The effects of blood pressure reduction on cognitive function: 
Objective: To review systematically and synthesize quantitatively the evidence from completed randomized, controlled trials of blood pressure reduction on cognitive performance.
Methods: MEDLINE, EMBASE and Cochrane databases were searched to identify randomized, controlled trials that measured the effect of blood pressure reduction on cognitive performance. Additional studies were identified by searching bibliographies of retrieved articles and contacting experts in the field. Data were extracted on study quality, blood pressure, performance on cognitive function tests, antihypertensive treatment regimens and the duration of treatment. Studies were reviewed and abstracted independently by two trained researchers.
Results: Sixteen studies with 19 501 subjects were identified. Modest reductions in blood pressure (< 5/3 mmHg) in 13 860 subjects were associated with improvements in Mini Mental State Examination score [weighted mean difference (WMD) = 0.19; 95% confidence interval (CI) = 0.19–0.19] and performance on immediate (WMD = 0.62; 95% CI = 0.21–1.02) and delayed (WMD = 0.67; 95% CI = 0.23–1.11) logical memory tasks. However, studies in 2380 subjects that included tests of perceptual processing and learning capacity (trail making test-A, paired associated learning test) showed impaired performance (WMD = -1.12 s; 95% CI = -1.22 to -1.02 and WMD = -0.04; 95% CI = -0.04 to -0.04) on these tests.
Conclusion: Blood pressure lowering may have a heterogeneous effect on different aspects of cognitive function. Future studies with specific cognitive end-points are needed for greater clarity to guide practice.
The role of hypertension in the aetiology of cerebrovascular disease and the beneficial effects of antihypertensive treatment are well established [1–3]. There is evidence to suggest that antihypertensive treatment may reduce stroke and cerebral white matter disease even in individuals with blood pressure below the current accepted threshold for treatment [2,3]. Although this suggests that lower blood pressures should preserve cognitive function, data from intervention and epidemiological studies show conflicting effects of lower blood pressure on cognitive function [4].
It is well-known that untreated hypertension is associated with increased cerebral white matter pathology, which increases with age and duration of hypertension [5–8]. In addition, recent studies have shown that atherosclerosis and poor blood pressure control contribute to the development of generalized cerebral atrophy and Alzheimer's dementia [9]. The characteristic neuropsychological profile of vascular cognitive impairment includes impairment of executive function (encompassing attention, information processing, volition, planning, purposive action and effective performance) but relative sparing of the episodic memory loss typical of Alzheimer's dementia [4]. Hence, the relationship between hypertension and cognitive decline may be complex, with several different mechanisms contributing to the process and different domains of cognitive performance being affected.
The difficulties in precisely defining the cognitive effects of antihypertensive treatment are reflected in the equivocal results in the literature. Significant reductions in cognitive decline with blood pressure reduction were demonstrated in studies using screening instruments for dementia [e.g. Mini Mental State Examination (MMSE)] [10–12]. By contrast, worsening of cognitive decline was observed in studies that used tests of perceptual processing and sequencing skills [13,14]. Uncertainty about the cognitive effects of blood pressure lowering is compounded by findings of large epidemiological studies in elderly people, which show lower blood pressures to be associated with increased cognitive decline and cerebral white matter disease load [15,16], lower cognitive function in those receiving antihypertensive treatment [17] and a decreased risk of cognitive impairment with higher blood pressure within the normal range [18,19].
Acknowledging that there may be significant differences in age, blood pressure, comorbidity, level of blood pressure control, antihypertensive treatment and methods of neuropsychological assessment between randomized, controlled trials and epidemiological studies, the effect of antihypertensive treatment on cognitive function remains unclear [20]. Many of the randomized studies on reduction of blood pressure were not designed to address cognitive issues and have not controlled at baseline for determinants of cognitive function, nor used assessments that are specific or sensitive to subtle changes in different aspects of cognition. The effect of lowering blood pressure on cognitive function is likely to be modest and requires sample sizes much greater than those included in many existing studies to demonstrate significant differences. Furthermore, heterogeneity in patient inclusion criteria, treatment protocols and use of antihypertensive agents known to have cognitive effects further confounds interpretation of the literature. The present study aimed to review systematically the evidence from completed randomized, controlled trials of blood pressure reduction on cognitive performance.
