, Volume 40, Issue 5–6, pp 485–496 | Cite as

Repeated Valsalva maneuvers promote symptomatic manifestations of cerebral microhemorrhages: implications for the pathogenesis of vascular cognitive impairment in older adults

  • Zoltan Ungvari
  • Andriy Yabluchanskiy
  • Stefano Tarantini
  • Peter Toth
  • Angelia C. Kirkpatrick
  • Anna Csiszar
  • Calin I. ProdanEmail author
Original Article


Multifocal cerebral microhemorrhages (CMHs, also known as “cerebral microbleeds”), which are associated with rupture of small intracerebral vessels, have been recognized as an important cause for cognitive decline in older adults. Although recent studies demonstrate that CMHs are highly prevalent in patients 65 and older, many aspects of the pathogenesis and clinical significance of CMHs remain obscure. In this longitudinal observational study, a case of a 77-year-old man with multifocal CMHs is described, in whom the rupture of intracerebral vessels could be linked to repeatedly performing extended Valsalva maneuvers. This patient was initially seen with acute aphasia after performing a prolonged Valsalva maneuver during underwater swimming. T2-weighted magnetic resonance imaging revealed a left acute frontal intracerebral hemorrhage (ICH) with multiple CMHs. The aphasia was resolved and no cognitive impairment was present. Two years later, he developed unsteadiness and confusion after performing two prolonged Valsalva maneuvers during underwater swimming separated by about 12 days. Repeat brain imaging revealed an acute right and a subacute left ICH, with a marked interval increase in the number of CMHs. The patient also exhibited manifest memory loss after the second admission and was diagnosed with dementia. These observations suggest that prolonged Valsalva maneuver is potentially a common precipitating cause of both CMHs and symptomatic ICHs. The Valsalva maneuver both increases the systolic arterial pressure and gives rise to a venous pressure wave transmitted to the brain in the absence of the competent antireflux jugular vein valves. This pressure increase is superimposed on existing hypertension and/or increases in blood pressure due to exercise and increased venous return due to immersion of the body in water. We advocate that further studies are needed to distinguish between CMHs with arterial and venous origins and their potential to lead to ICH induced by Valsalva maneuver as well as to determine whether these lesions have a predilection for a particular location.


Vascular contributors to cognitive impairment and dementia VCID Vascular cognitive impairment VCI Vascular aging Cerebrovascular Cerebromicrovascular Stroke Transient ischemic attack 


Funding information

This work was supported by grants from the American Heart Association (ST); the Oklahoma Center for the Advancement of Science and Technology (to AC, AY, and ZU); the National Center for Complementary and Alternative Medicine (R01-AT006526 to ZU); the National Institute on Aging (R01-AG055395, R01-AG047879, and R01-AG038747); the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS100782 and R01-NS056218); a Pilot Grant from the Stephenson Cancer Center funded by the National Cancer Institute Cancer Center Support Grant P30CA225520 awarded to the University of Oklahoma Stephenson Cancer Center; 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, and CP); the European Union-funded grants EFOP-3.6.1-16-2016-00008, 20765-3/2018/FEKUTSTRAT, EFOP-3.6.2.-16-2017-00008, GINOP-2.3.2-15-2016-00048, and GINOP-2.3.3-15-2016-00032; the National Research, Development and Innovation Office (NKFI-FK123798); and the Hungarian Academy of Sciences (Bolyai Research Scholarship BO/00634/15 to PT). The authors acknowledge the support from the NIA-funded Geroscience Training Program in Oklahoma (T32AG052363).

Compliance with ethical standards


The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.


