The rationale and design of the antihypertensives and vascular, endothelial, and cognitive function (AVEC) trial in elderly hypertensives with early cognitive impairment: role of the renin angiotensin system inhibition

Ihab Hajjar, Meaghan Hart, William Milberg, Vera Novak, Lewis Lipsitz, Ihab Hajjar, Meaghan Hart, William Milberg, Vera Novak, Lewis Lipsitz

Abstract

Background: Prior evidence suggests that the renin angiotensin system and antihypertensives that inhibit this system play a role in cognitive, central vascular, and endothelial function. Our objective is to conduct a double-blind randomized controlled clinical trial, the antihypertensives and vascular, endothelial, and cognitive function (AVEC), to compare 1 year treatment of 3 antihypertensives (lisinopril, candesartan, or hydrochlorothiazide) in their effect on memory and executive function, cerebral blood flow, and central endothelial function of seniors with hypertension and early objective evidence of executive or memory impairments.

Methods/design: The overall experimental design of the AVEC trial is a 3-arm double blind randomized controlled clinical trial. A total of 100 community eligible individuals (60 years or older) with hypertension and early cognitive impairment are being recruited from the greater Boston area and randomized to lisinopril, candesartan, or hydrochlorothiazide ("active control") for 12 months. The goal of the intervention is to achieve blood pressure control defined as SBP < 140 mm Hg and DBP < 90 mm Hg. Additional antihypertensives are added to achieve this goal if needed. Eligible participants are those with hypertension, defined as a blood pressure 140/90 mm Hg or greater, early cognitive impairment without dementia defined (10 or less out of 15 on the executive clock draw test or 1 standard deviation below the mean on the immediate memory subtest of the repeatable battery for the assessment of neuropsychological status and Mini-Mental-Status-exam >20 and without clinical diagnosis of dementia or Alzheimer's disease). Individuals who are currently receiving antihypertensives are eligible to participate if the participants and the primary care providers are willing to taper their antihypertensives. Participants undergo cognitive assessment, measurements of cerebral blood flow using Transcranial Doppler, and central endothelial function by measuring changes in cerebral blood flow in response to changes in end tidal carbon dioxide at baseline (off antihypertensives), 6, and 12 months. Our outcomes are change in cognitive function score (executive and memory), cerebral blood flow, and carbon dioxide cerebral vasoreactivity.

Discussion: The AVEC trial is the first study to explore impact of antihypertensives in those who are showing early evidence of cognitive difficulties that did not reach the threshold of dementia. Success of this trial will offer new therapeutic application of antihypertensives that inhibit the renin angiotensin system and new insights in the role of this system in aging.

Trial registration: Clinicaltrials.gov NCT00605072.

Figures

Figure 1
Figure 1
Study flow of the AVEC trial from the screening tothe study exit.
Figure 2
Figure 2
Power analysis for the minimum detectable difference between the 3 groups in the change in outcome from baseline to 12 months of the AVEC trial. (assuming alpha = 0.05 and power = 80%)

References

    1. Kilander L, Nyman H, Boberg M, Hansson L, Lithell H. Hypertension is related to cognitive impairment: a 20-year follow-up of 999 men. Hypertension. 1998;31:780–786.
    1. Paran E, Anson O, Reuveni H. Blood pressure and cognitive functioning among independent elderly. Am J Hypertens. 2003;16:818–826. doi: 10.1016/S0895-7061(03)01005-7.
    1. Launer LJ, Masaki K, Petrovitch H, Foley D, Havlik RJ. The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. Jama. 1995;274:1846–1851. doi: 10.1001/jama.274.23.1846.
    1. Knopman D, Boland LL, Mosley T, Howard G, Liao D, Szklo M, McGovern P, Folsom AR. Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology. 2001;56:42–48.
    1. Reinprecht F, Elmstahl S, Janzon L, Andre-Petersson L. Hypertension and changes of cognitive function in 81-year-old men: a 13-year follow-up of the population study "Men born in 1914", Sweden. J Hypertens. 2003;21:57–66. doi: 10.1097/00004872-200301000-00014.
