Hypertension

Aside from its acknowledged role in cardiovascular and renal disease, hypertension has also been implicated in the development of impaired cognitive function and vascular dementia in geriatric patients. Vascular dementia accounts for 30% of all dementia cases, ranking second only to Alzheimer's disease. (1) The Centers for Disease Control and Prevention reported in 1999 that dementia occurred in 2.8% of persons age 65 to 74 and in 28% of those over age 85. By the year 2040, 6.1 million to 9.8 million persons may be affected. (1,9)

Epidemiologic and interventional studies

The inverse association of blood pressure with cognitive dysfunction is not yet fully established, but epidemiologic and treatment studies support this hypothesis. A population-based study (1) in Uppsala, Sweden, tracked 999 men from age 50 to 70. At age 50, mean diastolic blood pressure (DBP) measured in the office was 82 mm Hg; at age 70, mean DBP assessed by 24-hour ambulatory blood pressure monitoring, was 76 mm Hg. At age 70, cognitive function was assessed using the Mini Mental State Examination (MMSE) and the Trail Making Test.

High DBP at baseline predicted later impaired cognitive performance, even after excluding participants with prior stroke. The relationship was especially strong in untreated men. Non-dipping of blood pressure during the evening hours, insulin resistance, and diabetes were also risk factors for impaired cognition in the same cohort. (1)

The Honolulu Asia Aging Study (2) tested 3,735 Japanese American men from 1965 to 1968 and again from 1991 to 1993 with the Cognitive Abilities Screening Instrument. Controlling for age and education, the study found that for each 10 mm Hg increase in systolic blood pressure (SBP), there was a 7% increased risk for intermediate cognitive function (score <92 to 82) and 9% for poor cognitive function. (2) The same group reported that elevated blood pressure in middle age men correlated with increased risk for late age dementia in men never treated for hypertension (score <82).

Data from the Framingham Heart Study indicates that attention and memory measures are inversely related to blood pressure levels and duration of hypertension. (3) A population-based, French study of 1,373 men and women (mean age 65) with SBP [greater than or equal to] 160 mm Hg and DBP [greater than or equal to] 95 mm Hg noted an association between high blood pressure at baseline and a 4-point decline in the MMSE after 4 years (OR, 2.8). In addition, untreated hypertensive individuals had a risk of 4.3 for cognitive decline, whereas the risk for treated individuals was 1.9. (4)

The Atherosclerosis Risk in Communities study assessed 10,963 persons age 47 to 70, 32.4% of whom were hypertensive (blood pressure [greater than or equal to]140/90 mm Hg) or using antihypertensive medication. The authors administered cognitive assessment on two occasions, 6 years apart. The authors administered the delayed word recall test, the digit symbol subtest of the Wechsler Adult Intelligence Scale-Revised, and the first letter word fluency test. In multivariate analysis, the presence of diabetes or hypertension at baseline was positively associated with cognitive decline. In 2 of the 3 cognitive tests used, the group with the lowest SBP had the least cognitive decline. These authors suggest that interventions initiated early--before age 60--might reduce the burden of cognitive impairment later in life. (5)

The Swedish Kungsholmen project, a cross-sectional, population-based study of 1,270 non-demented persons over age 75, found a biphasic or U-shaped relationship of SBP and risk of dementia. Participants with baseline SBP [greater than or equal to] 180 mm Hg had a relative risk (RR) for dementia of 1.6, compared with those with SBP 141 to 160 mm Hg. When education, vascular disease, and antihypertensive drug use were factored in, the association persisted but dropped below statistical significance (RR=1.4). Researchers found that use of antihypertensive medications (primarily diuretics) at baseline reduced the risk of dementia (RR=0.7; p=0.03). (6,7)

However, the same study found that SBP <140 mm Hg was associated with an increased risk of dementia. The authors suggest that the latter may be related to comorbidities causing both dementia and low blood pressure or low blood pressure that "may be secondary to the dementia process itself." (7)

Direct and indirect causes

The biological mechanisms linking hypertension and cognitive dysfunction may be direct or indirect. Longstanding hypertension may indirectly increase the risk of atherosclerosis, stroke, or cerebral infarction, which in turn may cause cognitive decline. Senile plaques and neurofibrillary tangles may be more prevalent in non-demented hypertensive subjects.

Directly, hypertension may affect brain volume. A small U.S. study reported that patients with hypertension (age 56 to 84) had smaller volumes of thalamic nuclei, larger volumes of cerebrospinal fluid in the cerebellum and temporal lobes, and performed worse on language and memory tests. This suggests that the temporal and occipital regions appear more vulnerable to brain atrophy due to the interactive effects of age and hypertension. (8)

Autopsies of 243 men in the Honolulu Asia Aging Study indicated that elevated SBP ([greater than or equal to]160 mm Hg) in midlife was associated with low brain weight and greater numbers of neurofibrillary tangles in the neocortex and hippocampus at death. (2) Researchers concluded that midlife SBP is a significant predictor of reduced cognitive function in later life. Higher DBP ([greater than or equal to]95 mm Hg) in these men was also associated with greater numbers of neurofibrillary tangles in the hippocampus.

