Advertisement

GeroScience

pp 1–15 | Cite as

Cerebral venous congestion promotes blood-brain barrier disruption and neuroinflammation, impairing cognitive function in mice

  • Gabor A. Fulop
  • Chetan Ahire
  • Tamas Csipo
  • Stefano Tarantini
  • Tamas Kiss
  • Priya Balasubramanian
  • Andriy Yabluchanskiy
  • Eszter Farkas
  • Attila Toth
  • Ádám Nyúl-Tóth
  • Peter Toth
  • Anna Csiszar
  • Zoltan UngvariEmail author
Original Article

Abstract

Cognitive impairment is one of the most common co-occurring chronic conditions among elderly heart failure patients (incidence: up to ~ 80%); however, the underlying mechanisms are not completely understood. It is hypothesized that in addition to decreased cardiac output, increases in central—and consequentially, cerebral—venous pressure (backward failure) also contribute significantly to the genesis of cognitive impairment. To test this hypothesis and elucidate the specific pathogenic role of venous congestion in the brain, we have established a novel model of increased cerebral venous pressure: mice with jugular vein ligation (JVL). To test the hypothesis that increased venous pressure in the brain contributes to the development of cognitive deficits by causing blood-brain barrier disruption, dysregulation of blood flow, and/or promoting neuroinflammation, in C57BL/6 mice, the internal and external jugular veins were ligated. Cognitive function (radial arm water maze), gait function (CatWalk), and motor coordination (rotarod) were tested post-JVL. Neurovascular coupling responses were assessed by measuring changes in cerebral blood flow in the whisker barrel cortex in response to contralateral whisker stimulation by laser speckle contrast imaging through a closed cranial window. Blood-brain barrier integrity (IgG extravasation) and microglia activation (Iba1 staining) were assessed in brain slices by immunohistochemistry. Neuroinflammation-related gene expression profile was assessed by a targeted qPCR array. After jugular vein ligation, mice exhibited impaired spatial learning and memory, altered motor coordination, and impaired gait function, mimicking important aspects of altered brain function observed in human heart failure patients. JVL did not alter neurovascular coupling responses. In the brains of mice with JVL, significant extravasation of IgG was detected, indicating blood-brain barrier disruption, which was associated with histological markers of neuroinflammation (increased presence of activated microglia) and a pro-inflammatory shift in gene expression profile. Thus, cerebral venous congestion per se can cause blood-brain barrier disruption and neuroinflammation, which likely contribute to the genesis of cognitive impairment. These findings have relevance to the pathogenesis of cognitive decline associated with heart failure as well as increased cerebal venous pressure due to increased jugular venous reflux in elderly human patients.

Keywords

Vascular contributions to cognitive impairment and dementia (VCID) VCI Vascular cognitive impairment Vein Cerebral circulation 

Notes

Acknowledgments

The authors acknowledge the support from the NIA-funded Geroscience Training Program in Oklahoma (T32AG052363).

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, PB, ZU), the American Federation for Aging Research (to PB), the National Institute on Aging (R01-AG055395, R01-AG047879, R01-AG038747), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS100782, R01-NS056218), and the Department of Veterans Affairs (Merit Number 1I01CX000340); 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), and the Presbyterian Health Foundation (to ZU, AC, AY); 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; a grant from the National Research, Development and Innovation Office (NKFI-FK123798); a grant from the Hungarian Academy of Sciences (Bolyai Research Scholarship BO/00634/15); and a grant from the ÚNKP-18-4-PTE-6 New National Excellence Program of the Ministry of Human Capacities (to PT).

Compliance with ethical standards

All procedures were approved by the Institutional Animal Use and Care Committees of the University of Oklahoma Health Sciences Center.

Conflict of interest

The authors declare that they have no conflict of interest.

