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National Research Council (US) Committee on Future Directions for Cognitive Research on Aging; Stern PC, Carstensen LL, editors. The Aging Mind: Opportunities in Cognitive Research. Washington (DC): National Academies Press (US); 2000.

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The Aging Mind: Opportunities in Cognitive Research.

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EHealth Effects on Cognitive Aging

Shari R. Waldstein

Intact cognitive function is a critical dimension of quality of life. Cognitive difficulties can be disruptive to individuals' sense of well-being and to their everyday functioning. Age-related decrements in cognition are well documented (Salthouse, 1991; Wilson et al., 1997), but they are not thought to be entirely due to primary biological aging processes. In this regard, it has been suggested that age-related cognitive changes are attributable, at least in part, to systemic medical diseases (here defined as nonneurological diseases that affect one or more physiological systems) that are common in older adults (Fozard et al., 1990). Indeed, approximately four out of five Americans over the age of 65 have at least one or more chronic medical conditions (La Rue, 1992).

In recent years, the relation of systemic disease to cognition has received increasingly intensive investigation. Results of numerous available studies indicate that diseases of virtually any physiological system can have deleterious effects on cognitive function (Elias et al., 1989; Siegler and Costa, 1985; Tarter et al., in press, 1988). Although these influences may be particularly pertinent to older adults, who experience an increased incidence and prevalence of disease, systemic diseases have been shown to affect cognitive performance in persons of all ages in both cross-sectional and longitudinal investigations. Therefore disease-cognition relations should viewed from a life-span perspective. In this regard, degree of lifetime exposure to systemic illness(es) may be of critical importance in determining cognitive outcomes in older age.

The purpose of this paper is, first, to provide a brief overview of the types of systemic diseases and several associated lifestyle and biological factors that are known to affect the normal range of cognitive functioning (in the absence of dementia). Next, a more detailed description of the relation of hypertension and other cardiovascular diseases to cognition is provided. Methodological and conceptual challenges to this field of research are discussed, and future research directions are enumerated.

In general, the investigations described in this paper utilized clinical neuropsychological tests to measure cognitive functioning. These tests can be grouped according to the major domain of cognitive functioning assessed and include measures of attention, learning and memory, executive functions, visuospatial and visuoconstructional skills, psychomotor abilities, perceptual skills, and language functions. Screening tests such as mental status examinations and composite measures such as intelligence tests were also used. The interested reader is referred to Lezak (1995) for a detailed discussion of this particular taxonomy of tests. In addition, an appendix at the end of this paper lists brief descriptions of the major domains of cognitive functions and several representative tests that are commonly used in the literature described below.

Health and Cognition

Numerous health-related factors have been demonstrated to influence cognition (with effect sizes ranging from small to large). Examples include lifestyle, endocrine, and genetic factors, systemic diseases, neurotoxic exposures, and medical and surgical treatments for disease. Each of these general areas is considered briefly below, with positive findings emphasized for illustrative purposes.

Lifestyle

A variety of lifestyle factors are known to affect cognitive function. Such factors may impact cognition by exerting direct biological influence on the brain or by promoting various systemic diseases (e.g., cardiovascular, pulmonary) that indirectly affect the brain. Less healthful lifestyles also tend to aggregate among individuals with lower levels of education and may, in part, explain previously noted associations between low education and/or socioeconomic status and poorer cognitive function (Kilander et al., 1997). Examples of such lifestyle factors include smoking, excessive alcohol consumption, illicit drug use, dietary factors, and physical inactivity.

With respect to health-compromising behaviors, several studies have revealed poorer cognitive performance among individuals who smoke tobacco products (M.F. Elias et al., in press; Galanis et al., 1997; Hill, 1989; Launer et al., 1996). Heavy alcohol consumption also has known deleterious effects on cognition (Rourke and Løberg, 1996; Tarter and Van Thiel, 1985). However, across a range of habitual drinking, several investigations have noted an inverted U-or J-shaped relation between alcohol consumption and cognitive function (Dufouil et al., 1997; M.F. Elias et al., in press; P.K. Elias et al., in press; Launer et al., 1996). Drugs of abuse (e.g., opiates, cocaine) have been associated with poorer cognitive performance (Carlin and O'Malley, 1996; Strickland and Stein, 1995). In addition, several dietary insufficiencies, such as vitamin B6, vitamin B12, thiamine, folate, and zinc, have been related to cognitive difficulties (Lester and Fishbein, 1988; Riggs et al., 1996; Whitehouse et al., 1993). Greater caloric consumption in middle age has been shown to predict poorer mental status in old age (Fraser et al., 1996), and a proportionally greater intake of dietary refined carbohydrates has predicted lower IQ scores in children (Lester et al., 1982).

Health-enhancing behaviors have been associated with better cognitive functioning. For example, greater intake of vitamin C, an antioxidant, has been related to enhanced cognitive test performance and/or a lower prevalence of cognitive impairment (Gale et al., 1996; Jama et al., 1996; Paleologos et al., 1998). Greater levels of physical fitness (or physical activity) have also been associated with higher levels of cognitive functioning (Dustman et al., 1994). In addition, several investigations have revealed improvements in cognitive performance with aerobic exercise training (Emery and Blumenthal, 1991; Kramer et al., 1998).