    1. Bellew KM, Pigeon JG, Stang PE, Fleischman W, Gardner RM, Baker WW. Hypertension and the rate of cognitive decline in patients with dementia of the Alzheimer type. Alzheimer Dis Assoc Disord. 2004;18:208–213.
    1. Goldstein FC, Ashley AV, Freedman LJ, Penix L, Lah JJ, Hanfelt J, Levey AI. Hypertension and cognitive performance in African Americans with Alzheimer disease. Neurology. 2005;64:899–901. doi: 10.1212/.
    1. Pugh KG, Kiely DK, Milberg WP, Lipsitz LA. Selective impairment of frontal-executive cognitive function in african americans with cardiovascular risk factors. J Am Geriatr Soc. 2003;51:1439–1444. doi: 10.1046/j.1532-5415.2003.51463.x.
    1. Saxby BK, Harrington F, McKeith IG, Wesnes K, Ford GA. Effects of hypertension on attention, memory, and executive function in older adults. Health Psychol. 2003;22:587–591. doi: 10.1037/0278-6133.22.6.587.
    1. Kuo HK, Sorond F, Iloputaife I, Gagnon M, Milberg W, Lipsitz LA. Effect of blood pressure on cognitive functions in elderly persons. J Gerontol A Biol Sci Med Sci. 2004;59:1191–1194.
    1. Royall DR, Lauterbach EC, Cummings JL, Reeve A, Rummans TA, Kaufer DI, LaFrance WC Jr, Coffey CE. Executive Control Function: A Review of Its Promise and Challenges for Clinical Research. A Report From the Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci. 2002;14:377–405.
    1. Royall DR, Cordes J, Polk M. Executive control and the comprehension of medical information by elderly retirees. Exp Aging Res. 1997;23:301–313. doi: 10.1080/03610739708254033.
    1. Cahn-Weiner DA, Malloy PF, Boyle PA, Marran M, Salloway S. Prediction of functional status from neuropsychological tests in community-dwelling elderly individuals. Clin Neuropsychol. 2000;14:187–195.
    1. Royall DR, Palmer R, Chiodo LK, Polk MJ. Declining executive control in normal aging predicts change in functional status: the Freedom House Study. J Am Geriatr Soc. 2004;52:346–352. doi: 10.1111/j.1532-5415.2004.52104.x.
    1. Grigsby J, Kaye K, Shetterly SM, Baxter J, Morgenstern NE, Hamman RF. Prevalence of disorders of executive cognitive functioning among the elderly: findings from the San Luis Valley Health and Aging Study. Neuroepidemiology. 2002;21:213–220. doi: 10.1159/000065638.
    1. Royall DR, Espino DV, Polk MJ, Palmer RF, Markides KS. Prevalence and patterns of executive impairment in community dwelling Mexican Americans: results from the Hispanic EPESE Study. Int J Geriatr Psychiatry. 2004;19:926–934. doi: 10.1002/gps.1185.
    1. Ruitenberg A, den Heijer T, Bakker SL, van Swieten JC, Koudstaal PJ, Hofman A, Breteler MM. Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study. Ann Neurol. 2005;57:789–794. doi: 10.1002/ana.20493.
    1. Maalikjy Akkawi N, Borroni B, Agosti C, Magoni M, Broli M, Pezzini A, Padovani A. Volume cerebral blood flow reduction in pre-clinical stage of Alzheimer disease: evidence from an ultrasonographic study. J Neurol. 2005;252:559–563. doi: 10.1007/s00415-005-0689-z.
    1. Silvestrini M, Pasqualetti P, Baruffaldi R, Bartolini M, Handouk Y, Matteis M, Moffa F, Provinciali L, Vernieri F. Cerebrovascular reactivity and cognitive decline in patients with Alzheimer disease. Stroke. 2006;37:1010–1015. doi: 10.1161/01.STR.0000206439.62025.97.