Disclaimer

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

References

  1. Adamski MG, Sternak M, Mohaissen T, Kaczor D, Wieronska JM, Malinowska M, Czaban I, Byk K, Lyngso KS, Przyborowski K, Hansen PBL, Wilczynski G, Chlopicki S (2018) Vascular cognitive impairment linked to brain endothelium inflammation in early stages of heart failure in mice. J Am Heart Assoc 7Google Scholar
  2. Akkawi NM, Agosti C, Borroni B, Rozzini L, Magoni M, Vignolo LA, Padovani A (2002) Jugular valve incompetence: a study using air contrast ultrasonography on a general population. J Ultrasound Med. 21:747–751CrossRefPubMedPubMedCentralGoogle Scholar
  3. Alosco ML, Brickman AM, Spitznagel MB, van Dulmen M, Raz N, Cohen R, Sweet LH, Colbert LH, Josephson R, Hughes J, Rosneck J, Gunstad J (2012) The independent association of hypertension with cognitive function among older adults with heart failure. J Neurol Sci. 323:216–220CrossRefPubMedPubMedCentralGoogle Scholar
  4. Alosco ML, Brickman AM, Spitznagel MB, Griffith EY, Narkhede A, Raz N, Cohen R, Sweet LH, Hughes J, Rosneck J, Gunstad J (2013) Independent and interactive effects of blood pressure and cardiac function on brain volume and white matter hyperintensities in heart failure. J Am Soc Hypertens. 7:336–343CrossRefPubMedPubMedCentralGoogle Scholar
  5. Alosco ML, Penn MS, Brickman AM, Spitznagel MB, Cleveland MJ, Griffith EY, Narkhede A, Gunstad J (2015) Preliminary observations on MRI correlates of driving independence and performance in persons with heart failure. Int J Neurosci. 125:424–432CrossRefPubMedPubMedCentralGoogle Scholar
  6. 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. 39:129–145CrossRefPubMedPubMedCentralGoogle Scholar
  7. Auletta L, Greco A, Albanese S, Meomartino L, Salvatore M, Mancini M (2017) Feasibility and safety of two surgical techniques for the development of an animal model of jugular vein occlusion. Exp Biol Med (Maywood). 242:22–28CrossRefPubMedPubMedCentralGoogle Scholar
  8. 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 (2012) 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 Biol Med Sci. 67:313–329CrossRefGoogle Scholar
  9. Beer C, Ebenezer E, Fenner S, Lautenschlager NT, Arnolda L, Flicker L, Almeida OP (2009) Contributors to cognitive impairment in congestive heart failure: a pilot case-control study. Intern Med J. 39:600–605CrossRefPubMedPubMedCentralGoogle Scholar
  10. Bernier M, Wahl D, Ali A, Allard J, Faulkner S, Wnorowski A, Sanghvi M, Moaddel R, Alfaras I, Mattison JA, Tarantini S, Tucsek Z, Ungvari Z, Csiszar A, Pearson KJ, de Cabo R (2016) Resveratrol supplementation confers neuroprotection in cortical brain tissue of nonhuman primates fed a high-fat/sucrose diet. Aging (Albany NY) 8:899–916CrossRefGoogle Scholar
  11. Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 8:57–69CrossRefPubMedPubMedCentralGoogle Scholar
  12. Bruce-Keller AJ, White CL, Gupta S, Knight AG, Pistell PJ, Ingram DK, Morrison CD, Keller JN (2010) NOX activity in brain aging: exacerbation by high fat diet. Free Radic Biol Med. 49:22–30CrossRefPubMedPubMedCentralGoogle Scholar
  13. Cannon JA, Moffitt P, Perez-Moreno AC, Walters MR, Broomfield NM, McMurray JJV, Quinn TJ (2017) Cognitive impairment and heart failure: systematic review and meta-analysis. J Card Fail. 23:464–475CrossRefPubMedPubMedCentralGoogle Scholar
  14. Carlson BW, Craft MA, Carlson JR, Razaq W, Deardeuff KK, Benbrook DM (2018) Accelerated vascular aging and persistent cognitive impairment in older female breast cancer survivors. Geroscience. 40:325–336CrossRefPubMedPubMedCentralGoogle Scholar
  15. Carreno-Muller E, Herrera AJ, de Pablos RM, Tomas-Camardiel M, Venero JL, Cano J, Machado A (2003) Thrombin induces in vivo degeneration of nigral dopaminergic neurones along with the activation of microglia. J Neurochem. 84:1201–1214CrossRefPubMedPubMedCentralGoogle Scholar
  16. Choi BR, Kim JS, Yang YJ, Park KM, Lee CW, Kim YH, Hong MK, Song JK, Park SW, Park SJ, Kim JJ (2006) Factors associated with decreased cerebral blood flow in congestive heart failure secondary to idiopathic dilated cardiomyopathy. Am J Cardiol. 97:1365–1369CrossRefPubMedPubMedCentralGoogle Scholar
