal of Vascular Surgery · doi:10.1016/j.jvs.2013.07.100 · Cited by 44 · cited 2× · see citing works
“Thus, although an experimental study failed to demon trated brain mitochondrial dysfunction in the setting of aortic cla ping [23], peripheral inflammatory factors released during the ischemic process have been shown to impair several remote organs, including the brain [24,25] (Figure 1).”
BackgroundHart, C. R., Layec, G., Trinity, J. D., Kwon, O. S., Zhao, J., Reese, V. R., Gifford, J. R., & Richardson, R. S. (2018) · Experimental Physiology · doi:10.1113/ep086905 · Cited by 44 · cited 1× · see citing works
“, the ABI was significantly correlated with intramuscular inflammation, oxidative stress, and mitochondrial reactive oxygen species (ROS) generation [33].”
BackgroundTang, Y. C. (2015) · Medical Science Monitor · doi:10.12659/msm.893935 · Cited by 40 · see citing works
Gmiat, A., Micielska, K., Kozłowska, M., Flis, D. J., Smaruj, M., Kujach, S., Jaworska, J., Lipińska, P., & Ziemann, E. (2017) · Physiology & Behavior · doi:10.1016/j.physbeh.2017.07.004 · Cited by 40 · cited 1× · see citing works
“found that a single bout of high-intensity circuit training was able to improve concentration and spatial memory in young women, and that irisin and IL-6 releases from exercise (respecting intensity and periods of adequate rest and nutrition) might be considered as a sensor stimulating BDNF synthesis [73].”
BackgroundObadia, N., Lessa, M. A., Daliry, A., Silvares, R. R., Gomes, F., Tibiriçá, E. V., & Estato, V. (2017) · BMC Neuroscience · doi:10.1186/s12868-017-0384-x · Cited by 39 · see citing works
Félix-Redondo, F. J., Fernandez-Berges, D. J., Grau, M., Baena-Díez, J. M., Mostaza, J. M., & Vila, J. (2012) · Revista Española de Cardiología · doi:10.1016/j.recesp.2012.03.008 · Cited by 38 · see citing works
Supervised Exercise Training for Intermittent Claudication: Lasting Benefit at Three Years
Ratliff, D. A., Puttick, M., Libertiny, G., Hicks, R. C. J., Earby, L. E., & Richards, T. (2007) · European Journal of Vascular and Endovascular Surgery · doi:10.1016/j.ejvs.2007.04.014 · Cited by 37 · see citing works
Correlates for a low ankle–brachial index in elderly Chinese
Woo, J., Lynn, H., Wong, S. Y. S., Hong, A. W. L., Tang, Y., Lau, W. Y., Lau, E., ORWOLL, E. S., & Kwok, T. C. Y. (2005) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2005.07.022 · Cited by 34 · cited 2× · see citing works
“The presence of cardiovascular diseases (stroke, hypertension, myocardial infarction) and cognitive impairment was positively associated with low ABI [35].”
BackgroundNeuropsychological function in peripheral vascular disease amputee patients
Phillips, N. A., Mate-Kole, C. C., & Kirby, R. L. (1993) · Archives of Physical Medicine and Rehabilitation · doi:10.1016/0003-9993(93)90085-o · Cited by 34 · cited 1× · see citing works
“The authors hypothesized that cognitive deficits may be the result of unrecognized concomitant cerebrovascular diseases, which are part of a generalized pattern of vascular disease [32].”
BackgroundFélix-Redondo, F. J., Fernandez-Berges, D. J., Grau, M., Baena-Díez, J. M., Mostaza, J. M., & Vila, J. (2012) · Revista Española de Cardiología (English Edition) · doi:10.1016/j.rec.2012.03.007 · Cited by 32 · see citing works
Gardner, A. W., Parker, D. E., & Montgomery, P. S. (2019) · Journal of Vascular Surgery · doi:10.1016/j.jvs.2018.12.056 · Cited by 32 · cited 1× · see citing works
“Even home-based exercise training improved circulating markers of antioxidant capacity, angiogenesis (VEGF), endothelium-derived inflammation (E-selectin), and blood glucose concentration [90].”
