Sex differences in cerebrovascular function across an aerobic exercise intervention in older adults using MRI: Results from the Brain in Motion study.

Publisher: published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society Country of Publication: United States NLM ID: 101607800 Publication Model: Print Cited Medium: Internet ISSN: 2051-817X (Electronic) Linking ISSN: 2051817X NLM ISO Abbreviation: Physiol Rep Subsets: MEDLINE

Original Publication: [Malden MA] : published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society, 2013-

Cerebrovascular Circulation*/physiology ; Exercise*/physiology ; Brain*/physiology ; Brain*/blood supply ; Brain*/diagnostic imaging; Magnetic Resonance Imaging/methods ; Humans ; Male ; Female ; Aged ; Middle Aged ; Sex Characteristics

Sex differences in cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) with aging, and across an aerobic exercise training intervention are poorly understood. The primary aim of this study was to investigate sex differences in cerebrovascular function in brain regions involved in verbal fluency, across an aerobic exercise intervention. CBF and CVR were assessed in 27 Brain in Motion study participants before, and after a 6-month aerobic exercise intervention. Resting CBF was measured using arterial spin labeling (ASL) magnetic resonance imaging (MRI) while CVR was quantified using blood oxygen level dependent (BOLD) MRI and a hypercapnic challenge. Compared to pre-intervention values, INLINEMATH increased (p < 0.001) while whole brain cerebrovascular measures were unchanged (all p > 0.05). There was no effect of the intervention or sex on CVR in the hippocampus, insula or left pars triangularis. There was a sex and intervention interaction in hippocampal, insula, and left pars triangularis blood flow (p < 0.05). These findings provide evidence of sex differences in regions of the brain involved in verbal fluency in response to an aerobic exercise intervention.
(© 2026 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Aanerud, J., Borghammer, P., Rodell, A., Jónsdottir, K. Y., & Gjedde, A. (2017). Sex differences of human cortical blood flow and energy metabolism. Journal of Cerebral Blood Flow and Metabolism, 37, 2433–2440.
Alisch, J. S. R., Khattar, N., Kim, R. W., Cortina, L. E., Rejimon, A. C., Qian, W., Ferrucci, L., Resnick, S. M., Spencer, R. G., & Bouhrara, M. (2021). Sex and age‐related differences in cerebral blood flow investigated using pseudo‐continuous arterial spin labeling magnetic resonance imaging. Aging, 13, 4911–4925.
Alwatban, M. R., Aaron, S. E., Kaufman, C. S., Barnes, J. N., Brassard, P., Ward, J. L., Miller, K. B., Howery, A. J., Labrecque, L., & Billinger, S. A. (2021). Effects of age and sex on middle cerebral artery blood velocity and flow pulsatility index across the adult lifespan. Journal of Applied Physiology, 130, 1675–1683.
Amen, D. G., Wu, J., George, N., & Newberg, A. (2020). Patterns of regional cerebral blood flow as a function of obesity in adults. Journal of Alzheimer's Disease, 77, 1331–1337.
Arenaza‐Urquijo, E. M., Boyle, R., Casaletto, K., Anstey, K. J., Vila‐Castelar, C., Colverson, A., Palpatzis, E., Eissman, J. M., Kheng Siang Ng, T., Raghavan, S., Akinci, M., Vonk, J. M. J., Machado, L. S., Zanwar, P. P., Shrestha, H. L., Wagner, M., Tamburin, S., Sohrabi, H. R., Loi, S., … Buckley, R. F. (2024). Sex and gender differences in cognitive resilience to aging and Alzheimer's disease. Alzheimer's & Dementia, 20, 5695–5719.
Beaudin, A. E., Hanly, P. J., Raneri, J. K., Sajobi, T. T., Anderson, T. J., & Poulin, M. J. (2019). Vascular responses to hypoxia are not impaired in obstructive sleep apnoea patients free of overt cardiovascular disease. Experimental Physiology, 104, 580–600.
Beavers, K. M., Brinkley, T. E., & Nicklas, B. J. (2010). Effect of exercise training on chronic inflammation. Clinica Chimica Acta, 411, 785–793.
