Abstract
There is correlative evidence that impaired cerebral blood flow (CBF) regulation, in addition to promoting cognitive impairment, is also associated with alterations in gait and development of falls in elderly people. CBF is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism becomes progressively impaired with age. To establish a direct cause-and-effect relationship between impaired NVC and gait abnormalities, we induced neurovascular uncoupling pharmacologically in young C57BL/6 mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor MSPPOH, the NO synthase inhibitor L-NAME, and the COX inhibitor indomethacin significantly decreased NVC mimicking the aging phenotype. Pharmacologically induced neurovascular uncoupling significantly decreased the dynamic gait parameter duty cycle, altered footfall patterns, and significantly increased phase dispersion, indicating impaired interlimb coordination. Impaired NVC also tended to increase gait variability. Thus, selective experimental disruption of NVC causes subclinical gait abnormalities, supporting the importance of CBF in both cognitive function and gait regulation.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Change history
21 February 2018
The original version of this article unfortunately contained an error.
References
Abellan van Kan G, Rolland Y, Andrieu S, Bauer J, Beauchet O, Bonnefoy M et al (2009) Gait speed at usual pace as a predictor of adverse outcomes in community-dwelling older people an International Academy on Nutrition and Aging (IANA) task force. J Nutr Health Aging 13(10):881–889. https://doi.org/10.1007/s12603-009-0246-z
Atkinson HH, Rosano C, Simonsick EM, Williamson JD, Davis C, Ambrosius WT, Rapp SR, Cesari M, Newman AB, Harris TB, Rubin SM, Yaffe K, Satterfield S, Kritchevsky SB, for the Health ABC study (2007) Cognitive function, gait speed decline, and comorbidities: the health, aging and body composition study. J Gerontol A Biol Sci Med Sci 62(8):844–850. https://doi.org/10.1093/gerona/62.8.844
Attwell D, Buchan AM, Charpak S, Lauritzen M, Macvicar BA, Newman EA (2010) Glial and neuronal control of brain blood flow. Nature 468(7321):232–243. https://doi.org/10.1038/nature09613
Balbi M, Ghosh M, Longden TA, Jativa Vega M, Gesierich B, Hellal F et al (2015) Dysfunction of mouse cerebral arteries during early aging. J Cereb Blood Flow Metab 35(9):1445–1453. https://doi.org/10.1038/jcbfm.2015.107
Beauchet O, Launay CP, Sekhon H, Barthelemy JC, Roche F, Chabot J, Levinoff EJ, Allali G (2017) Association of increased gait variability while dual tasking and cognitive decline: results from a prospective longitudinal cohort pilot study. Geroscience 39(4):439–445. https://doi.org/10.1007/s11357-017-9992-8
Belghali M, Chastan N, Cignetti F, Davenne D, Decker LM (2017) Loss of gait control assessed by cognitive-motor dual-tasks: pros and cons in detecting people at risk of developing Alzheimer’s and Parkinson’s diseases. Geroscience 39(3):305–329. https://doi.org/10.1007/s11357-017-9977-7
Biessels GJ, Reijmer YD (2014) Brain changes underlying cognitive dysfunction in diabetes: what can we learn from MRI? Diabetes 63(7):2244–2252. https://doi.org/10.2337/db14-0348
Brach JS, Studenski S, Perera S, VanSwearingen JM, Newman AB (2008) Stance time and step width variability have unique contributing impairments in older persons. Gait Posture 27(3):431–439. https://doi.org/10.1016/j.gaitpost.2007.05.016
Brand-Schieber E, Falck JF, Schwartzman M (2000) Selective inhibition of arachidonic acid epoxidation in vivo. J Physiol Pharmacol 51(4 Pt 1):655–672