Endocrine and Genetic Factors

Various hormonal factors have been associated with cognitive functioning. Again, direct biological effects on the brain are likely, in addition to indirect effects via promotion of systemic diseases. Relevant examples include poorer cognitive function in individuals with low levels of estrogen (Gordon et al., 1988; Erlanger et al., 1999), both high and low levels of various thyroid and pituitary hormones (Beckwith and Tucker, 1988; Gordon et al., 1988; Whitehouse et al., 1993; Erlanger et al., 1999), and either high basal levels of cortisol or greater stress-induced cortisol responses (Kirschbaum et al., 1996; Lupien and McEwen, 1997; McEwen and Sapolsky, 1995; Seeman et al., 1997; Erlanger et al., 1999). Beneficial effects of estrogen replacement therapy have also been noted (Haskell et al., 1997; Erlanger et al., 1999).

Genetic factors may predispose individuals to systemic diseases and influence numerous biological variables that can affect cognitive performance. One such factor that has received much recent attention is apolipoprotein E (APOE) polymorphism. Although most commonly examined in relation to dementias, the presence of one or two APOE-ε4 alleles has also been associated with poorer cognitive function, particularly on tests of learning, memory, and psychomotor speed, among nondemented individuals across a wide range of ages (Bondi et al., 1995; Carmelli et al., 1998; Flory et al., 1999; Yaffe et al., 1997). Genetic influences may also modify the impact of disease on cognition. In this regard, Haan et al. (1999) found that individuals with carotid atherosclerosis, peripheral vascular disease, or diabetes mellitus, in addition to an APOE-ε4 allele, experienced a significantly greater rate of cognitive decline than individuals without an APOE-ε4 allele and or cardiovascular disease.

Neurotoxicity

Environmental or occupational exposure to chemicals, such as solvents and lead, exerts direct neurotoxic effects on the brain and is associated with diminished cognitive functioning (Hartmann, 1995; Morrow et al., in press). Both peak exposures and chronic low-level exposures are of concern. Individuals of lower socioeconomic status may be more likely to experience neurotoxic exposures.

Systemic Diseases

Numerous systemic diseases have been associated with poorer cognitive functioning. Examples include cardiovascular diseases, such as hypertension and myocardial infarction (Waldstein and Elias, in press; Waldstein et al., in press); pulmonary diseases, such as chronic obstructive pulmonary disease and asthma (Fitzpatrick et al., 1991; Hopkins and Bigler, in press; Grant et al., 1987; Prigatano et al., 1983); pancreatic diseases, such as diabetes mellitus (Reaven et al., 1990; Ryan, in press; Ryan et al., 1993); hepatic diseases, such as cirrhosis (Moss et al., 1995; Tarter and Van Thiel, in press); renal diseases (Hart et al., 1983; Pliskin et al., in press); autoimmune diseases, such as systemic lupus erythematosus (Beers, in press; Glanz et al., 1997); various cancers (Berg, 1988); sleep disorders, such as obstructive sleep apnea syndrome (Bédard et al., 1993; Kelly and Coppel, in press); and the human immunodeficiency virus and AIDS (Heaton et al., 1995; Kelly et al., 1996).

Disparities in health status among racial and ethnic minority groups and individuals of lower socioeconomic status or educational attainment are well documented (Haan and Kaplan, 1985; Haan et al., 1989; Kaplan and Keil, 1993). It is therefore possible that comorbidities may, in part, explain prior relations of race/ethnicity (e.g., for black Americans), lower education, and low socioeconomic status to poorer performance on cognitive tests. Health status should therefore be controlled in such investigations (Whitfield et al., 2000).

Medical and Surgical Treatments

A variety of medical and surgical treatments for disease have been shown to impact cognitive performance. Improvements, decrements, and absence of change have been noted in association with various medications, such as antihypertensive agents (Muldoon et al., 1991, 1995) and corticosteroid or theophylline treatment for asthma (Hopkins and Bigler, in press; Stein et al., 1996). Mixed findings are also apparent in association with surgical interventions, such as coronary artery bypass surgery (Newman et al., in press). Some improvements in cognitive performance have been associated with oxygen-related treatments for chronic obstructive pulmonary disease and obstructive sleep apnea syndrome (Hopkins and Bigler, in press) and chronic hemodialysis (Pliskin et al., in press).

Summary

Numerous lifestyle, biological, disease-related, and iatrogenic factors have been shown to influence cognitive function in persons of all ages. Research associated with each particular factor poses several common and unique sets of methodological and conceptual challenges, discussion of which is beyond the scope of this paper. Findings in each area are often mixed and may, in part, reflect these challenges. As mentioned above, positive results have generally been highlighted here to illustrate the striking range of potential health effects on cognition. In the following section, a more detailed description of the relation of hypertension and other cardiovascular diseases to cognitive function is presented as an example of research on health and cognition and its associated challenges.