Brown, A. D., Mcmorris, C. A., Longman, R. S., Leigh, R., Hill, M. D., Friedenreich, C. M., & Poulin, M. J. (2010). Effects of cardiorespiratory fitness and cerebral blood flow on cognitive outcomes in older women. Neurobiology of Aging, 31, 2047–2057.
Bruce, R. A., Kusumi, F., & Hosmer, D. (1973). Maximal oxygen intake and nomographic assessment of functional aerobic impairment in cardiovascular disease. American Heart Journal, 85, 546–562.
Burley, C. V., Francis, S. T., Whittaker, A. C., Mullinger, K. J., & Lucas, S. J. E. (2021). Measuring resting cerebral haemodynamics using MRI arterial spin labelling and transcranial Doppler ultrasound: Comparison in younger and older adults. Brain and Behavior: A Cognitive Neuroscience Perspective, 11, e02126.
Carmeli, C., Donati, A., Antille, V., Viceic, D., Ghika, J., von Gunten, A., Clarke, S., Meuli, R., Frackowiak, R. S., & Knyazeva, M. G. (2013). Demyelination in mild cognitive impairment suggests progression path to Alzheimer's disease. PLoS One, 8, e72759.
Chen, J. J. (2018). Cerebrovascular‐reactivity mapping using MRI: Considerations for Alzheimer's disease. Frontiers in Aging Neuroscience, 10, 170.
Chow, L. S., Gerszten, R. E., Taylor, J. M., Pedersen, B. K., van Praag, H., Trappe, S., Febbraio, M. A., Galis, Z. S., Gao, Y., Haus, J. M., Lanza, I. R., Lavie, C. J., Lee, C. H., Lucia, A., Moro, C., Pandey, A., Robbins, J. M., Stanford, K. I., Thackray, A. E., … Snyder, M. P. (2022). Exerkines in health, resilience and disease. Nature Reviews. Endocrinology, 18, 273–289.
Claassen, J., Thijssen, D. H. J., Panerai, R. B., & Faraci, F. M. (2021). Regulation of cerebral blood flow in humans: Physiology and clinical implications of autoregulation. Physiological Reviews, 101, 1487–1559.
da Silva, R. F., Trapé, Á. A., Reia, T. A., Lacchini, R., Oliveira‐Paula, G. H., Pinheiro, L. C., Tanus‐Santos, J. E., Jacomini, A. M., Bueno Júnior, C. R., & Zago, A. S. (2018). Association of endothelial nitric oxide synthase (eNOS) gene polymorphisms and physical fitness levels with plasma nitrite concentrations and arterial blood pressure values in older adults. PLoS One, 13, e0206254.
Duan, W., Zhou, G. D., Balachandrasekaran, A., Bhumkar, A. B., Boraste, P. B., Becker, J. T., Kuller, L. H., Lopez, O. L., Gach, H. M., & Dai, W. (2021). Cerebral blood flow predicts conversion of mild cognitive impairment into Alzheimer's disease and cognitive decline: An arterial spin labeling follow‐up study. Journal of Alzheimer's Disease, 82, 293–305.
DuBose, L. E., Weng, T. B., Pierce, G. L., Wharff, C., Reist, L., Hamilton, C., O'Deen, A., Dubishar, K., Lane‐Cordova, A., & Voss, M. W. (2022). Association between cardiorespiratory fitness and cerebrovascular reactivity to a breath‐hold stimulus in older adults: Influence of aerobic exercise training. Journal of Applied Physiology (1985), 132, 1468–1479.
Elmer, S. (2016). Broca pars Triangularis constitutes a “hub” of the language‐control network during simultaneous language translation. Frontiers in Human Neuroscience, 10, 491.
Eskes, G. A., Longman, S., Brown, A. D., McMorris, C. A., Langdon, K. D., Hogan, D. B., & Poulin, M. (2010). Contribution of physical fitness, cerebrovascular reserve and cognitive stimulation to cognitive function in post‐menopausal women. Frontiers in Aging Neuroscience, 2, 137.
Fitzgerald, M. D., Tanaka, H., Tran, Z. V., & Seals, D. R. (1997). Age‐related declines in maximal aerobic capacity in regularly exercising vs. sedentary women: A meta‐analysis. Journal of Applied Physiology (Bethesda, MD: 1985), 83, 160–165.
Griffanti, L., Zamboni, G., Khan, A., Li, L., Bonifacio, G., Sundaresan, V., Schulz, U. G., Kuker, W., Battaglini, M., Rothwell, P. M., & Jenkinson, M. (2016). BIANCA (brain intensity AbNormality classification algorithm): A new tool for automated segmentation of white matter hyperintensities. NeuroImage, 141, 191–205.
