Functional vascular contributions to cognitive impairment and dementia: Mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging

American Journal of Physiology - Heart and Circulatory Physiology

Volumn 312, Issue 1, 2017, Pages H1-H20

  Toth, Peter ^a,b   Tarantini, Stefano ^a   Csiszar, Anna ^a,c   Ungvari, Zoltan ^a,c  

^a UNIVERSITY OF OKLAHOMA COLLEGE OF MEDICINE   (United States)

^b UNIVERSITY OF PÉCS   (Hungary)

^c UNIVERSITY OF SZEGED   (Hungary)

Author keywords

Alzheimer s disease; Blood brain barrier; Cerebral circulation; Cerebrovascular; Functional hyperemia; Geroscience; Microcirculation; Myogenic constriction; Neurovascular coupling; Senescence; Stroke; Vascular aging

Indexed keywords

AGE; AGING; AUTOREGULATION; BLOOD BRAIN BARRIER; BLOOD VESSEL FUNCTION; BRAIN BLOOD FLOW; BRAIN DAMAGE; BRAIN HEMORRHAGE; BRAIN ISCHEMIA; BRAIN METABOLISM; BRAIN MICROCIRCULATION; CEREBRAL AUTOREGULATION; CEREBROVASCULAR DISEASE; COGNITIVE DEFECT; DEGENERATIVE DISEASE; DEMENTIA; DISEASE EXACERBATION; ENDOTHELIAL DYSFUNCTION; HEMODYNAMICS; HUMAN; HYPEREMIA; MICROANGIOPATHY; MICROVASCULATURE; NERVOUS SYSTEM INFLAMMATION; NEUROPATHOLOGY; NEUROPROTECTION; NEUROVASCULAR COUPLING; NEUROVASCULAR UNCOUPLING; NONHUMAN; PRIORITY JOURNAL; REVIEW; VASOMOTOR REFLEX; BRAIN CIRCULATION; HOMEOSTASIS; MICROCIRCULATION; PATHOPHYSIOLOGY; VASCULAR ENDOTHELIUM;

AGING; CEREBROVASCULAR CIRCULATION; COGNITIVE DYSFUNCTION; DEMENTIA; ENDOTHELIUM, VASCULAR; HOMEOSTASIS; HUMANS; MICROCIRCULATION; NEUROVASCULAR COUPLING;

EID: 85008324974     PISSN: 03636135     EISSN: 15221539     Source Type: Journal    
DOI: 10.1152/ajpheart.00581.2016     Document Type: Review

References (309)

1. Abellan van Kan G, Rolland Y, Andrieu S, Bauer J, Beauchet O, Bonnefoy M, Cesari M, Donini LM, Gillette Guyonnet S, Inzitari M, Nourhashemi F, Onder G, Ritz P, Salva A, Visser M, Vellas B. Gait speed at usual pace as a predictor of adverse outcomes in communitydwelling older people an International Academy on Nutrition and Aging (IANA) Task Force. J Nutr Health Aging 13: 881–889, 2009. doi: 10.1007/s12603-009-0246-z.
2. Adlard PA, Sedjahtera A, Gunawan L, Bray L, Hare D, Lear J, Doble P, Bush AI, Finkelstein DI, Cherny RA. A novel approach to rapidly prevent age-related cognitive decline. Aging Cell 13: 351–359, 2014. doi: 10.1111/acel.12178.
3. Angelini A, Bendini C, Neviani F, Bergamini L, Manni B, Trenti T, Rovati R, Neri M. Insulin-like growth factor-1 (IGF-1): relation with cognitive functioning and neuroimaging marker of brain damage in a sample of hypertensive elderly subjects. Arch Gerontol Geriatr 49, Suppl 1: 5–12, 2009. doi: 10.1016/j.archger.2009.09.006.
4. Attwell D, Buchan AM, Charpak S, Lauritzen M, Macvicar BA, Newman EA. Glial and neuronal control of brain blood flow. Nature 468: 232–243, 2010. doi: 10.1038/nature09613.
5. Aukes AM, Vitullo L, Zeeman GG, Cipolla MJ. Pregnancy prevents hypertensive remodeling and decreases myogenic reactivity in posterior cerebral arteries from Dahl salt-sensitive rats: a role in eclampsia? Am J Physiol Heart Circ Physiol 292: H1071–H1076, 2007. doi: 10.1152/ ajpheart.00980.2006.
6. Austin SA, Santhanam AV, Hinton DJ, Choi DS, Katusic ZS. Endothelial nitric oxide deficiency promotes Alzheimer’s disease pathology. J Neurochem 127: 691–700, 2013. doi: 10.1111/jnc.12334.
7. Ayata C. Spreading depression and neurovascular coupling. Stroke 44, Suppl 1: S87–S89, 2013. doi: 10.1161/STROKEAHA.112.680264.
8. Ayata C, Lauritzen M. Spreading depression, spreading depolarizations, and the cerebral vasculature. Physiol Rev 95: 953–993, 2015. doi: 10.1152/physrev.00027.2014.
9. Ayata C, Ma J, Meng W, Huang P, Moskowitz MA. L-NA-sensitive rCBF augmentation during vibrissal stimulation in type III nitric oxide synthase mutant mice. J Cereb Blood Flow Metab 16: 539–541, 1996. doi: 10.1097/00004647-199607000-00002.
10. + events, and IKCa channels, reducing arteriolar tone. Proc Natl Acad Sci USA 109: 18174–18179, 2012. doi: 10.1073/pnas.1211946109.
11. Bailey-Downs LC, Mitschelen M, Sosnowska D, Toth P, Pinto JT, Ballabh P, Valcarcel-Ares MN, Farley J, Koller A, Henthorn JC, Bass C, Sonntag WE, Ungvari Z, Csiszar A. Liver-specific knockdown of IGF-1 decreases vascular oxidative stress resistance by impairing the Nrf2-dependent antioxidant response: a novel model of vascular aging. J Gerontol A Biol Sci Med Sci 67: 313–329, 2012. doi: 10.1093/gerona/ glr164.
12. Bailey-Downs LC, Sosnowska D, Toth P, Mitschelen M, Gautam T, Henthorn JC, Ballabh P, Koller A, Farley JA, Sonntag WE, Csiszar A, Ungvari Z. Growth hormone and IGF-1 deficiency exacerbate highfat diet-induced endothelial impairment in obese Lewis dwarf rats: implications for vascular aging. J Gerontol A Biol Sci Med Sci 67: 553–564, 2012. doi: 10.1093/gerona/glr197.
13. Balança B, Meiller A, Bezin L, Dreier JP, Marinesco S, Lieutaud T. Altered hypermetabolic response to cortical spreading depolarizations after traumatic brain injury in rats. J Cereb Blood Flow Metab pii: 0271678X16657571, 2016. doi: 10.1177/0271678X16657571.
14. Balbi M, Ghosh M, Longden TA, Jativa Vega M, Gesierich B, Hellal F, Lourbopoulos A, Nelson MT, Plesnila N. Dysfunction of mouse cerebral arteries during early aging. J Cereb Blood Flow Metab 35: 1445–1453, 2015. doi: 10.1038/jcbfm.2015.107.
15. Banki E, Sosnowska D, Tucsek Z, Gautam T, Toth P, Tarantini S, Tamas A, Helyes Z, Reglodi D, Sonntag WE, Csiszar A, Ungvari Z. Age-related decline of autocrine pituitary adenylate cyclase-activating polypeptide impairs angiogenic capacity of rat cerebromicrovascular endothelial cells. J Gerontol A Biol Sci Med Sci 70: 665–674, 2015. doi: 10.1093/gerona/glu116.
16. Barnes JN, Schmidt JE, Nicholson WT, Joyner MJ. Cyclooxygenase inhibition abolishes age-related differences in cerebral vasodilator responses to hypercapnia. J Appl Physiol (1985) 112: 1884–1890, 2012. doi: 10.1152/japplphysiol.01270.2011.
17. Baumbach GL, Dobrin PB, Hart MN, Heistad DD. Mechanics of cerebral arterioles in hypertensive rats. Circ Res 62: 56–64, 1988. doi: 10.1161/01.RES.62.1.56.
18. Baumbach GL, Heistad DD. Cerebral circulation in chronic arterial hypertension. Hypertension 12: 89–95, 1988. doi: 10.1161/01.HYP.12.2.89.
19. Baumbach GL, Heistad DD. Remodeling of cerebral arterioles in chronic hypertension. Hypertension 13: 968–972, 1989. doi: 10.1161/ 01.HYP.13.6.968.
20. Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, Zlokovic BV. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68: 409–427, 2010. doi: 10.1016/j.neuron.2010.09.043.
21. Bere Z, Obrenovitch TP, Bari F, Farkas E. Ischemia-induced depolarizations and associated hemodynamic responses in incomplete global forebrain ischemia in rats. Neuroscience 260: 217–226, 2014. doi: 10.1016/j.neuroscience.2013.12.032.
22. Bere Z, Obrenovitch TP, Kozák G, Bari F, Farkas E. Imaging reveals the focal area of spreading depolarizations and a variety of hemodynamic responses in a rat microembolic stroke model. J Cereb Blood Flow Metab 34: 1695–1705, 2014. doi: 10.1038/jcbfm.2014.136.
23. Bergsneider M, Alwan AA, Falkson L, Rubinstein EH. The relationship of pulsatile cerebrospinal fluid flow to cerebral blood flow and intracranial pressure: a new theoretical model. Acta Neurochir Suppl 71: 266–268, 1998.
24. Berkowitz DE, White R, Li D, Minhas KM, Cernetich A, Kim S, Burke S, Shoukas AA, Nyhan D, Champion HC, Hare JM. Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels. Circulation 108: 2000-2006, 2003. doi: 10.1161/01.CIR.0000092948.04444.C7.
25. Blackwell KA, Sorenson JP, Richardson DM, Smith LA, Suda O, Nath K, Katusic ZS. Mechanisms of aging-induced impairment of endothelium-dependent relaxation: role of tetrahydrobiopterin. Am J Physiol Heart Circ Physiol 287: H2448–H2453, 2004. doi: 10.1152/ ajpheart.00248.2004.
26. Bohlen HG, Harper SL. Evidence of myogenic vascular control in the rat cerebral cortex. Circ Res 55: 554–559, 1984. doi: 10.1161/ 01.RES.55.4.554.
27. Brayden JE, Earley S, Nelson MT, Reading S. Transient receptor potential (TRP) channels, vascular tone and autoregulation of cerebral blood flow. Clin Exp Pharmacol Physiol 35: 1116–1120, 2008. doi: 10.1111/j.1440-1681.2007.04855.x.
28. Brayden JE, Nelson MT. Regulation of arterial tone by activation of calcium-dependent potassium channels. Science 256: 532–535, 1992. doi: 10.1126/science.1373909.
29. Brickman AM, Guzman VA, Gonzalez-Castellon M, Razlighi Q, Gu Y, Narkhede A, Janicki S, Ichise M, Stern Y, Manly JJ, Schupf N, Marshall RS. Cerebral autoregulation, beta amyloid, and white matter hyperintensities are interrelated. Neurosci Lett 592: 54–58, 2015. doi: 10.1016/j.neulet.2015.03.005.
30. Brown KA, Didion SP, Andresen JJ, Faraci FM. Effect of aging, MnSOD deficiency, and genetic background on endothelial function: evidence for MnSOD haploinsufficiency. Arterioscler Thromb Vasc Biol 27: 1941–1946, 2007. doi: 10.1161/ATVBAHA.107.146852.
