• Changes in Cerebral Blood Flow (CBF) and cerebral vasoreactivity [ Time Frame: Baseline, then 6 and 12 months after BP control ] [ Designated as safety issue: No ]
• Endothelial function assessed using the flow mediated dilatation (FMD) procedure [ Time Frame: Baseline, then 6 and 12 months after BP control ] [ Designated as safety issue: No ]
• Biochemical measurement to monitor for adverse events: hyperkalemia, renal failure, leukopenia and liver function abnormalities [ Time Frame: Baseline, 2-4 weeks, 2, 4, 9, and 12 months ] [ Designated as safety issue: Yes ]

• Changes in Cerebral Blood Flow (CBF) and cerebral vasoreactivity [ Time Frame: Baseline, and 6 months after BP control ] [ Designated as safety issue: No ]
• Endothelial function assessed using the flow mediated dilatation (FMD) procedure [ Time Frame: Baseline, and 6 months after BP control ] [ Designated as safety issue: No ]
• Biochemical measurement to monitor for adverse events: hyperkalemia, renal failure, leukopenia and liver function abnormalities [ Time Frame: Baseline, 2-4 weeks, 2, 4, and 9 months ] [ Designated as safety issue: Yes ]

The purpose of this study is to examine the effects of blood pressure medications on cognition and blood flow in hypertensive elderly patients with cognitive impairment. The hypothesis is that treatment with an angiotensin receptor blocker (ARB) or an angiotensin-converting enzyme inhibitor (ACEI) will be associated with a slower rate of further cognitive decline, improved cerebral blood flow and its regulation, and preserved physical function as compared to treatment with a diuretic (HCTZ), independent of blood pressure level.

There is mounting evidence that hypertension, which affects more than 65% of the US elderly population, accelerates cognitive decline and increases the risk of functional disability among older individuals. Hypertension is also associated with cerebral blood flow reduction and dysregulation which contribute to further cognitive and functional impairment. Drugs that inhibit angiotensin II (ACEI and ARB) are commonly used antihypertensives and may have a protective effect on cognitive function, cerebral blood flow and physical function compared to other antihypertensives such as hydrochlorothiazide (HCTZ).

A total of 100 individuals will be recruited for this pilot 3-arm randomized study to investigate the effects of: (i) 12 months treatment with candesartan (ARB) compared to hydrochlorothiazide (HCTZ) and (ii) 12 months treatment with lisinopril (ACEI) compared to HCTZ and (iii) to estimate the effect size difference between lisinopril and losartan on cognition, cerebral blood flow regulation, and functional measures in a sample of elderly hypertensive individuals with objective evidence of cognitive impairment.

• Cognitive Impairment
• Hypertension
• Aging

• Drug: candesartan
• Drug: lisinopril
• Drug: hydrochlorothiazide
• Drug: nifedipine, long acting
• Drug: metoprolol, long-acting

• Experimental: Angiotensin Receptor Blocker
• Experimental: Angiotensin-Converting Enzyme (ACE) Inhibitor

• 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 Feb;45(2):216-21. Epub 2005 Jan 17.
• Waldstein SR, Katzel LI. Gender differences in the relation of hypertension to cognitive function in older adults. Neurol Res. 2004 Jul;26(5):502-6.
• 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 Oct;51(10):1439-44.
• 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 Nov;59(11):1191-4.

Inclusion Criteria:

• 60 years or older
• Hypertension
• Cognitive criteria: score either 10 or less out of 15 for the executive clock draw test 1 (CLOX1) or less than or equal to 1 standard deviation from the corresponding age specific mean on the immediate memory subtest

Exclusion Criteria:

• Intolerance to ACEI or ARB
• History of congestive heart failure
• History of diabetes mellitus
• History of stroke (less than 6 months)