Cardiovascular Disease and Cognition

Cardiovascular disease is the leading cause of death in the United States, affecting one in every five individuals (American Heart Association, 1998) and conferring substantially elevated risk for stroke and vascular dementia. However, prior to the development of cerebrovascular complications, even early manifestations of cardiovascular disease, such as hypertension, are associated with diminished cognitive function (Waldstein and Elias, in press; Waldstein et al., in press).

A deleterious impact of cardiovascular disease on the brain is not surprising when one considers the purpose of normal cardiovascular function. The cardiovascular system (i.e., the heart and vasculature) is responsible for supplying blood that transports oxygen, glucose, and other essential nutrients to all cells of the body. Because the brain is relatively unable to store nutrients, it is dependent on the cardiovascular system for a constant supply of blood and is highly vulnerable to interruptions of blood flow. Approximately one-fifth of the cardiac output is provided to the brain each minute, and even very brief cessation of this blood supply can damage the brain. Subtle reductions in cerebral blood flow that occur in association with cardiovascular disease (in addition to other mechanisms discussed below) can therefore have negative short-and long-term consequences for the brain.

When available studies to date are considered in aggregate, the relation of cardiovascular diseases to cognitive function has been one of the more extensively investigated of the research areas discussed above (Waldstein and Elias, in press; Waldstein et al., in press). Because hypertension is often one of the earliest manifestations of cardiovascular disease and can occur without substantial occult comorbidities, there is an opportunity to conduct tightly controlled investigations of hypertension and cognition. Perhaps for this reason, hypertension has been studied fairly intensively and thus is examined here as a pertinent illustration of health-cognition relations.

Hypertension

Hypertension—defined as a sustained systolic and diastolic blood pressure greater than or equal to 140 millimeters of mercury (mm Hg) and/or 90 mm Hg, respectively, as measured on at least two separate occasions (Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, 1997)—affects one in four adults in the United States, or 50 million individuals (American Heart Association, 1998). Approximately 90 to 95 percent of all cases involve essential hypertension, a term that refers to a sustained blood pressure elevation of unknown cause. However, the etiology of essential hypertension actually involves a complex interplay of genetic and environmental factors (Kaplan, 1998). Elevated blood pressure that is attributable to a known medical disorder is called secondary hypertension.

Risk factors for hypertension include a positive family history, older age, male gender (until age 55, after which prevalence rates are greater among women), black race, and numerous lifestyle and behavioral factors such as excess body weight, physical inactivity, dietary factors including high sodium and low potassium or calcium intake, excessive alcohol consumption, oral contraceptive use, various psychosocial factors, and stress-related cardiovascular reactivity (American Heart Association, 1998; Joint National Committee, 1997; Kaplan, 1998). Hypertension is a major risk factor for atherosclerosis, coronary heart disease, and stroke (Stamler, 1992).

Hypertension and Cognitive Function

The relation of hypertension to cognitive function has been studied for over 50 years (for reviews see M.F. Elias et al., in press; Elias and Robbins, 1991; Waldstein, 1995; Waldstein and Katzel, in press; Waldstein et al., 1991a). Results of numerous case-control and cross-sectional, population-based studies indicate that hypertensives generally perform more poorly than normotensives across multiple domains of cognitive function, including learning and memory, attention, abstract reasoning and other executive functions, visuospatial, visuoconstructional, perceptual, and psychormotor abilities (e.g., Boller et al., 1977; Blumenthal et al., 1993; Elias et al., 1987, 1990b; Robbins et al., 1994; Shapiro et al., 1982; Waldstein et al., 1991b, 1996; Wallace et al., 1985). To date, hypertension typically has not predicted poorer performance on tests of general verbal intelligence or language abilities, although further investigation is necessary (e.g., Blumenthal et al., 1993; Boller et al., 1977; Waldstein et al., 1991b, 1996). Dose-response relations have been observed between progressive increments in blood pressure level and reduced cognitive performance (e.g., Elias et al., 1990b, Robbins et al., 1994). In addition, low levels of blood pressure have been associated with poorer cognitive function (Costa et al., 1998; Guo et al., 1997), and curvilinear (inverted U-shaped) relations of blood pressure to cognitive performance have also been noted (Glynn et al., 1999).

Although it is generally presumed that alterations in cognition occur as a result of pathological consequences of hypertension, lower levels of cognitive test performance have also been found to precede blood pressure elevation in individuals who are at risk for hypertension. More specifically, normotensive young adults who have a parental history of hypertension show lower levels of performance on tests of visuopercepatial, visuospatial, and visuoconstructional skill and speed of short-term memory search in comparison to the young adult offspring of normotensive parents (Pierce and Elias, 1993; Waldstein et al., 1994). These associations may thus reflect genetic and or environmental factors that predispose individuals to the development of hypertension.

Longitudinal or follow-up studies generally note the persistence of hypertensive-normotensive differences in cognitive performance over time, often with additional cognitive decline among hypertensives (e.g., Haan et al., 1999; Miller et al., 1984; Elias et al., 1986, 1996, 1998; Wilkie and Eisdorfer, 1971). Chronicity of hypertension has been identified as a critical variable in such investigations. Indeed, life-time exposure to elevated blood pressure may be a more potent predictor of poor cognitive outcome in older adults than cross-sectionally measured blood pressure (Elias et al., 1993; Swan et al., 1998).