31. Bruhn H, Fransson P, Frahm J. Modulation of cerebral blood oxygenation by indomethacin: MRI at rest and functional brain activation. J Magn Reson Imaging 13: 325–334, 2001. doi: 10.1002/jmri.1047.
32. Bryan RM Jr, Marrelli SP, Steenberg ML, Schildmeyer LA, Johnson TD. Effects of luminal shear stress on cerebral arteries and arterioles. Am J Physiol Heart Circ Physiol 280: H2011–H2022, 2001.
33. Busija DW, Bari F, Domoki F, Louis T. Mechanisms involved in the cerebrovascular dilator effects of N-methyl-d-aspartate in cerebral cortex. Brain Res Brain Res Rev 56: 89–100, 2007. doi: 10.1016/j.brainresrev. 2007.05.011.
34. Campbell AJ, Spears GF, Borrie MJ. Examination by logistic regression modelling of the variables which increase the relative risk of elderly women falling compared to elderly men. J Clin Epidemiol 43: 1415-1420, 1990. doi: 10.1016/0895-4356 (90) 90110-B.
35. Carey BJ, Eames PJ, Blake MJ, Panerai RB, Potter JF. Dynamic cerebral autoregulation is unaffected by aging. Stroke 31: 2895–2900, 2000. doi: 10.1161/01.STR.31.12.2895.
36. Cauli B, Hamel E. Revisiting the role of neurons in neurovascular coupling. Front Neuroenergetics 2: 9, 2010. doi: 10.3389/fnene.2010.00009.
37. Chen BR, Kozberg MG, Bouchard MB, Shaik MA, Hillman EM. A critical role for the vascular endothelium in functional neurovascular coupling in the brain. J Am Heart Assoc 3: e000787, 2014. doi: 10.1161/ JAHA.114.000787.
38. Cheng J, Wu CC, Gotlinger KH, Zhang F, Falck JR, Narsimhaswamy D, Schwartzman ML. 20-Hydroxy-5, 8, 11, 14-eicosatetraenoic acid mediates endothelial dysfunction via IkappaB kinase-dependent endothelial nitric-oxide synthase uncoupling. J Pharmacol Exp Ther 332: 57–65, 2010. doi: 10.1124/jpet.109.159863.
39. Cho EB, Shin HY, Park SE, Chun P, Jang HR, Yang JJ, Kim HJ, Kim YJ, Jung NY, Lee JS, Lee J, Jang YK, Jang EY, Kang M, Lee JM, Kim C, Min JH, Ryu S, Na DL, Seo SW. Albuminuria, cerebrovascular disease and cortical atrophy: among cognitively normal elderly individuals. Sci Rep 6: 20692, 2016. doi: 10.1038/srep20692.
40. Cipolla MJ. The Cerebral Circulation. San Rafael, CA: Morgan & Claypool Life Sciences, 2009. 21452434
41. Cipolla MJ, Gokina NI, Osol G. Pressure-induced actin polymerization in vascular smooth muscle as a mechanism underlying myogenic behavior. FASEB J 16: 72–76, 2002. doi: 10.1096/cj.01-0104hyp.
42. Cipolla MJ, Sweet J, Chan SL, Tavares MJ, Gokina N, Brayden JE. Increased pressure-induced tone in rat parenchymal arterioles vs. middle cerebral arteries: role of ion channels and calcium sensitivity. J Appl Physiol (1985) 117: 53–59, 2014. doi: 10.1152/japplphysiol.00253.2014.
43. Clark D, Institoris A, Kozák G, Bere Z, Tuor U, Farkas E, Bari F. Impact of aging on spreading depolarizations induced by focal brain ischemia in rats. Neurobiol Aging 35: 2803–2811, 2014. doi: 10.1016/ j.neurobiolaging.2014.06.013.
44. Cooper LL, Woodard T, Sigurdsson S, van Buchem MA, Torjesen AA, Inker LA, Aspelund T, Eiriksdottir G, Harris TB, Gudnason V, Launer LJ, Mitchell GF. Cerebrovascular damage mediates relations between aortic stiffness and memory. Hypertension 67: 176–182, 2016. doi: 10.1161/HYPERTENSIONAHA.115.06398.
45. Corriveau RA, Bosetti F, Emr M, Gladman JT, Koenig JI, Moy CS, Pahigiannis K, Waddy SP, Koroshetz W. 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: 281–288, 2016. doi: 10.1007/ s10571-016-0334-7.
46. Csiszar A, Gautam T, Sosnowska D, Tarantini S, Banki E, Tucsek Z, Toth P, Losonczy G, Koller A, Reglodi D, Giles CB, Wren JD, Sonntag WE, Ungvari Z. Caloric restriction confers persistent antioxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats. Am J Physiol Heart Circ Physiol 307: H292–H306, 2014. doi: 10.1152/ajpheart.00307.2014.
47. Csiszar A, Labinskyy N, Perez V, Recchia FA, Podlutsky A, Mukhopadhyay P, Losonczy G, Pacher P, Austad SN, Bartke A, Ungvari Z. Endothelial function and vascular oxidative stress in long-lived GH/IGF-deficient Ames dwarf mice. Am J Physiol Heart Circ Physiol 295: H1882–H1894, 2008. doi: 10.1152/ajpheart.412.2008.
48. Csiszar A, Sosnowska D, Wang M, Lakatta EG, Sonntag WE, Ungvari Z. Age-associated proinflammatory secretory phenotype in vascular smooth muscle cells from the non-human primate Macaca mulatta: reversal by resveratrol treatment. J Gerontol A Biol Sci Med Sci 67: 811–820, 2012. doi: 10.1093/gerona/glr228.
49. Csiszar A, Tucsek Z, Toth P, Sosnowska D, Gautam T, Koller A, Deak F, Sonntag WE, Ungvari Z. Synergistic effects of hypertension and aging on cognitive function and hippocampal expression of genes involved in _-amyloid generation and Alzheimer’s disease. Am J Physiol Heart Circ Physiol 305: H1120–H1130, 2013. doi: 10.1152/ ajpheart.00288.2013.
50. Csiszar A, Ungvari Z, Edwards JG, Kaminski P, Wolin MS, Koller A, Kaley G. Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ Res 90: 1159–1166, 2002. doi: 10.1161/01.RES.0000020401.61826.EA.
51. D’Angelo G, Mogford JE, Davis GE, Davis MJ, Meininger GA. Integrin-mediated reduction in vascular smooth muscle [Ca2+]i induced by RGD-containing peptide. Am J Physiol Heart Circ Physiol 272: H2065–H2070, 1997.
52. Daulatzai MA. Cerebral hypoperfusion and glucose hypometabolism: key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer’s disease. J Neurosci Res. 2016. doi: 10.1002/jnr.23777.
53. de Cavanagh EM, Inserra F, Ferder L. Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition. Am J Physiol Heart Circ Physiol 309: H15–H44, 2015. doi: 10.1152/ajpheart. 00459.2014.
54. De Reuck JL, Deramecourt V, Auger F, Durieux N, Cordonnier C, Devos D, Defebvre L, Moreau C, Capparos-Lefebvre D, Pasquier F, Leys D, Maurage CA, Bordet R. The significance of cortical cerebellar microbleeds and microinfarcts in neurodegenerative and cerebrovascular diseases. A post-mortem 7.0-tesla magnetic resonance study with neuropathological correlates. Cerebrovasc Dis 39: 138-143, 2015. doi: 10.1159/000371488.
55. De Silva TM, Faraci FM. Microvascular dysfunction and cognitive impairment. Cell Mol Neurobiol 36: 241–258, 2016. doi: 10.1007/ s10571-015-0308-1.
56. Deer RR, Stallone JN. Effects of estrogen on cerebrovascular function: age-dependent shifts from beneficial to detrimental in small cerebral arteries of the rat. Am J Physiol Heart Circ Physiol 310: H1285–H1294, 2016. doi: 10.1152/ajpheart.00645.2015.
57. den Abeelen AS, Lagro J, van Beek AH, Claassen JA. Impaired cerebral autoregulation and vasomotor reactivity in sporadic Alzheimer’s disease. Curr Alzheimer Res 11: 11–17, 2014. doi: 10.2174/ 1567205010666131119234845.
58. den Heijer T, Launer LJ, Prins ND, van Dijk EJ, Vermeer SE, Hofman A, Koudstaal PJ, Breteler MM. Association between blood pressure, white matter lesions, and atrophy of the medial temporal lobe. Neurology 64: 263–267, 2005. doi: 10.1212/01.WNL.0000149641.55751.2E.
59. Di Marco LY, Venneri A, Farkas E, Evans PC, Marzo A, Frangi AF. Vascular dysfunction in the pathogenesis of Alzheimer’s disease—a review of endothelium-mediated mechanisms and ensuing vicious circles. Neurobiol Dis 82: 593–606, 2015. doi: 10.1016/j.nbd.2015.08.014.
60. Diaz-Otero JM, Garver H, Fink GD, Jackson WF, Dorrance AM. Aging is associated with changes to the biomechanical properties of the posterior cerebral artery and parenchymal arterioles. Am J Physiol Heart Circ Physiol 310: H365–H375, 2016. doi: 10.1152/ajpheart.00562.2015.
61. Díaz-Ruiz C, Wang J, Ksiezak-Reding H, Ho L, Qian X, Humala N, Thomas S, Martínez-Martín P, Pasinetti GM. Role of hypertension in aggravating Abeta neuropathology of AD type and tau-mediated motor impairment. Cardiovasc Psychiatry Neurol 2009: 107286, 2009. doi: 10.1155/2009/107286.
62. Dreier JP. The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med 17: 439–447, 2011. doi: 10.1038/nm.2333.
63. Dreier JP, Drenckhahn C, Woitzik J, Major S, Offenhauser N, Weber-Carstens S, Wolf S, Strong AJ, Vajkoczy P, Hartings JA; COSBID Study Group. Spreading ischemia after aneurysmal subarachnoid hemorrhage. Acta Neurochir Suppl 115: 125–129, 2013.
64. Dreier JP, Fabricius M, Ayata C, Sakowitz OW, William Shuttleworth C, Dohmen C, Graf R, Vajkoczy P, Helbok R, Suzuki M, Schiefecker AJ, Major S, Winkler MK, Kang EJ, Milakara D, Oliveira-Ferreira AI, Reiffurth C, Revankar GS, Sugimoto K, Dengler NF, Hecht N, Foreman B, Feyen B, Kondziella D, Friberg CK, Piilgaard H, Rosenthal ES, Westover MB, Maslarova A, Santos E, Hertle D, Sánchez-Porras R, Jewell SL, Balança B, Platz J, Hinzman JM, Lückl J, Schoknecht K, Schöll M, Drenckhahn C, Feuerstein D, Eriksen N, Horst V, Bretz JS, Jahnke P, Scheel M, Bohner G, Rostrup E, Pakkenberg B, Heinemann U, Claassen J, Carlson AP, Kowoll CM, Lublinsky S, Chassidim Y, Shelef I, Friedman A, Brinker G, Reiner M, Kirov SA, Andrew RD, Farkas E, Güresir E, Vatter H, Chung LS, Brennan KC, Lieutaud T, Marinesco S, Maas AI, Sahuquillo J, Dahlem MA, Richter F, Herreras O, Boutelle MG, Okonkwo DO, Bullock MR, Witte OW, Martus P, van den Maagdenberg AM, Ferrari MD, Dijkhuizen RM, Shutter LA, Andaluz N, Schulte AP, MacVicar B, Watanabe T, Woitzik J, Lauritzen M, Strong AJ, Hartings JA. Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: review and recommendations of the COSBID research group. J Cereb Blood Flow Metab pii: 0271678X16654496, 2016. doi: 10.1177/0271678X16654496.