Bruhn H, Fransson P, Frahm J (2001) Modulation of cerebral blood oxygenation by indomethacin: MRI at rest and functional brain activation. J Magn Reson Imaging 13(3):325–334. https://doi.org/10.1002/jmri.1047
Brundel M, van den Berg E, Reijmer YD, de Bresser J, Kappelle LJ, Biessels GJ (2012) Cerebral haemodynamics, cognition and brain volumes in patients with type 2 diabetes. J Diabetes Complicat 26(3):205–209. https://doi.org/10.1016/j.jdiacomp.2012.03.021
Brundel M, Reijmer YD, van Veluw SJ, Kuijf HJ, Luijten PR, Kappelle LJ, Biessels GJ, on behalf of the Utrecht Vascular Cognitive Impairment (VCI) Study Group (2014) Cerebral microvascular lesions on high-resolution 7-Tesla MRI in patients with type 2 diabetes. Diabetes 63(10):3523–3529. https://doi.org/10.2337/db14-0122
Callisaya ML, Blizzard L, Schmidt MD, McGinley JL, Srikanth VK (2010) Ageing and gait variability—a population-based study of older people. Age Ageing 39(2):191–197. https://doi.org/10.1093/ageing/afp250
Callisaya ML, Beare R, Phan T, Blizzard L, Thrift AG, Chen J, Srikanth VK (2015) Progression of white matter hyperintensities of presumed vascular origin increases the risk of falls in older people. J Gerontol A Biol Sci Med Sci 70(3):360–366. https://doi.org/10.1093/gerona/glu148
Callisaya ML, Launay CP, Srikanth VK, Verghese J, Allali G, Beauchet O (2017) Cognitive status, fast walking speed and walking speed reserve—the Gait and Alzheimer Interactions Tracking (GAIT) study. Geroscience 39(2):231–239. https://doi.org/10.1007/s11357-017-9973-y
Cedervall Y, Halvorsen K, Aberg AC (2014) A longitudinal study of gait function and characteristics of gait disturbance in individuals with Alzheimer’s disease. Gait Posture 39(4):1022–1027. https://doi.org/10.1016/j.gaitpost.2013.12.026
Chen BR, Kozberg MG, Bouchard MB, Shaik MA, Hillman EM (2014) A critical role for the vascular endothelium in functional neurovascular coupling in the brain. J Am Heart Assoc 3(3):e000787. https://doi.org/10.1161/JAHA.114.000787
Corriveau RA, Bosetti F, Emr M, Gladman JT, Koenig JI, Moy CS, Pahigiannis K, Waddy SP, Koroshetz W (2016) The science of vascular contributions to cognitive impairment and dementia (VCID): a framework for advancing research priorities in the cerebrovascular biology of cognitive decline. Cell Mol Neurobiol 36(2):281–288. https://doi.org/10.1007/s10571-016-0334-7
Csiszar A, Tarantini S, Fulop GA, Kiss T, Valcarcel-Ares MN, Galvan V et al (2017) Hypertension impairs neurovascular coupling and promotes microvascular injury: role in exacerbation of Alzheimer’s disease. Geroscience 39(4):359–372. https://doi.org/10.1007/s11357-017-9991-9
de Bresser J, Reijmer YD, van den Berg E, Breedijk MA, Kappelle LJ, Viergever MA, Biessels GJ, Utrecht Diabetic Encephalopathy Study Group (2010) Microvascular determinants of cognitive decline and brain volume change in elderly patients with type 2 diabetes. Dement Geriatr Cogn Disord 30(5):381–386. https://doi.org/10.1159/000321354
Decker LM, Cignetti F, Hunt N, Potter JF, Stergiou N, Studenski SA (2016) Effects of aging on the relationship between cognitive demand and step variability during dual-task walking. Age (Dordr) 38(4):363–375. https://doi.org/10.1007/s11357-016-9941-y
Duarte JV, Pereira JM, Quendera B, Raimundo M, Moreno C, Gomes L et al (2015) Early disrupted neurovascular coupling and changed event level hemodynamic response function in type 2 diabetes: an fMRI study. J Cereb Blood Flow Metab 35(10):1671–1680. https://doi.org/10.1038/jcbfm.2015.106