Guadagni, V., Drogos, L. L., Tyndall, A. V., Davenport, M. H., Anderson, T. J., Eskes, G. A., Longman, R. S., Hill, M. D., Hogan, D. B., & Poulin, M. J. (2020). Aerobic exercise improves cognition and cerebrovascular regulation in older adults. Neurology, 94, e2245–e2257.
Guelen, I., Westerhof, B. E., van der Sar, G. L., van Montfrans, G. A., Kiemeneij, F., Wesseling, K. H., & Bos, W. J. (2008). Validation of brachial artery pressure reconstruction from finger arterial pressure. Journal of Hypertension, 26, 1321–1327.
Haizlip, K. M., Harrison, B. C., & Leinwand, L. A. (2015). Sex‐based differences in skeletal muscle kinetics and fiber‐type composition. Physiology (Bethesda), 30, 30–39.
Hall, S. E., Lawal, O. A., Clark, C. M., Tyndall, A. V., Hill, M. D., Sajobi, T. T., & Poulin, M. J. (2019). Novel approach to characterize heterogeneity in an aerobic exercise intervention. Medicine and Science in Sports and Exercise, 51, 1506–1516.
Han, C., Sun, W., Zhang, D., Xi, X., Zhang, R., & Gong, W. (2023). Effects of different aerobic exercises on the global cognitive function of the elderly with mild cognitive impairment: A meta‐analysis. BMJ Open, 13, e067293.
Hoffmann, C. M., Petrov, M. E., & Lee, R. E. (2021). Aerobic physical activity to improve memory and executive function in sedentary adults without cognitive impairment: A systematic review and meta‐analysis. Preventive Medical Reports, 23, 101496.
Imholz, B. P., Wieling, W., van Montfrans, G. A., & Wesseling, K. H. (1998). Fifteen years experience with finger arterial pressure monitoring: Assessment of the technology. Cardiovascular Research, 38, 605–616.
Ishkhanyan, B., Michel Lange, V., Boye, K., Mogensen, J., Karabanov, A., Hartwigsen, G., & Siebner, H. R. (2020). Anterior and posterior left inferior frontal gyrus contribute to the implementation of grammatical determiners during language production. Frontiers in Psychology, 11, 685.
Ji, H., Gulati, M., Huang, T. Y., Kwan, A. C., Ouyang, D., Ebinger, J. E., Casaletto, K., Moreau, K. L., Skali, H., & Cheng, S. (2024). Sex differences in association of physical activity with all‐cause and cardiovascular mortality. Journal of the American College of Cardiology, 83, 783–793.
Juttukonda, M. R., Li, B., Almaktoum, R., Stephens, K. A., Yochim, K. M., Yacoub, E., Buckner, R. L., & Salat, D. H. (2021). Characterizing cerebral hemodynamics across the adult lifespan with arterial spin labeling MRI data from the human connectome project‐aging. NeuroImage, 230, 117807.
Krishnamurthy, V., Paredes Spir, I., Mammino, K. M., Nocera, J. R., McGregor, K. M., Crosson, B. A., & Krishnamurthy, L. C. (2022). The relationship between resting cerebral blood flow, Neurometabolites, cardio‐respiratory fitness and aging‐related cognitive decline. Frontiers in Psychiatry, 13, 923076.
Livingston, G., Huntley, J., Sommerlad, A., Ames, D., Ballard, C., Banerjee, S., Brayne, C., Burns, A., Cohen‐Mansfield, J., Cooper, C., Costafreda, S. G., Dias, A., Fox, N., Gitlin, L. N., Howard, R., Kales, H. C., Kivimäki, M., Larson, E. B., Ogunniyi, A., … Mukadam, N. (2020). Dementia prevention, intervention, and care: 2020 report of the lancet commission. The Lancet, 396, 413–446.
Lundberg, J. O., & Weitzberg, E. (2022). Nitric oxide signaling in health and disease. Cell, 185, 2853–2878.
MacDonald, M. E., Berman, A. J. L., Mazerolle, E. L., Williams, R. J., & Pike, G. B. (2018). Modeling hyperoxia‐induced BOLD signal dynamics to estimate cerebral blood flow, volume and mean transit time. NeuroImage, 178, 461–474.
Maeda, S., Iemitsu, M., Miyauchi, T., Kuno, S., Matsuda, M., & Tanaka, H. (2005). Aortic stiffness and aerobic exercise: Mechanistic insight from microarray analyses. Medicine and Science in Sports and Exercise, 37, 1710–1716.
McInnis, K. J., & Balady, G. J. (1994). Comparison of submaximal exercise responses using the Bruce vs modified Bruce protocols. Medicine and Science in Sports and Exercise, 26, 103–107.