65. Dunn KM, Renic M, Flasch AK, Harder DR, Falck J, Roman RJ. Elevated production of 20-HETE in the cerebral vasculature contributes to severity of ischemic stroke and oxidative stress in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 295: H2455–H2465, 2008. doi: 10.1152/ajpheart.00512.2008.
66. Enager P, Piilgaard H, Offenhauser N, Kocharyan A, Fernandes P, Hamel E, Lauritzen M. Pathway-specific variations in neurovascular and neurometabolic coupling in rat primary somatosensory cortex. J Cereb Blood Flow Metab 29: 976–986, 2009. doi: 10.1038/jcbfm. 2009.23.
67. Fabiani M, Gordon BA, Maclin EL, Pearson MA, Brumback-Peltz CR, Low KA, McAuley E, Sutton BP, Kramer AF, Gratton G. Neurovascular coupling in normal aging: a combined optical, ERP and fMRI study. Neuroimage 85: 592–607, 2014.
68. Fan F, Geurts AM, Murphy SR, Pabbidi MR, Jacob HJ, Roman RJ. Impaired myogenic response and autoregulation of cerebral blood flow is rescued in CYP4A1 transgenic Dahl salt-sensitive rat. Am J Physiol Regul Integr Comp Physiol 308: R379–R390, 2015. doi: 10.1152/ajpregu. 00256.2014.
69. Faraci FM, Baumbach GL, Heistad DD. Myogenic mechanisms in the cerebral circulation. J Hypertens Suppl 7: S61–S64; discussion S65, 1989.
70. Faraci FM, Heistad DD. Regulation of large cerebral arteries and cerebral microvascular pressure. Circ Res 66: 8–17, 1990. doi: 10.1161/ 01.RES.66.1.8.
71. Faraco G, Iadecola C. Hypertension: a harbinger of stroke and dementia. Hypertension 62: 810–817, 2013. doi: 10.1161/HYPERTENSIONAHA. 113.01063.
72. Faraco G, Park L, Zhou P, Luo W, Paul SM, Anrather J, Iadecola C. Hypertension enhances A_-induced neurovascular dysfunction, promotes _-secretase activity, and leads to amyloidogenic processing of APP. J Cereb Blood Flow Metab 36: 241–252, 2016. doi: 10.1038/ jcbfm.2015.79.
73. Farkas E, Bari F. Spreading depolarization in the ischemic brain: does aging have an impact? J Gerontol A Biol Sci Med Sci 69: 1363–1370, 2014. doi: 10.1093/gerona/glu066.
74. Farkas E, De Jong GI, Apró E, De Vos RA, Steur EN, Luiten PG. Similar ultrastructural breakdown of cerebrocortical capillaries in Alzheimer’s disease, Parkinson’s disease, and experimental hypertension. What is the functional link? Ann N Y Acad Sci 903: 72–82, 2000. doi: 10.1111/j.1749-6632.2000.tb06352.x.
75. Farkas E, Obrenovitch TP, Institóris Á, Bari F. Effects of early aging and cerebral hypoperfusion on spreading depression in rats. Neurobiol Aging 32: 1707–1715, 2011. doi: 10.1016/j.neurobiolaging.2009.10.002.
76. Fernandes J, Lorenzo IM, Andrade YN, Garcia-Elias A, Serra SA, Fernández-Fernández JM, Valverde MA. IP3 sensitizes TRPV4 channel to the mechano-and osmotransducing messenger 5=-6=-epoxyeicosatrienoic acid. J Cell Biol 181: 143–155, 2008. doi: 10.1083/jcb.200712058.
77. Fields LE, Burt VL, Cutler JA, Hughes J, Roccella EJ, Sorlie P. The burden of adult hypertension in the United States 1999 to 2000: a rising tide. Hypertension 44: 398–404, 2004. doi: 10.1161/01.HYP.0000142248.54761.56.
78. Filosa JA, Bonev AD, Straub SV, Meredith AL, Wilkerson MK, Aldrich RW, Nelson MT. Local potassium signaling couples neuronal activity to vasodilation in the brain. Nat Neurosci 9: 1397–1403, 2006. doi: 10.1038/nn1779.
79. Flavahan S, Chang F, Flavahan NA. Local renin-angiotensin system mediates endothelial dilator dysfunction in aging arteries. Am J Physiol Heart Circ Physiol 311: H849–H854, 2016. doi: 10.1152/ajpheart. 00422.2016.
80. Fog M. The relationship between the blood pressure and the tonic regulation of the pial arteries. J Neurol Psychiatry 1: 187–197, 1938. doi: 10.1136/jnnp.1.3.187.
81. Forbes HS. Regulation of the cerebral vessels; new aspects. AMA Arch Neurol Psychiatry 80: 689–695, 1958. doi: 10.1001/archneurpsyc. 1958.02340120025004.
82. Forette F, Seux ML, Staessen JA, Thijs L, Birkenhäger WH, Babarskiene MR, Babeanu S, Bossini A, Gil-Extremera B, Girerd X, Laks T, Lilov E, Moisseyev V, Tuomilehto J, Vanhanen H, Webster J, Yodfat Y, Fagard R. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 352: 1347–1351, 1998. doi: 10.1016/ S0140-6736 (98) 03086-4.
83. Fujii K, Heistad DD, Faraci FM. Effect of diabetes mellitus on flow-mediated and endothelium-dependent dilatation of the rat basilar artery. Stroke 23: 1494–1498, 1992. doi: 10.1161/01.STR.23.10.1494.
84. Fujishima M, Sadoshima S, Ogata J, Yoshida F, Shiokawa O, Ibayashi S, Omae T. Autoregulation of cerebral blood flow in young and aged spontaneously hypertensive rats (SHR). Gerontology 30: 30–36, 1984. doi: 10.1159/000212604.
85. Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors. FASEB J 3: 2007–2018, 1989.
86. Gano LB, Donato AJ, Pasha HM, Hearon CM Jr, Sindler AL, Seals DR. The SIRT1 activator SRT1720 reverses vascular endothelial dysfunction, excessive superoxide production, and inflammation with aging in mice. Am J Physiol Heart Circ Physiol 307: H1754–H1763, 2014. doi: 10.1152/ajpheart.00377.2014.
87. Garcia-Roldan JL, Bevan JA. Augmentation of endothelium-independent flow constriction in pial arteries at high intravascular pressures. Hypertension 17: 870–874, 1991. doi: 10.1161/01.HYP.17.6.870.
88. Garcia-Roldan JL, Bevan JA. Flow-induced constriction and dilation of cerebral resistance arteries. Circ Res 66: 1445–1448, 1990. doi: 10.1161/01.RES.66.5.1445.
89. Ge Y, Murphy SR, Fan F, Williams JM, Falck JR, Liu R, Roman RJ. Role of 20-HETE in the impaired myogenic and TGF responses of the Af-Art of Dahl salt-sensitive rats. Am J Physiol Renal Physiol 307: F509–F515, 2014. doi: 10.1152/ajprenal.00273.2014.
90. Gebremedhin D, Lange AR, Lowry TF, Taheri MR, Birks EK, Hudetz AG, Narayanan J, Falck JR, Okamoto H, Roman RJ, Nithipatikom K, Campbell WB, Harder DR. Production of 20-HETE and its role in autoregulation of cerebral blood flow. Circ Res 87: 60–65, 2000. doi: 10.1161/01.RES.87.1.60.
91. Gelber RP, Launer LJ, White LR. The Honolulu-Asia Aging Study: epidemiologic and neuropathologic research on cognitive impairment. Curr Alzheimer Res 9: 664–672, 2012. doi: 10.2174/156720512801322618.
92. Girouard H, Park L, Anrather J, Zhou P, Iadecola C. Cerebrovascular nitrosative stress mediates neurovascular and endothelial dysfunction induced by angiotensin II. Arterioscler Thromb Vasc Biol 27: 303–309, 2007. doi: 10.1161/01.ATV.0000253885.41509.25.
93. Gokina NI, Knot HJ, Nelson MT, Osol G. Increased Ca2+ sensitivity as a key mechanism of PKC-induced constriction in pressurized cerebral arteries. Am J Physiol Heart Circ Physiol 277: H1178–H1188, 1999.
94. Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, Launer LJ, Laurent S, Lopez OL, Nyenhuis D, Petersen RC, Schneider JA, Tzourio C, Arnett DK, Bennett DA, Chui HC, Higashida RT, Lindquist R, Nilsson PM, Roman GC, Sellke FW, Seshadri S; American Heart Association Stroke Council, Council on Epidemiology and Prevention, Council on Cardiovascular Nursing, Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery and Anesthesia. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 42: 2672–2713, 2011. doi: 10.1161/STR.0b013e3182299496.
95. Hajdu MA, Heistad DD, Siems JE, Baumbach GL. Effects of aging on mechanics and composition of cerebral arterioles in rats. Circ Res 66: 1747–1754, 1990. doi: 10.1161/01.RES.66.6.1747.
96. Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A, Sutherland BA, O’Farrell FM, Buchan AM, Lauritzen M, Attwell D. Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508: 55–60, 2014. doi: 10.1038/nature13165.
97. Halpern W, Osol G. Influence of transmural pressure of myogenic responses of isolated cerebral arteries of the rat. Ann Biomed Eng 13: 287–293, 1985. doi: 10.1007/BF02584246.
98. Harder DR, Narayanan J, Gebremedhin D. Pressure-induced myogenic tone and role of 20-HETE in mediating autoregulation of cerebral blood flow. Am J Physiol Heart Circ Physiol 300: H1557–H1565, 2011. doi: 10.1152/ajpheart.01097.2010.
99. Harper SL, Bohlen HG. Microvascular adaptation in the cerebral cortex of adult spontaneously hypertensive rats. Hypertension 6: 408–419, 1984. doi: 10.1161/01.HYP.6.3.408.
100. Harper SL, Bohlen HG, Rubin MJ. Arterial and microvascular contributions to cerebral cortical autoregulation in rats. Am J Physiol Heart Circ Physiol 246: H17–H24, 1984.
101. Hartings JA, Bullock MR, Okonkwo DO, Murray LS, Murray GD, Fabricius M, Maas AI, Woitzik J, Sakowitz O, Mathern B, Roozenbeek B, Lingsma H, Dreier JP, Puccio AM, Shutter LA, Pahl C, Strong AJ; Co-Operative Study on Brain Injury Depolarisations. Spreading depolarisations and outcome after traumatic brain injury: a prospective observational study. Lancet Neurol 10: 1058–1064, 2011. doi: 10.1016/S1474-4422 (11) 70243-5.
102. Hartings JA, Shuttleworth CW, Kirov SA, Ayata C, Hinzman JM, Foreman B, Andrew RD, Boutelle MG, Brennan KC, Carlson AP, Dahlem MA, Drenckhahn C, Dohmen C, Fabricius M, Farkas E, Feuerstein D, Graf R, Helbok R, Lauritzen M, Major S, Oliveira-Ferreira AI, Richter F, Rosenthal ES, Sakowitz OW, Sánchez-Porras R, Santos E, Schöll M, Strong AJ, Urbach A, Westover MB, Winkler MK, Witte OW, Woitzik J, Dreier JP. The continuum of spreading depolarizations in acute cortical lesion development: examining Leão’s legacy. J Cereb Blood Flow Metab pii: 0271678X16654495, 2016. doi: 10.1177/0271678X16654495.