Fitzpatrick AL, Buchanan CK, Nahin RL, Dekosky ST, Atkinson HH, Carlson MC et al (2007) Associations of gait speed and other measures of physical function with cognition in a healthy cohort of elderly persons. J Gerontol A Biol Sci Med Sci 62(11):1244–1251. https://doi.org/10.1093/gerona/62.11.1244
Gillain S, Drame M, Lekeu F, Wojtasik V, Ricour C, Croisier JL et al (2016) Gait speed or gait variability, which one to use as a marker of risk to develop Alzheimer disease? A pilot study. Aging Clin Exp Res 28(2):249–255. https://doi.org/10.1007/s40520-015-0392-6
Girouard H, Iadecola C (2006) Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol 100(1):328–335. https://doi.org/10.1152/japplphysiol.00966.2005
Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C et al (2011) Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42(9):2672–2713. https://doi.org/10.1161/STR.0b013e3182299496
Hajjar I, Yang F, Sorond F, Jones RN, Milberg W, Cupples LA, Lipsitz LA (2009) A novel aging phenotype of slow gait, impaired executive function, and depressive symptoms: relationship to blood pressure and other cardiovascular risks. J Gerontol A Biol Sci Med Sci 64(9):994–1001. https://doi.org/10.1093/gerona/glp075
Hamel E, Royea J, Ongali B, Tong XK (2016) Neurovascular and cognitive failure in Alzheimer’s disease: benefits of cardiovascular therapy. Cell Mol Neurobiol 36(2):219–232. https://doi.org/10.1007/s10571-015-0285-4
Herman T, Giladi N, Gurevich T, Hausdorff JM (2005) Gait instability and fractal dynamics of older adults with a “cautious” gait: why do certain older adults walk fearfully? Gait Posture 21(2):178–185. https://doi.org/10.1016/j.gaitpost.2004.01.014
Holtzer R, Verghese J, Xue X, Lipton RB (2006) Cognitive processes related to gait velocity: results from the Einstein Aging Study. Neuropsychology 20(2):215–223. https://doi.org/10.1037/0894-4105.20.2.215
Iadecola C, Park L, Capone C (2009) Threats to the mind: aging, amyloid, and hypertension. Stroke 40(3 Suppl):S40–S44. https://doi.org/10.1161/STROKEAHA.108.533638
Jor'dan AJ, Poole VN, Iloputaife I, Milberg W, Manor B, Esterman M et al (2017) Executive network activation is linked to walking speed in older adults: functional MRI and TCD ultrasound evidence from the MOBILIZE Boston study. J Gerontol A Biol Sci Med Sci 72(12):1669–1675. https://doi.org/10.1093/gerona/glx063
Kazama K, Wang G, Frys K, Anrather J, Iadecola C (2003) Angiotensin II attenuates functional hyperemia in the mouse somatosensory cortex. Am J Physiol Heart Circ Physiol 285(5):H1890–H1899. https://doi.org/10.1152/ajpheart.00464.2003
Kazama K, Anrather J, Zhou P, Girouard H, Frys K, Milner TA, Iadecola C (2004) Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals. Circ Res 95(10):1019–1026. https://doi.org/10.1161/01.RES.0000148637.85595.c5
Leithner C, Royl G, Offenhauser N, Fuchtemeier M, Kohl-Bareis M, Villringer A et al (2010) Pharmacological uncoupling of activation induced increases in CBF and CMRO2. J Cereb Blood Flow Metab 30(2):311–322. https://doi.org/10.1038/jcbfm.2009.211
Lind BL, Brazhe AR, Jessen SB, Tan FC, Lauritzen MJ (2013) Rapid stimulus-evoked astrocyte Ca2+ elevations and hemodynamic responses in mouse somatosensory cortex in vivo. Proc Natl Acad Sci U S A 110(48):E4678–E4687. https://doi.org/10.1073/pnas.1310065110
Liu X, Bhatt T, Wang S, Yang F, Pai YC (2017) Retention of the “first-trial effect” in gait-slip among community-living older adults. Geroscience 39(1):93–102. https://doi.org/10.1007/s11357-017-9963-0
Lourenco CF, Ledo A, Barbosa RM, Laranjinha J (2017) Neurovascular uncoupling in the triple transgenic model of Alzheimer’s disease: impaired cerebral blood flow response to neuronal-derived nitric oxide signaling. Exp Neurol 291:36–43. https://doi.org/10.1016/j.expneurol.2017.01.013