    1. Ameriso SF, Paganini-Hill A, Meiselman HJ, Fisher M. Correlates of middle cerebral artery blood velocity in the elderly. Stroke. 1990;21:1579–1583.
    1. Murphy DG, DeCarli C, McIntosh AR, Daly E, Mentis MJ, Pietrini P, Szczepanik J, Schapiro MB, Grady CL, Horwitz B, Rapoport SI. Sex differences in human brain morphometry and metabolism: an in vivo quantitative magnetic resonance imaging and positron emission tomography study on the effect of aging. Arch Gen Psychiatry. 1996;53:585–594.
    1. Krejza J, Mariak Z, Walecki J, Szydlik P, Lewko J, Ustymowicz A. Transcranial color Doppler sonography of basal cerebral arteries in 182 healthy subjects: age and sex variability and normal reference values for blood flow parameters. AJR Am J Roentgenol. 1999;172:213–218.
    1. Cavestri R, Radice L, Ferrarini F, Longhini M, Longhini E. Influence of erythrocyte aggregability and plasma fibrinogen concentration on CBF with aging. Acta Neurol Scand. 1992;85:292–298. doi: 10.1111/j.1600-0447.1992.tb01472.x.
    1. Kazama K, Wang G, Frys K, Anrather J, Iadecola C. Angiotensin II attenuates functional hyperemia in the mouse somatosensory cortex. Am J Physiol Heart Circ Physiol. 2003;285:H1890–1899.
    1. 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. 2005;98:151–159. doi: 10.1152/japplphysiol.00471.2004.
    1. Ando H, Zhou J, Macova M, Imboden H, Saavedra JM. Angiotensin II AT1 receptor blockade reverses pathological hypertrophy and inflammation in brain microvessels of spontaneously hypertensive rats. Stroke. 2004;35:1726–1731. doi: 10.1161/01.STR.0000129788.26346.18.
    1. Gard PR. The role of angiotensin II in cognition and behaviour. Eur J Pharmacol. 2002;438:1–14. doi: 10.1016/S0014-2999(02)01283-9.
    1. Saavedra JM, Nishimura Y. Angiotensin and cerebral blood flow. Cell Mol Neurobiol. 1999;19:553–573. doi: 10.1023/A:1006995016403.
    1. Kazama K, Anrather J, Zhou P, Girouard H, Frys K, Milner TA, Iadecola C. Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals. Circ Res. 2004;95:1019–1026. doi: 10.1161/01.RES.0000148637.85595.c5.
    1. Haberl RL, Decker PJ, Einhaupl KM. Angiotensin degradation products mediate endothelium-dependent dilation of rabbit brain arterioles. Circ Res. 1991;68:1621–1627.
    1. Dal-Ros S, Bronner C, Schott C, Kane MO, Chataigneau M, Schini-Kerth VB, Chataigneau T. Angiotensin II-induced hypertension is associated with a selective inhibition of endothelium-derived hyperpolarizing factor-mediated responses in the rat mesenteric artery. J Pharmacol Exp Ther. 2009;328:478–486. doi: 10.1124/jpet.108.145326.
    1. Dimitropoulou C, Chatterjee A, McCloud L, Yetik-Anacak G, Catravas JD. Angiotensin, bradykinin and the endothelium. Handb Exp Pharmacol. 2006. pp. 255–294. full_text.
    1. Khalil Z, LoGiudice D, Khodr B, Maruff P, Masters C. Impaired peripheral endothelial microvascular responsiveness in Alzheimer's disease. J Alzheimers Dis. 2007;11:25–32.
    1. Ghiadoni L, Virdis A. Aging and hypertension: what about the endothelium? J Hypertens. 2006;24:1243–1244. doi: 10.1097/01.hjh.0000234100.93120.c5.
    1. Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S. The ageing endothelium, cardiovascular risk and disease in man. Exp Physiol. 2009;94:317–321. doi: 10.1113/expphysiol.2008.043356.