  1. Aiello AE, Chiu YL, Frasca D (2017) How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms? Geroscience. 39:261–271CrossRefGoogle Scholar
  2. Al-Mujaini AS, Montana CC (2008) Valsalva retinopathy in pregnancy: a case report. J Med Case Rep 2:101CrossRefGoogle Scholar
  3. An JY, Quarles EK, Mekvanich S, Kang A, Liu A, Santos D, Miller RA, Rabinovitch PS, Cox TC, Kaeberlein M (2017) Rapamycin treatment attenuates age-associated periodontitis in mice. Geroscience 39:457–463CrossRefGoogle Scholar
  4. Ashpole NM, Logan S, Yabluchanskiy A, Mitschelen MC, Yan H, Farley JA, Hodges EL, Ungvari Z, Csiszar A, Chen S, Georgescu C, Hubbard GB, Ikeno Y, Sonntag WE (2017) IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan. Geroscience. 39:129–145CrossRefGoogle Scholar
  5. Benedictus MR, Goos JD, Binnewijzend MA, Muller M, Barkhof F, Scheltens P, Prins ND, van der Flier WM (2013) Specific risk factors for microbleeds and white matter hyperintensities in Alzheimer’s disease. Neurobiol Aging 34:2488–2494CrossRefGoogle Scholar
  6. Bennis MT, Schneider A, Victoria B, Do A, Wiesenborn DS, Spinel L, Gesing A, Kopchick JJ, Siddiqi SA, Masternak MM (2017) The role of transplanted visceral fat from the long-lived growth hormone receptor knockout mice on insulin signaling. Geroscience. 39:51–59CrossRefGoogle Scholar
  7. Biffi A, Greenberg SM (2011) Cerebral amyloid angiopathy: a systematic review. J Clin Neurol 7:1–9CrossRefGoogle Scholar
  8. Castillo-Carranza DL, Nilson AN, Van Skike CE, Jahrling JB, Patel K, Garach P, Gerson JE, Sengupta U, Abisambra J, Nelson P, Troncoso J, Ungvari Z, Galvan V, Kayed R (2017) Cerebral microvascular accumulation of tau oligomers in Alzheimer’s disease and related tauopathies. Aging Dis 8:257–266CrossRefGoogle Scholar
  9. Caunca MR, Del Brutto V, Gardener H, Shah N, Dequatre-Ponchelle N, Cheung YK, Elkind MS, Brown TR, Cordonnier C, Sacco RL, Wright CB (2016) Cerebral microbleeds, vascular risk factors, and magnetic resonance imaging markers: the northern Manhattan study. J Am Heart Assoc 5Google Scholar
  10. Chai C, Wang Z, Fan L, Zhang M, Chu Z, Zuo C, Liu L, Mark Haacke E, Guo W, Shen W, Xia S (2016) Increased number and distribution of cerebral microbleeds is a risk factor for cognitive dysfunction in hemodialysis patients: a longitudinal study. Medicine (Baltimore) 95:e2974CrossRefGoogle Scholar
  11. Chapman-Davies A, Lazarevic A (2002) Valsalva maculopathy. Clin Exp Optom 85:42–45CrossRefGoogle Scholar
  12. Chung CP, Beggs C, Wang PN, Bergsland N, Shepherd S, Cheng CY, Ramasamy DP, Dwyer MG, Hu HH, Zivadinov R (2014) Jugular venous reflux and white matter abnormalities in Alzheimer’s disease: a pilot study. J Alzheimers Dis 39:601–609CrossRefGoogle Scholar
  13. Cordonnier C, Al-Shahi Salman R, Wardlaw J (2007) Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. Brain 130:1988–2003CrossRefGoogle Scholar
  14. Csiszar A, Tarantini S, Fulop GA, Kiss T, Valcarcel-Ares MN, Galvan V, Ungvari Z, Yabluchanskiy A (2017) Hypertension impairs neurovascular coupling and promotes microvascular injury: role in exacerbation of Alzheimer’s disease. Geroscience. 39:359–372CrossRefGoogle Scholar
  15. Deepa SS, Bhaskaran S, Espinoza S, Brooks SV, McArdle A, Jackson MJ, Van Remmen H, Richardson A (2017) A new mouse model of frailty: the Cu/Zn superoxide dismutase knockout mouse. Geroscience. 39:187–198CrossRefGoogle Scholar
