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Cardiorespiratory Fitness and Gray Matter Volume in the Temporal, Frontal, and Cerebellar Regions in the General Population



      To analyze the association between cardiorespiratory fitness (CRF) and global and local brain volumes.

      Participants and Methods

      We studied 2103 adults (21-84 years old) from 2 independent population-based cohorts (Study of Health in Pomerania, examinations from June 25, 2008, through September 30, 2012). Cardiorespiratory fitness was measured using peak oxygen uptake (VO2peak), oxygen uptake at the anaerobic threshold (VO2@AT), and maximal power output from cardiopulmonary exercise testing on a bicycle ergometer. Magnetic resonance imaging brain data were analyzed by voxel-based morphometry using regression models with adjustment for age, sex, education, smoking, body weight, systolic blood pressure, glycated hemoglobin level, and intracranial volume.


      Volumetric analyses revealed associations of CRF with gray matter (GM) volume and total brain volume. After multivariable adjustment, a 1–standard deviation increase in VO2peak was related to a 5.31 cm³ (95% CI, 3.27 to 7.35 cm³) higher GM volume. Whole-brain voxel-based morphometry analyses revealed significant positive relations between CRF and local GM volumes. The VO2peak was strongly associated with GM volume of the left middle temporal gyrus (228 voxels), the right hippocampal gyrus (146 voxels), the left orbitofrontal cortex (348 voxels), and the bilateral cingulate cortex (68 and 43 voxels).


      Cardiorespiratory fitness was positively associated with GM volume, total brain volume, and specific GM and white matter clusters in brain areas not primarily involved in movement processing. These results, from a representative population sample, suggest that CRF might contribute to improved brain health and might, therefore, decelerate pathology-specific GM decrease.

      Abbreviations and Acronyms:

      AAL (automated anatomical labeling), CAT12 (Computational Anatomy Toolbox 12), CPET (cardiopulmonary exercise testing), CRF (cardiorespiratory fitness), FWE (familywise error), GM (gray matter), MRI (magnetic resonance imaging), Ppeak,FWE (familywise error–corrected peak-level P), SD (standard deviation), SHIP (Study of Health in Pomerania), TBV (total brain volume), VBM (voxel-based morphometry), [email protected] (oxygen uptake at the anaerobic threshold), VO2peak (peak oxygen uptake), WM (white matter), Wmax (maximal power output)
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        • World Health Organization
        Towards a Dementia Plan: A WHO Guide.
        (. Published)
        • Prince M.
        • Wimo A.
        • Guerchet M.
        • Ali G.-C.
        • Wu Y.-T.
        • Prina M.
        World Alzheimer Report 2015: The Global Impact of Dementia.
        Alzheimer’s Disease International, London, UK2015
        • Barnes D.E.
        • Yaffe K.
        The projected effect of risk factor reduction on Alzheimer’s disease prevalence.
        Lancet Neurol. 2011; 10: 819-828
        • Myers J.
        • McAuley P.
        • Lavie C.J.
        • Despres J.P.
        • Arena R.
        • Kokkinos P.
        Physical activity and cardiorespiratory fitness as major markers of cardiovascular risk: their independent and interwoven importance to health status.
        Prog Cardiovasc Dis. 2015; 57: 306-314
        • Swift D.L.
        • Lavie C.J.
        • Johannsen N.M.
        • et al.
        Physical activity, cardiorespiratory fitness, and exercise training in primary and secondary coronary prevention.
        Circ J. 2013; 77: 281-292
        • Gupta S.
        • Rohatgi A.
        • Ayers C.R.
        • et al.
        Cardiorespiratory fitness and classification of risk of cardiovascular disease mortality.
        Circulation. 2011; 123: 1377-1383
        • Wedell-Neergaard A.S.
        • Krogh-Madsen R.
        • Petersen G.L.
        • et al.
        Cardiorespiratory fitness and the metabolic syndrome: Roles of inflammation and abdominal obesity.
        PLoS One. 2018; 13: 1-16
        • Ingle L.
        • Mellis M.
        • Brodie D.
        • Sandercock G.R.
        Associations between cardiorespiratory fitness and the metabolic syndrome in British men.
        Heart. 2017; 103: 516-520
        • Kalaria R.N.
        • Maestre G.E.
        • Arizaga R.
        • et al.
        Alzheimer’s disease and vascular dementia in developing countries: prevalence, management, and risk factors.
        Lancet Neurol. 2008; 7: 812-826
        • Papasavvas T.
        • Bonow R.O.
        • Alhashemi M.
        • Micklewright D.
        Depression symptom severity and cardiorespiratory fitness in healthy and depressed adults: a systematic review and meta-analysis.
        Sport Med. 2016; 46: 219-230
        • Schmid D.
        • Leitzmann M.F.
        Cardiorespiratory fitness as predictor of cancer mortality: a systematic review and meta-analysis.
        Ann Oncol. 2015; 26: 272-278
        • Hall P.A.
        • Bickel W.K.
        • Erickson K.I.
        • Wagner D.D.
        Neuroimaging, neuromodulation, and population health: the neuroscience of chronic disease prevention.
        Ann N Y Acad Sci. 2018; 1428: 240-256
        • Sexton C.E.
        • Betts J.F.
        • Demnitz N.
        • Dawes H.
        • Ebmeier K.P.
        • Johansen-Berg H.
        A systematic review of MRI studies examining the relationship between physical fitness and activity and the white matter of the ageing brain.
        Neuroimage. 2016; 131: 81-90
        • Blondell S.J.
        • Hammersley-Mather R.
        • Veerman J.
        Does physical activity prevent cognitive decline and dementia? a systematic review and meta-analysis of longitudinal studies.
        BMC Public Health. 2014; 14: 1-12
        • Bherer L.
        • Erickson K.I.
        • Liu-Ambrose T.
        A review of the effects of physical activity and exercise on cognitive and brain functions in older adults.
        J Aging Res. 2013; 2013: 657508
        • Völzke H.
        • Alte D.
        • Schmidt C.O.
        • et al.
        Cohort profile: the study of health in Pomerania.
        Int J Epidemiol. 2011; 40: 294-307
        • Hegenscheid K.
        • Seipel R.
        • Schmidt C.O.
        • et al.
        Potentially relevant incidental findings on research whole-body MRI in the general adult population: frequencies and management.
        Eur Radiol. 2013; 23: 816-826
        • Fischl B.
        • Salat D.H.
        • Busa E.
        • et al.
        Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain.
        Neuron. 2002; 33: 341-355
        • Jones N.L.
        • Makrides L.
        • Hitchcock C.
        • Chypchar T.
        • McCartney N.
        Normal standards for an incremental progressive cycle ergometer test.
        Am Rev Respir Dis. 1985; 131: 700-708
        • Koch B.
        • Schäper C.
        • Ittermann T.
        • et al.
        Reference values for cardiopulmonary exercise testing in healthy volunteers: the SHIP study.
        Eur Respir J. 2009; 33: 389-397
        • Haahr M.E.
        • Fisher P.
        • Holst K.
        • et al.
        The 5-HT4 receptor levels in hippocampus correlates inversely with memory test performance in humans.
        Hum Brain Mapp. 2013; 34: 3066-3074
        • Sauerbrei W.
        • Royston P.
        Building multivariable prognostic and diagnostic models: transformation of the predictors by using fractional polynomials.
        J R Stat Soc Ser A Stat Soc. 1999; 162: 71-94
        • O’Brien L.M.
        • Ziegler D.A.
        • Deutsch C.K.
        • Frazier J.A.
        • Herbert M.R.
        • Locascio J.J.
        Statistical adjustments for brain size in volumetric neuroimaging studies: some practical implications in methods.
        Psychiatry Res. 2011; 193: 113-122
        • Ridgway G.R.
        • Omar R.
        • Ourselin S.
        • Hill D.L.G.
        • Warren J.D.
        • Fox N.C.
        Issues with threshold masking in voxel-based morphometry of atrophied brains.
        Neuroimage. 2009; 44: 99-111
        • Tzourio-Mazoyer N.
        • Landeau B.
        • Papathanassiou D.
        • et al.
        Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain.
        Neuroimage. 2002; 15: 273-289
        • Erickson K.I.
        • Leckie R.L.
        • Weinstein A.M.