    1. Taddei S, Virdis A, Ghiadoni L, Versari D, Salvetti A. Endothelium, aging, and hypertension. Curr Hypertens Rep. 2006;8:84–89. doi: 10.1007/s11906-006-0045-4.
    1. d'Alessio P. Aging and the endothelium. Exp Gerontol. 2004;39:165–171. doi: 10.1016/j.exger.2003.10.025.
    1. Moser DJ, Miller IN, Hoth KF, Correia M, Arndt S, Haynes WG. Vascular smooth muscle function is associated with initiation and processing speed in patients with atherosclerotic vascular disease. J Int Neuropsychol Soc. 2008;14:535–541. doi: 10.1017/S1355617708080697.
    1. Ainslie PN, Murrell C, Peebles K, Swart M, Skinner MA, Williams MJ, Taylor RD. Early morning impairment in cerebral autoregulation and cerebrovascular CO2 reactivity in healthy humans: relation to endothelial function. Exp Physiol. 2007;92:769–777. doi: 10.1113/expphysiol.2006.036814.
    1. Ai D, Fu Y, Guo D, Tanaka H, Wang N, Tang C, Hammock BD, Shyy JY, Zhu Y. Angiotensin II up-regulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo. Proc Natl Acad Sci USA. 2007;104:9018–9023. doi: 10.1073/pnas.0703229104.
    1. Murray MD, Lane KA, Gao S, Evans RM, Unverzagt FW, Hall KS, Hendrie H. Preservation of cognitive function with antihypertensive medications: a longitudinal analysis of a community-based sample of African Americans. Arch Intern Med. 2002;162:2090–2096. doi: 10.1001/archinte.162.18.2090.
    1. Manolio TA, Olson J, Longstreth WT. Hypertension and cognitive function: pathophysiologic effects of hypertension on the brain. Curr Hypertens Rep. 2003;5:255–261. doi: 10.1007/s11906-003-0029-6.
    1. Roig E, Perez-Villa F, Morales M, Jimenez W, Orus J, Heras M, Sanz G. Clinical implications of increased plasma angiotensin II despite ACE inhibitor therapy in patients with congestive heart failure. Eur Heart J. 2000;21:53–57. doi: 10.1053/euhj.1999.1740.
    1. Padmanabhan N, Jardine AG, McGrath JC, Connell JM. Angiotensin-converting enzyme-independent contraction to angiotensin I in human resistance arteries. Circulation. 1999;99:2914–2920.
    1. Tedesco MA, Ratti G, Mennella S, Manzo G, Grieco M, Rainone AC, Iarussi D, Iacono A. Comparison of losartan and hydrochlorothiazide on cognitive function and quality of life in hypertensive patients. Am J Hypertens. 1999;12:1130–1134. doi: 10.1016/S0895-7061(99)00156-9.
    1. Tzourio C, Anderson C, Chapman N, Woodward M, Neal B, MacMahon S, Chalmers J. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med. 2003;163:1069–1075. doi: 10.1001/archinte.163.9.1069.
    1. Cummings JL, Cole G. Alzheimer disease. Jama. 2002;287:2335–2338. doi: 10.1001/jama.287.18.2335.
    1. Benedict RH, Brandt J. Limitation of the Mini-Mental State Examination for the detection of amnesia. J Geriatr Psychiatry Neurol. 1992;5:233–237.
    1. Pogosova GV, Zhidko NI, Ivanishina NS, Gudkova OA, Avakian GN. [Ramipril in elderly patients with mild and moderate hypertension. Clinical efficacy, effect on cerebral blood flow and intellectual functioning] Kardiologiia. 2003;43:42–47.
    1. Braszko JJ, Karwowska-Polecka W, Halicka D, Gard PR. Captopril and enalapril improve cognition and depressed mood in hypertensive patients. J Basic Clin Physiol Pharmacol. 2003;14:323–343.
    1. Zuccala G, Onder G, Marzetti E, Monaco MR, Cesari M, Cocchi A, Carbonin P, Bernabei R. Use of angiotensin-converting enzyme inhibitors and variations in cognitive performance among patients with heart failure. Eur Heart J. 2005;26:226–233. doi: 10.1093/eurheartj/ehi058.
