Background: Aortic stiffness is associated with cardiovascular and cerebrovascular events and cognitive decline. This mini-review focuses on relations of aortic stiffness with microvascular dysfunction and discusses the contribution of abnormal pulsatile hemodynamics to cerebrovascular damage and cognitive decline. We also provide a rationale for considering aortic stiffness as a putative and important contributor to memory impairment in older individuals. Summary: Aging is associated with stiffening of the aorta but not the muscular arteries, which reduces wave reflection and increases the transmission of pulsatility into the periphery. Aortic stiffening thereby impairs a protective mechanism that shields the peripheral microcirculation from excessive pulsatility within downstream target organs. Beyond midlife, aortic stiffness increases rapidly and exposes the cerebral microcirculation to abnormal pulsatile mechanical forces that are associated with microvascular damage and remodeling in the brain. Aortic stiffening and high-flow pulsatility are associated with alterations in the microvasculature of the brain; however, a mechanistic link between aortic stiffness and memory has not been established. We showed that in a community-based sample of older individuals, cerebrovascular resistance and white matter hyperintensities - markers of cerebrovascular remodeling and damage - mediated the relation between higher aortic stiffness and lower performance on memory function tests. These data suggest that microvascular and white matter damage associated with excessive aortic stiffness contribute to impaired memory function with advancing age. Key Messages: Increasing evidence suggests that vascular etiologies - including aortic stiffness and microvascular damage - contribute to memory impairment and the pathogenesis of dementia, including Alzheimer's disease. Interventions that reduce aortic stiffness may delay memory decline among older individuals.

1.
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 2011;42:2672-2713.
2.
Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, Ducimetiere P, Benetos A: Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 2001;37:1236-1241.
3.
Laurent S, Katsahian S, Fassot C, Tropeano AI, Gautier I, Laloux B, Boutouyrie P: Aortic stiffness is an independent predictor of fatal stroke in essential hypertension. Stroke 2003;34:1203-1206.
4.
Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, Vita JA, Levy D, Benjamin EJ: Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation 2010;121:505-511.
5.
Mattace-Raso FU, van der Cammen TJ, Hofman A, van Popele NM, Bos ML, Schalekamp MA, Asmar R, Reneman RS, Hoeks AP, Breteler MM, Witteman JC: Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation 2006;113:657-663.
6.
Sutton-Tyrrell K, Najjar SS, Boudreau RM, Venkitachalam L, Kupelian V, Simonsick EM, Havlik R, Lakatta EG, Spurgeon H, Kritchevsky S, Pahor M, Bauer D, Newman A; Health ABC Study: Elevated aortic pulse wave velocity, a marker of arterial stiffness, predicts cardiovascular events in well-functioning older adults. Circulation 2005;111:3384-3390.
7.
Zlokovic BV: Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci 2011;12:723-738.
8.
Iadecola C: The pathobiology of vascular dementia. Neuron 2013;80:844-866.
9.
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 2016;67:176-182.
10.
Gorelick PB: Risk factors for vascular dementia and Alzheimer disease. Stroke 2004;35:2620-2622.
11.
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 2015;11:710-717.
12.
Adji A, O'Rourke MF, Namasivayam M: Arterial stiffness, its assessment, prognostic value, and implications for treatment. Am J Hypertens 2011;24:5-17.
13.
Cattan V, Kakou A, Louis H, Lacolley P: Pathophysiology, genetic, and therapy of arterial stiffness. Biomed Mater Eng 2006;16:S155-S161.
14.
Ben-Shlomo Y, Spears M, Boustred C, May M, Anderson SG, Benjamin EJ, Boutouyrie P, Cameron J, Chen CH, Cruickshank JK, Hwang SJ, Lakatta EG, Laurent S, Maldonado J, Mitchell GF, Najjar SS, Newman AB, Ohishi M, Pannier B, Pereira T, Vasan RS, Shokawa T, Sutton-Tyrell K, Verbeke F, Wang KL, Webb DJ, Willum Hansen T, Zoungas S, McEniery CM, Cockcroft JR, Wilkinson IB: Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects. J Am Coll Cardiol 2014;63:636-646.
15.
Pannier B, Guerin AP, Marchais SJ, Safar ME, London GM: Stiffness of capacitive and conduit arteries: prognostic significance for end-stage renal disease patients. Hypertension 2005;45:592-596.
16.
Mitchell GF, Wang N, Palmisano JN, Larson MG, Hamburg NM, Vita JA, Levy D, Benjamin EJ, Vasan RS: Hemodynamic correlates of blood pressure across the adult age spectrum: noninvasive evaluation in the Framingham Heart Study. Circulation 2010;122:1379-1386.
17.