        Physical activity, fitness, and gray matter volume.
        Neurobiol Aging. 2014; 35: S20-S28
        • Killgore W.D.S.
        • Olson E.A.
        • Weber M.
        Physical exercise habits correlate with gray matter volume of the hippocampus in healthy adult humans.
        Sci Rep. 2013; 3: 3457
        • Burgess N.
        • Maguire E.A.
        • O’Keefe J.
        The human hippocampus and spatial and episodic memory.
        Neuron. 2002; 35: 625-641
        • Snyder J.S.
        • Soumier A.
        • Brewer M.
        • Pickel J.
        • Cameron H.A.
        Adult hippocampal neurogenesis buffers stress responses and depressive behaviour.
        Nature. 2011; 476: 458-461
        • Mufson E.J.
        • Mahady L.
        • Waters D.
        • et al.
        Hippocampal plasticity during the progression of Alzheimer’s disease.
        Neuroscience. 2015; 309: 51-67
        • Malykhin N.V.
        • Coupland N.J.
        Hippocampal neuroplasticity in major depressive disorder.
        Neuroscience. 2015; 309: 200-213
        • Tamminga C.A.
        • Zukin R.S.
        Schizophrenia: evidence implicating hippocampal GluN2B protein and REST epigenetics in psychosis pathophysiology.
        Neuroscience. 2015; 309: 233-242
        • Kringelbach M.L.
        The human orbitofrontal cortex: linking reward to hedonic experience.
        Nat Rev Neurosci. 2005; 6: 691-702
        • Stimpson N.J.
        • Davison G.
        • Javadi A.H.
        Joggin’ the noggin: towards a physiological understanding of exercise-induced cognitive benefits.
        Neurosci Biobehav Rev. 2018; 88: 177-186
        • Huang T.
        • Larsen K.T.
        • Ried-Larsen M.
        • Møller N.C.
        • Andersen L.B.
        The effects of physical activity and exercise on brain-derived neurotrophic factor in healthy humans: a review.
        Scand J Med Sci Sport. 2014; 24: 1-10
        • Pietrelli A.
        • Matković L.
        • Vacotto M.
        • Lopez-Costa J.J.
        • Basso N.
        • Brusco A.
        Aerobic exercise upregulates the BDNF-serotonin systems and improves the cognitive function in rats.
        Neurobiol Learn Mem. 2018; 155: 528-542
        • Kanwisher N.
        • Yovel G.
        The fusiform face area: a cortical region specialized for the perception of faces.
        Philos Trans R Soc B Biol Sci. 2006; 361: 2109-2128
        • Kumfor F.
        • Hutchings R.
        • Irish M.
        • et al.
        Do I know you? examining face and object memory in frontotemporal dementia.
        Neuropsychologia. 2015; 71: 101-111
        • Grabe H.J.
        • Wittfeld K.
        • Hegenscheid K.
        • et al.
        Alexithymia and brain gray matter volumes in a general population sample.
        Hum Brain Mapp. 2014; 35: 5932-5945
        • De Borba A.T.
        • Jost R.T.
        • Gass R.
        • et al.
        The influence of active and passive smoking on the cardiorespiratory fitness of adults.
        Multidiscip Respir Med. 2014; 9: 1-8
        • Peter I.
        • Papandonatos G.D.
        • Belalcazar L.M.
        • et al.
        Genetic modifiers of cardiorespiratory fitness response to lifestyle intervention.
        Med Sci Sports Exerc. 2014; 46: 302-311
        • Batouli S.A.H.
        • Saba V.
        At least eighty percent of brain grey matter is modifiable by physical activity: a review study.
        Behav Brain Res. 2017; 332: 204-217
        • Verstynen T.D.
        • Lynch B.
        • Miller D.L.
        • et al.
        Caudate nucleus volume mediates the link between cardiorespiratory fitness and cognitive flexibility in older adults.
        J Aging Res. 2012; 2012: 939285
        • Whiteman A.S.
        • Young D.E.
        • Budson A.E.
        • Stern C.E.
        • Schon K.
        Entorhinal volume, aerobic fitness, and recognition memory in healthy young adults: a voxel-based morphometry study.
        Neuroimage. 2016; 126: 229-238
        • Brockett A.T.
        • LaMarca E.A.
        • Gould E.
        Physical exercise enhances cognitive flexibility as well as astrocytic and synaptic markers in the medial prefrontal cortex.
        PLoS One. 2015; 10: 1-11
        • Wasserman K.
        • Hansen J.E.
        • Sue D.Y.
        • Stringer W.W.
        • Sietsema K.E.
        • Sun X.-G.
        Principles of Exercise Testing and Interpretation: Including Pathophysiology and Clinical Applications.
        5th ed. Lippincott Williams & Wilkins, Philadelphia, PA2011
        • Delezie J.
        • Handschin C.
        Endocrine crosstalk between skeletal muscle and the brain.
        Front Neurol. 2018; 9: 698
        • Manto M.-U.
        • Bower J.M.
        • Gerwig M.
        Consensus paper: roles of the cerebellum in motor control: the diversity of ideas on cerebellar involvement in movement.
        . 2015; 11: 457-487
        • Voelcker-Rehage C.
        • Niemann C.
        Structural and functional brain changes related to different types of physical activity across the life span.
        Neurosci Biobehav Rev. 2013; 37: 2268-2295
        • Ekelund U.
        • Franks P.W.
        • Wareham N.J.
        • Åman J.
        Oxygen uptakes adjusted for body composition in normal-weight and obese adolescents.
        Obes Res. 2004; 12: 513-520
        • Toth M.J.
        • Goran M.I.
        • Ades P.A.
        • Howard D.B.
        • Poehlman E.T.
        Examination of data normalization procedures for expressing peak VO2 data.
        J Appl Physiol. 1993; 75: 2288-2292

      Linked Article

      • Cardiorespiratory Fitness and Brain Volumes
        Mayo Clinic ProceedingsVol. 95Issue 1
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          The role of exercise and brain health has been a very popular topic of discussion in recent years. The National Academies of Sciences concluded that aerobic exercise may be useful in slowing cognitive changes in aging, and the Lancet Commission similarly reported the value of aerobic training and cognitive outcomes.1,2 In addition, the World Health Organization endorsed exercise as a means of intervening on the progression of cognitive impairment.3 In an evidence-based medicine review of the literature, the American Academy of Neurology concluded that exercise may be useful in slowing clinical progression from mild cognitive impairment to dementia.
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