  16. Diaz-Otero JM, Garver H, Fink GD, Jackson WF, Dorrance AM (2016) 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–H375CrossRefGoogle Scholar
  17. Fan YH, Zhang L, Lam WW, Mok VC, Wong KS (2003) Cerebral microbleeds as a risk factor for subsequent intracerebral hemorrhages among patients with acute ischemic stroke. Stroke 34:2459–2462CrossRefGoogle Scholar
  18. Fang Y, McFadden S, Darcy J, Hill CM, Huber JA, Verhulst S, Kopchick JJ, Miller RA, Sun LY, Bartke A (2017) Differential effects of early-life nutrient restriction in long-lived GHR-KO and normal mice. Geroscience. 39:347–356CrossRefGoogle Scholar
  19. Fisher J, Vaghaiwalla F, Tsitlik J, Levin H, Brinker J, Weisfeldt M, Yin F (1982) Determinants and clinical significance of jugular venous valve competence. Circulation 65:188–196CrossRefGoogle Scholar
  20. Fisher M, Vasilevko V, Passos GF, Ventura C, Quiring D, Cribbs DH (2011) Therapeutic modulation of cerebral microhemorrhage in a mouse model of cerebral amyloid angiopathy. Stroke 42:3300–3303CrossRefGoogle Scholar
  21. Goos JD, Kester MI, Barkhof F, Klein M, Blankenstein MA, Scheltens P, van der Flier WM (2009) Patients with Alzheimer disease with multiple microbleeds: relation with cerebrospinal fluid biomarkers and cognition. Stroke 40:3455–3460CrossRefGoogle Scholar
  22. 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 (2011) Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42:2672–2713CrossRefGoogle Scholar
  23. Heringa SM, Reijmer YD, Leemans A, Koek HL, Kappelle LJ, Biessels GJ (2014) Multiple microbleeds are related to cerebral network disruptions in patients with early Alzheimer’s disease. J Alzheimers Dis 38:211–221CrossRefGoogle Scholar
  24. Hilal S, Saini M, Tan CS, Catindig JA, Koay WI, Niessen WJ, Vrooman HA, Wong TY, Chen C, Ikram MK, Venketasubramanian N (2014) Cerebral microbleeds and cognition: the epidemiology of dementia in Singapore study. Alzheimer Dis Assoc Disord 28:106–112CrossRefGoogle Scholar
  25. Jackson SE, Redeker A, Arens R, van Baarle D, van den Berg SPH, Benedict CA, Cicin-Sain L, Hill AB, Wills MR (2017) CMV immune evasion and manipulation of the immune system with aging. Geroscience. 39:273–291CrossRefGoogle Scholar
  26. Jeerakathil T, Wolf PA, Beiser A, Hald JK, Au R, Kase CS, Massaro JM, DeCarli C (2004) Cerebral microbleeds: prevalence and associations with cardiovascular risk factors in the Framingham study. Stroke 35:1831–1835CrossRefGoogle Scholar
  27. Kroeker EJ, Wood EH (1956) Beat-to-beat alterations in relationship of simultaneously recorded central and peripheral arterial pressure pulses during Valsalva maneuver and prolonged expiration in man. J Appl Physiol 8:483–494CrossRefGoogle Scholar
  28. De Lee GJ, Matthews MB and Sharpey-Schafer EP. The effect of the Valsalva manoeuver on the systemic and pulmonary arterial pressure in man. Br Heart J 1954;16:311–316Google Scholar
  29. Lee SH, Bae HJ, Ko SB, Kim H, Yoon BW, Roh JK (2004) Comparative analysis of the spatial distribution and severity of cerebral microbleeds and old lacunes. J Neurol Neurosurg Psychiatry 75:423–427CrossRefGoogle Scholar
  30. Leng SX, Kamil J, Purdy JG, Lemmermann NA, Reddehase MJ, Goodrum FD (2017) Recent advances in CMV tropism, latency, and diagnosis during aging. Geroscience. 39:251–259CrossRefGoogle Scholar