BackgroundLeardini-Tristão, M., Borges, J. P., de Freitas, F. S. S., Silvares, R. R., Daliry, A., Tibiriçá, E. V., & Estato, V. (2016) · Brain Research · doi:10.1016/j.brainres.2016.11.030 · Cited by 31 · see citing works
Chang, P., Nead, K. T., Olin, J. W., MYERS, J. N., Cooke, J. P., & Leeper, N. J. (2015) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2014.12.016 · Cited by 30 · see citing works
Cavalcante, B. R., Germano-Soares, A. H., Gerage, A. M., Leicht, A. S., Tassitano, R. M., Bortolotti, H., Franco, F. G. D. M., Wolosker, N., Cucato, G. G., & Ritti‐Dias, R. M. (2018) · European Journal of Vascular and Endovascular Surgery · doi:10.1016/j.ejvs.2018.02.010 · Cited by 28 · cited 1× · see citing works
“[29], cognitive performance in patients with PAD is positively associated with walking ability and moderate to vigorous intensity physical activity.”
BackgroundMa, S.-H., Zhuang, Q., Shen, W., Peng, Y.-P., & Qiu, Y. (2015) · Cell Calcium · doi:10.1016/j.ceca.2015.06.006 · Cited by 27 · cited 1× · see citing works
“A number of studies have reported elevated levels of IL-6 during central nervous system (CNS) disorders [65], but on the other hand Ma and co-workers [71], demonstrated that IL-6 reduced neuronal cytosolic Ca2+ overload, mitochondrial membrane depolarization, and neuronal induced by NMDA, demonstrating that IL-6 has a…”
BackgroundBrunt, A., Albines, D., & Hopkins-Rosseel, D. H. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8030294 · Cited by 26 · cited 1× · see citing works
“Further, combined interventions might be more efficient than endurance and resistance training alone [93].”
BackgroundEspeland, M. A., Newman, A. B., Sink, K. M., Gill, T. M., King, A. C., Miller, M. E., Guralnik, J. M., Katula, J. A., Church, T. S., Manini, T. M., et al. (2015) · Journal of the American Medical Directors Association · doi:10.1016/j.jamda.2015.03.010 · Cited by 24 · see citing works
A low ankle-brachial index is associated with cognitive impairment: The APAC study
Wang, A., Jiang, R., Su, Z., Jia, J., Zhang, N., Wu, J., Chen, S., & Zhao, X. (2016) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2016.11.005 · Cited by 21 · cited 1× · see citing works
“This association between ABI and cognitive impairment was confirmed in a cross-sectional study where aging resulted in a higher proportion of individuals with low ABI or cognitive impairment [37].”
ResultGreek goddess or Greek myth: the effects of exercise on irisin/FNDC5 in humans
Atherton, P. J., & Phillips, B. E. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2013.265371 · Cited by 20 · cited 1× · see citing works
“showing that exercise increases irisin in mice and humans [54], others proposed negative evidence of a possible expression and concentrations of irisin in skeletal muscles and serum during exercise or training [55,56] and the physiological role of FNDC5/irisin in mediating responses to exercise was challenged [57].”
BackgroundModerate Exercise Allows for shorter Recovery Time in Critical Limb Ischemia
Lejay, A., LAVERNY, G., Paradis, S., Schlagowski, A.-I., Charles, A., Singh, F., Zoll, J., Thaveau, F., Lonsdorfer‐Wolf, E., Dufour, S. P., et al. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00523 · Cited by 20 · cited 2× · see citing works
“Even in the case of chronic critical limb ischemia, experimental data support that moderate exercise can reduce skeletal muscle damage, improving functional scores, restoring mitochondrial respiration and calcium retention capacity, and enhancing anti-oxidant defenses, such as superoxide dismutase 1 and 2, and catalas…”
BackgroundKarimi, N., Haghani, M., Noorafshan, A., & Moosavi, S. M. S. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.06.058 · Cited by 19 · cited 2× · see citing works
“Thus, although an experimental study failed to demon trated brain mitochondrial dysfunction in the setting of aortic cla ping [23], peripheral inflammatory factors released during the ischemic process have been shown to impair several remote organs, including the brain [24,25] (Figure 1).”