Chronicity of hypertension was emphasized in several recent epidemiological studies in which persistent blood pressure elevation, measured across numerous examinations, predicted poorer cognitive functioning and/or greater rate of cognitive decline (Elias et al., 1993, 1998; Swan et al., 1998). Similarly, higher blood pressure during middle age has been shown to predict poorer cognitive outcomes in older age (Elias et al., 1993; Swan et al., 1996; Launer et al., 1995; Kilander et al., 1998).

Moderator Variables

Although many studies have revealed lower average levels of cognitive function in hypertensive groups, there is also pronounced interindividual variability within these groups with respect to performance (Waldstein, 1995). This variability may be explained, in part, by relevant moderators. In this regard, hypertension has been shown to interact with both age and education in studies of cognitive function.

Age as Moderator Several investigations have found interactions of age and hypertension such that young (less than 40 to 50 years of age) hypertensives performed more poorly than young normotensives on tests of attention, memory, executive functions, and psychomotor abilities, whereas middle-aged (upper limits ranging from 56 to 72 years) hypertensive and normotensive groups performed comparably (Elias et al., 1990b; Schultz et al., 1979; Waldstein et al., 1996). Madden and Blumenthal (1998) also noted that both young (ages 18 to 40) and middle-aged (ages 41 to 59) hypertensives displayed a slightly greater error rate on a test of visual selective attention than young or middle-aged normotensives, whereas older (ages 60 to 78) hypertensives and normotensives did not differ in performance. In contrast, such interactions were not noted among three age cohorts (55–64, 65–74, and 75–88 years) in a sample of 1,695 participants in the Framingham Heart Study on tests of memory, visual organization, attention, verbal comprehension, and concept formation (Elias et al., 1995).

In sum, when interactive effects of age and hypertension (or blood pressure) are noted, poorer performance tends to aggregate among the younger individuals in any particular investigation. Waldstein (1995) suggests that such trends may reflect survival effects and selective attrition from studies (see Feinleib and Pinsky, 1992), as individuals with early-onset hypertension develop cardiovascular and cerebrovascular complications and are thus excluded from investigations. Furthermore, it is possible that early-onset hypertension confers greater risk for cognitive impairment than late-onset hypertension. In general, interactions of age and hypertension may best be examined in longitudinal studies in order to address some of these methodological difficulties.

Other Moderators In one study, hypertensives having lower levels of educational attainment performed more poorly than comparably educated normotensives, whereas more highly educated hypertensives and normotensives did not differ in their performance (Elias et al., 1987). Relative preservation of cognitive function among more highly educated persons has also been noted in other contexts and may suggest protective effects associated with higher socioeconomic status and or an enhanced ''cognitive reserve" (Katzman, 1993).

Another source of variability in cognitive performance among hypertensives relates to the heterogeneity of this disorder (Kaplan, 1998; Streeten et al., 1992). In this regard, it is possible that certain subgroups of hypertensives are more likely than others to experience diminished cognitive performance. For example, hyperinsulinemic hypertensives perform more poorly than either normoinsulinemic hypertensives or normotensives (Kuusisto et al., 1993). In addition, high levels of sympathetic nervous system arousal (as indicated by increased plasma renin activity) have been associated with diminished psychomotor performance among hypertensives (Light, 1975Light, 1978).

Mediation of Age-Related Variance

Continuous blood pressure levels have been found to partially mediate age-related variance in cognitive performance. In one investigation, systolic and diastolic blood pressure attenuated by almost 58 percent the age-related variance in performance of an attention-shift reaction time task (Madden and Blumenthal, 1998). Similarly, Elias et al. (1998) found that longitudinally assessed systolic blood pressure was associated with a 50 percent reduction in the relation between age and performance of Wechsler Adult Intelligence Scale (WAIS) subtests reflecting visualization-performance ability. These findings suggest that blood pressure is an important mediator of cognitive aging.

Methodological Issues

The study of hypertension and cognition faces a number of methodological challenges (Waldstein et al., 1998). For example, the accurate measurement of blood pressure is critical to any investigation of hypertension and cognition. Interpretation of a number of studies, particularly several population-based investigations, has been limited by the measurement of blood pressure on a single occasion. This methodology greatly limits measurement reliability (Llabre et al., 1988) and precludes hypertension classification (Joint National Committee, 1997). Other studies have relied on self-reported hypertensive status (Zelinski et al., 1998; Desmond et al., 1993). A sole reliance on self-reported health status should be avoided, if possible, due to limits in reliability and validity and likely underestimation of health-cognition relations.

Measurement of cognitive function, again particularly in certain population-based investigations, has been limited by use of brief screening measures (such as a mental status exam) or very few cognitive tests. Sampling of a broad range of cognitive functions is critical to understanding hypertension-cognition relations.

Investigations of hypertension and cognition typically control for numerous confounding variables by statistical adjustment (covariance), matching procedures, and/or study exclusions. Control variables often include age, education, alcohol consumption, anxiety, and depression, and they sometimes include smoking status, occupational status, race/ethnicity, socioeconomic status, and (if relevant) antihypertensive medications. Particularly in case-control studies, hypertensives are commonly either unmedicated or are removed from antihypertensive medication prior to the study. Individuals with medical, neurological, or psychiatric comorbidities are generally excluded from case-control studies. However, because of the resultant exclusion of hypertensives with major end-organ damage, the impact of hypertension on cognition may be underestimated, particularly among older adults.