    1. Skoog I, Lithell H, Hansson L, Elmfeldt D, Hofman A, Olofsson B, Trenkwalder P, Zanchetti A. Effect of baseline cognitive function and antihypertensive treatment on cognitive and cardiovascular outcomes: Study on COgnition and Prognosis in the Elderly (SCOPE) Am J Hypertens. 2005;18:1052–1059. doi: 10.1016/j.amjhyper.2005.02.013.
    1. Wagner C, Kramer BK, Hinder M, Kieninger M, Kurtz A. T-type and L-type calcium channel blockers exert opposite effects on renin secretion and renin gene expression in conscious rats. Br J Pharmacol. 1998;124:579–585. doi: 10.1038/sj.bjp.0701861.
    1. Nascimento L, Ayala JM, Baquero RA, Martinez-Maldonado M. Renin release by diuretics. J Pharmacol Exp Ther. 1979;208:522–526.
    1. Di Bari M, Pahor M, Franse LV, Shorr RI, Wan JY, Ferrucci L, Somes GW, Applegate WB. Dementia and disability outcomes in large hypertension trials: lessons learned from the systolic hypertension in the elderly program (SHEP) trial. Am J Epidemiol. 2001;153:72–78. doi: 10.1093/aje/153.1.72.
    1. Sadoshima S, Nagao T, Ibayashi S, Fujishima M. Inhibition of angiotensin-converting enzyme modulates the autoregulation of regional cerebral blood flow in hypertensive rats. Hypertension. 1994;23:781–785.
    1. Dupuis F, Atkinson J, Liminana P, Chillon JM. Captopril improves cerebrovascular structure and function in old hypertensive rats. Br J Pharmacol. 2005;144:349–356. doi: 10.1038/sj.bjp.0706001.
    1. Nishimura Y, Ito T, Saavedra JM. Angiotensin II AT(1) blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spontaneously hypertensive rats. Stroke. 2000;31:2478–2486.
    1. Ito T, Yamakawa H, Bregonzio C, Terron JA, Falcon-Neri A, Saavedra JM. Protection against ischemia and improvement of cerebral blood flow in genetically hypertensive rats by chronic pretreatment with an angiotensin II AT1 antagonist. Stroke. 2002;33:2297–2303. doi: 10.1161/01.STR.0000027274.03779.F3.
    1. Yamakawa H, Jezova M, Ando H, Saavedra JM. Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition. J Cereb Blood Flow Metab. 2003;23:371–380. doi: 10.1097/00004647-200303000-00012.
    1. Demirci B, McKeown PP, Bayraktutan U. Blockade of angiotensin II provides additional benefits in hypertension- and ageing-related cardiac and vascular dysfunctions beyond its blood pressure-lowering effects. J Hypertens. 2005;23:2219–2227. doi: 10.1097/.
    1. Hatazawa J, Shimosegawa E, Osaki Y, Ibaraki M, Oku N, Hasegawa S, Nagata K, Hirata Y, Miura Y. Long-term angiotensin-converting enzyme inhibitor perindopril therapy improves cerebral perfusion reserve in patients with previous minor stroke. Stroke. 2004;35:2117–2122. doi: 10.1161/01.STR.0000136034.86144.e9.
    1. Lipsitz LA, Gagnon M, Vyas M, Iloputaife I, Kiely DK, Sorond F, Serrador J, Cheng DM, Babikian V, Cupples LA. Antihypertensive therapy increases cerebral blood flow and carotid distensibility in hypertensive elderly subjects. Hypertension. 2005;45:216–221. doi: 10.1161/01.HYP.0000153094.09615.11.
    1. Moriwaki H, Uno H, Nagakane Y, Hayashida K, Miyashita K, Naritomi H. Losartan, an angiotensin II (AT1) receptor antagonist, preserves cerebral blood flow in hypertensive patients with a history of stroke. J Hum Hypertens. 2004;18:693–699. doi: 10.1038/sj.jhh.1001735.