Mitchell GF, Parise H, Benjamin EJ, Larson MG, Keyes MJ, Vita JA, Vasan RS, Levy D: Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart Study. Hypertension 2004;43:1239-1245.
18.
Mitchell GF: Effects of central arterial aging on the structure and function of the peripheral vasculature: implications for end-organ damage. J Appl Physiol 2008;105:1652-1660.
19.
Williamson GA, Loutzenhiser R, Wang X, Griffin K, Bidani AK: Systolic and mean blood pressures and afferent arteriolar myogenic response dynamics: a modeling approach. Am J Physiol Regul Integr Comp Physiol 2008;295:R1502-R1511.
20.
Loutzenhiser R, Bidani A, Chilton L: Renal myogenic response: kinetic attributes and physiological role. Circ Res 2002;90:1316-1324.
21.
Mitchell GF, Vita JA, Larson MG, Parise H, Keyes MJ, Warner E, Vasan RS, Levy D, Benjamin EJ: Cross-sectional relations of peripheral microvascular function, cardiovascular disease risk factors, and aortic stiffness: the Framingham Heart Study. Circulation 2005;112:3722-3728.
22.
Schillaci G, Bilo G, Pucci G, Laurent S, Macquin-Mavier I, Boutouyrie P, Battista F, Settimi L, Desamericq G, Dolbeau G, Faini A, Salvi P, Mannarino E, Parati G: Relationship between short-term blood pressure variability and large-artery stiffness in human hypertension: findings from 2 large databases. Hypertension 2012;60:369-377.
23.
Mitchell GF: Cerebral small vessel disease: role of aortic stiffness and pulsatile hemodynamics. J Hypertens 2015;33:2025-2028.
24.
Mitchell GF, van Buchem MA, Sigurdsson S, Gotal JD, Jonsdottir MK, Kjartansson O, 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 2011;134:3398-3407.
25.
Woodard T, Sigurdsson S, Gotal JD, Torjesen AA, Inker LA, Aspelund T, Eiriksdottir G, Gudnason V, Harris TB, Launer LJ, Levey AS, Mitchell GF: Mediation analysis of aortic stiffness and renal microvascular function. J Am Soc Nephrol 2015;26:1181-1187.
26.
Pase MP, Himali JJ, Mitchell GF, Beiser A, Maillard P, Tsao C, Larson MG, DeCarli C, Vasan RS, Seshadri S: Association of aortic stiffness with cognition and brain aging in young and middle-aged adults: the Framingham Third Generation Cohort Study. Hypertension 2016;67:513-519.
27.
Maillard P, Mitchell GF, Himali JJ, Beiser A, Tsao CW, Pase MP, Satizabal CL, Vasan RS, Seshadri S, DeCarli C: Effects of arterial stiffness on brain integrity in young adults from the Framingham Heart Study. Stroke 2016;47:1030-1036.
28.
Tsao CW, Himali JJ, Beiser AS, Larson MG, DeCarli C, Vasan RS, Mitchell GF, Seshadri S: Association of arterial stiffness with progression of subclinical brain and cognitive disease. Neurology 2016;86:619-626.
29.
Prins ND, van Dijk EJ, den Heijer T, Vermeer SE, Jolles J, Koudstaal PJ, Hofman A, Breteler MM: Cerebral small-vessel disease and decline in information processing speed, executive function and memory. Brain 2005;128:2034-2041.
30.
Jokinen H, Kalska H, Ylikoski R, Madureira S, Verdelho A, van der Flier WM, Scheltens P, Barkhof F, Visser MC, Fazekas F, Schmidt R, O'Brien J, Waldemar G, Wallin A, Chabriat H, Pantoni L, Inzitari D, Erkinjuntti T; LADIS Group: Longitudinal cognitive decline in subcortical ischemic vascular disease - the LADIS Study. Cerebrovasc Dis 2009;27:384-391.
31.
Poels MM, van Oijen M, Mattace-Raso FU, Hofman A, Koudstaal PJ, Witteman JC, Breteler MM: Arterial stiffness, cognitive decline, and risk of dementia: the Rotterdam Study. Stroke 2007;38:888-892.
32.
Watson NL, Sutton-Tyrrell K, Rosano C, Boudreau RM, Hardy SE, Simonsick EM, Najjar SS, Launer LJ, Yaffe K, Atkinson HH, Satterfield S, Newman AB: Arterial stiffness and cognitive decline in well-functioning older adults. J Gerontol A Biol Sci Med Sci 2011;66:1336-1342.
33.
Grool AM, van der Graaf Y, Mali WP, Geerlings MI; SMART Study Group: Location of cerebrovascular and degenerative changes, depressive symptoms and cognitive functioning in later life: the SMART-Medea Study. J Neurol Neurosurg Psychiatry 2011;82:1093-1100.