  31. Meschiari CA, Ero OK, Pan H, Finkel T, Lindsey ML (2017) The impact of aging on cardiac extracellular matrix. Geroscience. 39:7–18CrossRefGoogle Scholar
  32. Monge Garcia MI, Gil Cano A, Diaz Monrove JC (2009) Arterial pressure changes during the Valsalva maneuver to predict fluid responsiveness in spontaneously breathing patients. Intensive Care Med 35:77–84CrossRefGoogle Scholar
  33. Neuropathology Group. Medical Research Council Cognitive F and Aging S. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Lancet 2001;357:169–175Google Scholar
  34. Ni J, Auriel E, Martinez-Ramirez S, Keil B, Reed AK, Fotiadis P, Gurol EM, Greenberg SM, Viswanathan A (2015) Cortical localization of microbleeds in cerebral amyloid angiopathy: an ultra high-field 7T MRI study. J Alzheimers Dis 43:1325–1330CrossRefGoogle Scholar
  35. Nighoghossian N, Hermier M, Adeleine P, Blanc-Lasserre K, Derex L, Honnorat J, Philippeau F, Dugor JF, Froment JC, Trouillas P (2002) Old microbleeds are a potential risk factor for cerebral bleeding after ischemic stroke: a gradient-echo T2*-weighted brain MRI study. Stroke 33:735–742CrossRefGoogle Scholar
  36. Nikolich-Zugich J, van Lier RAW (2017) Cytomegalovirus (CMV) research in immune senescence comes of age: overview of the 6th International Workshop on CMV and Immunosenescence. Geroscience. 39:245–249CrossRefGoogle Scholar
  37. van Norden AG, van den Berg HA, de Laat KF, Gons RA, van Dijk EJ, de Leeuw FE (2011) Frontal and temporal microbleeds are related to cognitive function: the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) Study. Stroke 42:3382–3386CrossRefGoogle Scholar
  38. Pettersen JA, Sathiyamoorthy G, Gao FQ, Szilagyi G, Nadkarni NK, St George-Hyslop P, Rogaeva E, Black SE (2008) Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study. Arch Neurol 65:790–795CrossRefGoogle Scholar
  39. Phan TS, Li JK, Segers P, Chirinos JA (2016) Misinterpretation of the determinants of elevated forward wave amplitude inflates the role of the proximal aorta. J Am Heart Assoc 5Google Scholar
  40. Podlutsky A, Valcarcel-Ares MN, Yancey K, Podlutskaya V, Nagykaldi E, Gautam T, Miller RA, Sonntag WE, Csiszar A, Ungvari Z (2017) The GH/IGF-1 axis in a critical period early in life determines cellular DNA repair capacity by altering transcriptional regulation of DNA repair-related genes: implications for the developmental origins of cancer. Geroscience. 39:147–160CrossRefGoogle Scholar
  41. Poels MM, Vernooij MW, Ikram MA, Hofman A, Krestin GP, van der Lugt A, Breteler MM (2010) Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study. Stroke 41:S103–S106CrossRefGoogle Scholar
  42. Poels MM, Ikram MA, van der Lugt A, Hofman A, Krestin GP, Breteler MM, Vernooij MW (2011) Incidence of cerebral microbleeds in the general population: the Rotterdam Scan Study. Stroke 42:656–661CrossRefGoogle Scholar
  43. Poels MM, Ikram MA, van der Lugt A, Hofman A, Niessen WJ, Krestin GP, Breteler MM and Vernooij MW. Cerebral microbleeds are associated with worse cognitive function: the Rotterdam Scan Study. Neurology 2012;78:326–333Google Scholar
  44. Reyes AJ, Dubra JE, Mastrascusi MC, Nin C and De Bayarres MA. Arterial blood pressure response to the Valsalva maneuver in normal persons and hypertensive patients. Arq Bras Cardiol 1967;20:101–103Google Scholar