103. Hartings JA, Wilson JA, Hinzman JM, Pollandt S, Dreier JP, DiNapoli V, Ficker DM, Shutter LA, Andaluz N. Spreading depression in continuous electroencephalography of brain trauma. Ann Neurol 76: 681–694, 2014. doi: 10.1002/ana.24256.
104. Hashimoto J, Ito S. Central pulse pressure and aortic stiffness determine renal hemodynamics: pathophysiological implication for microalbuminuria in hypertension. Hypertension 58: 839–846, 2011. doi: 10.1161/ HYPERTENSIONAHA.111.177469.
105. Hatake K, Kakishita E, Wakabayashi I, Sakiyama N, Hishida S. Effect of aging on endothelium-dependent vascular relaxation of isolated human basilar artery to thrombin and bradykinin. Stroke 21: 1039–1043, 1990. doi: 10.1161/01.STR.21.7.1039.
106. Heckmann JG, Brown CM, Cheregi M, Hilz MJ, Neundörfer B. Delayed cerebrovascular autoregulatory response to ergometer exercise in normotensive elderly humans. Cerebrovasc Dis 16: 423–429, 2003. doi: 10.1159/000072567.
107. Hertelendy P, Menyhárt Á, Makra P, Süle Z, Kiss T, Tóth G, Ivánkovits-Kiss O, Bari F, Farkas E. Advancing age and ischemia elevate the electric threshold to elicit spreading depolarization in the cerebral cortex of young adult rats. J Cereb Blood Flow pii: 0271678X16643735, 2016.
108. Hinzman JM, Andaluz N, Shutter LA, Okonkwo DO, Pahl C, Strong AJ, Dreier JP, Hartings JA. Inverse neurovascular coupling to cortical spreading depolarizations in severe brain trauma. Brain 137: 2960–2972, 2014. doi: 10.1093/brain/awu241.
109. Hock C, Villringer K, Müller-Spahn F, Wenzel R, Heekeren H, Schuh-Hofer S, Hofmann M, Minoshima S, Schwaiger M, Dirnagl U, Villringer A. Decrease in parietal cerebral hemoglobin oxygenation during performance of a verbal fluency task in patients with Alzheimer’s disease monitored by means of near-infrared spectroscopy (NIRS)--correlation with simultaneous rCBF-PET measurements. Brain Res 755: 293–303, 1997. doi: 10.1016/S0006-8993 (97) 00122-4.
110. Hoffman LB, Schmeidler J, Lesser GT, Beeri MS, Purohit DP, Grossman HT, Haroutunian V. Less Alzheimer disease neuropathology in medicated hypertensive than nonhypertensive persons. Neurology 72: 1720–1726, 2009. doi: 10.1212/01.wnl.0000345881.82856.d5.
111. Hoffman WE, Albrecht RF, Miletich DJ. The influence of aging and hypertension on cerebral autoregulation. Brain Res 214: 196–199, 1981. doi: 10.1016/0006-8993 (81) 90454-6.
112. Hongo K, Nakagomi T, Kassell NF, Sasaki T, Lehman M, Vollmer DG, Tsukahara T, Ogawa H, Torner J. Effects of aging and hypertension on endothelium-dependent vascular relaxation in rat carotid artery. Stroke 19: 892–897, 1988. doi: 10.1161/01.STR.19.7.892.
113. Hortobágyi L, Kis B, Hrabák A, Horváth B, Huszty G, Schweer H, Benyó B, Sándor P, Busija DW, Benyó Z. Adaptation of the hypothalamic blood flow to chronic nitric oxide deficiency is independent of vasodilator prostanoids. Brain Res 1131: 129–137, 2007. doi: 10.1016/ j.brainres.2006.11.009.
114. Iadecola C. Hypertension and dementia. Hypertension 64: 3–5, 2014. doi: 10.1161/HYPERTENSIONAHA.114.03040.
115. Iadecola C. The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathol 120: 287–296, 2010. doi: 10.1007/s00401-010-0718-6.
116. Iadecola C. The pathobiology of vascular dementia. Neuron 80: 844-866, 2013. doi: 10.1016/j.neuron.2013.10.008.
117. Iadecola C, Davisson RL. Hypertension and cerebrovascular dysfunction. Cell Metab 7: 476–484, 2008. doi: 10.1016/j.cmet.2008.03.010.
118. Iadecola C, Park L, Capone C. Threats to the mind: aging, amyloid, and hypertension. Stroke 40, Suppl: S40–S44, 2009. doi: 10.1161/ STROKEAHA.108.533638.
119. Ighodaro ET, Abner EL, Fardo DW, Lin AL, Katsumata Y, Schmitt FA, Kryscio RJ, Jicha GA, Neltner JH, Monsell SE, Kukull WA, Moser DK, Appiah F, Bachstetter AD, Van Eldik LJ, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Nelson PT. Risk factors and global cognitive status related to brain arteriolosclerosis in elderly individuals. J Cereb Blood Flow Metab pii: 0271678X16643735, 2016. 10.1177/0271678X15621574.
120. Inaba M, White L, Bell C, Chen R, Petrovitch H, Launer L, Abbott RD, Ross GW, Masaki K. White matter lesions on brain magnetic resonance imaging scan and 5-year cognitive decline: the Honolulu-Asia aging study. J Am Geriatr Soc 59: 1484–1489, 2011. doi: 10.1111/j.1532-5415.2011.03490.x.
121. Israeli-Korn SD, Masarwa M, Schechtman E, Abuful A, Strugatsky R, Avni S, Farrer LA, Friedland RP, Inzelberg R. Hypertension increases the probability of Alzheimer’s disease and of mild cognitive impairment in an Arab community in northern Israel. Neuroepidemiology 34: 99–105, 2010. doi: 10.1159/000264828.
122. Ivanov AI, Malkov AE, Waseem T, Mukhtarov M, Buldakova S, Gubkina O, Zilberter M, Zilberter Y. Glycolysis and oxidative phosphorylation in neurons and astrocytes during network activity in hippocampal slices. J Cereb Blood Flow Metab 34: 397–407, 2014. doi: 10.1038/jcbfm.2013.222.
123. Janik R, Thomason LA, Chaudhary S, Dorr A, Scouten A, Schwindt G, Masellis M, Stanisz GJ, Black SE, Stefanovic B. Attenuation of functional hyperemia to visual stimulation in mild Alzheimer’s disease and its sensitivity to cholinesterase inhibition. Biochim Biophys Acta 1862: 957–965, 2016. doi: 10.1016/j.bbadis.2015.10.023.
124. Jessen NA, Munk AS, Lundgaard I, Nedergaard M. The glymphatic system: a beginner’s guide. Neurochem Res 40: 2583–2599, 2015. doi: 10.1007/s11064-015-1581-6.
125. Jessen SB, Mathiesen C, Lind BL, Lauritzen M. Interneuron deficit associates attenuated network synchronization to mismatch of energy supply and demand in aging mouse brains. Cereb Cortex pii: bhv261, 2015.
126. Johnsen SP, Hundborg HH, Sørensen HT, Orskov H, Tjønneland A, Overvad K, Jørgensen JO. Insulin-like growth factor (IGF) I,-II, and IGF binding protein-3 and risk of ischemic stroke. J Clin Endocrinol Metab 90: 5937–5941, 2005. doi: 10.1210/jc.2004-2088.
127. Kario K, Pickering TG, Umeda Y, Hoshide S, Hoshide Y, Morinari M, Murata M, Kuroda T, Schwartz JE, Shimada K. Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives: a prospective study. Circulation 107: 1401–1406, 2003. doi: 10.1161/01.CIR.0000056521.67546.AA.
128. Katakam PV, Gordon AO, Sure VN, Rutkai I, Busija DW. Diversity of mitochondria-dependent dilator mechanisms in vascular smooth muscle of cerebral arteries from normal and insulin-resistant rats. Am J Physiol Heart Circ Physiol 307: H493–H503, 2014. doi: 10.1152/ajpheart. 00091.2014.
129. Katakam PV, Snipes JA, Steed MM, Busija DW. Insulin-induced generation of reactive oxygen species and uncoupling of nitric oxide synthase underlie the cerebrovascular insulin resistance in obese rats. J Cereb Blood Flow Metab 32: 792–804, 2012. doi: 10.1038/ jcbfm.2011.181.
130. Katusic ZS. Mechanisms of endothelial dysfunction induced by aging: role of arginase I. Circ Res 101: 640–641, 2007. doi: 10.1161/CIRCRESAHA. 107.162701.
131. Katusic ZS, Austin SA. Endothelial nitric oxide: protector of a healthy mind. Eur Heart J 35: 888–894, 2014. doi: 10.1093/eurheartj/eht544.
132. Katusic ZS, Austin SA. Neurovascular protective function of endothelial nitric oxide–recent advances. Circ J 80: 1499–1503, 2016. doi: 10.1253/circj.CJ-16-0423.
133. Keleshian VL, Modi HR, Rapoport SI, Rao JS. Aging is associated with altered inflammatory, arachidonic acid cascade, and synaptic markers, influenced by epigenetic modifications, in the human frontal cortex. J Neurochem 125: 63–73, 2013. doi: 10.1111/jnc.12153.
134. Kemper TL, Blatt GJ, Killiany RJ, Moss MB. Neuropathology of progressive cognitive decline in chronically hypertensive rhesus monkeys. Acta Neuropathol 101: 145–153, 2001.
135. Kim YJ, Kwon HK, Lee JM, Cho H, Kim HJ, Park HK, Jung NY, San Lee J, Lee J, Jang YK, Kim ST, Lee KH, Choe YS, Kim YJ, Na DL, Seo SW. Gray and white matter changes linking cerebral small vessel disease to gait disturbances. Neurology 86: 1199–1207, 2016. doi: 10.1212/WNL.0000000000002516.
136. Kim YS, Bogert LW, Immink RV, Harms MP, Colier WN, van Lieshout JJ. Effects of aging on the cerebrovascular orthostatic response. Neurobiol Aging 32: 344–353, 2011. doi: 10.1016/j.neurobiolaging. 2009.02.019.
137. Kimbrough IF, Robel S, Roberson ED, Sontheimer H. Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer’s disease. Brain 138: 3716–3733, 2015. doi: 10.1093/brain/awv327.
138. Knot HJ, Nelson MT. Regulation of arterial diameter and wall [Ca2+] in cerebral arteries of rat by membrane potential and intravascular pressure. J Physiol 508: 199–209, 1998. doi: 10.1111/j.1469-7793.1998.199br.x.
139. Knot HJ, Nelson MT. Regulation of membrane potential and diameter by voltage-dependent K_ channels in rabbit myogenic cerebral arteries. Am J Physiol Heart Circ Physiol 269: H348–H355, 1995.
140. Knot HJ, Standen NB, Nelson MT. Ryanodine receptors regulate arterial diameter and wall [Ca2+] in cerebral arteries of rat via Ca2+-dependent K_ channels. J Physiol 508: 211–221, 1998. doi: 10.1111/ j.1469-7793.1998.211br.x.
141. Koller A, Toth P. Contribution of flow-dependent vasomotor mechanisms to the autoregulation of cerebral blood flow. J Vasc Res 49: 375–389, 2012. doi: 10.1159/000338747.
142. Kontos HA, Wei EP, Navari RM, Levasseur JE, Rosenblum WI, Patterson JL Jr. Responses of cerebral arteries and arterioles to acute hypotension and hypertension. Am J Physiol Heart Circ Physiol 234: H371–H383, 1978.
143. Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D, Xie L, Kang H, Xu Q, Liew JA, Plog BA, Ding F, Deane R, Nedergaard M. Impairment of paravascular clearance pathways in the aging brain. Ann Neurol 76: 845–861, 2014. doi: 10.1002/ana.24271.