    1. Kario K, Ishikawa J, Hoshide S, Matsui Y, Morinari M, Eguchi K, Ishikawa S, Shimada K. Diabetic brain damage in hypertension: role of renin-angiotensin system. Hypertension. 2005;45:887–893. doi: 10.1161/01.HYP.0000163460.07639.3f.
    1. Morimoto S, Maki K, Aota Y, Sakuma T, Iwasaka T. Beneficial effects of combination therapy with angiotensin II receptor blocker and angiotensin-converting enzyme inhibitor on vascular endothelial function. Hypertens Res. 2008;31:1603–1610. doi: 10.1291/hypres.31.1603.
    1. Schiffrin EL, Park JB, Pu Q. Effect of crossing over hypertensive patients from a beta-blocker to an angiotensin receptor antagonist on resistance artery structure and on endothelial function. J Hypertens. 2002;20:71–78. doi: 10.1097/00004872-200201000-00011.
    1. Braszko JJ. AT(2) but not AT(1) receptor antagonism abolishes angiotensin II increase of the acquisition of conditioned avoidance responses in rats. Behav Brain Res. 2002;131:79–86. doi: 10.1016/S0166-4328(01)00349-7.
    1. Wilms H, Rosenstiel P, Unger T, Deuschl G, Lucius R. Neuroprotection with angiotensin receptor antagonists: a review of the evidence and potential mechanisms. Am J Cardiovasc Drugs. 2005;5:245–253. doi: 10.2165/00129784-200505040-00004.
    1. Chrysant SG, Chrysant GS. The pleiotropic effects of Angiotensin receptor blockers. J Clin Hypertens (Greenwich) 2006;8:261–268. doi: 10.1111/j.1524-6175.2005.05264.x.
    1. Sonoda M, Aoyagi T, Takenaka K, Uno K, Nagai R. A one-year study of the antiatherosclerotic effect of the angiotensin-II receptor blocker losartan in hypertensive patients. A comparison with angiotension-converting enzyme inhibitors. Int Heart J. 2008;49:95–103. doi: 10.1536/ihj.49.95.
    1. Royall DR, Cordes JA, Polk M. CLOX: an executive clock drawing task. J Neurol Neurosurg Psychiatry. 1998;64:588–594. doi: 10.1136/jnnp.64.5.588.
    1. Randolph C, Tierney MC, Mohr E, Chase TN. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol. 1998;20:310–319. doi: 10.1076/jcen.20.3.310.823.
    1. Duff K, Patton D, Schoenberg MR, Mold J, Scott JG, Adams RL. Age- and education-corrected independent normative data for the RBANS in a community dwelling elderly sample. Clin Neuropsychol. 2003;17:351–366.
    1. Bis JC, Smith NL, Psaty BM, Heckbert SR, Edwards KL, Lemaitre RN, Lumley T, Rosendaal FR. Angiotensinogen Met235Thr polymorphism, angiotensin-converting enzyme inhibitor therapy, and the risk of nonfatal stroke or myocardial infarction in hypertensive patients. Am J Hypertens. 2003;16:1011–1017. doi: 10.1016/j.amjhyper.2003.07.018.
    1. Washburn RA, Ficker JL. Physical Activity Scale for the Elderly (PASE): the relationship with activity measured by a portable accelerometer. J Sports Med Phys Fitness. 1999;39:336–340.
    1. Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist. 1969;9:179–186.
    1. Kurtz TW, Griffin KA, Bidani AK, Davisson RL, Hall JE. Recommendations for blood pressure measurement in humans and experimental animals. Part 2: Blood pressure measurement in experimental animals: a statement for professionals from the subcommittee of professional and public education of the American Heart Association council on high blood pressure research. Hypertension. 2005;45:299–310. doi: 10.1161/01.HYP.0000150857.39919.cb.