Two researchers (J.B., L.K.) independently identified publications from searches of the Cochrane Library, EMBASE, MEDLINE (from 1 January 1980 to 1 March 2005), previous reviews and reference lists from identified articles. The search strategy was built on hypertension (patient type) and blood pressure reduction (treatment type).
Completed and published randomized, controlled trials that measured the effect of blood pressure reduction on any measure of cognitive performance were included (Appendix 1). Trials comparing antihypertensive treatment with placebo and comparing different antihypertensive treatments were included. Publication language other than English was not an exclusion criterion. Inclusion of articles was based on agreement between the two independent reviewers (J.B., L.K.). The following MeSH and keywords were used: blood pressure; hypertension; hypertensive; antihypertensive; cognition; cognitive function; cognitive performance; intellect; intellectual function; neuropsychological; psychomotor.
The studies were assessed by two independent reviewers (J.B., L.K.) for quality of randomization, blinding, reporting of withdrawals, generation of random numbers, and concealment of allocation. Trials scored one point for each area addressed and were scored between 0 and 5 (highest level of quality) [21].
The following trial information and data by treatment group were extracted: (i) protocol, including cognitive tests undertaken, type and dose of antihypertensive medication(s), length of treatment, and follow-up period; (ii) numbers of patients; (iii) mean ± SD blood pressure values in each patient group at baseline and study completion; and (iv) mean ± SD performance scores on individual cognitive tests at baseline and trial completion. In studies where data were lacking, the authors were contacted directly.
Cognitive tests undertaken in more than one randomized study were divided into those used mainly as screening instruments for dementia (MMSE), tests of memory (immediate and delayed logical memory), tests of perceptual processing and executive function (digit span, trail-making, digit symbol substitution) and assessments of learning capacity (paired associate learning) [22].
Different cognitive tests were used in different studies. A preliminary analysis of pooled data from relevant studies was undertaken for each test to estimate heterogeneity and crude effect size. Because this showed significant heterogeneity, trials that included antihypertensive agents known to have a detrimental cognitive effect and trials with small sample sizes contributing to heterogeneity were excluded to create homogeneous samples for definitive analysis. The effect of blood pressure lowering on cognitive performance for each individual cognitive test was assessed, regardless of the type of treatment used (Fig. 1). In studies comparing two different antihypertensive treatments, the treatment with greater antihypertensive effect was considered to be the intervention arm of the trial. A pooled analysis was undertaken to estimate the magnitude of systolic (Fig. 2) and diastolic (Fig. 3) blood pressure change in studies that measured different cognitive functions.
Sixteen trials with 19 501 subjects were identified for inclusion in the analysis [10–14,23–35]. These trials investigated the effects of reducing systolic and/or diastolic hypertension and varied in size between 16 and 6105 subjects. Eight trials were placebo-controlled [10–14,23,27,31,34,35] whereas eight trials compared different antihypertensive treatment regimens [24–26,28–30,32,33]. The average age of subjects varied from 42–76 years. The mean baseline systolic blood pressure varied from 191 to 138 mmHg and the mean baseline diastolic blood pressure varied from 101 to 77 mmHg. The follow-up period varied from to 0.5–60 months (mean 18 months; median 5 months). The mean reduction of blood pressure in intervention arms of trials varied between 33.5–7.7 mmHg for systolic and 13.7–2.0 mmHg for diastolic blood pressure.
The median quality score of included trials was 4; six had a quality score of 3 [14,25,27,29–33], six trials had a quality score of 4 [23,24,26,30–32] and four had a quality score of 5. [10,12,13,35] All trials were randomized, and 13 of the 16 trials gave adequate details of withdrawals. Five studies were excluded from the meta-analysis because of inadequate information regarding cognitive test results in two studies [14,23] and blood pressure in three studies (Appendix 1) [25,26,31].
The effect of blood pressure reduction on MMSE performance was assessed in four studies involving 13 212 individuals [10,11,30,34]. The mean starting blood pressure was 167/93 mmHg, the mean MMSE score was 28.3 (range 0–30) and the mean duration of treatment was 17.7 months. Pooled analysis after excluding a small study (n = 69) to achieve homogeneity [30], showed a weighted mean difference (WMD) in blood pressure of -4.8/-2.6 mmHg between control and intervention limbs, which was associated with a better MMSE performance [WMD = 0.19; 95% confidence interval (CI) = 0.19–0.19] in the intervention limb (Figs 1–3).