  45. Romero JR, Preis SR, Beiser A, DeCarli C, Viswanathan A, Martinez-Ramirez S, Kase CS, Wolf PA, Seshadri S (2014) Risk factors, stroke prevention treatments, and prevalence of cerebral microbleeds in the Framingham Heart Study. Stroke 45:1492–1494CrossRefGoogle Scholar
  46. Roob G, Schmidt R, Kapeller P, Lechner A, Hartung HP, Fazekas F (1999) MRI evidence of past cerebral microbleeds in a healthy elderly population. Neurology 52:991–994CrossRefGoogle Scholar
  47. Rosidi NL, Zhou J, Pattanaik S, Wang P, Jin W, Brophy M, Olbricht WL, Nishimura N, Schaffer CB (2011) Cortical microhemorrhages cause local inflammation but do not trigger widespread dendrite degeneration. PLoS One 6:e26612CrossRefGoogle Scholar
  48. Sharpey-Schafer EP (1953) The mechanism of syncope after coughing. Br Med J 2:860–863CrossRefGoogle Scholar
  49. Souquette A, Frere J, Smithey M, Sauce D, Thomas PG (2017) A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness. Geroscience. 39:293–303CrossRefGoogle Scholar
  50. Springo Z, Tarantini S, Toth P, Tucsek Z, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2015a) Aging exacerbates pressure-induced mitochondrial oxidative stress in mouse cerebral arteries. J Gerontol A Biol Sci Med Sci 70:1355–1359CrossRefGoogle Scholar
  51. Springo Z, Toth P, Tarantini S, Ashpole NM, Tucsek Z, Sonntag WE, Csiszar A, Koller A, Ungvari ZI (2015b) Aging impairs myogenic adaptation to pulsatile pressure in mouse cerebral arteries. J Cereb Blood Flow Metab 35:527–530CrossRefGoogle Scholar
  52. Sveinbjornsdottir S, Sigurdsson S, Aspelund T, Kjartansson O, Eiriksdottir G, Valtysdottir B, Lopez OL, van Buchem MA, Jonsson PV, Gudnason V, Launer LJ (2008) Cerebral microbleeds in the population based AGES-Reykjavik study: prevalence and location. J Neurol Neurosurg Psychiatry 79:1002–1006CrossRefGoogle Scholar
  53. Takashima Y, Mori T, Hashimoto M, Kinukawa N, Uchino A, Yuzuriha T, Yao H (2011) Clinical correlating factors and cognitive function in community-dwelling healthy subjects with cerebral microbleeds. J Stroke Cerebrovasc Dis 20:105–110CrossRefGoogle Scholar
  54. 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 (2016a) Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging. Age (Dordr) 38:273–289CrossRefGoogle Scholar
  55. Tarantini S, Giles CB, Wren JD, Ashpole NM, Valcarcel-Ares MN, Wei JY, Sonntag WE, Ungvari Z, Csiszar A (2016b) IGF-1 deficiency in a critical period early in life influences the vascular aging phenotype in mice by altering miRNA-mediated post-transcriptional gene regulation: implications for the developmental origins of health and disease hypothesis. Age (Dordr) 38:239–258CrossRefGoogle Scholar
  56. Tarantini S, Valcarcel-Ares NM, Yabluchanskiy A, Springo Z, Fulop GA, Ashpole N, Gautam T, Giles CB, Wren JD, Sonntag WE, Csiszar A, Ungvari Z (2017a) Insulin-like growth factor 1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype. Aging Cell 16:469–479CrossRefGoogle Scholar
  57. Tarantini S, Fulop GA, Kiss T, Farkas E, Zolei-Szenasi D, Galvan V, Toth P, Csiszar A, Ungvari Z, Yabluchanskiy A (2017b) Demonstration of impaired neurovascular coupling responses in TG2576 mouse model of Alzheimer’s disease using functional laser speckle contrast imaging. Geroscience. 39:465–473CrossRefGoogle Scholar
