Shari R. Waldstein1
Department of Psychology, University of Maryland, Baltimore County, Baltimore, Maryland; Division of Gerontology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland; and Geriatrics Research, Education, and Clinical Center, Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
Hypertension is an established risk factor for stroke. However, prior to such a major clinical event, hypertension exerts a more subtle impact on the brain that is revealed by diminished cognitive function. Studies comparing the performance of people with high and normal blood pressure levels have shown that high blood pressure or hypertension is related to poorer performance on tests of attention, learning and memory, executive functions, visuospatial skills, psychomotor abilities, and perceptual skills. Hypertension is also predictive of cognitive decline. Variables that may alter (i.e., moderate) the relation of hypertension to cognitive function include age, education, several biological characteristics of hypertension, and the presence of concurrent diseases. Although hypertensives are not clinically impaired, their diminished levels of cognitive performance could affect their perceived quality of life. Various brain mechanisms may explain the relation of hypertension to lower levels of cognitive function. Further understanding of the relation between hypertension and cognition is critical to the preservation of cognitive function across the life span.
hypertension; blood pressure; cognitive function; neuropsychology; brain
Hypertension, or a persistently high blood pressure, is a common form of cardiovascular disease that affects one in every five people in the United States. The current definition of hypertension is a sustained systolic blood pressure of 140 millimeters of mercury (mm Hg) or more, sustained diastolic blood pressure of 90 mm Hg or more, or both. Nearly all adults with hypertension (90-95%) have what is called essential (or primary) hypertension, which means that the specific cause of the elevation in blood pressure is unknown. However, essential hypertension is actually thought to be determined by many genetic and environmental factors. Hypertension due to known medical disease (e.g., chronic renal disease) is called secondary hypertension.
It is well known that hypertension causes damage to many of the body’s organs, including the heart, kidneys, eyes, and brain, and it is a major risk factor for coronary heart disease and stroke. However, the impact of hypertension on the brain prior to stroke is presently underrecognized. Even in otherwise healthy people, hypertension can lead to mild to moderate alterations in the brain’s structure and function, including its ability to efficiently process information (known as cognitive function). These early hypertension-related changes in the brain can be detected by sophisticated brain scans and by neuropsychological assessment of cognitive abilities. In this article, I examine our knowledge of the relation of essential hypertension (which I refer to hereafter as simply hypertension) to cognitive function.
The relation of hypertension to cognitive function is frequently studied by comparing the cognitive performance of people with normal blood pressure (or normotensives) with that of hypertensives at one point in time. Commonly assessed cognitive functions include attention, learning and memory, executive functions (i.e., self-regulatory behaviors such as planning and organization, mental flexibility, and response inhibition), visuospatial skills, psychomotor abilities, perceptual skills, and language abilities. Typically, the hypertensives in these studies have been diagnosed by physicians and either are unmedicated or stop taking their antihypertensive medication prior to cognitive testing (because antihypertensive medications can exert small but significant effects of their own on cognitive function; for a review, see Muldoon, Waldstein, & Jennings, 1995). Overall, results of these investigations indicate that hypertensives perform more poorly than normotensives in virtually all domains of cognitive function (for reviews, see Waldstein, 1995; Waldstein & Katzel, 2001; Waldstein, Manuck, Ryan, & Muldoon, 1991), including learning and memory, attention, abstract reasoning, executive functions, and visuospatial, perceptual, and psychomotor abilities. However, hypertension is generally unrelated to verbal intelligence or language abilities.
Another way to study hypertension and cognition is to assess blood pressure levels across a sample of individuals and examine the relation between blood pressure and their test performance at one point in time. Results of such studies generally indicate that increases in blood pressure are associated with incremental reductions in cognitive function. Interestingly, though, several studies have instead found that low levels of blood pressure are associated with poorer cognitive function. Indeed, one recent investigation found that both high and low blood pressure were associated with lower levels of cognitive performance (Glynn et al., 1999).