Ma J, Ayata C, Huang PL, Fishman MC, Moskowitz MA (1996) Regional cerebral blood flow response to vibrissal stimulation in mice lacking type I NOS gene expression. Am J Phys 270(3 Pt 2):H1085–H1090
McNeil JJ, Woods RL, Nelson MR, Murray AM, Reid CM, Kirpach B, Storey E, Shah RC, Wolfe RS, Tonkin AM, Newman AB, Williamson JD, Lockery JE, Margolis KL, Ernst ME, Abhayaratna WP, Stocks N, Fitzgerald SM, Trevaks RE, Orchard SG, Beilin LJ, Donnan GA, Gibbs P, Johnston CI, Grimm RH (2017) Baseline characteristics of participants in the ASPREE (Aspirin in Reducing Events in the Elderly) study. J Gerontol A Biol Sci Med Sci. https://doi.org/10.1093/gerona/glw342
Mielke MM, Roberts RO, Savica R, Cha R, Drubach DI, Christianson T, Pankratz VS, Geda YE, Machulda MM, Ivnik RJ, Knopman DS, Boeve BF, Rocca WA, Petersen RC (2013) Assessing the temporal relationship between cognition and gait: slow gait predicts cognitive decline in the Mayo Clinic Study of Aging. J Gerontol A Biol Sci Med Sci 68(8):929–937. https://doi.org/10.1093/gerona/gls256
Mignardot JB, Deschamps T, Barrey E, Auvinet B, Berrut G, Cornu C et al (2014) Gait disturbances as specific predictive markers of the first fall onset in elderly people: a two-year prospective observational study. Front Aging Neurosci 6:22
Miralbell J, Lopez-Cancio E, Lopez-Oloriz J, Arenillas JF, Barrios M, Soriano-Raya JJ et al (2013) Cognitive patterns in relation to biomarkers of cerebrovascular disease and vascular risk factors. Cerebrovasc Dis 36(2):98–105. https://doi.org/10.1159/000352059
Montero-Odasso M, Oteng-Amoako A, Speechley M, Gopaul K, Beauchet O, Annweiler C, Muir-Hunter SW (2014) The motor signature of mild cognitive impairment: results from the gait and brain study. J Gerontol A Biol Sci Med Sci 69(11):1415–1421. https://doi.org/10.1093/gerona/glu155
Nadkarni NK, Nunley KA, Aizenstein H, Harris TB, Yaffe K, Satterfield S, Newman AB, Rosano C, for the Health ABC Study (2014) Association between cerebellar gray matter volumes, gait speed, and information-processing ability in older adults enrolled in the Health ABC study. J Gerontol A Biol Sci Med Sci 69(8):996–1003. https://doi.org/10.1093/gerona/glt151
Nakamura T, Meguro K, Sasaki H (1996) Relationship between falls and stride length variability in senile dementia of the Alzheimer type. Gerontology 42(2):108–113. https://doi.org/10.1159/000213780
Obayashi K, Saeki K, Maegawa T, Sakai T, Kitagawa M, Otaki N, Kataoka H, Kurumatani N (2016) Association of serum asymmetric dimethylarginine with muscle strength and gait speed: a cross-sectional study of the HEIJO-KYO cohort. J Bone Miner Res 31(5):1107–1113. https://doi.org/10.1002/jbmr.2773
Ongali B, Nicolakakis N, Tong XK, Aboulkassim T, Papadopoulos P, Rosa-Neto P, Lecrux C, Imboden H, Hamel E (2014) Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer’s disease model. Neurobiol Dis 68:126–136. https://doi.org/10.1016/j.nbd.2014.04.018
Palta P, Schneider AL, Biessels GJ, Touradji P, Hill-Briggs F (2014) Magnitude of cognitive dysfunction in adults with type 2 diabetes: a meta-analysis of six cognitive domains and the most frequently reported neuropsychological tests within domains. J Int Neuropsychol Soc 20(3):278–291. https://doi.org/10.1017/S1355617713001483
Papadopoulos P, Tong XK, Imboden H, Hamel E (2017) Losartan improves cerebrovascular function in a mouse model of Alzheimer’s disease with combined overproduction of amyloid-beta and transforming growth factor-beta1. J Cereb Blood Flow Metab 37(6):1959–1970. https://doi.org/10.1177/0271678X16658489