Longitudinal studies of hypertension and cognition do not always control for comorbidities such as diabetes mellitus and coronary heart disease. This is an important consideration, because hypertension is highly prevalent among individuals having certain medical or psychiatric comorbidities (e.g, depression, diabetes mellitus). Furthermore, hypertension may bear relatively stronger or weaker relations to cognition in the presence of more severe cardiovascular or metabolic diseases. For example, Elias et al. (1997) have found synergistic effects of hypertension and noninsulin-dependent diabetes mellitus with respect to diminished cognitive function. However, Phillips and Mate-Kole (1997) did not find hypertension to be a predictor of cognitive performance in patients with peripheral vascular disease. In this group of patients, more potent manifestations of cardiovascular disease may have overshadowed any effects of hypertension.

Longitudinal investigations also have to contend with problems related to study attrition. It is often the least healthy or least motivated individuals who drop out of ongoing studies. Several available statistical methods for analyzing longitudinal datasets, such as two-stage growth curve analysis and survival analysis, will take such attrition into consideration (Collins and Horn, 1991; Dwyer and Feinleib, 1992; McCardle et al., 1991)

Clinical Significance

Although hypertensives generally should not be characterized as clinically impaired on cognitive tests (Elias et al., 1987), the impact of hypertension on cognition can be considered clinically significant at an individual level and significant at the population level. In this regard, although a full range of effect sizes is apparent (from d < 0.1 to d > 1.0), numerous case-control studies have found that hypertensive-normotensive differences in cognitive test scores are characterized by large effect sizes (Waldstein et al., 1991a). Indeed, several studies have found that the performance of hypertensives falls below that of normotensives by up to one standard deviation (Waldstein et al., 1991a, 1991b). At the individual level, this magnitude of difference could, for example, translate into a below-average versus average (or average versus above-average) test score. Among individuals, even subtle alterations in cognitive functioning can have negative consequences. Such changes can be distressing and may thus impact quality of life.

Lowering of cognitive performance associated with hypertension is also considered significant at the population level (M.F. Elias et al., in press). In this regard, a significantly increased risk for poor cognitive performance, both cross-sectionally and longitudinally, is associated with hypertension or progressive increments in blood pressure (M.F. Elias et al., in press). Data from the Framingham Heart Study indicate that chronic hypertensives displayed an increased risk of performing in the lowest quartile of the distribution of scores on several learning and memory tests, with odds ratios ranging from 1.29 to 1.62 (Elias et al., 1995).

Underlying Mechanisms

Numerous neurobiological mechanisms have been proposed to underlie the relation between hypertension and diminished cognitive function (see Elias and Robbins, 1991; Waldstein, 1995; Waldstein et al., 1991a; Waldstein and Katzel, in press). In this regard, studies have demonstrated that hypertensives exhibit reduced cerebral blood flow and/or metabolism, particularly in frontal, temporal, "watershed," and subcortical (e.g., basal ganglia) regions, autoregulatory disturbance, endothelial dysfunction, increased atherosclerosis in carotid and large cerebral arteries, increased cerebral white matter disease, silent infarction, cerebral atrophy, and cellular and neuro-chemical dysfunction (for a review, see Waldstein and Katzel, in press). However, it is rare that such mechanistic factors are considered in conjunction with cognitive performance. In this regard, both van Swieten et al. (1991) and Schmidt et al. (1993) found that hypertensives having significant white matter disease performed more poorly than either normotensives or hypertensives without notable white matter disease. However, because white matter lesions are generally not seen in young or middle-aged persons, it has been hypothesized that alterations in neurophysiology are more likely to account for the cognitive difficulties noted among hypertensives in these age groups (Waldstein, 1995).

Waldstein and Katzel (in press) have suggested that numerous factors may promote the neuropathological changes that can influence cognitive performance in hypertensives. These include the direct effects of elevated blood pressure, in addition to other factors that tend to co-occur with hypertension, such as the metabolic syndrome (e.g., hyperinsulinemia, dyslipidemia, central adiposity) and enhanced stress-induced cardiovascular and neuroendocrine (e.g., cortisol) reactivity. Furthermore, a variety of genetic and environmental factors may indirectly affect cognition by promoting hypertension, the metabolic syndrome, physiological reactivity, and associated neuropathology. This model therefore suggests that there are characteristics of hypertensives, other than elevated blood pressure per se, that are important to the development of diminished cognitive functioning.

Genetic and environmental influences may also exert direct effects on brain structure and function (and thereby cognition) or act as "third variables" that simultaneously influence both the development of hypertension and altered cognitive function, perhaps via similar neurobiological mechanisms. In this regard, findings indicating that the normotensive offspring of hypertensive parents display diminished cognitive performance are intriguing. It is important to note that the mechanisms underlying hypertension-cognition relations may vary over the course of the life span and among different subgroups of hypertensives (Waldstein, 1995).