Still other studies have examined the relation between blood pressure levels or diagnosed hypertension and changes in cognitive function over time (even while people are taking their antihypertensive medications). These longitudinal investigations generally show persisting differences in the cognitive performance of hypertensives and normotensives, and hypertensives often display cognitive decline. Chronicity of hypertension is an important consideration in these studies because it is believed that elevated blood pressure over a protracted period may be a more powerful predictor of poor cognitive outcome, particularly in older adults, than high blood pressure assessed at one point in time. Examining participants in the Framingham Heart Study, M.F. Elias, Wolf, D'Agostino, Cobb, and White (1993) found that individuals with persistent blood pressure elevation (measured over about 10 years) had poorer cognitive function 12 to 14 years later compared with those who had lower blood pressure levels. Similarly, in an analysis of data from the Western Collaborative Group Study, Swan, Carmelli, and La Rue (1996) found that elevations in both systolic and diastolic blood pressure, assessed over about 10 years during middle age, predicted cognitive impairment 25 years later.
Although many studies have found that, on average, hypertensives perform more poorly than normotensives, different hypertensive individuals do not all have the same degree of cognitive difficulty. It is thought that a number of variables alter (i.e., moderate) the relation of hypertension to cognitive function.
We are only beginning to understand the characteristics of hypertensives that may affect whether they experience cognitive difficulties. Important moderator variables identified thus far include age, education, several biological characteristics of hypertension, and the presence of concurrent diseases. Specifically, several studies have found that the performance differentials between hypertensives and normotensives are more pronounced for young than for middle-aged groups, thus suggesting that early-onset hypertension may confer greater risk for cognitive impairment than late-onset hypertension (for alternative explanations, see Waldstein, 1995, 2000). Hypertensives who have lower levels of educational attainment are also more prone to cognitive difficulties than highly educated hypertensives (for discussion, see Waldstein, 2000). Certain biological subgroups of hypertensives, such as those with high blood levels of insulin (a hormone that facilitates the entry of glucose into tissue cells) or high levels of sympathetic nervous system2 activity, are more likely than others to experience diminished cognitive performance.
Hypertension may also interact with other cardiovascular risk factors or cardiovascular and metabolic diseases to affect cognitive function (see M.F. Elias, Elias, Robbins, Wolf, & D'Agostino, 2001). This is a particularly important consideration because hypertension is very common among individuals having certain medical or psychiatric disorders (e.g., diabetes mellitus, depression),. P.K. Elias et al. (1997) have shown that having both hypertension and diabetes mellitus leads to worse cognitive function than having either alone. However, having a more severe cardiovascular disease may overshadow the effects of hypertension on cognition.
Hypertensives are not clinically impaired on cognitive tests. They do not have the severe cognitive impairment known as dementia, and their test performance most commonly falls within the normal range. However, the impact of hypertension on cognition can be considered clinically meaningful. For example, data from the Framingham Heart Study showed that hypertensives had a 29 to 62% increase in risk for their scores on several learning and memory tests to fall within the bottom fourth of the distribution of scores (P.K. Elias, D’Agostino, Elias, & Wolf, 1995). In addition, several studies have found that the size of the performance differential between hypertensives and normotensives is large enough that hypertensive individuals who might have scored in the average to above-average range (if their blood pressure were normal) may instead score in the below-average to average range (see Waldstein et al., 1991). Even for normally functioning individuals, such subtle alterations in cognitive performance can be distressing and may reduce the quality of life.
Hypertension affects the brain in many ways that could explain its link to cognitive difficulties (see Waldstein & Katzel, 2001). For example, studies have demonstrated that hypertensives exhibit reduced cerebral blood flow and metabolism (utilization of glucose to obtain energy), particularly in certain brain regions, such as the frontal and temporal lobes and subcortical areas. Reductions in cerebral blood flow are worse among unmedicated than medicated hypertensives. Recent findings have also shown that hypertensives show smaller cerebral blood flow responses than normotensives during memory tasks (Jennings et al., 1998). This is important because adequate cerebral blood flow responses are needed for memory (and other cognitive) function. Neurochemical transmission within the brain and basic cellular functions are also affected by hypertension. Thus, a variety of neurophysiological characteristics of hypertensives could, at least in part, explain their cognitive difficulties. Several of these characteristics can also predispose the brain to later pathological changes in its anatomy.
The large blood vessels that supply the brain (such as the carotid arteries) and the large and small blood vessels within the brain are also affected by hypertension. For example, hypertension can lead to damage to the inner lining (i.e., the endothelium) of the cerebral arteries. Such damage can disrupt the blood-brain barrier, thus allowing the entry of substances that are toxic to the brain. Other structural changes to the blood vessels that are common in hypertension decrease blood supply to the brain. These include atherosclerosis in the larger arteries and blockages of the smaller arterioles. In turn, these processes can lead to disease of the white matter (the portions of the brain involved in transmitting messages from one region to another), and “mini-strokes” known as silent infarction (because the symptoms are not always apparent). Medicated hypertensives display less white matter disease than unmedicated hypertensives, and among medicated hypertensives, those having poorer blood pressure control show the most extensive pathology. Finally, the brains of hypertensives have been shown to experience shrinkage (atrophy). Many of these alterations in brain structure mark the gradual emergence of vascular disease of the brain that may ultimately result in a major stroke or a vascular dementia.