144. La Favor JD, Kraus RM, Carrithers JA, Roseno SL, Gavin TP, Hickner RC. Sex differences with aging in nutritive skeletal muscle blood flow: impact of exercise training, nitric oxide, and _-adrenergicmediated mechanisms. Am J Physiol Heart Circ Physiol 307: H524-H532, 2014. doi: 10.1152/ajpheart.00247.2014.
145. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a “set up” for vascular disease. Circulation 107: 139-146, 2003. doi: 10.1161/ 01.CIR.0000048892.83521.58.
146. Laron Z, Klinger B, Silbergeld A. Patients with Laron syndrome have osteopenia/osteoporosis. J Bone Miner Res 14: 156–157, 1999. doi: 10.1359/jbmr.1999.14.1.156.
147. Lartaud I, Bray-des-Boscs L, Chillon JM, Atkinson J, Capdeville-Atkinson C. In vivo cerebrovascular reactivity in Wistar and Fischer 344 rat strains during aging. Am J PhysiolHeart Circ Physiol 264: H851-H858, 1993.
148. Lassen NA. Autoregulation of cerebral blood flow. Circ Res 15, Suppl: 201–204, 1964.
149. Lipsitz LA, Mukai S, Hamner J, Gagnon M, Babikian V. Dynamic regulation of middle cerebral artery blood flow velocity in aging and hypertension. Stroke 31: 1897–1903, 2000. doi: 10.1161/01.STR.31. 8.1897.
150. Liu GS, Zhang ZS, Yang B, He W. Resveratrol attenuates oxidative damage and ameliorates cognitive impairment in the brain of senescenceaccelerated mice. Life Sci 91: 872–877, 2012. doi: 10.1016/j.lfs. 2012.08.033.
151. Liu J, Tseng BY, Khan MA, Tarumi T, Hill C, Mirshams N, Hodics TM, Hynan LS, Zhang R. Individual variability of cerebral autoregulation, posterior cerebral circulation and white matter hyperintensity. J Physiol 594: 3141–3155, 2016. doi: 10.1113/JP271068.
152. Liu X, Li C, Falck JR, Roman RJ, Harder DR, Koehler RC. Interaction of nitric oxide, 20-HETE, and EETs during functional hyperemia in whisker barrel cortex. Am J Physiol Heart Circ Physiol 295: H619–H631, 2008. doi: 10.1152/ajpheart.01211.2007.
153. Liu X, Li C, Gebremedhin D, Hwang SH, Hammock BD, Falck JR, Roman RJ, Harder DR, Koehler RC. Epoxyeicosatrienoic acid-dependent cerebral vasodilation evoked by metabotropic glutamate receptor activation in vivo. Am J Physiol Heart Circ Physiol 301: H373–H381, 2011. doi: 10.1152/ajpheart.00745.2010.
154. Longden T, Nelson M. Recruitment of the vascular endothelium into neurovascular coupling. Proc Br Pharmacol Soc 9: 062P, 2011.
155. Lucas RA, Cotter JD, Morrison S, Ainslie PN. The effects of ageing and passive heating on cardiorespiratory and cerebrovascular responses to orthostatic stress in humans. Exp Physiol 93: 1104–1117, 2008. doi: 10.1113/expphysiol.2008.042580.
156. Lückl J, Dreier JP, Szabados T, Wiesenthal D, Bari F, Greenberg JH. Peri-infarct flow transients predict outcome in rat focal brain ischemia. Neuroscience 226: 197–207, 2012. doi: 10.1016/j.neuroscience.2012.08.049.
157. Ma J, Ayata C, Huang PL, Fishman MC, Moskowitz MA. Regional cerebral blood flow response to vibrissal stimulation in mice lacking type I NOS gene expression. Am J Physiol Heart Circ Physiol 270: H1085-H1090, 1996.
158. Madden JA, Christman NJ. Integrin signaling, free radicals, and tyrosine kinase mediate flow constriction in isolated cerebral arteries. Am J Physiol Heart Circ Physiol 277: H2264–H2271, 1999.
159. Mathiesen C, Brazhe A, Thomsen K, Lauritzen M. Spontaneous calcium waves in Bergman glia increase with age and hypoxia and may reduce tissue oxygen. J Cereb Blood Flow Metab 33: 161–169, 2013. doi: 10.1038/jcbfm.2012.175.
160. Mathiesen C, Caesar K, Akgören N, Lauritzen M. Modification of activity-dependent increases of cerebral blood flow by excitatory synaptic activity and spikes in rat cerebellar cortex. J Physiol 512: 555–566, 1998. doi: 10.1111/j.1469-7793.1998.555be.x.
161. Mayhan WG, Faraci FM, Baumbach GL, Heistad DD. Effects of aging on responses of cerebral arterioles. Am J Physiol Heart Circ Physiol 258: H1138–H1143, 1990.
162. Mayhan WG, Werber AH, Heistad DD. Protection of cerebral vessels by sympathetic nerves and vascular hypertrophy. Circulation 75: I107-I112, 1987.
163. McGuinness B, Todd S, Passmore P, Bullock R. Blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive impairment and dementia. Cochrane Database Syst Rev 4: CD004034, 2009. doi: 10.1002/14651858.CD004034.pub3.
164. McHedlishvili G. Physiological mechanisms controlling cerebral blood flow. Stroke 11: 240–248, 1980. doi: 10.1161/01.STR.11.3.240.
165. McHedlishvili GI, Mitagvaria NP, Ormotsadze LG. Vascular mechanisms controlling a constant blood supply to the brain (“autoregulation”). Stroke 4: 742–750, 1973. doi: 10.1161/01.STR.4.5.742.
166. Mehagnoul-Schipper DJ, Vloet LC, Colier WN, Hoefnagels WH, Jansen RW. Cerebral oxygenation declines in healthy elderly subjects in response to assuming the upright position. Stroke 31: 1615–1620, 2000. doi: 10.1161/01.STR.31.7.1615.
167. Mellander S. Functional aspects of myogenic vascular control. J Hypertens Suppl 7: S21–S30; discussion S31, 1989.
168. Menyhárt Á, Makra P, Szepes BE, Tóth OM, Hertelendy P, Bari F, Farkas E. High incidence of adverse cerebral blood flow responses to spreading depolarization in the aged ischemic rat brain. Neurobiol Aging 36: 3269–3277, 2015. doi: 10.1016/j.neurobiolaging.2015.08.014.
169. Mitchell GF, van Buchem MA, Sigurdsson S, Gotal JD, Jonsdottir MK, Kjartansson Ó, Garcia M, Aspelund T, Harris TB, Gudnason V, Launer LJ. Arterial stiffness, pressure and flow pulsatility and brain structure and function: the Age, Gene/Environment Susceptibility--Reykjavik study. Brain 134: 3398–3407, 2011. doi: 10.1093/brain/awr253.
170. Modrick ML, Didion SP, Sigmund CD, Faraci FM. Role of oxidative stress and AT1 receptors in cerebral vascular dysfunction with aging. Am J Physiol Heart Circ Physiol 296: H1914–H1919, 2009. doi: 10.1152/ ajpheart.00300.2009.
171. Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, Toga AW, Jacobs RE, Liu CY, Amezcua L, Harrington MG, Chui HC, Law M, Zlokovic BV. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85: 296–302, 2015. doi: 10.1016/ j.neuron.2014.12.032.
172. Moss MB, Jonak E. Cerebrovascular disease and dementia: a primate model of hypertension and cognition. Alzheimers Dement 3, Suppl: S6–S15, 2007. doi: 10.1016/j.jalz.2007.01.002.
173. Mueller SM, Heistad DD. Effect of chronic hypertension on the bloodbrain barrier. Hypertension 2: 809–812, 1980. doi: 10.1161/01.HYP.2.6.809.
174. Mueller SM, Heistad DD, Marcus ML. Total and regional cerebral blood flow during hypotension, hypertension, and hypocapnia. Effect of sympathetic denervation in dogs. Circ Res 41: 350–356, 1977. doi: 10.1161/01.RES.41.3.350.
175. Narayanan K, Collins JJ, Hamner J, Mukai S, Lipsitz LA. Predicting cerebral blood flow response to orthostatic stress from resting dynamics: effects of healthy aging. Am J Physiol Regul Integr Comp Physiol 281: R716–R722, 2001.
176. Nelson JW, Young JM, Borkar RN, Woltjer RL, Quinn JF, Silbert LC, Grafe MR, Alkayed NJ. Role of soluble epoxide hydrolase in age-related vascular cognitive decline. Prostaglandins Other Lipid Mediat 113-115: 30–37, 2014. doi: 10.1016/j.prostaglandins.2014.09.003.
177. Nelson MT, Conway MA, Knot HJ, Brayden JE. Chloride channel blockers inhibit myogenic tone in rat cerebral arteries. J Physiol 502: 259–264, 1997. doi: 10.1111/j.1469-7793.1997.259bk.x.
178. Nevitt C, McKenzie G, Christian K, Austin J, Hencke S, Hoying J, LeBlanc A. Physiological levels of thrombospondin-1 decrease NOdependent vasodilation in coronary microvessels from aged rats. Am J Physiol Heart Circ Physiol 310: H1842–H1850, 2016. doi: 10.1152/ ajpheart.00086.2016.
179. New DI, Chesser AM, Thuraisingham RC, Yaqoob MM. Cerebral artery responses to pressure and flow in uremic hypertensive and spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 284: H1212–H1216, 2003. doi: 10.1152/ajpheart.00644.2002.
180. Nicolakakis N, Aboulkassim T, Ongali B, Lecrux C, Fernandes P, Rosa-Neto P, Tong XK, Hamel E. Complete rescue of cerebrovascular function in aged Alzheimer’s disease transgenic mice by antioxidants and pioglitazone, a peroxisome proliferator-activated receptor gamma agonist. J Neurosci 28: 9287–9296, 2008. doi: 10.1523/JNEUROSCI.3348-08.2008.
181. Nilius B, Watanabe H, Vriens J. The TRPV4 channel: structurefunction relationship and promiscuous gating behaviour. Pflugers Arch 446: 298–303, 2003. doi: 10.1007/s00424-003-1028-9.
182. O’Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy. Hypertension 46: 200–204, 2005. doi: 10.1161/01.HYP.0000168052.00426.65.
183. Oh-Park M, Holtzer R, Xue X, Verghese J. Conventional and robust quantitative gait norms in community-dwelling older adults. J Am Geriatr Soc 58: 1512–1518, 2010. doi: 10.1111/j.1532-5415.2010.02962.x.
184. Oomen CA, Farkas E, Roman V, van der Beek EM, Luiten PG, Meerlo P. Resveratrol preserves cerebrovascular density and cognitive function in aging mice. Front Aging Neurosci 1: 4, 2009. doi: 10.3389/ neuro.24.004.2009.
185. Osol G, Halpern W. Myogenic properties of cerebral blood vessels from normotensive and hypertensive rats. Am J Physiol Heart Circ Physiol 249: H914–H921, 1985.
186. Osol G, Laher I, Cipolla M. Protein kinase C modulates basal myogenic tone in resistance arteries from the cerebral circulation. Circ Res 68: 359–367, 1991. doi: 10.1161/01.RES.68.2.359.
187. Østergaard L, Dreier JP, Hadjikhani N, Jespersen SN, Dirnagl U, Dalkara T. Neurovascular coupling during cortical spreading depolarization and-depression. Stroke 46: 1392–1401, 2015. doi: 10.1161/ STROKEAHA.114.008077.