Menon, R. S. (2002). Postacquisition suppression of large‐vessel BOLD signals in high‐resolution fMRI. Magnetic Resonance in Medicine, 47, 1–9.
Moradi, F., & Buxton, R. B. (2013). Adaptation of cerebral oxygen metabolism and blood flow and modulation of neurovascular coupling with prolonged stimulation in human visual cortex. NeuroImage, 82, 182–189.
Muer, J. D., Didier, K. D., Wannebo, B. M., Sanchez, S., Khademi Motlagh, H., Haley, T. L., Carter, K. J., Banks, N. F., Eldridge, M. W., Serlin, R. C., Wieben, O., & Schrage, W. G. (2024). Sex differences in gray matter, white matter, and regional brain perfusion in young, healthy adults. American Journal of Physiology. Heart and Circulatory Physiology, 327, H847–h858.
Ngandu, T., Lehtisalo, J., Solomon, A., Levälahti, E., Ahtiluoto, S., Antikainen, R., Bäckman, L., Hänninen, T., Jula, A., Laatikainen, T., Lindström, J., Mangialasche, F., Paajanen, T., Pajala, S., Peltonen, M., Rauramaa, R., Stigsdotter‐Neely, A., Strandberg, T., Tuomilehto, J., … Kivipelto, M. (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.
Perko, D., Pretnar‐Oblak, J., Sabovic, M., Zvan, B., & Zaletel, M. (2011). Differences between cerebrovascular reactivity to L‐arginine in the anterior and posterior cerebral circulation. Cerebrovascular Diseases (Basel, Switzerland), 31, 358–364.
Sáez de Asteasu, M. L., Martínez‐Velilla, N., Zambom‐Ferraresi, F., Casas‐Herrero, Á., & Izquierdo, M. (2017). Role of physical exercise on cognitive function in healthy older adults: A systematic review of randomized clinical trials. Ageing Research Reviews, 37, 117–134.
Schmidt, C. S. M., Nitschke, K., Bormann, T., Römer, P., Kümmerer, D., Martin, M., Umarova, R. M., Leonhart, R., Egger, K., Dressing, A., Musso, M., Willmes, K., Weiller, C., & Kaller, C. P. (2019). Dissociating frontal and temporal correlates of phonological and semantic fluency in a large sample of left hemisphere stroke patients. NeuroImage: Clinical, 23, 101840.
Smith, E. C., Pizzey, F. K., Askew, C. D., Mielke, G. I., Ainslie, P. N., Coombes, J. S., & Bailey, T. G. (2021). Effects of cardiorespiratory fitness and exercise training on cerebrovascular blood flow and reactivity: A systematic review with meta‐analyses. American Journal of Physiology. Heart and Circulatory Physiology, 321, H59–h76.
Smith, K. J., & Ainslie, P. N. (2017). Regulation of cerebral blood flow and metabolism during exercise. Experimental Physiology, 102, 1356–1371.
Spencer, M. D., Tyndall, A. V., Davenport, M. H., Argourd, L., Anderson, T. J., Eskes, G. A., Friedenreich, C. M., Hogan, D. B., Leigh, R., Meshi, B., Smith, E. E., Wilson, B. J., Wilton, S. B., & Poulin, M. J. (2015). Cerebrovascular responsiveness to hypercapnia is stable over six months in older adults. PLoS One, 10, e0143059.
Stelken, A. M., Younis, L. T., Jennison, S. H., Miller, D. D., Miller, L. W., Shaw, L. J., Kargl, D., & Chaitman, B. R. (1996). Prognostic value of cardiopulmonary exercise testing using percent achieved of predicted peak oxygen uptake for patients with ischemic and dilated cardiomyopathy. Journal of the American College of Cardiology, 27, 345–352.
Subramanian, S., Pallati, P. K., Rai, V., Sharma, P., Agrawal, D. K., & Nandipati, K. C. (2017). Increased expression of triggering receptor expressed on myeloid cells‐1 in the population with obesity and insulin resistance. Obesity (Silver Spring), 25, 527–538.
Szucs, D., & Ioannidis, J. P. (2020). Sample size evolution in neuroimaging research: An evaluation of highly‐cited studies (1990–2012) and of latest practices (2017–2018) in high‐impact journals. NeuroImage, 221, 117164.
Tancredi, F. B., Lajoie, I., & Hoge, R. D. (2014). A simple breathing circuit allowing precise control of inspiratory gases for experimental respiratory manipulations. BMC Research Notes, 7, 235.