Although all of these changes in the brain could explain why hypertension is related to decreased cognitive function, few studies have actually examined these mechanisms in conjunction with cognitive performance. In one study, hypertensives having significant white matter disease performed more poorly than either hypertensives without notable white matter disease or normotensives (Schmidt et al., 1993).
Although many of the brain pathologies I have mentioned are thought to result from elevated blood pressure per se, Katzel and I (Waldstein & Katzel, 2001) have suggested that other biological characteristics of hypertensives may further promote brain (and thus cognitive) dysfunction. For example, cardiovascular risk factors that often co-occur with hypertension also affect the brain. Examples include high insulin and cholesterol levels and enhanced stress-induced cardiovascular and hormonal (e.g., cortisol) responses. Several genetic and environmental (e.g., lifestyle) factors may also directly affect the brain’s structure and function, and indeed may lead to both the development of hypertension and poor cognitive function, perhaps via similar neurobiological mechanisms. In this regard, several studies have shown that normotensive young adults who have a parent with hypertension perform more poorly than the offspring of normotensive parents on cognitive tests (e.g., Waldstein, Ryan, Polefrone, & Manuck, 1994). Thus, lower cognitive performance may precede elevated blood pressure in individuals who are at risk for hypertension. The relation between parental history of hypertension and lower levels of cognitive function may reflect genetic or environmental factors (or both) that predispose individuals to the development of hypertension.
Despite the large body of research indicating that hypertension is associated with poorer cognitive function across multiple domains of performance, many important questions remain unanswered or insufficiently answered and thus require further investigation (see Waldstein, 2000). It remains important for researchers to use comprehensive test batteries to further identify what domains of cognitive function are most affected by hypertension, and whether particular subgroups of hypertensives are most affected. Study of the potential interaction of hypertension with age, education, gender, race or ethnicity, socioeconomic status, lifestyle factors, genetics, and other biological factors thus remains critical. Future investigations should also determine the impact of hypertension on cognition in the presence of other cardiovascular risk factors and both cardiovascular and noncardiovascular diseases. Further study of the relation between low blood pressure and cognitive function is also needed.
Longitudinal studies of the relation between blood pressure and cognitive function should continue to consider the chronicity of hypertension and the degree to which blood pressure is controlled by antihypertensive medications. It would be useful to determine whether hypertensives having the lowest levels of cognitive performance are at greatest risk for future stroke. It is also important to examine whether the cognitive correlates of hypertension affect daily functioning or quality of life. Better understanding of the complicated mechanisms underlying the hypertension-cognition association is necessary. Predictors of cognitive functioning, and the mechanisms underlying cognitive difficulties, may differ among subgroups of hypertensives, and between hypertensives and normotensive people with hypertensive parents.
Because hypertension is increasingly common as people age, the study of hypertension and cognition is pertinent to the study of cognitive aging. Studies of "normal aging" need to measure, and control for, blood pressure levels. Indeed, blood pressure levels have been found to partially explain the relation of age to cognitive performance. For example, M.F. Elias, Robbins, Elias, and Streeten (1998) found that controlling statistically for systolic blood pressure, assessed over time, reduced the correlation between age and several subtests of the Wechsler Adult Intelligence Scale by about 50%. Blood pressure thus appears to partially explain the relation of age to cognitive decline. Controlling for blood pressure (and other cardiovascular risk factors) is also important in research on cognitive function in people with neurological diseases such as Alzheimer’s disease.
In sum, the results of decades of investigations indicate that diagnosed hypertension, or high blood pressure, is associated with a reduced level of cognitive function. Further understanding of the relation between hypertension and cognitive function is critical to the development of preventive strategies and interventions geared toward preserving cognitive function across the life span.