Summary, Clinical Significance, and Future Directions

In sum, results of a large body of research indicate that hypertension is associated with poorer cognitive functioning across multiple domains of performance, and that chronic hypertension predicts cognitive decline over time. Although, to date, there has been fairly extensive investigation of hypertension-cognition relations, many questions remain. Further study of the patterns, predictors, and mechanisms of cognitive function (or dysfunction) among subgroup of hypertensives of differing ages remains critical.

Despite an overall increase in hypertension-related risk for poor cognitive function, the striking interindividual variability in performance noted within hypertensive groups suggests that it is important to continue to identify pertinent predictors of poor cognitive function among hypertensives. Identification of such factors could assist in determining potential areas for further prevention or intervention efforts. Thus far, age and education have been identified as important moderating variables. However, more research is needed with respect to these factors. Interactive effects of hypertension with many other sociodemographic (e.g., gender, race/ethnicity, socioeconomic status), lifestyle, genetic, and other biological factors are also possible, yet they remain virtually unexplored.

Further study of the relation of low blood pressure to cognitive performance (and associated mechanisms) is also necessary. Nonlinear statistics should be used to evaluate the potential presence of an inverted-U or a J-shaped cross-sectional relation between blood pressure and cognitive function. Further investigation of the performance of the normotensive offspring of hypertensive parents would also be useful. Both family history studies and hypertension studies could include some evaluation of the numerous candidate genes that have been implicated as determinants of interindividual variability in blood pressure (Krushkal et al., 1999).

Cross-sectional and longitudinal studies should determine the impact of hypertension on cognition in the presence of other cardiovascular risk factors and both cardiovascular and noncardiovascular diseases. Longitudinal studies should continue to consider chronicity of hypertension and the impact of long-term antihypertensive therapy and relative degree of blood pressure control with respect to cognitive outcomes. It would also be useful to determine whether hypertensives who display the lowest levels of cognitive performance are at greatest risk for future cerebrovascular events.

Further elucidation of the complicated mechanisms underlying hypertension-cognition relations is also necessary. As mentioned previously, predictors of cognitive functioning, and the mechanisms underlying these difficulties, may differ among subgroups of hypertensives and at distinct points in the life span. Future studies should sample numerous mechanistic variables in conjunction with measures of cognitive function and use statistical methods such as structural equation modeling to determine the interrelations among these variables.

Other Cardiovascular Diseases and Cognition

Hypertension is only one of several risk factors for later manifestations of cardiovascular disease that have been shown to impact cognitive function. Other cardiovascular risk factors that have been associated with poorer cognitive function include both high and low levels of total serum cholesterol (Benton, 1995; Desmond et al., 1993; Muldoon et al., 1997; Swan et al., 1992), insulin-dependent and noninsulin-dependent diabetes mellitus (Ryan, in press), and lifestyle factors such as smoking (discussed above, see M.F. Elias et al., in press). Epidemiological research indicates incrementally greater risk for cognitive impairment with increasing numbers of cardiovascular risk factors (M.F. Elias et al., in press).

Relatively few studies have examined the impact of later manifestations of cardiovascular disease (e.g., atherosclerosis, coronary heart disease, peripheral vascular disease) on cognition. Results of available research indicates that a greater extent of carotid atherosclerosis predicts poorer performance on various tests of cognitive function, such as memory, executive functions, psychomotor abilities, and mental status (Auperin et al., 1996; Breteler et al., 1994; Cerhan et al., 1998; Everson et al., in press). Because atherosclerosis tends to co-occur in carotid, coronary, and peripheral arteries, research has also examined cognitive function in peripheral vascular disease patients. Results indicate compromised performance on tests of attention, memory, and visuospatial, executive, and psychomotor functions in patients with peripheral vascular disease (Breteler et al., 1994; Phillips, in press), in comparison to both healthy control subjects (Phillips and Mate-Kole, 1997; Waldstein et al., 1999) and hypertensives (Waldstein et al., 1999). Phillips and Mate-Kole (1997) found that, in some instances, the performance of peripheral vascular disease patients was as poor as that of a control group of stroke patients.

Cognitive difficulties have also been noted in patients following myocardial infarction (Barclay et al., 1988; Breteler et al., 1994; Vingerhoets, in press) and in patients with cardiac arrhythmias such as atrial fibrillation (Kilander et al., 1998; Rockwood et al., 1992; Vingerhoets, in press). Studies of cognitive outcomes in patients who have been resuscitated following cardiac arrest also reveal cognitive (particularly memory) difficulties that range from mild to severe (Bertini et al., 1990; Roine et al., 1993; Vingerhoets, in press; Volpe et al., 1986). Results of the above studies indicate that numerous cognitive abilities are affected, including mental status, attention, memory, executive functions, and visuospatial and psychomotor abilities. In contrast to the frequently mild to moderate cognitive difficulties associated with hypertension, cholesterol levels, and diabetes mellitus, studies of the cognitive concomitants of cardiac arrhythmias, cardiac arrest, myocardial infarction, and peripheral vascular disease sometimes identify more severe cognitive impairment or even dementia in a subgroup of patients (Phillips, in press; Vingerhoets, in press). This suggests the possibility of a continuum of cognitive impairment associated with increasingly severe manifestations of cardiovascular disease.