Terstege, D. J., Ren, Y., Ahn, B. Y., Seo, H., Adigun, K., Galea, L. A. M., Sargin, D., & Epp, J. R. (2025). Impaired parvalbumin interneurons in the retrosplenial cortex as the cause of sex‐dependent vulnerability in Alzheimer's disease. Science Advances, 11, eadt8976.
Tousoulis, D., Kampoli, A. M., Tentolouris, C., Papageorgiou, N., & Stefanadis, C. (2012). The role of nitric oxide on endothelial function. Current Vascular Pharmacology, 10, 4–18.
Tyndall, A. V., Argourd, L., Sajobi, T. T., Davenport, M. H., Forbes, S. C., Gill, S. J., Parboosingh, J. S., Anderson, T. J., Wilson, B. J., Smith, E. E., Hogan, D. B., Hill, M. D., & Poulin, M. J. (2016). Cardiometabolic risk factors predict cerebrovascular health in older adults: Results from the brain in motion study. Physiological Reports, 4, e12733.
Tyndall, A. V., Davenport, M. H., Wilson, B. J., Burek, G. M., Arsenault‐Lapierre, G., Haley, E., Eskes, G. A., Friedenreich, C. M., Hill, M. D., Hogan, D. B., Longman, R. S., Anderson, T. J., Leigh, R., Smith, E. E., & Poulin, M. J. (2013). The brain‐in‐motion study: Effect of a 6‐month aerobic exercise intervention on cerebrovascular regulation and cognitive function in older adults. BMC Geriatrics, 13, 21.
Willeumier, K. C., Taylor, D. V., & Amen, D. G. (2011). Elevated BMI is associated with decreased blood flow in the prefrontal cortex using SPECT imaging in healthy adults. Obesity (Silver Spring), 19, 1095–1097.
Williams, R. J., Specht, J. L., Mazerolle, E. L., Lebel, R. M., MacDonald, M. E., & Pike, G. B. (2023). Correspondence between BOLD fMRI task response and cerebrovascular reactivity across the cerebral cortex. Frontiers in Physiology, 14, 1167148.
Wilson, T. M., & Tanaka, H. (2000). Meta‐analysis of the age‐associated decline in maximal aerobic capacity in men: Relation to training status. American Journal of Physiology. Heart and Circulatory Physiology, 278, H829–H834.
Wolters, F. J., Zonneveld, H. I., Hofman, A., van der Lugt, A., Koudstaal, P. J., Vernooij, M. W., & Ikram, M. A. (2017). Cerebral perfusion and the risk of dementia: A population‐based study. Circulation, 136, 719–728.
Xu, B., Vu, C., Borzage, M., González‐Zacarías, C., Shen, J., & Wood, J. (2023). Improved cerebrovascular reactivity mapping using coherence weighted general linear model in the frequency domain. NeuroImage, 284, 120448.
Xu, F., Li, W., Liu, P., Hua, J., Strouse, J. J., Pekar, J. J., Lu, H., Van Zijl, P. C. M., & Qin, Q. (2018). Accounting for the role of hematocrit in between‐subject variations of MRI‐derived baseline cerebral hemodynamic parameters and functional BOLD responses. Human Brain Mapping, 39, 344–353.
Xu, M., Liang, X., Ou, J., Li, H., Luo, Y. J., & Tan, L. H. (2020). Sex differences in functional brain networks for language. Cerebral Cortex, 30, 1528–1537.
Zeller, N. P., Miller, K. B., Zea, R. D., Howery, A. J., Labrecque, L., Aaron, S. E., Brassard, P., Billinger, S. A., & Barnes, J. N. (2022). Sex‐specific effects of cardiorespiratory fitness on age‐related differences in cerebral hemodynamics. Journal of Applied Physiology, 132, 1310–1317.
Zhang, J., Liu, Y., Zheng, Y., Luo, Y., Du, Y., Zhao, Y., Guan, J., Zhang, X., & Fu, J. (2020). TREM‐2‐p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus. Journal of Neuroinflammation, 17, 2.

AI-DEI 2020 Alberta Innovates (AI); 10025902 Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (NSERC); RT751959 Brenda Strafford Foundation Chair in Alzheimer Research; Canadian Institutes of Health Research (CIHR); Alberta Innovates Health Solution and NSERC Postdoctoral Fellowships; Canadian Alzheimer Society, Campus Alberta Neuroscience

Keywords: cardiorespiratory fitness; cerebral blood flow; cerebrovascular reactivity; magnetic resonance imaging; sex differences

Date Created: 20260418 Date Completed: 20260418 Latest Revision: 20260420

20260420

PMC13090539

10.14814/phy2.70880

41999060