BackgroundRitti‐Dias, R. M., Correia, M. D. A., Andrade-Lima, A., & Cucato, G. G. (2018) · Expert Review of Cardiovascular Therapy · doi:10.1080/14779072.2019.1553676 · Cited by 16 · cited 1× · see citing works
“Regarding intensity, a body of evidence suggests that higher exercise intensities may maximize the health outcomes of PAD patients [91].”
BackgroundGardner, A. W., Waldstein, S. R., Montgomery, P. S., & Zhao, Y. D. (2015) · Journal of Vascular Surgery · doi:10.1016/j.jvs.2015.08.064 · Cited by 14 · cited 2× · see citing works
“[28], patients with PAD were grouped according to their performance on a mini-mental state examination (MMSE).”
BackgroundMethodWilliams, R. M., Turner, A. P., Green, M., Norvell, D. C., Henderson, A. W., Hakimi, K. N., Blake, D. J., & Czerniecki, J. M. (2013) · Archives of Physical Medicine and Rehabilitation · doi:10.1016/j.apmr.2013.11.013 · Cited by 12 · cited 1× · see citing works
“The authors suggested that this improvement was associated with the perceived increase in general health [31].”
BackgroundAnkle brachial index, MRI markers and cognition: The Epidemiology of Dementia in Singapore study
Shaik, M. A., Venketasubramanian, N., Cheng, C., Wong, T. Y., Vrooman, H. A., Ikram, M. K., Hilal, S., & Chen, C. (2017) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2017.07.002 · Cited by 10 · cited 2× · see citing works
“Further, individuals with low ABI had a higher frequency of cerebral lacunar infarcts, intracranial stenosis, cortical thinning, and lower verbal memory performance [38].”
Background
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Muscle–Organ Crosstalk: The Emerging Roles of Myokines
Severinsen, M. C. K., & Pedersen, B. K. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnaa016 · Cited by 1,226 · see citing works
“The finding that muscle contraction is sensed by the brain suggests that peripheral factors induced by exercise may be involved in direct crosstalk between working muscle and brain function (7, 29, 30, 83) (Fig.”
BackgroundMuscle-Organ Crosstalk: Focus on Immunometabolism
Bay, M. L., & Pedersen, B. K. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.567881 · Cited by 110 · see citing works
Lang, X., Zhao, N., He, Q., Li, X., Li, X., Sun, C., & Zhang, X. (2020) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2020.09.015 · Cited by 57 · see citing works
Pizzimenti, M., Riou, M., Charles, A., Talha, S., Meyer, A., Andrès, E., Chakfé, N., Lejay, A., & Gény, B. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8122125 · Cited by 40 · see citing works
“PAD is also often associated with cognitive dysfunction characterized by reduced performance in nonverbal reasoning, reduced verbal fluency, and decreased information processing speed [4].”
BackgroundThe link between impaired oxygen supply and cognitive decline in peripheral artery disease
Burtscher, J., Millet, G. P., Fresa, M., Lanzi, S., Mazzolai, L., & Pellegrin, M. (2023) · Progress in Cardiovascular Diseases · doi:10.1016/j.pcad.2023.12.002 · Cited by 17 · see citing works
Paradis, S., Charles, A., Georg, I., Goupilleau, F., Meyer, A., Kindo, M. J., LAVERNY, G., METZGER, D., & Gény, B. (2019) · Antioxidants · doi:10.3390/antiox8060168 · Cited by 17 · see citing works
Exercise and Cognitive Function
Loprinzi, P. D., & Lovorn, A. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8101707 · Cited by 11 · see citing works
“[22] To illustrate the fact that patients suffering from PAD show cognitive dysfunction, and, through exercise, brain function could be protected.”