The cardiovascular diseases discussed above predispose to stroke (Kannel, 1992) and may be associated with diminished cognitive performance via many of the same neurobiological mechanisms as hypertension (see Vingerhoets, in press). Examples include increased atherosclerotic (macrovascular) disease, microvascular disease (e.g., white matter disease, silent infarction), and decreased cerebral perfusion. In addition, certain manifestations of cardiovascular disease, such as myocardial infarction and cardiac arrhythmias, often lead to diminished ventricular function that can result in a decreased cardiac output and perhaps decreased cerebral perfusion (or hypoxia). Cardiac arrhythmias are frequently associated with cardiogenic embolism. Furthermore, the cerebral consequences of cardiac arrest include hypoxia and complete anoxia.

Treatments for Cardiovascular Disease and Cognition

The degree to which cognitive difficulties associated with cardiovascular disease are reversible with treatment remains unclear. Insofar as cardiovascular disease leads to morphological changes in the brain, one may not necessarily expect treatment to be associated with cognitive improvements. However, it is possible that certain physiological mechanisms underlying cognitive dysfunction could be altered by various treatments. Furthermore, treatment for cardiovascular disease may avert further cognitive decline.

As discussed above, medical and surgical treatments for cardiovascular disease have been variously associated with cognitive improvements, further decrements, and no change. Studies of the short-and long-term effects of antihypertensive medications have yielded mixed findings (Jonas et al., in press; Muldoon et al., 1991, 1995), a conclusion that has not been clarified by examining studies according to class of medication or relative lipophilicity. Nonetheless, it is generally thought to be unlikely that hypertension-related cognitive deficits are completely reversed by antihypertensive agents and, on average, any direct treatment effects on cognition are believed to be small (Muldoon et al., 1991). However, long-term blood pressure control with antihypertensive therapy is likely to be critical for preservation of cognitive functioning over time.

The impact of coronary artery bypass surgery, a surgical treatment for coronary artery disease, on cognitive function is also inconclusive (Newman et al., in press). Whereas a number of studies have suggested a short-term (1–2 week) deterioration in cognitive function from preoperative status after surgery (Blumenthal et al., 1991; Hammeke and Hastings, 1988; Shaw et al., 1986; Townes et al., 1989), studies having longer-term follow-up (1–24 months) often suggest no change in the mean cognitive performance of patients from preoperative to postoperative periods (Hammeke and Hastings, 1988; Mattlar et al., 1991; Sellman et al., 1992; Townes et al., 1989; Waldstein et al., in press). However, the use of cutoff scores to characterize patients as deteriorated or improved from preoperative levels suggests that 7 to 57 percent of patients may exhibit impairments at approximately six months following coronary artery bypass surgery. It is thus likely that a subgroup of individuals experience negative cognitive consequences of coronary artery bypass surgery, possibly due to various mechanisms such as microemboli during surgery (Newman et al., in press).

With respect to other surgical procedures, studies generally find a lack of cognitive improvement in patients following heart transplantation (Bornstein, in press; Nussbaum and Goldstein, 1992) and carotid endarterectomy (Baird and Pieroth, in press). However, as in other medical and surgical literatures, it remains important to determine relevant predictors of good versus poor treatment outcomes with respect to cognitive functioning.

Future Directions for Research on Health and Cognition

The research presented in this paper strongly suggests a multitude of health (and illness) effects on cognitive function. Because of the greater incidence and prevalence of disease with increasing age, these findings are highly pertinent to the study of cognitive aging and indicate a need to characterize, and control for, health status in studies of "normal aging" (Fozard et al., 1990). Absence of control for health status may also partially explain mixed findings associated with research on neurological diseases and cognition. Most importantly, the promising findings emanating from the research reviewed here indicate a need for further investigation to enhance an understanding of health-cognition relations.

As illustrated by the example of hypertension-cognition relations, there are many avenues of research to pursue in terms of further characterizing the relation of health and illness to cognitive function. Discussion of the unique conceptual and methodological challenges associated with each specific sub-topic in the broad field of health and cognition is beyond the scope of this paper. However, several common challenges can be identified.

Within any particular subtopic area, it remains critical to further identify, using comprehensive test batteries, what domains of cognitive function are most affected, and whether particular subgroups of individuals are most affected. In this regard, identification of pertinent moderating variables is critical. Examples include (but are not limited to) age, education, gender, race or ethnicity, socioeconomic status, genetic polymorphisms, and other biological variation.

It is important to define the magnitude of health effects on different types of cognitive processes. In this regard, it is helpful when individual studies provide an index of effect size. Determination of the clinical significance of these effects is necessary at an individual level and at a population level. With respect to individuals, it is important to determine whether daily functioning and quality of life are affected. In this regard, prior research has indicated that poor performance on certain cognitive tests predicts lower scores on self-reported quality of life in patients with chronic obstructive pulmonary disease (McSweeney and Labuhn, 1996) and poorer functional outcomes in peripheral vascular disease patients (Phillips, in press). In the instance of more severe disease-related cognitive difficulties, characterization of the magnitude and patterning of performance problems may be critical to medical management efforts, such as patients' ability to follow physicians' instructions and associated treatment (e.g., medication) regimens or to participate in rehabilitation programs (e.g., cardiac, exercise). As another example, Phillips (in press) highlights potential difficulties for peripheral vascular disease amputees in learning to use prosthetic devices.

