Journal of Human Hypertension (2009) 23, 86–96
& 2009 Macmillan Publishers Limited All rights reserved 0950-9240/09 $32.00
www.nature.com/jhh
REVIEW
Cognitive function and hypertension
J Birns and L Kalra
King’s College London, Department of Stroke Medicine, Academic Neurosciences Centre, Institute of
Psychiatry, London, UK
The importance of lowering blood pressure (BP) in
hypertensive subjects is well known but the relationship
between hypertension and cognitive function is controversial. This article reviews the role of hypertension
in the aetiology of cognitive impairment and the
relationships between BP, cerebral perfusion and cognition. It also summarizes findings of studies addressing
the effect of antihypertensive therapy and cognition. An
electronic database search of MEDLINE, EMBASE and
the Cochrane Library and extensive manual searching of
articles were conducted to identify studies that have
used objective measurements of BP and neuropsychological tests to investigate the relationship among
hypertension, cognitive function and/or antihypertensive treatment. In total, 28 cross-sectional studies, 22
longitudinal studies and 8 randomized placebo-controlled trials met the inclusion criteria. Cross-sectional
studies showed mixed relationships between higher BP
and cognition, with many studies showing no correla-
tion or even J- or U-shaped associations. The majority of
longitudinal studies demonstrated elevated BP to be
associated with cognitive decline. Randomized studies
demonstrated heterogeneous and, sometimes conflicting, effects of BP lowering on cognitive function.
Suggested reasons for this heterogeneity include multiple mechanisms by which hypertension affects the
brain, the variety of cognitive instruments used for
assessment and differences in antihypertensive treatments. Although lowering the BP is beneficial in most
patients with vascular risk factors, the effects of BP
reduction on cognition remain unclear. Given the
predicted upswing in people with cognitive impairments, the time is right for randomized clinical trials
with specific cognitive end points to examine the
relationship between cognitive function and hypertension and guide practice.
Journal of Human Hypertension (2009) 23, 86–96;
doi:10.1038/jhh.2008.80; published online 24 July 2008
Keywords: blood pressure; cognitive impairment; antihypertensive treatment; neuropsychological tests; ageing
Introduction
The role of hypertension in the aetiology of vascular
disease and the beneficial effects of antihypertensive treatment are well established.1,2 There is
evidence to suggest that antihypertensive treatment
may reduce stroke and cerebral white matter disease
even in individuals with blood pressure (BP) below
the current accepted threshold for treatment.3,4
Although this suggests that lower BPs should
preserve cognitive function, the relationship between BP and cognition is a subject of much
discussion. In this article, we examine the physiological mechanisms underlying the relationship
between hypertension and cognitive function. We
also summarize the findings from epidemiological
studies and randomized clinical trials addressing
the relationship of BP and antihypertensive therapy
Correspondence: Professor L Kalra, King’s College London,
Department of Stroke Medicine, Academic Neurosciences
Centre, PO41, Institute of Psychiatry, Denmark Hill, London
SE5 8AF, UK.
E-mail: [email protected]
Received 21 April 2008; revised 24 June 2008; accepted 25 June
2008; published online 24 July 2008
to cognitive function and consider the implications
of these findings for future management.