  17. Chung CP, Hu HH (2010) Pathogenesis of leukoaraiosis: role of jugular venous reflux. Med Hypotheses. 75:85–90CrossRefPubMedPubMedCentralGoogle Scholar
  18. Cornwell WK III, Levine BD (2015) Patients with heart failure with reduced ejection fraction have exaggerated reductions in cerebral blood flow during upright posture. JACC Heart Fail. 3:176–179CrossRefPubMedPubMedCentralGoogle Scholar
  19. 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. 39:359–372CrossRefPubMedPubMedCentralGoogle Scholar
  20. Davalos D, Ryu JK, Merlini M, Baeten KM, Le Moan N, Petersen MA, Deerinck TJ, Smirnoff DS, Bedard C, Hakozaki H, Gonias Murray S, Ling JB, Lassmann H, Degen JL, Ellisman MH, Akassoglou K (2012) Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation. Nat Commun. 3:1227CrossRefPubMedPubMedCentralGoogle Scholar
  21. De Silva TM, Faraci FM (2012) Effects of angiotensin II on the cerebral circulation: role of oxidative stress. Front Physiol. 3:484CrossRefPubMedPubMedCentralGoogle Scholar
  22. 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. 39:187–198CrossRefPubMedPubMedCentralGoogle Scholar
  23. Dhanger S, Vaidiyanathan B, Tripathy DK (2016) Internal jugular venous valve: well known but mostly neglected. Indian J Anaesth. 60:602–603CrossRefPubMedPubMedCentralGoogle Scholar
  24. Dinc N, Won SY, Eibach M, Quick-Weller J, Keil F, Berkefeld J, Konczalla J, Marquardt G, Seifert V (2019) Thrombosis of the straight sinus and microbleedings due to deep seated arteriovenous fistula - hemodynamic changes, cognitive impairment and improvement after microsurgery. A technical report. J Clin Neurosci 68:317–321CrossRefPubMedPubMedCentralGoogle Scholar
  25. Dunn KM, Nelson MT (2014) Neurovascular signaling in the brain and the pathological consequences of hypertension. Am J Physiol Heart Circ Physiol. 306:H1–H14Google Scholar
  26. 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. 39:347–356CrossRefPubMedPubMedCentralGoogle Scholar
  27. Faraco G, Park L, Zhou P, Luo W, Paul SM, Anrather J, Iadecola C (2016) Hypertension enhances Abeta-induced neurovascular dysfunction, promotes beta-secretase activity, and leads to amyloidogenic processing of APP. J Cereb Blood Flow Metab. 36:241–252CrossRefPubMedPubMedCentralGoogle Scholar
  28. Fernandez-Vizarra P, Lopez-Franco O, Mallavia B, Higuera-Matas A, Lopez-Parra V, Ortiz-Munoz G, Ambrosio E, Egido J, Almeida OF, Gomez-Guerrero C (2012) Immunoglobulin G Fc receptor deficiency prevents Alzheimer-like pathology and cognitive impairment in mice. Brain. 135:2826–2837CrossRefPubMedPubMedCentralGoogle Scholar
  29. Fulop GA, Kiss T, Tarantini S, Balasubramanian P, Yabluchanskiy A, Farkas E, Bari F, Ungvari Z, Csiszar A (2018) Nrf2 deficiency in aged mice exacerbates cellular senescence promoting cerebrovascular inflammation. Geroscience. 40:513–521CrossRefPubMedPubMedCentralGoogle Scholar
  30. Fulop GA, Tarantini S, Yabluchanskiy A, Molnar A, Prodan CI, Kiss T, Csipo T, Lipecz A, Balasubramanian P, Farkas E, Toth P, Sorond F, Csiszar A, Ungvari Z (2019) Role of age-related alterations of the cerebral venous circulation in the pathogenesis of vascular cognitive impairment. Am J Physiol Heart Circ Physiol. 316:H1124–H1140CrossRefPubMedPubMedCentralGoogle Scholar
  31. Gao HM, Liu B, Zhang W, Hong JS (2003) Critical role of microglial NADPH oxidase-derived free radicals in the in vitro MPTP model of Parkinson’s disease. Faseb J. 17:1954–1956CrossRefPubMedPubMedCentralGoogle Scholar
  32. Geraldes R, Albuquerque L, Ferro JM, Sousa R, Sequeira P, Campos J (2012) Rapidly progressive cognitive impairment, ataxia, and myoclonus: an unusual presentation of a dural arteriovenous fistula. J Stroke Cerebrovasc Dis 21:619 e3–619 e5CrossRefGoogle Scholar
  33. Gruhn N, Larsen FS, Boesgaard S, Knudsen GM, Mortensen SA, Thomsen G, Aldershvile J (2001) Cerebral blood flow in patients with chronic heart failure before and after heart transplantation. Stroke. 32:2530–2533CrossRefPubMedPubMedCentralGoogle Scholar