    1. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, Jones DW, Kurtz T, Sheps SG, Roccella EJ. Recommendations for blood pressure measurement in humans and experimental animals: Part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension. 2005;45:142–161.
    1. Crum RM, Anthony JC, Bassett SS, Folstein MF. Population-based norms for the Mini-Mental State Examination by age and educational level. Jama. 1993;269:2386–2391. doi: 10.1001/jama.269.18.2386.
    1. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–198. doi: 10.1016/0022-3956(75)90026-6.
    1. Shapiro AM, Benedict RH, Schretlen D, Brandt J. Construct and concurrent validity of the Hopkins Verbal Learning Test-revised. Clin Neuropsychol. 1999;13:348–358.
    1. Kreiner DS, Ryan JJ. Memory and motor skill components of the WAIS-III Digit Symbol-Coding subtest. Clin Neuropsychol. 2001;15:109–113.
    1. Wechsler D. WMS-R: Wechsler Memory Scale--Revised: manual. San Antonio: Psychological Corp: Harcourt Brace Jovanovich; 1987.
    1. Lipsitz LA, Mukai S, Hamner J, Gagnon M, Babikian V. Dynamic regulation of middle cerebral artery blood flow velocity in aging and hypertension. Stroke. 2000;31:1897–1903.
    1. Newell DW, Aaslid R. Transcranial Doppler: clinical and experimental uses. Cerebrovasc Brain Metab Rev. 1992;4:122–143.
    1. Aaslid R, Markwalder TM, Nornes H. Noninvasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries. J Neurosurg. 1982;57:769–774. doi: 10.3171/jns.1982.57.6.0769.
    1. Lipsitz LA, Mukai S, Hamner J, Gagnon M, Babikian V. Dynamic Regulation of Middle Cerebral Artery Blood Flow Velocity in Aging and Hypertension. Stroke. 2000;31:1897–1903.
    1. Cartledge S, Lawson N. Aldosterone and renin measurements. Ann Clin Biochem. 2000;37(Pt 3):262–278. doi: 10.1258/0004563001899401.
    1. Underwood RH, Williams GH. The simultaneous measurement of aldosterone, cortisol, and corticosterone in human peripheral plasma by displacement analysis. J Lab Clin Med. 1972;79:848–862.
    1. Emanuel RL, Cain JP, Williams GH. Double antibody radioimmunoassay of renin activity and angiotensin II in human peripheral plasma. J Lab Clin Med. 1973;81:632–640.
    1. Dicpinigaitis PV. Angiotensin-Converting Enzyme Inhibitor-Induced Cough: ACCP Evidence-Based Clinical Practice Guidelines. Chest. 2006;129:169S–173. doi: 10.1378/chest.129.1_suppl.169S.
    1. Kostis JB, Kim HJ, Rusnak J, Casale T, Kaplan A, Corren J, Levy E. Incidence and Characteristics of Angioedema Associated With Enalapril. Arch Intern Med. 2005;165:1637–1642. doi: 10.1001/archinte.165.14.1637.
    1. Diggle P, Liang K, Zeger S. Analysis of Longitudinal Data. Oxford University Press; 1994.
    1. McCullagh P, Nelder J. Generalized Liner Models. London.: Chapman and Hall; 1987.
    1. Nilsson SE, Read S, Berg S, Johansson B, Melander A, Lindblad U. Low systolic blood pressure is associated with impaired cognitive function in the oldest old: longitudinal observations in a population-based sample 80 years and older. Aging Clin Exp Res. 2007;19:41–47.
    1. Kilander L, Nyman H, Boberg M, Lithell H. The association between low diastolic blood pressure in middle age and cognitive function in old age. A population-based study. Age Ageing. 2000;29:243–248. doi: 10.1093/ageing/29.3.243.
    1. Axelsson J, Reinprecht F, Siennicki-Lantz A, Elmstahl S. Low ambulatory blood pressure is associated with lower cognitive function in healthy elderly men. Blood Press Monit. 2008;13:269–275. doi: 10.1097/MBP.0b013e32830d4be6.

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