Hypertension and cognition
Hypertension accelerates arteriosclerotic changes in
the brain predisposing to atheroma formation in
large diameter blood vessels and arteriosclerosis and
arteriolar tortuosity of small vessels of the cerebral
vasculature.5 These vascular changes, incorporating
medial thickening and intimal proliferation, result
in a reduction of luminal diameter, increased
resistance to flow and decline in perfusion.6 Such
hypoperfusion can produce discrete regions of
cerebral infarction and diffuse ischaemic changes
in the periventricular and deep white matter
(leukoaraisosis) causing vascular cognitive impairment and also contribute to the pathogenesis of
Alzheimer’s disease by destabilizing neurons and
synapses.7,8 Indeed, neuropathological studies have
linked atherosclerotic burden in the brain to the
pathological changes of both Alzheimer’s disease
and vascular cognitive impairment.9,10
Alzheimer’s disease and vascular cognitive impairment are the two most common causes of
cognitive impairment with the former characterized
Cognitive function and hypertension
J Birns and L Kalra
87
by early loss of episodic memory and the latter
typically involving impairment of attention, information processing and executive function.11 It has
been suggested that decreased BP reduces mechanisms contributing to Alzheimer’s disease and generalized neurodegenerative changes, which may
account for improvements in impairments on memory tasks.12 Impairments of attention, perceptual
processing and executive function, on the other
hand, reflect more specific damage to deep subcortical white matter circuits, many of which are
located in the internal watershed area of the frontal
lobe.13 Chronic hypertension has a disproportionate
effect on these areas because accelerated arteriosclerotic changes of non-communicating perforating
arteries may not be reversible by BP reduction once
these changes are established.14 Furthermore, episodic or sustained hypotension, and possibly excessive treatment of hypertension, may induce cerebral
hypoperfusion, ischaemia and hypoxia that may in
turn compromise neuronal function and eventually
evolve into a neurodegenerative process.15–17
Methods
In January 2008, an electronic database search was
performed of MEDLINE, EMBASE and the Cochrane
Library using the following MeSH and keywords:
BP, hypertension, hypertensive, antihypertensive,
cognition, cognitive function, cognitive performance, intellect, intellectual function, neuropsychological and psychomotor. The resultant
information was supplemented by extensive manual
searching of references (Figure 1). Studies investigating the relationships between BP and cognitive
function, measured with various neuropsychological tests, were examined, whereas studies assessing
the relationship between BP and dementia, diagnosed on the basis of clinical assessment scales,
were excluded. Studies that did not use neuropsychological tests as outcome measures were excluded
to maintain homogeneity in the presentation of
findings from the literature.
Cognitive outcome measures
Neuropsychological tests are standardized techniques that yield quantifiable and reproducible results
that are referable to the scores of normal persons of
age and demographic background similar to those of
the individual being tested. A wide selection of tests
exist, each of differing sensitivity and specificity for
particular brain function deficits. In general, simple
tests that elicit discrete responses are valuable in
determining focal brain damage, whereas assessments of particular cognitive domains are useful in
characterizing the neuropsychological profile of
specific neurodegenerative processes. On the other
hand, multi-dimensional tests, being dependent
upon several aspects of cerebral function, tend to
be nonspecific but very sensitive to changes in
general intellect and mental efficiency.
Epidemiological studies
Many cross-sectional studies have assessed the
relationship of BP and cognition (Table 1).18–45
These studies have showed conflicting relationships
between cognitive function and BP with positive
and negative associations, and J- and U-shaped
relationships being demonstrated in addition to five
studies reporting no significant association between
BP and cognition. Most studies were populationbased, involving a large number of subjects. However, studies varied in their exclusion criteria,
classification of hypertension and range of BP
values of the participating individuals. Cognitive
function was assessed using different neuropsychological instruments; 15 studies used a cognitive
battery covering various cognitive domains and 16
used measures of global cognition such as the minimental state examination. All but two studies26,38
adjusted for age, gender and education but other
studies varied in additional covariates (such as
vascular risk factors) included in multivariate
analyses.
Cross-sectional studies are limited in determining
the direction of an association because both exposure and outcome are assessed simultaneously.
Longitudinal studies have therefore been suggested
to be more appropriate in assessing the relationship
between BP and cognitive function, but they remain
time dependent. The majority of longitudinal studies demonstrated elevated BP to be associated with
cognitive decline25,31,46–58 but some studies showed
quadratic, J- and U-shaped relationships between BP
and cognitive performance33,45,59–61 in addition to
three studies showing elevated BP to be associated
with
improved
cognitive
performance27,43,49
(Table 2). Sample sizes ranged from 155 to 10 963
and duration of follow-up ranged from 1.5 to 30
years. Studies also differed in their inclusion and
exclusion criteria, BP levels of participating individuals and use of antihypertensive treatments. Again,
a variety of cognitive measures were employed with
12 studies using a battery of neuropsychological
tests designed to assess different cognitive domains
and 16 studies using measures of global cognition.