Park L, Anrather J, Girouard H, Zhou P, Iadecola C (2007) Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain. J Cereb Blood Flow Metab 27(12):1908–1918. https://doi.org/10.1038/sj.jcbfm.9600491
Peng X, Carhuapoma JR, Bhardwaj A, Alkayed NJ, Falck JR, Harder DR, Traystman RJ, Koehler RC (2002) Suppression of cortical functional hyperemia to vibrissal stimulation in the rat by epoxygenase inhibitors. Am J Physiol Heart Circ Physiol 283(5):H2029–H2037. https://doi.org/10.1152/ajpheart.01130.2000
Reijmer YD, van den Berg E, de Bresser J, Kessels RP, Kappelle LJ, Algra A et al (2011) Accelerated cognitive decline in patients with type 2 diabetes: MRI correlates and risk factors. Diabetes Metab Res Rev 27(2):195–202. https://doi.org/10.1002/dmrr.1163
Rosano C, Brach J, Studenski S, Longstreth WT Jr, Newman AB (2007) Gait variability is associated with subclinical brain vascular abnormalities in high-functioning older adults. Neuroepidemiology 29(3–4):193–200. https://doi.org/10.1159/000111582
Rosso AL, Olson Hunt MJ, Yang M, Brach JS, Harris TB, Newman AB, Satterfield S, Studenski SA, Yaffe K, Aizenstein HJ, Rosano C, Health ABC study (2014) Higher step length variability indicates lower gray matter integrity of selected regions in older adults. Gait Posture 40(1):225–230. https://doi.org/10.1016/j.gaitpost.2014.03.192
Ruis C, Biessels GJ, Gorter KJ, van den Donk M, Kappelle LJ, Rutten GE (2009) Cognition in the early stage of type 2 diabetes. Diabetes Care 32(7):1261–1265. https://doi.org/10.2337/dc08-2143
Ryan JP, Fine DF, Rosano C (2014) Type 2 diabetes and cognitive impairment: contributions from neuroimaging. J Geriatr Psychiatry Neurol 27(1):47–55. https://doi.org/10.1177/0891988713516543
Ryan CM, van Duinkerken E, Rosano C (2016) Neurocognitive consequences of diabetes. Am Psychol 71(7):563–576. https://doi.org/10.1037/a0040455
Snyder HM, Corriveau RA, Craft S, Faber JE, Greenberg SM, Knopman D, Lamb BT, Montine TJ, Nedergaard M, Schaffer CB, Schneider JA, Wellington C, Wilcock DM, Zipfel GJ, Zlokovic B, Bain LJ, Bosetti F, Galis ZS, Koroshetz W, Carrillo MC (2015) Vascular contributions to cognitive impairment and dementia including Alzheimer’s disease. Alzheimers Dement 11(6):710–717. https://doi.org/10.1016/j.jalz.2014.10.008
Sorond FA, Galica A, Serrador JM, Kiely DK, Iloputaife I, Cupples LA, Lipsitz LA (2010) Cerebrovascular hemodynamics, gait, and falls in an elderly population: MOBILIZE Boston study. Neurology 74(20):1627–1633. https://doi.org/10.1212/WNL.0b013e3181df0982
Sorond FA, Kiely DK, Galica A, Moscufo N, Serrador JM, Iloputaife I, Egorova S, Dell'Oglio E, Meier DS, Newton E, Milberg WP, Guttmann CRG, Lipsitz l (2011) Neurovascular coupling is impaired in slow walkers: the MOBILIZE Boston study. Ann Neurol 70(2):213–220. https://doi.org/10.1002/ana.22433
Sorond FA, Hurwitz S, Salat DH, Greve DN, Fisher ND (2013) Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people. Neurology 81(10):904–909. https://doi.org/10.1212/WNL.0b013e3182a351aa
Stefanova I, Stephan T, Becker-Bense S, Dera T, Brandt T, Dieterich M (2013) Age-related changes of blood-oxygen-level-dependent signal dynamics during optokinetic stimulation. Neurobiol Aging 34(10):2277–2286. https://doi.org/10.1016/j.neurobiolaging.2013.03.031
Stobart JL, Lu L, Anderson HD, Mori H, Anderson CM (2013) Astrocyte-induced cortical vasodilation is mediated by D-serine and endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 110(8):3149–3154. https://doi.org/10.1073/pnas.1215929110