188. Østergaard L, Engedal TS, Moreton F, Hansen MB, Wardlaw JM, Dalkara T, Markus HS, Muir KW. Cerebral small vessel disease: capillary pathways to stroke and cognitive decline. J Cereb Blood Flow Metab 36: 302–325, 2016. doi: 10.1177/0271678X15606723.
189. Park L, Anrather J, Girouard H, Zhou P, Iadecola C. Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain. J Cereb Blood Flow Metab 27: 1908–1918, 2007. doi: 10.1038/sj.jcbfm.9600491.
190. Park L, Anrather J, Zhou P, Frys K, Pitstick R, Younkin S, Carlson GA, Iadecola C. NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide. J Neurosci 25: 1769–1777, 2005. doi: 10.1523/JNEUROSCI. 5207-04.2005.
191. Park L, Zhou P, Pitstick R, Capone C, Anrather J, Norris EH, Younkin L, Younkin S, Carlson G, McEwen BS, Iadecola C. Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc Natl Acad Sci USA 105: 1347–1352, 2008. doi: 10.1073/pnas.0711568105.
192. Park SY, Ives SJ, Gifford JR, Andtbacka RH, Hyngstrom JR, Reese V, Layec G, Bharath LP, Symons JD, Richardson RS. Impact of age on the vasodilatory function of human skeletal muscle feed arteries. Am J Physiol Heart Circ Physiol 310: H217–H225, 2016. doi: 10.1152/ ajpheart.00716.2015.
193. Paterno R, Faraci FM, Heistad DD. Age-related changes in release of endothelium-derived relaxing factor from the carotid artery. Stroke 25: 2457–2460; discussion 2461–2452, 1994.
194. Paternò R, Heistad DD, Faraci FM. Potassium channels modulate cerebral autoregulation during acute hypertension. Am J Physiol Heart Circ Physiol 278: H2003–H2007, 2000.
195. Paulson OB, Hasselbalch SG, Rostrup E, Knudsen GM, Pelligrino D. Cerebral blood flow response to functional activation. J Cereb Blood Flow Metab 30: 2–14, 2010. doi: 10.1038/jcbfm.2009.188.
196. Paulson OB, Newman EA. Does the release of potassium from astrocyte endfeet regulate cerebral blood flow? Science 237: 896–898, 1987. doi: 10.1126/science.3616619.
197. Paulson OB, Strandgaard S, Edvinsson L. Cerebral autoregulation. Cerebrovasc Brain Metab Rev 2: 161–192, 1990.
198. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8: 157–168, 2008. doi: 10.1016/ j.cmet.2008.06.011.
199. Petrovitch H, White LR, Izmirilian G, Ross GW, Havlik RJ, Markesbery W, Nelson J, Davis DG, Hardman J, Foley DJ, Launer LJ. Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Honolulu-Asia aging Study. Neurobiol Aging 21: 57–62, 2000. doi: 10.1016/S0197-4580 (00) 00106-8.
200. Phan TS, Li JK, Segers P, Chirinos JA. Misinterpretation of the determinants of elevated forward wave amplitude inflates the role of the proximal aorta. J Am Heart Assoc 5: e003069, 2016. doi: 10.1161/ JAHA.115.003069.
201. Pinter D, Enzinger C, Fazekas F. Cerebral small vessel disease, cognitive reserve and cognitive dysfunction. J Neurol 262: 2411–2419, 2015. doi: 10.1007/s00415-015-7776-6.
202. Poels MM, Ikram MA, van der Lugt A, Hofman A, Krestin GP, Breteler MM, Vernooij MW. Incidence of cerebral microbleeds in the general population: the Rotterdam Scan Study. Stroke 42: 656–661, 2011. doi: 10.1161/STROKEAHA.110.607184.
203. Porter JT, McCarthy KD. Hippocampal astrocytes in situ respond to glutamate released from synaptic terminals. J Neurosci 16: 5073–5081, 1996.
204. PROGRESS Collaborative Group. Randomised trial of a perindoprilbased blood-pressure-lowering regimen among 6, 105 individuals with previous stroke or transient ischaemic attack. Lancet 358: 1033–1041, 2001. doi: 10.1016/S0140-6736 (01) 06178-5.
205. Purkayastha S, Fadar O, Mehregan A, Salat DH, Moscufo N, Meier DS, Guttmann CR, Fisher ND, Lipsitz LA, Sorond FA. Impaired cerebrovascular hemodynamics are associated with cerebral white matter damage. J Cereb Blood Flow Metab 34: 228–234, 2014. doi: 10.1038/ jcbfm.2013.180.
206. Raju K, Doulias PT, Evans P, Krizman EN, Jackson JG, Horyn O, Daikhin Y, Nissim I, Yudkoff M, Nissim I, Sharp KA, Robinson MB, Ischiropoulos H. Regulation of brain glutamate metabolism by nitric oxide and S-nitrosylation. Sci Signal 8: ra68, 2015. doi: 10.1126/scisignal. aaa4312.
207. Reading SA, Brayden JE. Central role of TRPM4 channels in cerebral blood flow regulation. Stroke 38: 2322–2328, 2007. doi: 10.1161/ STROKEAHA.107.483404.
208. Reitz C, Tang MX, Manly J, Mayeux R, Luchsinger JA. Hypertension and the risk of mild cognitive impairment. Arch Neurol 64: 1734–1740, 2007. doi: 10.1001/archneur.64.12.1734.
209. Robertson AD, Edgell H, Hughson RL. Assessing cerebrovascular autoregulation from critical closing pressure and resistance area product during upright posture in aging and hypertension. Am J Physiol Heart Circ Physiol 307: H124–H133, 2014. doi: 10.1152/ajpheart.00086.2014.
210. Rombouts SA, Barkhof F, Veltman DJ, Machielsen WC, Witter MP, Bierlaagh MA, Lazeron RH, Valk J, Scheltens P. Functional MR imaging in Alzheimer’s disease during memory encoding. AJNR Am J Neuroradiol 21: 1869–1875, 2000.
211. Rosendorff C, Beeri MS, Silverman JM. Cardiovascular risk factors for Alzheimer’s disease. Am J Geriatr Cardiol 16: 143–149, 2007. doi: 10.1111/j.1076-7460.2007.06696.x.
212. Rosengarten B, Aldinger C, Spiller A, Kaps M. Neurovascular coupling remains unaffected during normal aging. J Neuroimaging 13: 43–47, 2003. doi: 10.1111/j.1552-6569.2003.tb00155.x.
213. Ross AJ, Gao Z, Pollock JP, Leuenberger UA, Sinoway LI, Muller MD. _-Adrenergic receptor blockade impairs coronary exercise hyperemia in young men but not older men. Am J Physiol Heart Circ Physiol 307: H1497–H1503, 2014. doi: 10.1152/ajpheart.00584.2014.
214. Sabayan B, Westendorp RG, Grond J, Stott DJ, Sattar N, van Osch MJ, van Buchem MA, de Craen AJ. Markers of endothelial dysfunction and cerebral blood flow in older adults. Neurobiol Aging 35: 373–377, 2014. doi: 10.1016/j.neurobiolaging.2013.08.020.
215. Sadoshima S, Fujishima M, Yoshida F, Ibayashi S, Shiokawa O, Omae T. Cerebral autoregulation in young spontaneously hypertensive rats. Effect of sympathetic denervation. Hypertension 7: 392–397, 1985.
216. Sadoshima S, Yoshida F, Ibayashi S, Shiokawa O, Fujishima M. Upper limit of cerebral autoregulation during development of hypertension in spontaneously hypertensive rats-effect of sympathetic denervation. Stroke 16: 477–481, 1985. doi: 10.1161/01.STR.16.3.477.
217. Sagare AP, Bell RD, Zhao Z, Ma Q, Winkler EA, Ramanathan A, Zlokovic BV. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat Commun 4: 2932, 2013. doi: 10.1038/ncomms3932.
218. Sakowitz OW, Santos E, Nagel A, Krajewski KL, Hertle DN, Vajkoczy P, Dreier JP, Unterberg AW, Sarrafzadeh AS. Clusters of spreading depolarizations are associated with disturbed cerebral metabolism in patients with aneurysmal subarachnoid hemorrhage. Stroke 44: 220–223, 2013. doi: 10.1161/STROKEAHA.112.672352.
219. Sanders M, Meel van den Abeelen A, Slump C, Lagro J, Claassen J. Reduced cerebral autoregulation as the genesis of symptoms in orthostatic intolerance in elderly. FASEB J 28, Suppl: 1069.3, 2014.
220. Sarrafzadeh A, Santos E, Wiesenthal D, Martus P, Vajkoczy P, Oehmchen M, Unterberg A, Dreier JP, Sakowitz O. Cerebral glucose and spreading depolarization in patients with aneurysmal subarachnoid hemorrhage. Acta Neurochir Suppl 115: 143–147, 2013.
221. Schaafsma A, Veen L, Vos JP. Three cases of hyperperfusion syndrome identified by daily transcranial Doppler investigation after carotid surgery. Eur J Vasc Endovasc Surg 23: 17–22, 2002. doi: 10.1053/ ejvs.2001.1545.
222. Schretzenmayr A. Über Kreislaufregulatorische Vorgange an den grossen Arterien bei der Muskelarbeit. Pflugers Arch 232: 743–748, 1933. doi: 10.1007/BF01754829.
223. Schubert R, Lidington D, Bolz SS. The emerging role of Ca2+ sensitivity regulation in promoting myogenic vasoconstriction. Cardiovasc Res 77: 8–18, 2008.
224. Schubert R, Mulvany MJ. The myogenic response: established facts and attractive hypotheses. Clin Sci (Lond) 96: 313–326, 1999. doi: 10.1042/cs0960313.
225. Serrador JM, Sorond FA, Vyas M, Gagnon M, Iloputaife ID, Lipsitz LA. Cerebral pressure-flow relations in hypertensive elderly humans: transfer gain in different frequency domains. J Appl Physiol (1985) 98: 151–159, 2005. doi: 10.1152/japplphysiol.00471.2004.
226. Sinclair LI, Tayler HM, Love S. Synaptic protein levels altered in vascular dementia. Neuropathol Appl Neurobiol 41: 533–543, 2015. doi: 10.1111/nan.12215.
227. Skoog I, Gustafson D. Update on hypertension and Alzheimer’s disease. Neurol Res 28: 605–611, 2006. doi: 10.1179/016164106X130506.
228. Smeda JS, VanVliet BN, King SR. Stroke-prone spontaneously hypertensive rats lose their ability to auto-regulate cerebral blood flow prior to stroke. J Hypertens 17: 1697–1705, 1999. doi: 10.1097/00004872-199917120-00006.
229. 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. Vascular contributions to cognitive impairment and dementia including Alzheimer’s disease. Alzheimers Dement 11: 710–717, 2015. doi: 10.1016/ j.jalz.2014.10.008.
230. Solano Fonseca R, Mahesula S, Apple DM, Raghunathan R, Dugan A, Cardona A, O’Connor J, Kokovay E. Neurogenic niche microglia undergo positional remodeling and progressive activation contributing to age-associated reductions in neurogenesis. Stem Cells Dev 25: 542–555, 2016. doi: 10.1089/scd.2015.0319.
231. Solfrizzi V, Panza F, Colacicco AM, D’Introno A, Capurso C, Torres F, Grigoletto F, Maggi S, Del Parigi A, Reiman EM, Caselli RJ, Scafato E, Farchi G, Capurso A; Italian Longitudinal Study on Aging Working Group. Vascular risk factors, incidence of MCI, and rates of progression to dementia. Neurology 63: 1882–1891, 2004. doi: 10.1212/01.WNL.0000144281.38555.E3.