  58. Tarantini S, Yabluchanksiy A, Fulop GA, Hertelendy P, Valcarcel-Ares MN, Kiss T, Bagwell JM, O'Connor D, Farkas E, Sorond F, Csiszar A, Ungvari Z (2017c) Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice. Geroscience. 39:601–614CrossRefGoogle Scholar
  59. Tiecks FP, Lam AM, Matta BF, Strebel S, Douville C, Newell DW (1995) Effects of the Valsalva maneuver on cerebral circulation in healthy adults. A transcranial Doppler study. Stroke 26:1386–1392CrossRefGoogle Scholar
  60. 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 33:1732–1742CrossRefGoogle Scholar
  61. Toth P, Tarantini S, Springo Z, Tucsek Z, Gautam T, Giles CB, Wren JD, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2015) Aging exacerbates hypertension-induced cerebral microhemorrhages in mice: role of resveratrol treatment in vasoprotection. Aging Cell 14:400–408CrossRefGoogle Scholar
  62. 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:H1–H20CrossRefGoogle Scholar
  63. Tsushima Y, Aoki J, Endo K (2003) Brain microhemorrhages detected on T2*-weighted gradient-echo MR images. AJNR Am J Neuroradiol 24:88–96PubMedGoogle Scholar
  64. 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 69:1212–1226CrossRefGoogle Scholar
  65. 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 69:1339–1352CrossRefGoogle Scholar
  66. Tucsek Z, Noa Valcarcel-Ares M, Tarantini S, Yabluchanskiy A, Fulop G, Gautam T, Orock A, Csiszar A, Deak F, Ungvari Z (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. 39:385–406CrossRefGoogle Scholar
  67. Ungvari Z, Tarantini S, Kirkpatrick AC, Csiszar A, Prodan CI (2017a) Cerebral microhemorrhages: mechanisms, consequences, and prevention. Am J Physiol Heart Circ Physiol 312:H1128–H1143CrossRefGoogle Scholar
  68. Ungvari Z, Tarantini S, Hertelendy P, Valcarcel-Ares MN, Fulop GA, Logan S, Kiss T, Farkas E, Csiszar A, Yabluchanskiy A (2017b) Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence. Geroscience. 39:33–42CrossRefGoogle Scholar
  69. Ungvari Z, Valcarcel-Ares MN, Tarantini S, Yabluchanskiy A, Fulop GA, Kiss T, Csiszar A (2017c) Connective tissue growth factor (CTGF) in age-related vascular pathologies. Geroscience. 39:491–498CrossRefGoogle Scholar
  70. Urfer SR, Kaeberlein TL, Mailheau S, Bergman PJ, Creevy KE, Promislow DE, Kaeberlein M (2017) Asymptomatic heart valve dysfunction in healthy middle-aged companion dogs and its implications for cardiac aging. Geroscience. 39:43–50CrossRefGoogle Scholar
  71. Valenti R, Del Bene A, Poggesi A, Ginestroni A, Salvadori E, Pracucci G, Ciolli L, Marini S, Nannucci S, Pasi M, Pescini F, Diciotti S, Orlandi G, Cosottini M, Chiti A, Mascalchi M, Bonuccelli U, Inzitari D, Pantoni L (2016) Cerebral microbleeds in patients with mild cognitive impairment and small vessel disease: the Vascular Mild Cognitive Impairment (VMCI)-Tuscany study. J Neurol Sci 368:195–202CrossRefGoogle Scholar
  72. Vernooij MW, van der Lugt A, Ikram MA, Wielopolski PA, Niessen WJ, Hofman A, Krestin GP, Breteler MM (2008) Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology 70:1208–1214CrossRefGoogle Scholar
  73. Vinters HV, Gilbert JJ (1983) Cerebral amyloid angiopathy: incidence and complications in the aging brain. II. The distribution of amyloid vascular changes. Stroke 14:924–928CrossRefGoogle Scholar
  74. Werring DJ (2011) Cerebral microbleeds. Cambridge University Press, New YorkCrossRefGoogle Scholar