Studenski S, Perera S, Patel K, Rosano C, Faulkner K, Inzitari M, Brach J, Chandler J, Cawthon P, Connor EB, Nevitt M, Visser M, Kritchevsky S, Badinelli S, Harris T, Newman AB, Cauley J, Ferrucci L, Guralnik J (2011) Gait speed and survival in older adults. JAMA 305(1):50–58. https://doi.org/10.1001/jama.2010.1923
Szabo K, Rosengarten B, Juhasz T, Lako E, Csiba L, Olah L (2014) Effect of non-steroid anti-inflammatory drugs on neurovascular coupling in humans. J Neurol Sci 336(1–2):227–231. https://doi.org/10.1016/j.jns.2013.10.048
Takano T, Tian GF, Peng W, Lou N, Libionka W, Han X, Nedergaard M (2006) Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 9(2):260–267. https://doi.org/10.1038/nn1623
Tarantini S, Hertelendy P, Tucsek Z, Valcarcel-Ares MN, Smith N, Menyhart A, Farkas E, Hodges EL, Towner R, Deak F, Sonntag WE, Csiszar A, Ungvari Z, Toth P (2015) Pharmacologically-induced neurovascular uncoupling is associated with cognitive impairment in mice. J Cereb Blood Flow Metab 35(11):1871–1881. https://doi.org/10.1038/jcbfm.2015.162
Tarantini S, Tran CH, Gordon GR, Ungvari Z, Csiszar A (2016) Impaired neurovascular coupling in aging and Alzheimer’s disease: contribution of astrocyte dysfunction and endothelial impairment to cognitive decline. Exp Gerontol. https://doi.org/10.1016/j.exger.2016.1011.1004
Tarantini S, Fulop GA, Kiss T, Farkas E, Zolei-Szenasi D, Galvan V et al (2017) Demonstration of impaired neurovascular coupling responses in TG2576 mouse model of Alzheimer’s disease using functional laser speckle contrast imaging. Geroscience 39(4):465–473. https://doi.org/10.1007/s11357-017-9980-z
Tian Q, Chastan N, Bair WN, Resnick SM, Ferrucci L, Studenski SA (2017) The brain map of gait variability in aging, cognitive impairment and dementia—a systematic review. Neurosci Biobehav Rev 74(Pt A):149–162
Tong XK, Lecrux C, Rosa-Neto P, Hamel E (2012) Age-dependent rescue by simvastatin of Alzheimer’s disease cerebrovascular and memory deficits. J Neurosci 32(14):4705–4715. https://doi.org/10.1523/JNEUROSCI.0169-12.2012
Topcuoglu MA, Aydin H, Saka E (2009) Occipital cortex activation studied with simultaneous recordings of functional transcranial Doppler ultrasound (fTCD) and visual evoked potential (VEP) in cognitively normal human subjects: effect of healthy aging. Neurosci Lett 452(1):17–22. https://doi.org/10.1016/j.neulet.2009.01.030
Toth P, Tucsek Z, Sosnowska D, Gautam T, Mitschelen M, Tarantini S, Deak F, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2013) Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. J Cereb Blood Flow Metab 33(11):1732–1742. https://doi.org/10.1038/jcbfm.2013.143
Toth P, Tarantini S, Tucsek Z, Ashpole NM, Sosnowska D, Gautam T, Ballabh P, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2014) Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicrovascular endothelial function and down-regulation of NADPH oxidase. Am J Physiol Heart Circ Physiol 306(3):H299–H308. https://doi.org/10.1152/ajpheart.00744.2013
Toth P, Tarantini S, Ashpole NM, Tucsek Z, Milne GL, Valcarcel-Ares NM, Menyhart A, Farkas E, Sonntag WE, Csiszar A, Ungvari Z (2015a) IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging. Aging Cell 14(6):1034–1044. https://doi.org/10.1111/acel.12372
Toth P, Tarantini S, Davila A, Valcarcel-Ares MN, Tucsek Z, Varamini B, Ballabh P, Sonntag WE, Baur JA, Csiszar A, Ungvari Z (2015b) Purinergic glio-endothelial coupling during neuronal activity: role of P2Y1 receptors and eNOS in functional hyperemia in the mouse somatosensory cortex. Am J Physiol Heart Circ Physiol 309(11):H1837–H1845. https://doi.org/10.1152/ajpheart.00463.2015