232. Sonntag WE, Carter CS, Ikeno Y, Ekenstedt K, Carlson CS, Loeser RF, Chakrabarty S, Lee S, Bennett C, Ingram R, Moore T, Ramsey M. Adult-onset growth hormone and insulin-like growth factor I deficiency reduces neoplastic disease, modifies age-related pathology, and increases life span. Endocrinology 146: 2920–2932, 2005. doi: 10.1210/ en.2005-0058.
233. Sonntag WE, Deak F, Ashpole N, Toth P, Csiszar A, Freeman W, Ungvari Z. Insulin-like growth factor-1 in CNS and cerebrovascular aging. Front Aging Neurosci 5: 27, 2013. doi: 10.3389/fnagi.2013.00027.
234. Sorond FA, Galica A, Serrador JM, Kiely DK, Iloputaife I, Cupples LA, Lipsitz LA. Cerebrovascular hemodynamics, gait, and falls in an elderly population: MOBILIZE Boston Study. Neurology 74: 1627-1633, 2010. doi: 10.1212/WNL.0b013e3181df0982.
235. Sorond FA, Hurwitz S, Salat DH, Greve DN, Fisher ND. Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people. Neurology 81: 904–909, 2013. doi: 10.1212/WNL.0b013e3182a351aa.
236. Sorond FA, Khavari R, Serrador JM, Lipsitz LA. Regional cerebral autoregulation during orthostatic stress: age-related differences. J Gerontol A Biol Sci Med Sci 60: 1484–1487, 2005. doi: 10.1093/gerona/ 60.11.1484.
237. Sorond FA, Kiely DK, Galica A, Moscufo N, Serrador JM, Iloputaife I, Egorova S, Dell’Oglio E, Meier DS, Newton E, Milberg WP, Guttmann CR, Lipsitz LA. Neurovascular coupling is impaired in slow walkers: the MOBILIZE Boston Study. Ann Neurol 70: 213–220, 2011. doi: 10.1002/ana.22433.
238. Sorond FA, Schnyer DM, Serrador JM, Milberg WP, Lipsitz LA. Cerebral blood flow regulation during cognitive tasks: effects of healthy aging. Cortex 44: 179–184, 2008. doi: 10.1016/j.cortex.2006.01.003.
239. Sörös P, Whitehead S, Spence JD, Hachinski V. Antihypertensive treatment can prevent stroke and cognitive decline. Nat Rev Neurol 9: 174–178, 2013. doi: 10.1038/nrneurol.2012.255.
240. Sparks DL, Scheff SW, Liu H, Landers TM, Coyne CM, Hunsaker JC III. Increased incidence of neurofibrillary tangles (NFT) in nondemented individuals with hypertension. J Neurol Sci 131: 162–169, 1995. doi: 10.1016/0022-510X (95) 00105-B.
241. Springo Z, Tarantini S, Toth P, Tucsek Z, Koller A, Sonntag WE, Csiszar A, Ungvari Z. Aging exacerbates pressure-induced mitochondrial oxidative stress in mouse cerebral arteries. J Gerontol A Biol Sci Med Sci 70: 1355–1359, 2015. doi: 10.1093/gerona/glu244.
242. Springo Z, Toth P, Tarantini S, Ashpole NM, Tucsek Z, Sonntag WE, Csiszar A, Koller A, Ungvari ZI. Aging impairs myogenic adaptation to pulsatile pressure in mouse cerebral arteries. J Cereb Blood Flow Metab 35: 527–530, 2015. doi: 10.1038/jcbfm.2014.256.
243. Stefanova I, Stephan T, Becker-Bense S, Dera T, Brandt T, Dieterich M. Age-related changes of blood-oxygen-level-dependent signal dynamics during optokinetic stimulation. Neurobiol Aging 34: 2277–2286, 2013. doi: 10.1016/j.neurobiolaging.2013.03.031.
244. Stobart JL, Lu L, Anderson HD, Mori H, Anderson CM. Astrocyteinduced cortical vasodilation is mediated by D-serine and endothelial nitric oxide synthase. Proc Natl Acad Sci USA 110: 3149–3154, 2013. doi: 10.1073/pnas.1215929110.
245. Strandgaard S. Autoregulation of cerebral blood flow in hypertensive patients. The modifying influence of prolonged antihypertensive treatment on the tolerance to acute, drug-induced hypotension. Circulation 53: 720–727, 1976. doi: 10.1161/01.CIR.53.4.720.
246. Strandgaard S, Jones JV, MacKenzie ET, Harper AM. Upper limit of cerebral blood flow autoregulation in experimental renovascular hypertension in the baboon. Circ Res 37: 164–167, 1975. doi: 10.1161/ 01.RES.37.2.164.
247. Strandgaard S, Olesen J, Skinhoj E, Lassen NA. Autoregulation of brain circulation in severe arterial hypertension. BMJ 1: 507–510, 1973. doi: 10.1136/bmj.1.5852.507.
248. Strandgaard S, Paulson OB. Cerebral blood flow and its pathophysiology in hypertension. Am J Hypertens 2: 486–492, 1989.
249. Stromberg DD, Fox JR. Pressures in the pial arterial microcirculation of the cat during changes in systemic arterial blood pressure. Circ Res 31: 229–239, 1972. doi: 10.1161/01.RES.31.2.229.
250. Szabo K, Rosengarten B, Juhasz T, Lako E, Csiba L, Olah L. Effect of non-steroid anti-inflammatory drugs on neurovascular coupling in humans. J Neurol Sci 336: 227–231, 2014. doi: 10.1016/j.jns.2013. 10.048.
251. 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. Pharmacologically-induced neurovascular uncoupling is associated with cognitive impairment in mice. J Cereb Blood Flow Metab 35: 1871–1881, 2015. doi: 10.1038/jcbfm.2015.162.
252. Tarantini S, Toth P, Sosnowska D, Gautam T, Tucsek Z, Koller A, Sonntag WE, Csiszar A, Ungvari Z. Aging exacerbates hypertensioninduced intracerebral microbleeds in mice. Aging Cell 28, Suppl: 1079.1076, 2014.
253. Tarantini S, Tucsek Z, Valcarcel-Ares MN, Toth P, Gautam T, Giles CB, Ballabh P, Wei JY, Wren JD, Ashpole NM, Sonntag WE, Ungvari Z, Csiszar A. Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging. Age (Dordr) 38: 273–289, 2016. doi: 10.1007/s11357-016-9931-0.
254. Tarumi T, Ayaz Khan M, Liu J, Tseng BY, Parker R, Riley J, Tinajero C, Zhang R. Cerebral hemodynamics in normal aging: central artery stiffness, wave reflection, and pressure pulsatility. J Cereb Blood Flow Metab 34: 971–978, 2014. doi: 10.1038/jcbfm.2014.44.
255. Tiecks FP, Lam AM, Matta BF, Strebel S, Douville C, Newell DW. Effects of the valsalva maneuver on cerebral circulation in healthy adults. A transcranial Doppler study. Stroke 26: 1386–1392, 1995. doi: 10.1161/ 01.STR.26.8.1386.
256. Tomoto T, Sugawara J, Nogami Y, Aonuma K, Maeda S. The influence of central arterial compliance on cerebrovascular hemodynamics: insights from endurance training intervention. J Appl Physiol (1985) 119: 445–451, 2015. doi: 10.1152/japplphysiol.00129.2015.
257. Tong XK, Lecrux C, Rosa-Neto P, Hamel E. Age-dependent rescue by simvastatin of Alzheimer’s disease cerebrovascular and memory deficits. J Neurosci 32: 4705–4715, 2012. doi: 10.1523/JNEUROSCI.0169-12.2012.
258. Topcuoglu MA, Aydin H, Saka E. 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: 17–22, 2009. doi: 10.1016/j.neulet.2009.01.030.
259. Toth P, Csiszar A, Tucsek Z, Sosnowska D, Gautam T, Koller A, Laniado Schwartzman M, Sonntag WE, Ungvari ZI. Role of 20-HETE, TRP channels, and BKCa in dysregulation of pressure-induced Ca2+ signaling and myogenic constriction of cerebral arteries in aged hypertensive mice. Am J Physiol Heart Circ Physiol 305: H1698-H1708, 2013. doi: 10.1152/ajpheart.00377.2013.
260. Toth P, Koller A, Pusch G, Bosnyak E, Szapary L, Komoly S, Marko L, Nagy J, Wittmann I. Microalbuminuria, indicated by total versus immunoreactive urinary albumins, in acute ischemic stroke patients. J Stroke Cerebrovasc Dis 20: 510–516, 2011. doi: 10.1016/j.jstrokecerebrovasdis. 2010.03.002.
261. Toth P, Rozsa B, Springo Z, Doczi T, Koller A. Isolated human and rat cerebral arteries constrict to increases in flow: role of 20-HETE and TP receptors. J Cereb Blood Flow Metab 31: 2096–2105, 2011. doi: 10.1038/jcbfm.2011.74.
262. Toth P, Tarantini S, Ashpole NM, Tucsek Z, Milne GL, Valcarcel-Ares NM, Menyhart A, Farkas E, Sonntag WE, Csiszar A, Ungvari Z. IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging. Aging Cell 14: 1034–1044, 2015. doi: 10.1111/acel.12372.
263. Toth P, Tarantini S, Davila A, Valcarcel-Ares MN, Tucsek Z, Varamini B, Ballabh P, Sonntag WE, Baur JA, Csiszar A, Ungvari Z. 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: H1837–H1845, 2015. doi: 10.1152/ajpheart.00463.2015.
264. Toth P, Tarantini S, Springo Z, Tucsek Z, Gautam T, Giles CB, Wren JD, Koller A, Sonntag WE, Csiszar A, Ungvari Z. Aging exacerbates hypertension-induced cerebral microhemorrhages in mice: role of resveratrol treatment in vasoprotection. Aging Cell 14: 400–408, 2015. doi: 10.1111/acel.12315.
265. Toth P, Tarantini S, Tucsek Z, Ashpole NM, Sosnowska D, Gautam T, Ballabh P, Koller A, Sonntag WE, Csiszar A, Ungvari Z. Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicrovascular endothelial function and downregulation of NADPH oxidase. Am J Physiol Heart Circ Physiol 306: H299–H308, 2014. doi: 10.1152/ajpheart.00744.2013.
266. Toth P, Tucsek Z, Sosnowska D, Gautam T, Mitschelen M, Tarantini S, Deak F, Koller A, Sonntag WE, Csiszar A, Ungvari Z. Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. J Cereb Blood Flow Metab 33: 1732–1742, 2013. doi: 10.1038/jcbfm.2013.143.
267. Toth P, Tucsek Z, Tarantini S, Sosnowska D, Gautam T, Mitschelen M, Koller A, Sonntag WE, Csiszar A, Ungvari Z. IGF-1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice. J Cereb Blood Flow Metab 34: 1887–1897, 2014. doi: 10.1038/jcbfm.2014.156.
268. Toyoda K, Fujii K, Takata Y, Ibayashi S, Fujikawa M, Fujishima M. Effect of aging on regulation of brain stem circulation during hypotension. J Cereb Blood Flow Metab 17: 680–685, 1997. doi: 10.1097/ 00004647-199706000-00009.
269. Trenkwalder P. The Study on COgnition and Prognosis in the Elderly (SCOPE)-recent analyses. J Hypertens Suppl 24, Suppl 1: S107–S114, 2006. doi: 10.1097/01.hjh.0000220415.99610.22.