All but one study59 adjusted for age, gender and
education but studies varied in additional covariates, particularly the use of antihypertensive treatments, included in multivariate analyses.
A number of different genetic, demographic and
atherosclerotic risk factors for cognitive impairment
have been demonstrated in cross-sectional and
longitudinal studies.62 These factors may play an
important role in driving the relationship between
hypertension and cognition and were often not
included as covariates in the analyses of the studies
included in this review. Examples include ethnicity,
hyperinsulinaemia and hyperhomocystinaemia that
Journal of Human Hypertension
Cognitive function and hypertension
J Birns and L Kalra
88
Search of MEDLINE, EMBASE and Cochrane electronic databases
and citation list of relevant publications
for studies investigating the relationships between cognitive function and
hypertension
Documentation
of blood pressure
data
Documentation
of performance
on cognitive
function tests
Documentation
of relationships
between blood
pressure and
cognitive function
No
documentation of
blood pressure
data
No
documentation of
performance on
cognitive function
tests
No Documentation
of relationships
between blood
pressure and
cognitive function
Study excluded
Study excluded
Study excluded
28 cross-sectional studies, 22 longitudinal studies and 8 randomized placebocontrolled trials investigating the relationships between cognitive function and
hypertension
Figure 1 Search strategy.
have been shown to have a significant impact on
cognitive impairment in recent studies.63–65 Furthermore, existing data suggest that the effect of
hypertension on cognition may be affected by a
patient’s duration of hypertension and level of BP
control in addition to the duration and choice of any
antihypertensive treatment and again, these factors
were often not taken into account in the analyses of
these studies.66
Randomized controlled trials
Observational studies may demonstrate associations
but do not determine causality; the latter only being
shown by intervention studies. Only eight completed randomized placebo-controlled clinical trials
of BP-lowering agents have reported the effects of
treatment on the risk of cognitive impairment, and
Journal of Human Hypertension
the effect of antihypertensive treatment on cognitive
function remains a matter of debate (Table 3).67–74
The Syst-Eur trial included a side project on 2418
subjects in whom cognitive function was assessed.
Subjects were taking active treatment with nitrendipine±enalapril and/or hydrochlorothiazide or
placebo. The follow-up was only 2 years as the trial
was terminated early because of significant differences in the incidence of stroke, the primary end
point. Compared with placebo, active treatment
reduced decline in mini-mental state examination
score and lowered the incidence of dementia by
50% from 7.7 to 3.8 cases per 1000 patient-years.71
The PROGRESS (Perindopril Protection against
Recurrent Stroke Study) study randomized 6105
people with prior stroke or transient ischaemic
attack to either active treatment with perindopril
±indapamide or matching placebo(s). After a mean
follow-up of 3.9 years, cognitive decline occurred in
Table 1 Cross-sectional studies assessing the effect of BP on cognitive function
Classification of hypertension
Neuropsychological test(s)
Results/conclusions
Wallace et al.18
2433 subjects; ageX65 years;
stroke-free
SBPX140 mm Hg (systolic hypertension);
DBPX90 mm Hg (diastolic hypertension)
Free-recall memory test
Significantly lower cognitive performance in patients
with diastolic but not systolic hypertension compared
with normotensives
Farmer et al.19
2032 subjects; age 55–89 years;
stroke-free
BPX160/95 mm Hg (hypertension);
SBPX140 mm Hg and DBPo90 mm Hg