BackgroundRouyer, O., Auger, C., Charles, A., Talha, S., Meyer, A., Piquard, F., Andrès, E., Schini‐Kerth, V. B., & Gény, B. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8060859 · Cited by 9 · see citing works
Skeletal Muscle as Endocrine Organ
Ma, M., Zhang, Z., Hai, B., & Zhang, Y. (2025) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-88361-3_22 · Cited by 6 · see citing works
Irisin, the Myokine: Guardian and Mediator in Cardiovascular System
Lan, T., Yan, X., Li, J., Gu, H., Hou, Q., He, E., & Yang, Q. (2025) · Endocrinology Diabetes & Metabolism · doi:10.1002/edm2.70097 · Cited by 5 · see citing works
“The anti-inflammatory properties of Irisin are associated with cytokine regulation, exerting anti-inflammatory effects by activating multiple signalling pathways and enhancing the anti-inflammatory phenotype of microglial cells [175–177].”
Envejecimiento neural, plasticidad cerebral y ejercicio: Avances desde la óptica de Fisioterapia
Ríos, I. D. P., & Collazos, J. E. M. (2019) · Archivos de Medicina (Manizales) · doi:10.30554/archmed.20.1.3459.2020 · Cited by 6 · see citing works
Kanegusuku, H., Correia, M. D. A., Longano, P., Ritti‐Dias, R. M., Wolosker, N., & Cucato, G. G. (2022) · PLoS ONE · doi:10.1371/journal.pone.0267849 · Cited by 2 · see citing works
“In this context, as patients with PAD commonly present impairments in cerebral vascular functions [46, 47], it is possible that the systemic cardiovascular effects of ACT can improve cognitive functions.”
Tan, Y., Chen, Y., Bai, Y., Zhang, S., Yang, C., Feng, J., Jia, J., Wang, X., & Zhou, J. F. (2022) · Research Square · doi:10.21203/rs.3.rs-2382599/v1 · Cited by 1 · see citing works
Arch Med (Manizales) 20(1) 2020 Fascículo completo.
Castrillón, J. J. C. (2020) · Archivos de Medicina (Manizales) · doi:10.30554/archmed.20.1.3702.2020
Impact of Dementia on Treatment of Peripheral Arterial Disease, Hip and Vertebral Bone Fracture
Feller, K., Heinz, A., von Beckerath, O., Juntermanns, B., Kröger, K., & Santosa, F. (2023) · Family Medicine and Primary Care Open Access · doi:10.29011/26887460.100225
Damle, P. D. (2023) · International Journal of Science and Research (IJSR) · doi:10.21275/sr23623135602
Ishola, A., White, E., Fierek, J., Busutill, A., Abdelkhalek, H., Bergman, M., & Bergman, M. (2026) · JVS-Vascular Insights · doi:10.1016/j.jvsvi.2026.100406
- Authors
- Leardini-Tristao, M., Charles, A.-L., Lejay, A., Pizzimenti, M., Meyer, A., Estato, V., Tibiriçá, E., Andres, E., & Geny, B.
- Affiliations
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, FIOCRUZ, Avenida Brasil 4365, Rio de Janeiro 21040-360, Brazil
- Université de Strasbourg (FR)
- Hôpitaux Universitaires de Strasbourg (FR)
- Instituto Oswaldo Cruz (BR)
- Instituto Nacional de Cardiologia (BR)
- Service de Médecine Interne, Diabète et Maladies Métaboliques, Pôle M.I.R.N.E.D., Hôpitaux Universitaires, CHRU Strasbourg, 67000 CEDEX, France
- Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Faculté de Médecine, Equipe d’Accueil 3072, 11 Rue Humann, 67000 Strasbourg, France
- ORCID
- Venue
- Journal of Clinical Medicine
- Publisher
- MDPI AG
- Published
- 2019-05-10
- Volume
- 8
- Issue
- 5
- Pages
- 653
- ISSN
- 2077-0383 (ISSN-L)
- PMC
- PMC6571759
- OpenAlex
- W2945945060
- Cited by
- 17
- References
- 97
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 3 · 2022: 2 · 2020: 4 · 2019: 5
- FWCI
- 0.57
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Journal of Clinical Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Surgery › Peripheral Artery Disease Management
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- peripheral arterial disease, cognitive function, physical activity, myokines, microglia, anti-inflammatory phenotype, cognitive impairment, dementia risk, intermittent claudication, processing speed, verbal fluency
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