Lesions in the cerebral white matter of hypertensives detected by MRI suggest that hypertension may cause demyelination of the white matter and consequent cognitive decline. (9) The Epidemiology of Vascular Aging study found that hypertension is a major risk factor for severe white matter lesions, but that risk was reduced in hypertensive subjects taking antihypertensive medication and who have their blood pressure under control. (10)

Moderately elevated blood pressure levels have been considered acceptable in geriatric patients, for fear of inducing stroke or hypotensive states with treatment. However, many trials completed in the last decade confirmed that treating SBP to <140 mm Hg or DBP to <90 mm Hg is safe and beneficial for older persons. (19)

In recent years, SBP has been recognized as a far more important contributor to end organ damage than DBP.11 SBP rises steadily from age 30 through age 84, due to increasing age-related large artery stiffness, while DBP rises until the sixth decade, then declines. (11) Isolated systolic hypertension (ISH)--SBP >140 mm Hg accompanied by DBP <90 mm Hg--is the predominant form of hypertension in persons over age 50. (12) Since SBP has a stronger relation to vascular events, the best target for treatment (in uncomplicated hypertension) is SBP <140 mm Hg rather than DBP <90 mm Hg. (13)

Cognitive improvement

Studies have assessed whether antihypertensive treatment might actually improve cognitive function. Several studies suggest a strong protective effect of BP lowering. The Systolic Hypertension in Europe study (Syst Eur) included older patients with ISH randomized to treatment with the dihydropyridine calcium channel blocker nitrendipine, or placebo. [Editor's note: Nitrendipine is not FDA-approved for use in the U.S. Equivalent medications include amlodipine and felodipine.] The primary outcome was reduction in cardiovascular events. The Syst Eur trial was terminated early, only 2 years after randomization, because a clear benefit was demonstrated in the treated group for the primary endpoint. The investigators continued the project as an open label, active treatment study based on nitrendipine, plus enalapril and hydrochlorothiazide as needed. They then applied the same treatment standards to the 1,417 patients originally randomized to placebo and to the 1,485 who received active treatment in the first phase of the study. After 1.9 years of follow-up, the original placebo group, who received fewer years of treatment, recorded 43 cases of dementia (as measured by DSM III R criteria and MMSE scores) compared with 21 in the active cohort, or 7.4 to 3.3 cases per 1,000 patient years (p<0.001), respectively, giving an adjusted hazard rate for nitrendipine use of 0.38 (p<0.001). (14)

The observational, prospective, population based Rotterdam Study followed 6,416 subjects age >55 who were non-demented at baseline. After a mean 2.2 years, they were screened with the MMSE, and dementia was diagnosed using DSM III R criteria. The investigators determined that 70 of 4,401 non-users of antihypertensive drugs, and 48 of 2,016 treated subjects had become demented. Overall, there was no significant risk reduction for users of antihypertensive medications for dementia in general, however, there was an adjusted RR of 0.30 for vascular dementia for subjects taking antihypertensive medication at baseline. (15) Both Syst Eur and the Rotterdam study imply that starting treatment early or maintaining it for a long period of time may lead to better outcomes.

Using the MMSE with 387 subjects from the 1,083 subjects in the Medical Research Council (MRC) Treatment Trial of Hypertension in Older Adults, researchers found no association between baseline SBP or DBP and cognitive outcome, but did observe an association between poor response of SBP to treatment and poorer cognitive outcome. (16)

Several clinical trials of agents targeting the renin angiotensin aldosterone system tested whether treating hypertension can reduce cognitive dysfunction. The Perindopril Protection Against Recurrent Stroke Study examined whether use of an angiotensin converting enzyme (ACE) inhibitor (with or without a diuretic) affected incidence of dementia or cognitive impairment in secondary prevention. Treatment resulted in a non-significant risk reduction for dementia of 12% overall, but a significant reduction of 34% in patients with prior stroke. (17)

The Study on COgnition and Prognosis in the Elderly (SCOPE) recruited 4,937 patients age 70 to 89 (mean 76) with blood pressure 160-179/90-99 mm Hg and fairly preserved cognitive function. The trial tested the angiotensin receptor blocker (ARB) candesartan against an active treatment control arm using a low dose diuretic. The primary end point of the study was reduction in composite cardiovascular events. An important secondary endpoint was the change in cognitive function utilizing the MMSE score. SCOPE investigators found that patients with an initial MMSE score of [greater than or equal to] 29 experienced no deterioration over the 5-year follow-up period. For patients with an MMSE score of [less than or equal to] 28, candesartan therapy proved significantly more effective than conventional therapy in preventing cognitive function decline. (18)

The results of the Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial (ALLHAT)--the largest hypertension trial ever conducted--confirmed previous observations and validated the recommendation of the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). (19) In ALLHAT, diuretics were more effective than ACE inhibitors in preventing strokes and heart failure and more effective than calcium antagonists in preventing development of heart failure.