  34. Hai J, Wan JF, Lin Q, Wang F, Zhang L, Li H, Zhang L, Chen YY, Lu Y (2009) Cognitive dysfunction induced by chronic cerebral hypoperfusion in a rat model associated with arteriovenous malformations. Brain Res. 1301:80–88CrossRefPubMedPubMedCentralGoogle Scholar
  35. Hooghiemstra AM, Bertens AS, Leeuwis AE, Bron EE, Bots ML, Brunner-La Rocca HP, de Craen AJM, van der Geest RJ, Greving JP, Kappelle LJ, Niessen WJ, van Oostenbrugge RJ, van Osch MJP, de Roos A, van Rossum AC, Biessels GJ, van Buchem MA, Daemen M, van der Flier WM, Heart-Brain Connection C (2017) The missing link in the pathophysiology of vascular cognitive impairment: design of the heart-brain study. Cerebrovasc Dis Extra. 7:140–152CrossRefPubMedPubMedCentralGoogle Scholar
  36. Hurst RW, Bagley LJ, Galetta S, Glosser G, Lieberman AP, Trojanowski J, Sinson G, Stecker M, Zager E, Raps EC, Flamm ES (1998) Dementia resulting from dural arteriovenous fistulas: the pathologic findings of venous hypertensive encephalopathy. AJNR Am J Neuroradiol 19:1267–1273PubMedPubMedCentralGoogle Scholar
  37. Inano S, Itoh D, Takao H, Hayashi N, Mori H, Kunimatsu A, Abe O, Aoki S, Ohtomo K (2010) High signal intensity in the dural sinuses on 3D-TOF MR angiography at 3.0 T. Clin Imaging. 34:332–336CrossRefPubMedPubMedCentralGoogle Scholar
  38. Jang J, Kim BS, Kim BY, Choi HS, Jung SL, Ahn KJ, Byun JY (2013) Reflux venous flow in dural sinus and internal jugular vein on 3D time-of-flight MR angiography. Neuroradiology. 55:1205–1211CrossRefPubMedPubMedCentralGoogle Scholar
  39. Jefferson AL, Himali JJ, Beiser AS, Au R, Massaro JM, Seshadri S, Gona P, Salton CJ, DeCarli C, O’Donnell CJ, Benjamin EJ, Wolf PA, Manning WJ (2010) Cardiac index is associated with brain aging: the Framingham Heart Study. Circulation. 122:690–697CrossRefPubMedPubMedCentralGoogle Scholar
  40. Jorgensen DR, Shaaban CE, Wiley CA, Gianaros PJ, Mettenburg J, Rosano C (2018) A population neuroscience approach to the study of cerebral small vessel disease in midlife and late life: an invited review. Am J Physiol Heart Circ Physiol. 314:H1117–H1136CrossRefPubMedPubMedCentralGoogle Scholar
  41. Justice JN, Silverstein-Metzler MG, Uberseder B, Appt SE, Clarkson TB, Register TC, Kritchevsky SB, Shively CA (2017) Relationships of depressive behavior and sertraline treatment with walking speed and activity in older female nonhuman primates. Geroscience. 39:585–600CrossRefPubMedPubMedCentralGoogle Scholar
  42. Kaneko YS, Nakashima A, Mori K, Nagatsu T, Nagatsu I, Ota A (2012) Microglial activation in neuroinflammation: implications for the etiology of neurodegeneration. Neurodegener Dis. 10:100–103CrossRefPubMedPubMedCentralGoogle Scholar
  43. Kang Y, Kim E, Kim JH, Choi BS, Jung C, Bae YJ, Lee KM, Lee DH (2015) Time of flight MR angiography assessment casts doubt on the association between transient global amnesia and intracranial jugular venous reflux. Eur Radiol. 25:703–709CrossRefPubMedPubMedCentralGoogle Scholar
  44. Kazama K, Anrather J, Zhou P, Girouard H, Frys K, Milner TA, Iadecola C (2004) Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals. Circ Res. 95:1019–1026CrossRefPubMedPubMedCentralGoogle Scholar
  45. Kim E, Kim JH, Choi BS, Jung C, Lee DH (2014) MRI and MR angiography findings to differentiate jugular venous reflux from cavernous dural arteriovenous fistula. AJR Am J Roentgenol. 202:839–846CrossRefPubMedPubMedCentralGoogle Scholar
  46. Kudo K, Terae S, Ishii A, Omatsu T, Asano T, Tha KK, Miyasaka K (2004) Physiologic change in flow velocity and direction of dural venous sinuses with respiration: MR venography and flow analysis. AJNR Am J Neuroradiol. 25:551–557PubMedPubMedCentralGoogle Scholar
  47. Labeyrie MA, Lenck S, Saint-Maurice JP, Bresson D, Houdart E (2014) Dural arteriovenous fistulas presenting with reversible dementia are associated with a specific venous drainage. Eur J Neurol. 21:545–547CrossRefPubMedPubMedCentralGoogle Scholar