Five studies including 717 subjects investigated the effect of blood pressure reduction on logical memory tasks [24,27–29,33]. The mean starting blood pressure was 171/99 mmHg and memory scores were 7.5 for logical and 6 for delayed logical memory. A reduction in blood pressure of -3.2/-1.5 mmHg after 5.2 months of treatment in the intervention limb was associated with better performance on immediate (WMD = 0.62, 95% CI = 0.21–1.02) and delayed (WMD = 0.67, 95% CI = 0.23–1.11) logical memory tasks (Figs 1–3).
Perceptual processing and sequencing abilities were assessed in four studies involving 2396 individuals using the trail making test (TMT)-A [13,24,27,29]. The mean starting blood pressure was 177/94 mmHg and the mean duration of treatment was 18.3 months. The mean ± SD time taken to complete TMT-A was 47.1 ± 16.3 s. A mean reduction in blood pressure of -17.1/-7.0 mmHg in the intervention limb was associated with a small but significant decline in TMT A performance (WMD = -1.12 s; 95% CI = -1.22 to -1.02 s). Paired associate learning was also assessed in three of these trials and included 2184 subjects. The mean starting paired associates learning test score was 15 and a reduction of -17.1/-7.0 mmHg in blood pressure was associated with a small but significant decline in performance (WMD = -0.04; 95% CI = -0.04 to -0.04) (Figs 1–3).
The Veterans Affairs study (n = 351) was the only eligible study that investigated changes in digit span tests, symbol digit substitution test and TMT-B with lowering of blood pressure [24]. This study showed no significant reduction in blood pressure with intervention or change in the performance of these cognitive tests.
This systematic review shows a heterogeneous effect of blood pressure lowering on different aspects of cognitive function. There is little uncertainty that lowering blood pressure improves performance on screening tests for dementia and memory tasks, which supports the present view that a reduction of blood pressure reduces cerebrovascular morbidity. However, performance on perceptual processing and learning capacity tasks may not provide any benefit to the same extent, and there was a suggestion that these functions continue to deteriorate despite significant blood pressure reduction. The clinical impact of these apparently opposing effects in the performance of tasks related to different cognitive functions remains difficult to predict, especially because these differences existed against a background of unequal reductions in blood pressure. Blood pressure reduction in studies that showed better performance on memory tasks and measurements of global cerebral function were modest compared with the more substantial reductions in systolic and diastolic blood pressure observed in studies that assessed performance on information processing tasks.
The differential effect of blood pressure lowering on different aspects of cognition, if confirmed in larger, specifically designed trials, raises some important issues. It is well-known that hypertension affects cognition in several ways. Many cross-sectional and longitudinal studies have shown hypertension to be independently associated with cerebral white matter disease, which has been specifically related to impairments in attention and executive function [3–8,36]. The Austrian Stroke Prevention Study suggested that white matter lesion progression precedes loss of brain parenchymal volume and that, other than age and education, brain volume loss is the highest predictor of decline in executive function in addition to decline in memory and visuopractical cognitive domains [37]. Hypertension has also been shown to be associated with increased numbers of neurofibrillary tangles and to accelerate changes associated with Alzheimer's disease [9,38,39]. Skoog et al. [40] demonstrated that, in the very old, overt development of Alzheimer's disease (but not vascular cognitive impairment), was preceded by a spontaneous decline in blood pressure, with white matter lesions appearing to predispose to this development. Skoog et al. [40] proposed that Alzheimer-type lesions in prefrontal areas involved in central blood pressure regulation may have a causative role. Conversely, it has been suggested that the decrement in blood pressure, through periods of cerebral ischaemia, may further the pathogenesis of Alzheimer disease [41].