(isolated systolic hypertension);
DBPX90 mm Hg (diastolic hypertension)
Logical memory-immediate recall,
visual reproduction, paired associate
learning, digits forwards, digits
backwards, word fluency, logical
memory-delayed recall tests
No significant relationship between BP and cognitive
performance
Elias et al.20
301 subjects; age 20–75 years
BPX140/90 mm Hg (hypertension)
Digit symbol substitution, categories,
tactile perception, finger tapping,
trail-making tests
Significantly lower cognitive performance in patients
with high SBP and high DBP
Scherr et al.21
3809 subjects; ageX65 years
SBPX140 mm Hg (systolic hypertension);
DBPX90 mm Hg (diastolic hypertension)
Negative association between DBP and digit span
Immediate memory, delayed memory,
mental status questionnaire, digit span scores; no other significant relationships between BP
and cognitive performance
tests
Starr et al.22
598 subjects; ageX70 years;
mean BP 160/86 mm Hg
41 SD above mean BP (high BP); within
1 SD of mean BP (medium BP); 41 SD
below mean BP (low BP)
MMSE
Significantly lower cognitive performance in patients
with high SBP and high DBP
Desmond et al.23
249 subjects; mean age 71 years;
stroke-free
BPX160/95 mm Hg (hypertension)
Selective reminding, Benton visual
retention, similarities, verbal function,
Rosen figure drawing, timed targetfinding task tests
No significant relationship between BP and cognitive
performance
Kuusisto et al.24
744 subjects; mean age 73 years;
stroke-free; non-diabetic
BPX160/95 mm Hg or on antihypertensive
treatment (hypertension)
MMSE, Russell adaptation of visual
reproduction, trail making, verbal
fluency, selective reminding tests
Significantly lower cognitive performance in patients
with high SBP and high DBP
Launer et al.25
3682 subjects; mean age 78 years
BPo110/80 mm Hg (low BP); SBP 110–
139 mm Hg and DBP 80–89 mm Hg (normal BP);
SBP 140–159 mm Hg and DBP 90–94 mm Hg
(borderline BP); BPX160/95 mm Hg (high BP)
Cognitive abilities screening
instrument
No significant relationship between BP and cognitive
performance
Gale et al.26
973 subjects; ageX65 years
DBP495 mm Hg (diastolic hypertension)
Hodkinson abbreviated mental test
Negative association between cognitive performance
and DBP; no relationship between cognitive
performance and SBP
Guo et al.27
1736 subjects; ageX75 years
SBPo130 mm Hg (low SBP); SBP 130–
159 mm Hg (medium SBP); SBP
160–179 mm Hg (mildly elevated SBP);
BP4180/95 mm Hg (severe hypertension)
MMSE
Positive association between cognitive performance and
SBP and between cognitive performance and DBP
Cacciatore et al.28
1106 subjects; age
65–95 years; stroke-free; mean
BP 145/82 mm Hg
NA
MMSE
Positive association between cognitive performance and
DBP but not SBP; DBP but not SBP predictive of
cognitive performance in regression analysis
van Boxtel et al.29
936 subjects; age 24–81 years;
mean BP 131/74 mm Hg; MMSE
score424; free from stroke,
chronic neurologic disease
BPX140/95 mm Hg (hypertension)
Word learning task, concept shifting
task, stroop colour word, letter/digit
substitution, word fluency tests
Hypertensive subjects performed worse than
normotensives at letter/digit copying; no other
significant relationships between BP and cognitive
performance
Cerhan et al.30
13 913 subjects; age 45–64 years;
stroke-free
BPX160/95 mm Hg (hypertension)
Delayed word recall, digit symbol,
word fluency tests
Hypertensive women performed worse than
normotensives in digit symbol tests; no other significant
relationships between BP and cognitive performance
Cognitive function and hypertension
J Birns and L Kalra
Subjects
89
Journal of Human Hypertension
Study
90
Journal of Human Hypertension
Table 1 Continued
Subjects
Classification of hypertension
Neuropsychological test(s)
Results/conclusions
Kilander et al.31
999 subjects; age 69–75 years;
mean BP 148/85 mm Hg