34.
Schmidt R, Ropele S, Enzinger C, Petrovic K, Smith S, Schmidt H, Matthews PM, Fazekas F: White matter lesion progression, brain atrophy, and cognitive decline: the Austrian Stroke Prevention Study. Ann Neurol 2005;58:610-616.
35.
Kloppenborg RP, Nederkoorn PJ, Geerlings MI, van den Berg E: Presence and progression of white matter hyperintensities and cognition: a meta-analysis. Neurology 2014;82:2127-2138.
36.
Jokinen H, Gouw AA, Madureira S, Ylikoski R, van Straaten EC, van der Flier WM, Barkhof F, Scheltens P, Fazekas F, Schmidt R, Verdelho A, Ferro JM, Pantoni L, Inzitari D, Erkinjuntti T; LADIS Group: Incident lacunes influence cognitive decline: the LADIS Study. Neurology 2011;76:1872-1878.
37.
Wahlin A, Ambarki K, Birgander R, Malm J, Eklund A: Intracranial pulsatility is associated with regional brain volume in elderly individuals. Neurobiol Aging 2014;35:365-372.
38.
Mackinnon DP, Fairchild AJ: Current directions in mediation analysis. Curr Dir Psychol Sci 2009;18:16.
39.
Hayes AF: An Introduction to Mediation, Moderation, and Conditional Process Analysis: A Regression-Based Approach. New York, Guilford Press, 2013.
40.
Valeri L, VanderWeele TJ: SAS macro for causal mediation analysis with survival data. Epidemiology 2015;26:e23-e24.
41.
Tarumi T, Shah F, Tanaka H, Haley AP: Association between central elastic artery stiffness and cerebral perfusion in deep subcortical gray and white matter. Am J Hypertens 2011;24:1108-1113.
42.
Qiu CX, von Strauss E, Fastbom J, Winblad B, Fratiglioni L: Low blood pressure and risk of dementia in the Kungsholmen project - a 6-year follow-up study. Arch Neurol 2003;60:223-228.
43.
Carare RO, Hawkes CA, Jeffrey M, Kalaria RN, Weller RO: Review: cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy. Neuropathol Appl Neurobiol 2013;39:593-611.
44.
Shah NS, Vidal JS, Masaki K, Petrovitch H, Ross GW, Tilley C, DeMattos RB, Tracy RP, White LR, Launer LJ: Midlife blood pressure, plasma β-amyloid, and the risk for Alzheimer disease: the Honolulu Asia Aging Study. Hypertension 2012;59:780-786.
45.
Hughes TM, Kuller LH, Barinas-Mitchell EJM, Mackey RH, McDade EM, Klunk WE, Aizenstein HJ, Cohen AD, Snitz BE, Mathis CA, DeKosky ST, Lopez OL: Pulse wave velocity is associated with β-amyloid deposition in the brains of very elderly adults. Neurology 2013;81:1711-1718.
46.
Hughes TM, Kuller LH, Barinas-Mitchell EJM, McDade EM, Klunk WE, Cohen AD, Mathis CA, DeKosky ST, Price JC, Lopez OL: Arterial stiffness and β-amyloid progression in nondemented elderly adults. JAMA Neurol 2014;71:562-568.
47.
Bangen KJ, Nation DA, Delano-Wood L, Weissberger GH, Hansen LA, Galasko DR, Salmon DP, Bondi MW: Aggregate effects of vascular risk factors on cerebrovascular changes in autopsy-confirmed Alzheimer's disease. Alzheimers Dement 2014;11:394-403.
48.
Spilt A, Box FMA, van der Geest RJ, Reiber JHC, Kunz P, Kamper AM, Blauw GJ, van Buchem MA: Reproducibility of total cerebral blood flow measurements using phase contrast magnetic resonance imaging. J Magn Reson Imaging 2002;16:1-5.
49.
Kalaria RN, Akinyemi R, Ihara M: Does vascular pathology contribute to Alzheimer changes? J Neurol Sci 2012;322:141-147.
50.
Scuteri A, Stone J, O'Rourke MF: The relationship between aortic stiffness, microvascular disease in the brain and cognitive decline: insights into the emerging epidemic of Alzheimer's disease; in Safar ME, O'Rourke MF, Frohlich ED (eds): Blood Pressure and Arterial Wall Mechanics in Cardiovascular Diseases. London, Springer, 2014, pp 307-320.
51.
DeCarli C: Clinically asymptomatic vascular brain injury: a potent cause of cognitive impairment among older individuals. J Alzheimers Dis 2013;33(suppl 1):S417-S426.
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