Elias, M.F., Elias, P.K., Robbins, M.A., Wolf, P.A., & D'Agostino, R.B. (2001). (See References)
Waldstein, S.R. (1995). (See References)
Waldstein, S.R., & Katzel, L.I. (2001). (See References)
Waldstein, S.R., Manuck, S.B., Ryan, C.M., & Muldoon, M.F. (1991). (See References)
1. Address correspondence to Shari R. Waldstein, Department of Psychology, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250; mail: email@example.com.
2. The sympathetic nervous system is a division of the autonomic branch of the central nervous system. It activates and prepares the body to deal with stress.
Acknowledgments--Preparation of this article was supported, in part, by Grant R29 AG15112 from the National Institute on Aging to the author.
Elias, M.F., Elias, P.K., Robbins, M.A., Wolf, P.A., & D'Agostino, R.B. (2001). Cardiovascular risk factors and cognitive functioning: An epidemiological perspective. In S.R. Waldstein & M.F. Elias (Eds.), Neuropsychology of cardiovascular disease (pp. 83-104). Mahwah, NJ: Erlbaum.
Elias, M.F., Robbins, M.A., Elias, P.K., & Streeten, D.H.P. (1998). A longitudinal study of blood pressure in relation to performance on the Wechsler Adult Intelligence Scale. Health Psychology, 17, 486-493.
Elias, M.F., Wolf, P.A., D'Agostino, R.B., Cobb, J., & White, L.R. (1993). Untreated blood pressure level is inversely related to cognitive functioning: The Framingham Study. American Journal of Epidemiology, 138, 353-364.
Elias, P.K, D’Agostino, R.B., Elias, M.F., & Wolf, P.A. (1995). Blood pressure, hypertension, and age as risk factors for poor cognitive performance. Experimental Aging Research, 21, 393-417.
Elias, P.K., Elias, M.F., D'Agostino, R.B., Cupples, L.A., Wilson, P.W., Silbershatz, H., & Wolf, P.A. (1997). NIDDM and blood pressure as risk factors for poor cognitive performance. Diabetes Care, 20, 1388-1395.
Glynn, R.J., Beckett, L.A., Hebert, L.E., Morris, M.C., Scherr, P.A., & Evans, D.A. (1999). Current and remote blood pressure and cognitive decline. Journal of the American Medical Association, 281, 438-445.
Jennings, J.R., Muldoon, M.F., Ryan, C.M., Mintun, M.A., Meltzer, C.C., Townsend, D.W., Sutton-Tyrrell, K., Shapiro, A.P., & Manuck, S.B. (1998). Cerebral blood flow in hypertensive patients: An initial report of reduced and compensatory blood flow responses during performance of two cognitive tasks. Hypertension, 31, 1216-1222.
Muldoon, M.F., Waldstein, S.R., & Jennings, J.R. (1995). Neuropsychological consequences of antihypertensive medication use. Experimental Aging Research, 21, 353-368.
Schmidt, R., Fazekas, F., Offenbacher, H., Dusek, T., Zach, E., Reinhart, B., Grieshofer, P., Freidl, W., Eber, B., Schumacher, M., Koch, M., & Lechner, H. (1993). Neuropsychologic correlates of MRI white matter hyperintensities: A study of 150 normal volunteers. Neurology, 43, 2490-2494.
Swan, G.E., Carmelli, D., & La Rue, A. (1996). Relationship between blood pressure during middle age and cognitive impairment in old age: The Western Collaborative Group Study. Aging, Neuropsychology, and Cognition, 3, 241-250.
Waldstein, S.R. (1995). Hypertension and neuropsychological function: A lifespan perspective. Experimental Aging Research, 21, 321-352.
Waldstein, S.R. (2000). Health effects on cognitive aging. In P.C. Stern & L.L. Carstensen (Eds.), The aging mind: Opportunities in cognitive research (pp. 189-217). Washington, DC: National Academy Press.
Waldstein, S.R., & Katzel, L.I. (2001). Hypertension and cognitive function. In S.R. Waldstein & M.F. Elias (Eds.), Neuropsychology of cardiovascular disease (pp. 15-36). Mahwah, NJ: Erlbaum.
Waldstein, S.R., Manuck, S.B., Ryan, C.M., & Muldoon, M.F. (1991). Neuropsychological correlates of hypertension: Review and methodologic considerations. Psychological Bulletin, 110, 451-468.
Waldstein, S.R., Ryan, C.M., Polefrone, J.M., & Manuck, S.B. (1994). Neuropsychological performance of young men who vary in familial risk for hypertension. Psychosomatic Medicine, 56, 449-456.