Toth P, Tarantini S, Springo Z, Tucsek Z, Gautam T, Giles CB, Wren JD, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2015c) Aging exacerbates hypertension-induced cerebral microhemorrhages in mice: role of resveratrol treatment in vasoprotection. Aging Cell 14(3):400–408. https://doi.org/10.1111/acel.12315
Toth P, Tarantini S, Csiszar A, Ungvari Z (2017) Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging. Am J Physiol Heart Circ Physiol 312(1):H1–H20. https://doi.org/10.1152/ajpheart.00581.2016
Tucsek Z, Toth P, Sosnowska D, Gautam T, Mitschelen M, Koller A, et al (2014) Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer’s disease. J Gerontol A Biol Sci Med Sci 69(11):1339–1352. https://doi.org/10.1093/gerona/glu080
Tucsek Z, Toth P, Sosnowska D, Gautam T, Mitschelen M, Koller A, Szalai G, Sonntag WE, Ungvari Z, Csiszar A (2014a) Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer’s disease. J Gerontol A Biol Sci Med Sci 69(10):1212–1226. https://doi.org/10.1093/gerona/glt177
Tucsek Z, Toth P, Tarantini S, Sosnowska D, Gautam T, Warrington JP, Giles CB, Wren JD, Koller A, Ballabh P, Sonntag WE, Ungvari Z, Csiszar A (2014b) Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice. J Gerontol A Biol Sci Med Sci 69(11):1339–1352. https://doi.org/10.1093/gerona/glu080
Tucsek Z, Noa Valcarcel-Ares M, Tarantini S, Yabluchanskiy A, Fulop G, Gautam T et al (2017) Hypertension-induced synapse loss and impairment in synaptic plasticity in the mouse hippocampus mimics the aging phenotype: implications for the pathogenesis of vascular cognitive impairment. Geroscience 39(4):385–406. https://doi.org/10.1007/s11357-017-9981-y
Ungvari Z, Tarantini S, Hertelendy P, Valcarcel-Ares MN, Fulop GA, Logan S et al (2017a) Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence. Geroscience 39(1):33–42. https://doi.org/10.1007/s11357-017-9964-z
Ungvari Z, Tarantini S, Kirkpatrick AC, Csiszar A, Prodan CI (2017b) Cerebral microhemorrhages: mechanisms, consequences, and prevention. Am J Physiol Heart Circ Physiol 312(6):H1128–H1143. https://doi.org/10.1152/ajpheart.00780.2016
van den Berg E, Dekker JM, Nijpels G, Kessels RP, Kappelle LJ, de Haan EH et al (2008) Cognitive functioning in elderly persons with type 2 diabetes and metabolic syndrome: the Hoorn study. Dement Geriatr Cogn Disord 26(3):261–269. https://doi.org/10.1159/000160959
van den Berg E, Kloppenborg RP, Kessels RP, Kappelle LJ, Biessels GJ (2009) Type 2 diabetes mellitus, hypertension, dyslipidemia and obesity: a systematic comparison of their impact on cognition. Biochim Biophys Acta 1792(5):470–481. https://doi.org/10.1016/j.bbadis.2008.09.004
van den Berg E, Reijmer YD, de Bresser J, Kessels RP, Kappelle LJ, Biessels GJ (2010) A 4 year follow-up study of cognitive functioning in patients with type 2 diabetes mellitus. Diabetologia 53(1):58–65. https://doi.org/10.1007/s00125-009-1571-9
Verghese J, Lipton RB, Hall CB, Kuslansky G, Katz MJ, Buschke H (2002) Abnormality of gait as a predictor of non-Alzheimer’s dementia. N Engl J Med 347(22):1761–1768. https://doi.org/10.1056/NEJMoa020441
Verghese J, Wang C, Lipton RB, Holtzer R, Xue X (2007) Quantitative gait dysfunction and risk of cognitive decline and dementia. J Neurol Neurosurg Psychiatry 78(9):929–935. https://doi.org/10.1136/jnnp.2006.106914
Verghese J, Robbins M, Holtzer R, Zimmerman M, Wang C, Xue X, Lipton RB (2008) Gait dysfunction in mild cognitive impairment syndromes. J Am Geriatr Soc 56(7):1244–1251. https://doi.org/10.1111/j.1532-5415.2008.01758.x
Verghese J, Holtzer R, Lipton RB, Wang C (2009) Quantitative gait markers and incident fall risk in older adults. J Gerontol A Biol Sci Med Sci 64(8):896–901. https://doi.org/10.1093/gerona/glp033