  75. Werring DJ, Frazer DW, Coward LJ, Losseff NA, Watt H, Cipolotti L, Brown MM, Jager HR (2004) Cognitive dysfunction in patients with cerebral microbleeds on T2*-weighted gradient-echo MRI. Brain 127:2265–2275CrossRefGoogle Scholar
  76. Werring DJ, Gregoire SM, Cipolotti L (2010) Cerebral microbleeds and vascular cognitive impairment. J Neurol Sci 299:131–135CrossRefGoogle Scholar
  77. Wiegman AF, Meier IB, Schupf N, Manly JJ, Guzman VA, Narkhede A, Stern Y, Martinez-Ramirez S, Viswanathan A, Luchsinger JA, Greenberg SM, Mayeux R, Brickman AM (2014) Cerebral microbleeds in a multiethnic elderly community: demographic and clinical correlates. J Neurol Sci 345:125–130CrossRefGoogle Scholar
  78. Wu R, Feng C, Zhao Y, Jin AP, Fang M, Liu X (2014) A meta-analysis of association between cerebral microbleeds and cognitive impairment. Med Sci Monit 20:2189–2198CrossRefGoogle Scholar
  79. Wysoki MG, Covey A, Pollak J, Rosenblatt M, Aruny J, Denbow N (2001) Evaluation of various maneuvers for prevention of air embolism during central venous catheter placement. J Vasc Interv Radiol 12:764–766CrossRefGoogle Scholar
  80. Yakushiji Y and Werring DJ. Cerebrovascular disease: lobar cerebral microbleeds signal early cognitive impairment. Nat Rev Neurol 2016;12:680–682Google Scholar
  81. Yakushiji Y, Noguchi T, Charidimou A, Eriguchi M, Nishihara M, Hara M, Nanri Y, Horikawa E, Nishiyama M, Werring DJ, Hara H (2015) Basal ganglia cerebral microbleeds and global cognitive function: the Kashima Scan Study. J Stroke Cerebrovasc Dis 24:431–439CrossRefGoogle Scholar
  82. Yang Q, Yang Y, Li C, Li J, Liu X, Wang A, Zhao J, Wang M, Zeng X, Fan D (2015) Quantitative assessment and correlation analysis of cerebral microbleed distribution and leukoaraiosis in stroke outpatients. Neurol Res 37:403–409CrossRefGoogle Scholar
  83. Yates PA, Sirisriro R, Villemagne VL, Farquharson S, Masters CL, Rowe CC (2011) Cerebral microhemorrhage and brain beta-amyloid in aging and Alzheimer disease. Neurology 77:48–54CrossRefGoogle Scholar
  84. Yates PA, Desmond PM, Phal PM, Steward C, Szoeke C, Salvado O, Ellis KA, Martins RN, Masters CL, Ames D, Villemagne VL, Rowe CC (2014) Incidence of cerebral microbleeds in preclinical Alzheimer disease. Neurology 82:1266–1273CrossRefGoogle Scholar
  85. Zivadinov R (2013) Is there a link between the extracranial venous system and central nervous system pathology? BMC Med 11:259CrossRefGoogle Scholar
  86. Zivadinov R, Chung CP (2013) Potential involvement of the extracranial venous system in central nervous system disorders and aging. BMC Med 11:260CrossRefGoogle Scholar

Copyright information

© American Aging Association 2018

Authors and Affiliations

  1. 1.Vascular Cognitive Impairment Program, Reynolds Oklahoma Center on AgingUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  2. 2.Translational Geroscience Laboratory, Department of Geriatric MedicineUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  3. 3.Institute for Translational MedicineUniversity of Pecs Medical SchoolPecsHungary
  4. 4.Cerebrovascular Laboratory, Department of Neurosurgery and Szentagothai Research CenterUniversity of Pecs Medical SchoolPecsHungary
  5. 5.Veterans Affairs Medical CenterOklahoma CityUSA
  6. 6.Department of MedicineUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  7. 7.Department of NeurologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA

Personalised recommendations