A recent randomized, controlled study demonstrated antihypertensive treatment to reduce white matter disease progression on brain magnetic resonance imaging [3]. However, the study did not measure parencyhmal volume or cognitive performance. Furthermore, no similar neuroimaging studies evaluating antihypertensive treatment on Alzheimer's disease progression have been carried out. A possible explanation of the observed differences in the effects of antihypertensive treatment on different cognitive functions may be that lowering blood pressure reduces mechanisms contributing to Alzheimer's disease and generalized neurodegenerative changes, which may account for improvements in impairments on memory or dementia screen tasks. On the other hand, impairments of attention, perceptual processing and executive function reflect more specific damage to deep subcortical white matter circuits, many of which are located in the internal watershed area of the frontal lobe [36,42]. Chronic hypertension has a disproportionate effect on these areas because accelerated arteriosclerotic changes of non-communicating perforating arteries may not be reversible by blood pressure reduction once these changes are established [4]. An alternative explanation, as suggested by Qiu et al. [9], is that although appropriate antihypertensive treatment reduces dementia risk and slows down cognitive decline, episodic or sustained hypotension, and possibly excessive treatment of hypertension, may induce cerebral hypoperfusion, ischaemia and hypoxia which may in turn destabilize neurones and synapses and eventually evolve into a neurodegenerative process [9].
The level of blood pressure reduction may be potentially important and needs further investigation. This meta-analysis found that greater falls in blood pressure were associated with poorer performance in perceptual processing tasks predominantly testing the function of subcortical circuits in the internal watershed. This is reminiscent of findings of U-shaped relationships between blood pressure levels and cognitive impairment in cross-sectional and prospective longitudinal studies in 3657 and 1876 elderly individuals, respectively [18–19]. Prospective studies have also shown that nocturnal dipping is associated with increases in the severity of subcortical damage in subjects with cerebral white matter disease [43]. These studies suggest that individuals with advanced cerebrovascular arteriosclerosis lack compensatory reserve for sudden changes in blood pressure and may require a very gradual lowering of blood pressure to avoid provoking ischaemic injury [44].
Limitations of this analysis include the non-availability of detailed cognitive test performance data from the Systolic Hypertension in the Elderly Program, although the results have been reported to show no significant difference in changes in neuropsychological test scores between groups despite a -12/-4 mmHg change in blood pressure in the intervention limb [23]. The exclusion of some small trials to achieve homogeneity of data may also be a source of bias, but findings of the preliminary analyses, which included data from these studies, are comparable with those presented.
Existing data suggest that the effect of hypertension and blood pressure reduction on cognition may be affected by a patient's age, duration of hypertension and level of blood pressure control, in addition to the duration and choice of antihypertensive treatment. The studies included in this meta-analysis employed different antihypertensive agents and follow-up periods, and involved patients of varying ages and levels and duration of blood pressure. Therefore, great care was taken to achieve homogeneous samples for definitive analysis, and we also paid attention to the use of multiple search strategies in identifying randomized, controlled trials and conducted eligibility decisions and data abstraction in duplicate. Included studies represent the best evidence available on cognitive effects of lowering blood pressure; however, the extent of underlying cerebrovascular disease in trial subjects was not measured and may be an unquantifiable source of heterogeneity in the analysis.
There was a significant difference in blood pressure reduction between studies showing better and those showing poorer cognitive performance; it is not known whether cognitive changes would have been more consistent if the overall magnitude of blood pressure change was comparable for studies incorporating memory or dementia tests and those testing perceptual or learning functions. There is no overlap in the analyses between studies that have investigated MMSE or memory impairments and those that have investigated perceptual and learning abilities; findings of differing effects of blood pressure lowering on different aspects of cognitive function would have been strengthened if these effects were observed in the same pool of subjects. Interestingly, one relatively small cross-sectional study (n = 495) that combined MMSE with tests of concentration, visual retention and verbal fluency showed a discordant relationship between MMSE and other cognitive functions, suggesting that there were different patterns of association between blood pressure and different dimensions of cognition [15]. However, there are no randomized, controlled trials with interventions that could support these observations.
This meta-analysis demonstrates that antihypertensive treatment reduces decline in global cortical function and memory but may not have a similar effect on subcortical executive function and learning capacity. The benefits of antihypertensive treatment for the vast majority of individuals are well established and recent studies show that control of hypertension may also reduce white matter disease progression. However, whether this results in improvement in specific perceptual and executive functions associated with such damage remains to be proven. Further studies are needed to assess the consequences of graduated blood pressure reduction in subjects in whom the cerebrovascular disease load is well characterized by using assessments that are sensitive to changes in specific cognitive functions.
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Hypertension Octubre 2006