  48. Labinskyy V, Bellomo M, Chandler MP, Young ME, Lionetti V, Qanud K, Bigazzi F, Sampietro T, Stanley WC, Recchia FA (2007) Chronic activation of peroxisome proliferator-activated receptor-alpha with fenofibrate prevents alterations in cardiac metabolic phenotype without changing the onset of decompensation in pacing-induced heart failure. J Pharmacol Exp Ther. 321:165–171CrossRefPubMedPubMedCentralGoogle Scholar
  49. Lei B, Lionetti V, Young ME, Chandler MP, d’Agostino C, Kang E, Altarejos M, Matsuo K, Hintze TH, Stanley WC, Recchia FA (2004) Paradoxical downregulation of the glucose oxidation pathway despite enhanced flux in severe heart failure. J Mol Cell Cardiol. 36:567–576CrossRefPubMedPubMedCentralGoogle Scholar
  50. Leng SX, Kamil J, Purdy JG, Lemmermann NA, Reddehase MJ, Goodrum FD (2017) Recent advances in CMV tropism, latency, and diagnosis during aging. Geroscience. 39:251–259CrossRefPubMedPubMedCentralGoogle Scholar
  51. Lepori D, Capasso P, Fournier D, Genton CY, Schnyder P (1999) High-resolution ultrasound evaluation of internal jugular venous valves. Eur Radiol. 9:1222–1226CrossRefPubMedPubMedCentralGoogle Scholar
  52. Leto L, Feola M (2014) Cognitive impairment in heart failure patients. J Geriatr Cardiol. 11:316–328PubMedPubMedCentralGoogle Scholar
  53. Lionetti V, Linke A, Chandler MP, Young ME, Penn MS, Gupte S, d’Agostino C, Hintze TH, Stanley WC, Recchia FA (2005) Carnitine palmitoyl transferase-I inhibition prevents ventricular remodeling and delays decompensation in pacing-induced heart failure. Cardiovasc Res. 66:454–461CrossRefPubMedPubMedCentralGoogle Scholar
  54. Loncar G, Bozic B, Lepic T, Dimkovic S, Prodanovic N, Radojicic Z, Cvorovic V, Markovic N, Brajovic M, Despotovic N, Putnikovic B, Popovic-Brkic V (2011) Relationship of reduced cerebral blood flow and heart failure severity in elderly males. Aging Male. 14:59–65CrossRefPubMedPubMedCentralGoogle Scholar
  55. MacLaren DA, Santini JA, Russell AL, Markovic T, Clark SD (2014) Deficits in motor performance after pedunculopontine lesions in rats - impairment depends on demands of task. Eur J Neurosci 40:3224–3236CrossRefPubMedPubMedCentralGoogle Scholar
  56. Makedonov I, Black SE, MacIntosh BJ (2013) Cerebral small vessel disease in aging and Alzheimer’s disease: a comparative study using MRI and SPECT. Eur J Neurol. 20:243–250CrossRefPubMedPubMedCentralGoogle Scholar
  57. Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM, Herbert RL, Longo DL, Allison DB, Young JE, Bryant M, Barnard D, Ward WF, Qi W, Ingram DK, de Cabo R (2012) Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature. 489:318–321CrossRefPubMedPubMedCentralGoogle Scholar
  58. Mattison JA, Wang M, Bernier M, Zhang J, Park SS, Maudsley S, An SS, Santhanam L, Martin B, Faulkner S, Morrell C, Baur JA, Peshkin L, Sosnowska D, Csiszar A, Herbert RL, Tilmont EM, Ungvari Z, Pearson KJ, Lakatta EG, de Cabo R (2014) Resveratrol prevents high fat/sucrose diet-induced central arterial wall inflammation and stiffening in nonhuman primates. Cell Metab. 20:183–190CrossRefPubMedPubMedCentralGoogle Scholar
  59. Mayhan WG, Heistad DD (1986) Role of veins and cerebral venous pressure in disruption of the blood-brain barrier. Circ Res. 59:216–220CrossRefPubMedPubMedCentralGoogle Scholar
  60. Moody DM, Brown WR, Challa VR, Anderson RL (1995) Periventricular venous collagenosis: association with leukoaraiosis. Radiology. 194:469–476CrossRefPubMedPubMedCentralGoogle Scholar
  61. Morparia N, Miller G, Rabinstein A, Lanzino G, Kumar N (2012) Cognitive decline and hypersomnolence: thalamic manifestations of a tentorial dural arteriovenous fistula (dAVF). Neurocrit Care. 17:429–433CrossRefPubMedPubMedCentralGoogle Scholar
  62. Pistell PJ, Morrison CD, Gupta S, Knight AG, Keller JN, Ingram DK, Bruce-Keller AJ (2010) Cognitive impairment following high fat diet consumption is associated with brain inflammation. J Neuroimmunol. 219:25–32CrossRefPubMedPubMedCentralGoogle Scholar
  63. Racine CA, Lawton MT, Hetts SW, Josephson SA (2008) Neuropyschological profile of reversible cognitive impairment in a patient with a dural arteriovenous fistula. Neurocase. 14:231–238CrossRefPubMedPubMedCentralGoogle Scholar