Further characterization of the mechanisms underlying the relation of health effects to cognitive function is necessary using diverse methodologies such as neuroimaging, molecular biology, and psychophysiology. Identification of underlying mechanisms is necessary in order to further develop preventive strategies and methods of intervention geared toward preserving cognitive function. Relevant to the latter issue is the question of whether the impact of disease on cognition is, at least in part, modifiable. In this regard, further identification of the effects of medical and surgical treatments for disease on cognition is important, including a better understanding of the variables that predict treatment-related improvements versus decline.

It is critical to examine the impact of co-occurring medical diseases on cognition. To date, the cognitive consequences of various diseases have typically been studied in isolation. However, comorbidities are extremely common, particularly among older adults. Consider, as one example, that the coexistence of smoking, heavy alcohol consumption, physical inactivity, hypertension, dyslipidemia, diabetes mellitus, atherosclerosis, cardiac arrhythmias, myocardial infarction, and various medications in an individual patient is not unusual. As mentioned above, recent research has indicated that the presence of several cardiovascular risk factors (e.g., hypertension, diabetes, smoking) confers greater risk for poor cognitive performance than any single factor considered in isolation (M.F. Elias et al., in press). In addition, interactive effects of cardiovascular and metabolic disease have been noted (Elias et al., 1997).

Creative, multidisciplinary research is needed to address the research issues posed above. This exciting research area would benefit from collaborative work by individuals in such disciplines as neuropsychology, health psychology and behavioral medicine, aging and gerontology, medicine (e.g., internal medicine, cardiology, radiology, neurology), epidemiology, molecular biology, neuroscience, and genetics. Such collaboration is necessary to generate research on health-cognition relations that can effectively address issues that range from basic mechanisms to the real-life impact of cognitive problems.

Appendix

Commonly Assessed Domains of Cognitive Functioning and Representative Tests

Attention Basic attention involves the ability to selectively focus on, or perceive, specific incoming information while excluding other input; concentration refers to a heightened state of attention. Vigilance requires sustaining one's attention over time. Representative tests include Digit Span, Digit Vigilance, and the Continuous Performance Test.

Executive Function Executive functions are a series of self-regulatory processes, such as planning and organizational abilities, that are thought to be mediated largely by intact functioning of the frontal lobes. Mental flexibility, or the ability to shift one's cognitive or behavioral "set" in order to adapt to the current situation, is also considered to be a dimension of executive function. Representative tests include the Trail Making Test, the Stroop Color-Word Test, the Category Test, and the Wisconsin Card Sorting Test.

Learning and Memory Learning refers to the ability to acquire new information, whereas memory involves the storage and retrieval of information. Learning and memory tests are typically subclassified according to mode of acquisition (e.g., verbal, visual). Representative tests include Logical Memory, Visual Reproductions, Verbal Paired-Associate Learning, the Benton Visual Retention Test, the Tactual Performance Test, the Symbol-Digit Learning Test, and free recall of word lists.

Visuospatial/Visuoconstructional Ability Visuospatial ability involves the perception of spatial aspects of visual stimuli. Visuoconstructional skills, such as drawing, building, and assembling, typically require visuoperceptual ability, spatial skill, and a motor response. Hemiinattention, or neglect (spatial or personal), involves the failure to orient to, report, or respond to stimuli presented contralateral to a brain lesion. Representative tests include Block Design, Object Assembly, and the Rey-Osterreith Complex Figure.

Psychomotor Ability Psychomotor ability is abroad category that encompasses multiple areas of function. Examples include simple motor speed, perceptuo-motor speed, and speed of information processing. Manual dexterity, another aspect of psychomotor function, refers to relative agility in manipulation. Representative tests include the Finger Tapping Test, the Grooved Pegboard, the Digit-Symbol Substitution Test, simple and choice reaction time, and speed of short-term memory search.

Perceptual Ability Perceptual abilities reflect the acquisition of simple sensory stimuli (e.g., visual, auditory, tactual) and/or their integration into meaningful information. Representative tests include the Critical Flicker Fusion test, determination of auditory thresholds, and time estimation.

Language Abilities Language abilities include skills such as comprehension, verbal expression, confrontation naming (ability to find a correct word on command), and fluency. Pronounced disorders of language are referred to as aphasias. Representative tests include the Boston Naming Test, the Controlled Oral Word Association Test, the Token Test, and subscales of the Boston Diagnostic Aphasia Examination.

Estimates of General Intelligence General intelligence involves multidimensional capabilities in addition to a general ability factor. Many unspeeded, verbally based measures of general intelligence are thought to be greatly influenced by level of education, socioeconomic status, and acculturation. Representative tests include the Weschler Adult Intelligence Scale (WAIS) or WAIS-Revised or its subscales. Estimates of general verbal intelligence are often derived from the Information or Vocabulary subscales.

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