Verghese J, Ambrose AF, Lipton RB, Wang C (2010) Neurological gait abnormalities and risk of falls in older adults. J Neurol 257(3):392–398. https://doi.org/10.1007/s00415-009-5332-y
Verlinden VJ, van der Geest JN, Hoogendam YY, Hofman A, Breteler MM, Ikram MA (2013) Gait patterns in a community-dwelling population aged 50 years and older. Gait Posture 37(4):500–505. https://doi.org/10.1016/j.gaitpost.2012.09.005
Visser H (1983) Gait and balance in senile dementia of Alzheimer’s type. Age Ageing 12(4):296–301. https://doi.org/10.1093/ageing/12.4.296
von Vierordt K (1881) Über das Gehen des Menschen in Gesunden und Kranken Zustaenden nach Selbstregistrireden Methoden, (On human gait in health and disease using a self-recording method) edn. Laupp, Tuebigen, Germany
Wakisaka Y, Chu Y, Miller JD, Rosenberg GA, Heistad DD (2010) Spontaneous intracerebral hemorrhage during acute and chronic hypertension in mice. J Cereb Blood Flow Metab 30(1):56–69. https://doi.org/10.1038/jcbfm.2009.183
Waldstein SR, Wendell CR, Seliger SL, Ferrucci L, Metter EJ, Zonderman AB (2010) Nonsteroidal anti-inflammatory drugs, aspirin, and cognitive function in the Baltimore longitudinal study of aging. J Am Geriatr Soc 58(1):38–43. https://doi.org/10.1111/j.1532-5415.2009.02618.x
Watson NL, Rosano C, Boudreau RM, Simonsick EM, Ferrucci L, Sutton-Tyrrell K, Hardy SE, Atkinson HH, Yaffe K, Satterfield S, Harris TB, Newman AB, Health ABC Study (2010) Executive function, memory, and gait speed decline in well-functioning older adults. J Gerontol A Biol Sci Med Sci 65(10):1093–1100. https://doi.org/10.1093/gerona/glq111
Witte AV, Kerti L, Margulies DS, Floel A (2014) Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. J Neurosci 34(23):7862–7870. https://doi.org/10.1523/JNEUROSCI.0385-14.2014
Wittwer JE, Webster KE, Hill K (2013) Reproducibility of gait variability measures in people with Alzheimer’s disease. Gait Posture 38(3):507–510. https://doi.org/10.1016/j.gaitpost.2013.01.021
Zlokovic BV (2011) Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci 12(12):723–738. https://doi.org/10.1038/nrn3114
Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, Carmignoto G (2003) Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci 6(1):43–50. https://doi.org/10.1038/nn980
Acknowledgements
The authors acknowledge that this work was supported by grants from the American Heart Association (ST, ZU and AC), the Oklahoma Center for the Advancement of Science and Technology (to AC, AY, ZU), the National Center for Complementary and Alternative Medicine (R01-AT006526 to ZU), the National Institute on Aging (R01-AG055395, R01-AG047879; R01-AG038747; R01-AG055395), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS100782, R01-NS056218), the Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (U54GM104938, to AY), the Presbyterian Health Foundation (to ZU, AC, AY), the EU-funded Hungarian grant EFOP-3.6.1-16-2016-00008, and from the NIA-funded Geroscience Training Program in Oklahoma (T32AG052363).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
All the performed procedures were approved by the Institutional Animal Care and Use Committee of the University of Oklahoma Health Sciences Center.
Additional information
A correction to this article is available online at https://doi.org/10.1007/s11357-018-0012-4.
About this article
Cite this article
Tarantini, S., Yabluchanksiy, A., Fülöp, G.A. et al. Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice. GeroScience 39, 601–614 (2017). https://doi.org/10.1007/s11357-017-0003-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11357-017-0003-x