Conclusion

Evidence is convincing that elevated blood pressure is a strong risk factor for vascular dementia and decline of cognitive function in middle age and older patients, and that antihypertensive treatment reduces the risk of developing these conditions. Clinical trials and observational studies show that treating hypertension to [less than or equal to] 140/90 mm Hg lessens morbidity and mortality, and improves quality of life by lessening the cognitive complications of hypertension.

The greatest benefit from hypertension control is the reduction of risk for stroke, which is the strongest contributor to dementia and cognitive function decline. Numerous studies have shown that optimal treatment of hypertension will prevent more than 40% of strokes, regardless of the agent used. Most published studies used diuretic-based regimens and demonstrated impressive reductions in strokes and other cardiovascular complications. Comparative studies, such as LIFE and SCOPE, suggest ARBs may be particularly effective in preventing strokes.

Diuretics should remain the preferred class of agents for initial treatment of hypertension in older adults. Since most patients in clinical practice will require 2 or more drugs for blood pressure control, combinations of diuretics with other agents such as ACE inhibitors, ARBs, beta blockers, or calcium antagonists are appropriate. Treating blood pressure to target is important, and by doing so, many cardiovascular complications and the decline of cognitive function can be prevented.

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(3):780-6.

(2.) 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(23):1846-51.

(3.) Elias MF, Wolf PA, D'Agostino RB, Cobb J, White LR. Untreated blood pressure level is inversely related to cognitive functioning: the Framingham Study. Am J Epidemiol 1993; 138(6):353-64.

(4.) Tzourio C, Dufouil C, Ducimetiere P, Alperovitch, and the Epidemiology of Vascular Aging Study Group. A Cognitive decline in individuals with high blood pressure: A longitudinal study in the elderly. Neurology 1999; 53(9):1948-52.

(5.) Knopman D, Boland LL, Mosley T, et al. Cardiovascular risk factors and cognitive decline in middle aged adults. Neurology 2001; 56(1):42-8.

(6.) Guo Z, Fratiglioni L, Zhu L, Fastbom J, Winblad B, Viitanen M. Occurrence and progression of dementia in a community population aged 75-years and older: relationship of antihypertensive medication use. Arch Neurol 1999; 56(8):991-6.

(7.) Guo Z, Qiu C, Viitanen M, Fastbom J, Winblad B, Fratiglioni L. Blood pressure and dementia in persons 75+ years old: 3 year follow up results from the Kungsholmen Project. J Alzheimers Dis 2001; 3(6):585-91.

(8.) Strassburger TL, Lee HC, Daly EM, et al. Interactive effects of age and hypertension on volumes of brain structures. Stroke 1997; 28(7):1410-7.

(9.) van Swieten JC, Geyskes GG, Derix MM, et al. Hypertension in the elderly is associated with white matter lesions and cognitive decline. Ann Neurol 1991; 30(6):825-30.

(10.) Dufouil C, de Kersaint Gilly A, Besancon V, et al. Longitudinal study of blood pressure and white matter hyperintensity: The EVA MRI Cohort. Neurology 2001; 56(7):921-6.

(11.) Franklin SS, Gustin W, Wong ND, et al. Hemodynamic patterns of age related changes in blood pressure. The Framingham Heart Study. Circulation 1997; 96(1):308-15.

(12.) Chae CU, Lloyd-Jones DM. Isolated systolic hypertension in the elderly. Curr Treat Op Cardiovasc Med 2002; 4(1):87-93.

(13.) Izzo JL Jr, Levy D, Black HR. Clinical Advisory Statement. Importance of systolic blood pressure in older Americans. Hypertension 2000; 35(5):1021-4.

(14.) Forette F, Seux ML, Staessen JA, et al. The prevention of dementia with antihypertensive treatment. Arch Intern Med 2002; 162(18): 2046-52.

(15.) Veld BA, Ruitenberg A, Holman A, Stricker BH, Breteler MM. Antihypertensive drugs and incidence of dementia: the Rotterdam Study. Neurobiol Aging 2001; 22(3):407-12.

(16.) Cervilla JA, Prince M, Joels S, Lovestone S, Mann A. Long-term predictors of cognitive outcome in a cohort of older people with hypertension. Br J Psychiatry 2000; 177:66-71.

(17.) Tzourio C, Anderson C, Chapman N, et al. Reduction in the risk of dementia and severe cognitive decline in patients with stroke: The PROGRESS Study. Presented at: International Society of Hypertension/European Society of Hypertension; June 23-27, 2002; Prague, Czech Republic.

(18.) Hansson L. Study on Cognition and Prognosis in the Elderly (SCOPE). Presented at: International Society of Hypertension/European Society of Hypertension; June 27, 2002; Prague, Czech Republic.

(19.) ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288(23):2981-97.

Dr. Papademetriou is professor of medicine, cardiology, Georgetown University, Washington, DC; and consultant to the Department of Veterans Affairs Medical Centers, Washington, DC.

Disclosure: Dr. Papademetriou is supported by an unrestricted educational grant by Astra Zeneca.

COPYRIGHT 2005 Advanstar Communications, Inc.
COPYRIGHT 2005 Gale Group