270. Tsao CW, Seshadri S, Beiser AS, Westwood AJ, Decarli C, Au R, Himali JJ, Hamburg NM, Vita JA, Levy D, Larson MG, Benjamin EJ, Wolf PA, Vasan RS, Mitchell GF. Relations of arterial stiffness and endothelial function to brain aging in the community. Neurology 81: 984–991, 2013. doi: 10.1212/WNL.0b013e3182a43e1c.
271. Tucsek Z, Toth P, Sosnowska D, Gautam T, Mitschelen M, Koller A, Szalai G, Sonntag WE, Ungvari Z, Csiszar A. 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: 1212–1226, 2014. doi: 10.1093/gerona/glt177.
272. 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. Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice. J Gerontol A Biol Sci Med Sci 69: 1339–1352, 2014. doi: 10.1093/gerona/ glu080.
273. Ungvari Z, Bagi Z, Feher A, Recchia FA, Sonntag WE, Pearson K, de Cabo R, Csiszar A. Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am J Physiol Heart Circ Physiol 299: H18–H24, 2010. doi: 10.1152/ajpheart. 00260.2010.
274. Ungvari Z, Bailey-Downs L, Gautam T, Sosnowska D, Wang M, Monticone RE, Telljohann R, Pinto JT, de Cabo R, Sonntag WE, Lakatta EG, Csiszar A. Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-kappaB activation in the nonhuman primate Macaca mulatta. J Gerontol A Biol Sci Med Sci 66: 866–875, 2011. doi: 10.1093/ gerona/glr092.
275. Ungvari Z, Bailey-Downs L, Sosnowska D, Gautam T, Koncz P, Losonczy G, Ballabh P, de Cabo R, Sonntag WE, Csiszar A. Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response. Am J Physiol Heart Circ Physiol 301: H363–H372, 2011. doi: 10.1152/ajpheart.01134.2010.
276. Ungvari Z, Csiszar A. The emerging role of IGF-1 deficiency in cardiovascular aging: recent advances. J Gerontol A Biol Sci Med Sci 67: 599–610, 2012. doi: 10.1093/gerona/gls072.
277. Ungvari Z, Labinskyy N, Mukhopadhyay P, Pinto JT, Bagi Z, Ballabh P, Zhang C, Pacher P, Csiszar A. Resveratrol attenuates mitochondrial oxidative stress in coronary arterial endothelial cells. Am J Physiol Heart Circ Physiol 297: H1876–H1881, 2009. doi: 10.1152/ ajpheart.00375.2009.
278. Ungvari Z, Orosz Z, Labinskyy N, Rivera A, Xiangmin Z, Smith K, Csiszar A. Increased mitochondrial H2O2 production promotes endothe-lial NF-B activation in aged rat arteries. Am J Physiol Heart Circ Physiol 293: H37–H47, 2007. doi: 10.1152/ajpheart.01346.2006.
279. Ungvari Z, Orosz Z, Rivera A, Labinskyy N, Xiangmin Z, Olson S, Podlutsky A, Csiszar A. Resveratrol increases vascular oxidative stress resistance. Am J Physiol Heart Circ Physiol 292: H2417–H2424, 2007. doi: 10.1152/ajpheart.01258.2006.
280. Ungvari Z, Tucsek Z, Sosnowska D, Toth P, Gautam T, Podlutsky A, Csiszar A, Losonczy G, Valcarcel-Ares MN, Sonntag WE, Csiszar A. Aging-induced dysregulation of dicer1-dependent microRNA expression impairs angiogenic capacity of rat cerebromicrovascular endothelial cells. J Gerontol A Biol Sci Med Sci 68: 877–891, 2013. doi: 10.1093/ gerona/gls242.
281. Valcarcel-Ares MN, Gautam T, Warrington JP, Bailey-Downs L, Sosnowska D, de Cabo R, Losonczy G, Sonntag WE, Ungvari Z, Csiszar A. Disruption of Nrf2 signaling impairs angiogenic capacity of endothelial cells: implications for microvascular aging. J Gerontol A Biol Sci Med Sci 67: 821–829, 2012. doi: 10.1093/gerona/glr229.
282. Varga DP, Puskás T, Menyhárt Á, Hertelendy P, Zölei-Szénási D, Tóth R, Ivánkovits-Kiss O, Bari F, Farkas E. Contribution of prostanoid signaling to the evolution of spreading depolarization and the associated cerebral blood flow response. Sci Rep 6: 31402, 2016. doi: 10.1038/srep31402.
283. Vates GE, Takano T, Zlokovic B, Nedergaard M. Pericyte constriction after stroke: the jury is still out. Nat Med 16: 959, 2010. doi: 10.1038/ nm0910-959.
284. Vavrinec P, Henning RH, Goris M, Landheer SW, Buikema H, van Dokkum RP. Renal myogenic constriction protects the kidney from age-related hypertensive renal damage in the Fawn-Hooded rat. J Hypertens 31: 1637–1645, 2013. doi: 10.1097/HJH.0b013e328361d506.
285. Verghese J, Ambrose AF, Lipton RB, Wang C. Neurological gait abnormalities and risk of falls in older adults. J Neurol 257: 392–398, 2010. doi: 10.1007/s00415-009-5332-y.
286. Verghese J, Holtzer R, Lipton RB, Wang C. Quantitative gait markers and incident fall risk in older adults. J Gerontol A Biol Sci Med Sci 64: 896–901, 2009. doi: 10.1093/gerona/glp033.
287. Verghese J, LeValley A, Hall CB, Katz MJ, Ambrose AF, Lipton RB. Epidemiology of gait disorders in community-residing older adults. J Am Geriatr Soc 54: 255–261, 2006. doi: 10.1111/j.1532-5415.2005.00580.x.
288. Vinall PE, Simeone FA. Cerebral autoregulation: an in vitro study. Stroke 12: 640–642, 1981. doi: 10.1161/01.STR.12.5.640.
289. von Bornstädt D, Houben T, Seidel JL, Zheng Y, Dilekoz E, Qin T, Sandow N, Kura S, Eikermann-Haerter K, Endres M, Boas DA, Moskowitz MA, Lo EH, Dreier JP, Woitzik J, Sakadžic S, Ayata C. Supply-demand mismatch transients in susceptible peri-infarct hot zones explain the origins of spreading injury depolarizations. Neuron 85: 1117–1131, 2015. doi: 10.1016/j.neuron.2015.02.007.
290. Wagerle LC, Busija DW. Effect of thromboxane A2/endoperoxide antagonist SQ29548 on the contractile response to acetylcholine in newborn piglet cerebral arteries. Circ Res 66: 824–831, 1990. doi: 10.1161/01.RES.66.3.824.
291. Wang L, Du Y, Wang K, Xu G, Luo S, He G. Chronic cerebral hypoperfusion induces memory deficits and facilitates A_ generation in C57BL/6J mice. Exp Neurol 283, Pt A: 353–364, 2016. doi: 10.1016/ j.expneurol.2016.07.006.
292. Wang N, Allali G, Kesavadas C, Noone ML, Pradeep VG, Blumen HM, Verghese J. Cerebral small vessel disease and motoric cognitive risk syndrome: results from the Kerala-Einstein Study. J Alzheimers Dis 50: 699–707, 2015. doi: 10.3233/JAD-150523.
293. Webb AJ, Simoni M, Mazzucco S, Kuker W, Schulz U, Rothwell PM. Increased cerebral arterial pulsatility in patients with leukoaraiosis: arterial stiffness enhances transmission of aortic pulsatility. Stroke 43: 2631–2636, 2012. doi: 10.1161/STROKEAHA.112.655837.
294. Welsh DG, Morielli AD, Nelson MT, Brayden JE. Transient receptor potential channels regulate myogenic tone of resistance arteries. Circ Res 90: 248–250, 2002. doi: 10.1161/hh0302.105662.
295. Werber AH, Heistad DD. Effects of chronic hypertension and sympathetic nerves on the cerebral microvasculature of stroke-prone spontaneously hypertensive rats. Circ Res 55: 286–294, 1984. doi: 10.1161/ 01.RES.55.3.286.
296. Winkler EA, Bell RD, Zlokovic BV. Central nervous system pericytes in health and disease. Nat Neurosci 14: 1398–1405, 2011. doi: 10.1038/ nn.2946.
297. Winkler EA, Bell RD, Zlokovic BV. Pericyte-specific expression of PDGF beta receptor in mouse models with normal and deficient PDGF beta receptor signaling. Mol Neurodegener 5: 32, 2010. doi: 10.1186/ 1750-1326-5-32.
298. Winkler MK, Dengler N, Hecht N, Hartings JA, Kang EJ, Major S, Martus P, Vajkoczy P, Woitzik J, Dreier JP. Oxygen availability and spreading depolarizations provide complementary prognostic information in neuromonitoring of aneurysmal subarachnoid hemorrhage patients. J Cereb Blood Flow Metab pii: 0271678X16641424, 2016. doi: 10.1177/0271678X16641424.
299. Witthoft A, Filosa JA, Karniadakis GE. Potassium buffering in the neurovascular unit: models and sensitivity analysis. Biophys J 105: 2046–2054, 2013. doi: 10.1016/j.bpj.2013.09.012.
300. Woitzik J, Hecht N, Pinczolits A, Sandow N, Major S, Winkler MK, Weber-Carstens S, Dohmen C, Graf R, Strong AJ, Dreier JP, Vajkoczy P; COSBID Study Group. Propagation of cortical spreading depolarization in the human cortex after malignant stroke. Neurology 80: 1095–1102, 2013. doi: 10.1212/WNL.0b013e3182886932.
301. Wollner L, McCarthy ST, Soper ND, Macy DJ. Failure of cerebral autoregulation as a cause of brain dysfunction in the elderly. BMJ 1: 1117–1118, 1979. doi: 10.1136/bmj.1.6171.1117.
302. Yam AT, Lang EW, Lagopoulos J, Yip K, Griffith J, Mudaliar Y, Dorsch NW. Cerebral autoregulation and ageing. J Clin Neurosci 12: 643–646, 2005. doi: 10.1016/j.jocn.2004.08.017.
303. Yu W, Juang S, Lee J, Liu T, Cheng J. Decrease of neuronal nitric oxide synthase in the cerebellum of aged rats. Neurosci Lett 291: 37–40, 2000. doi: 10.1016/S0304-3940 (00) 01377-X.
304. Zaletel M, Strucl M, Pretnar-Oblak J, Zvan B. Age-related changes in the relationship between visual evoked potentials and visually evoked cerebral blood flow velocity response. Funct Neurol 20: 115–120, 2005.
305. Zhang F, Xu S, Iadecola C. Role of nitric oxide and acetylcholine in neocortical hyperemia elicited by basal forebrain stimulation: evidence for an involvement of endothelial nitric oxide. Neuroscience 69: 1195-1204, 1995. doi: 10.1016/0306-4522 (95) 00302-Y.
306. Zhao YN, Li WF, Li F, Zhang Z, Dai YD, Xu AL, Qi C, Gao JM, Gao J. Resveratrol improves learning and memory in normally aged mice through microRNA-CREB pathway. Biochem Biophys Res Commun 435: 597–602, 2013. doi: 10.1016/j.bbrc.2013.05.025.
307. Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57: 178–201, 2008. doi: 10.1016/j.neuron. 2008.01.003.
308. Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci 12: 723–738, 2011. doi: 10.1038/nrn3114.
309. Zou AP, Fleming JT, Falck JR, Jacobs ER, Gebremedhin D, Harder DR, Roman RJ. 20-HETE is an endogenous inhibitor of the largeconductance Ca2+-activated K_ channel in renal arterioles. Am J Physiol Regul Integr Comp Physiol 270: R228–R237, 1996.