  64. Randall A, Ellis R, Hywel B, Davies RR, Alusi SH, Larner AJ (2015) Rapid cognitive decline: not always Creutzfeldt-Jakob disease. J R Coll Physicians Edinb. 45:209–212CrossRefPubMedPubMedCentralGoogle Scholar
  65. Reglodi D, Atlasz T, Szabo E, Jungling A, Tamas A, Juhasz T, Fulop BD, Bardosi A (2018) PACAP deficiency as a model of aging. Geroscience. 40:437–452CrossRefPubMedPubMedCentralGoogle Scholar
  66. Roy B, Woo MA, Wang DJJ, Fonarow GC, Harper RM, Kumar R (2017) Reduced regional cerebral blood flow in patients with heart failure. Eur J Heart Fail. 19:1294–1302CrossRefPubMedPubMedCentralGoogle Scholar
  67. Shukitt-Hale B, McEwen JJ, Szprengiel A, Joseph JA (2004) Effect of age on the radial arm water maze-a test of spatial learning and memory. Neurobiol Aging. 25:223–229CrossRefPubMedPubMedCentralGoogle Scholar
  68. Sung SH, Lee CW, Wang PN, Lee HY, Chen CH, Chung CP (2019) Cognitive functions and jugular venous reflux in severe mitral regurgitation: a pilot study. PLoS One. 14:e0207832CrossRefPubMedPubMedCentralGoogle Scholar
  69. Tarantini S, Hertelendy P, Tucsek Z, Valcarcel-Ares MN, Smith N, Menyhart A, Farkas E, Hodges E, Towner R, Deak F, Sonntag WE, Csiszar A, Ungvari Z, Toth P (2015) Pharmacologically-induced neurovascular uncoupling is associated with cognitive impairment in mice. J Cereb Blood Flow Metab 35(11):1871–1881.  https://doi.org/10.1038/jcbfm.2015.162 CrossRefPubMedPubMedCentralGoogle Scholar
  70. 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. 16:469–479CrossRefPubMedPubMedCentralGoogle Scholar
  71. 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. 39:465–473CrossRefPubMedPubMedCentralGoogle Scholar
  72. 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. 39:601–614CrossRefPubMedPubMedCentralGoogle Scholar
  73. Tarantini S, Tran CHT, Gordon GR, Ungvari Z, Csiszar A (2017d) Impaired neurovascular coupling in aging and Alzheimer’s disease: contribution of astrocyte dysfunction and endothelial impairment to cognitive decline. Exp Gerontol 94:52–58CrossRefPubMedPubMedCentralGoogle Scholar
  74. Tarantini S, Valcarcel-Ares NM, Yabluchanskiy A, Fulop GA, Hertelendy P, Gautam T, Farkas E, Perz A, Rabinovitch PS, Sonntag WE, Csiszar A, Ungvari Z (2018a) Treatment with the mitochondrial-targeted antioxidant peptide SS-31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice. Aging Cell 17(2).  https://doi.org/10.1111/acel.12731
  75. Tarantini S, Valcarcel-Ares MN, Yabluchanskiy A, Tucsek Z, Hertelendy P, Kiss T, Gautam T, Zhang XA, Sonntag WE, de Cabo R, Farkas E, Elliott ME, Kinter MT, Deak F, Ungvari Z, Csiszar A (2018b) Nrf2 deficiency exacerbates obesity-induced oxidative stress, neurovascular dysfunction, blood brain barrier disruption, neuroinflammation, amyloidogenic gene expression and cognitive decline in mice, mimicking the aging phenotype. J Gerontol A Biol Sci Med Sci 73(7):853–863.  https://doi.org/10.1093/gerona/glx177
  76. Tarantini S, Valcarcel-Ares MN, Toth P, Yabluchanskiy A, Tucsek Z, Kiss T, Hertelendy P, Kinter M, Ballabh P, Sule Z, Farkas E, Baur JA, Sinclair DA, Csiszar A, Ungvari Z (2019) Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biol. 24:101192CrossRefPubMedPubMedCentralGoogle Scholar
  77. 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. 33:1732–1742CrossRefPubMedPubMedCentralGoogle Scholar
  78. Toth P, Tarantini S, Tucsek Z, Ashpole NM, Sosnowska D, Gautam T, Ballabh P, Koller A, Sonntag WE, Csiszar A, Ungvari ZI (2014) Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicrovascular endothelial function and down-regulation of NADPH oxidas. Am J Physiol Heart Circ Physiol. 306:H299–H308CrossRefPubMedPubMedCentralGoogle Scholar
  79. Toth P, Tarantini S, Springo Z, Tucsek Z, Gautam T, Giles CB, Wren JD, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2015a) Aging exacerbates hypertension-induced cerebral microhemorrhages in mice: role of resveratrol treatment in vasoprotection. Aging Cell. 14:400–408CrossRefPubMedPubMedCentralGoogle Scholar
  80. Toth P, Tarantini S, Ashpole NM, Tucsek Z, Milne GL, Valcarcel-Ares NM, Menyhart A, Farkas E, Sonntag WE, Csiszar A, Ungvari Z (2015b) IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging. Aging Cell. 14:1034–1044CrossRefPubMedPubMedCentralGoogle Scholar
  81. 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–H20CrossRefPubMedPubMedCentralGoogle Scholar
  82. Tucsek Z, Toth P, Sosnowsk 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. 69:1212–1226CrossRefPubMedPubMedCentralGoogle Scholar
  83. 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. 69:1339–1352CrossRefPubMedPubMedCentralGoogle Scholar
  84. 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. 39:385–406CrossRefPubMedPubMedCentralGoogle Scholar
  85. Uchino A, Nomiyama K, Takase Y, Nakazono T, Tominaga Y, Imaizumi T, Kudo S (2007) Retrograde flow in the dural sinuses detected by three-dimensional time-of-flight MR angiography. Neuroradiology. 49:211–215CrossRefPubMedPubMedCentralGoogle Scholar
  86. Ungvari Z, Tarantini S, Hertelendy P, Valcarcel-Ares MN, Fulop GA, Logan S, Kiss T, Farkas E, Csiszar A, Yabluchanskiy A (2017a) Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence. Geroscience. 39:33–42CrossRefPubMedPubMedCentralGoogle Scholar
  87. Ungvari Z, Tarantini S, Kirkpatrick AC, Csiszar A, Prodan CI (2017b) Cerebral microhemorrhages: mechanisms, consequences, and prevention. Am J Physiol Heart Circ Physiol. 312:H1128–H1143CrossRefPubMedPubMedCentralGoogle Scholar
  88. Ungvari Z, Yabluchanskiy A, Tarantini S, Toth P, Kirkpatrick AC, Csiszar A, Prodan CI (2018) Repeated Valsalva maneuvers promote symptomatic manifestations of cerebral microhemorrhages: implications for the pathogenesis of vascular cognitive impairment in older adults. Geroscience. 40:485–496CrossRefPubMedPubMedCentralGoogle Scholar
  89. 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. 39:43–50CrossRefPubMedPubMedCentralGoogle Scholar
  90. Valcarcel-Ares MN, Tucsek Z, Kiss T, Giles CB, Tarantini S, Yabluchanskiy A, Balasubramanian P, Gautam T, Galvan V, Ballabh P, Richardson A, Freeman WM, Wren JD, Deak F, Ungvari Z, Csiszar A (2018) Obesity in aging exacerbates neuroinflammation, dysregulating synaptic function-related genes and altering eicosanoid synthesis in the mouse hippocampus: potential role in impaired synaptic plasticity and cognitive decline. J Gerontol A Biol Sci Med Sci 74(3):290–298.  https://doi.org/10.1093/gerona/gly127
  91. Valecchi D, Bacci D, Gulisano M, Sgambati E, Sibilio M, Lipomas M, Macchi C (2010) Internal jugular vein valves: an assessment of prevalence, morphology and competence by color Doppler echography in 240 healthy subjects. Ital J Anat Embryol. 115:185–189PubMedPubMedCentralGoogle Scholar
  92. Van Skike CE, Jahrling JB, Olson AB, Sayre NL, Hussong SA, Ungvari Z, Lechleiter JD, Galvan V (2018) Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer’s disease and vascular cognitive impairment. Am J Physiol Heart Circ Physiol. 314:H693–H703CrossRefPubMedPubMedCentralGoogle Scholar
  93. Watson RD, Gibbs CR, Lip GY (2000) ABC of heart failure. Clinical features and complications. BMJ. 320:236–239CrossRefPubMedPubMedCentralGoogle Scholar
  94. White CL, Pistell PJ, Purpera MN, Gupta S, Fernandez-Kim SO, Hise TL, Keller JN, Ingram DK, Morrison CD, Bruce-Keller AJ (2009) Effects of high fat diet on Morris maze performance, oxidative stress, and inflammation in rats: contributions of maternal diet. Neurobiol Dis. 35:3–13CrossRefPubMedPubMedCentralGoogle Scholar
  95. Woo MA, Kumar R, Macey PM, Fonarow GC, Harper RM (2009) Brain injury in autonomic, emotional, and cognitive regulatory areas in patients with heart failure. J Card Fail. 15:214–223CrossRefPubMedPubMedCentralGoogle Scholar
  96. Zhang NN, Zhao KT, Zhao ZA, Chen WL, Xu HB, Chen HS (2019) A novel rat model of cerebral artery occlusion complicated with prior venous stagnation. J Neurosci Methods. 318:100–103CrossRefPubMedPubMedCentralGoogle Scholar
  97. Zivadinov R, Chung CP (2013) Potential involvement of the extracranial venous system in central nervous system disorders and aging. BMC Med. 11:260CrossRefPubMedPubMedCentralGoogle Scholar
  98. Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 57:178–201CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© American Aging Association 2019

Authors and Affiliations

  • Gabor A. Fulop
    • 1
    • 2
    • 3
  • Chetan Ahire
    • 1
  • Tamas Csipo
    • 1
    • 2
    • 4
  • Stefano Tarantini
    • 1
    • 4
  • Tamas Kiss
    • 1
    • 5
  • Priya Balasubramanian
    • 1
  • Andriy Yabluchanskiy
    • 1
  • Eszter Farkas
    • 5
  • Attila Toth
    • 2
  • Ádám Nyúl-Tóth
    • 1
    • 6
  • Peter Toth
    • 1
    • 7
    • 8
  • Anna Csiszar
    • 1
    • 5
    • 9
  • Zoltan Ungvari
    • 1
    • 4
    • 5
    Email author
  1. 1.Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience, Department of Biochemistry and Molecular BiologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  2. 2.International Training Program in Geroscience, Division of Clinical Physiology, Department of Cardiology/Kálmán Laki Doctoral School of Biomedical and Clinical Sciences, Faculty of MedicineUniversity of DebrecenDebrecenHungary
  3. 3.Heart and Vascular CenterSemmelweis UniversityBudapestHungary
  4. 4.International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public HealthSemmelweis UniversityBudapestHungary
  5. 5.International Training Program in Geroscience, Theoretical Medicine Doctoral School, Department of Medical Physics and InformaticsUniversity of SzegedSzegedHungary
  6. 6.International Training Program in Geroscience, Institute of BiophysicsBiological Research CentreSzegedHungary
  7. 7.International Training Program in Geroscience, Department of Neurosurgery and Szentagothai Research CenterUniversity of Pecs, Medical SchoolPecsHungary
  8. 8.Institute for Translational MedicineUniversity of Pecs, Medical School PecsHungary
  9. 9.International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Institute of Clinical Experimental ResearchSemmelweis UniversityBudapestHungary

Personalised recommendations