NA
MMSE, trail-making test
Negative association between cognitive performance
and SBP and between cognitive performance and DBP
Seux et al.32
2252 subjects; ageX60 years;
mean BP 173/86 mm Hg
SBP 160–219 mm Hg
(systolic hypertension)
MMSE
Negative association between cognitive performance
and SBP but not DBP
Glynn et al.33
3576 subjects; ageX65 years
NA
East Boston memory test, Pfeiffer
SPMSQ
U-shaped relationship between SPMSQ performance
and SBP and DBP
Harrington et al.34
BP4160/90 mm Hg (hypertension)
223 subjects; age 70–89 years;
MMSE score424; free from cardiac
disease, peripheral vascular disease,
cerebrovascular disease, diabetes
Simple reaction time, choice reaction
time, number vigilance, memory
scanning, word recognition, picture
recognition, spatial memory tests
Hypertensive subjects performed worse than
normotensives in all tests except for choice reaction
time test
Di Carlo et al.35
3425 subjects; age 65–84 years
SBPX140 mm Hg and DBPX90 mm Hg
(hypertension)
MMSE, Cambridge Cognitive
Examination
No significant relationship between BP and cognitive
performance
Stewart et al.36
278 subjects; age 55–75 years
Previously diagnosed hypertension
MMSE, verbal recall, word list
recognition, visual association, visual
recall, trail making, clock drawing,
Boston naming, verbal fluency tests
Hypertension significantly associated with cognitive
impairment
Andre-Petersson
et al.37
500 men; age 68–69 years
BPp140/90 mm Hg (normotensive);
SBP 140–159 mm Hg or DBP 90–99 mm Hg
(hypertension stage 1); SBP 160–179 mm Hg
or DBP 100–109 mm Hg (hypertension
stage 2); SBPX180 mm Hg or
DBPX110 mm Hg (hypertension stage 3)
Synonyms, block design, paired
associates, digit symbol substitution,
Benton visual retention tests
Hypertension stage 3 associated with lower
performance on psychomotor speed and visuospatial
memory tests; hypertension stage 1 associated with
higher performance on tests measuring verbal and
constructional ability
Izquierdo-Porrera
and Waldstein38
43 subjects; age 43–82 years; free
NA
from neoplasia, stroke, cardiac
disease, peripheral vascular disease,
renal or liver disease, arthritis mean
BP 136/78 mm Hg; MMSE424
Digits forward, digits backwards, word No significant relationship between BP and cognitive
list learning, EXIT 25 executive
performance
functioning, clock drawing tests
Morris et al.39
5816 subjects; ageX65 years;
mean BP 139/76 mm Hg
MMSE, East Boston memory, symbol
digit modalities tests
Inverted U-shaped relationship between cognitive
performance and SBP and between cognitive
performance and DBP
Budge et al.40
158 subjects; age 60–91 years; mean NA
BP 153/82 mm Hg; MMSE423
MMSE, Cambridge Examination for
Mental Disorders of the Elderly
Cognitive Section
Significant negative association between cognitive
performance and SBP
Paran et al.41
495 subjects; age 70–85 years; free
from neoplasia, stroke, cardiac
disease, liver disease, renal disease,
Parkinson’s disease, dementia;
mean BP 142/79 mm Hg
MMSE, Buschke selective reminding,
trail making, Russell adaptation of
visual reproduction, verbal
fluency tests
Significant linear positive association between MMSE
and concentration and BP; inverted U-shaped
relationship between memory and visual retention and
BP; no significant relationship between verbal fluency
and BP
Pandav et al.42
4810 Indian subjects; ageX55 years; NA
mean BP 115/74 mm Hg, 636 North
American subjects; ageX75 years;
mean BP 141/76 mm Hg
MMSE, delayed recall tests
Negative association between cognitive performance
and SBP and between cognitive performance and DBP
in Indian population; no significant relationship
between BP and cognitive performance in North
American population
BPX160/90 mm Hg (hypertension)
SBPo140 mm Hg not on treatment
(normotensive); SBPo140 mm Hg on
treatment (normalized hypertensive);
SBPX140 mm Hg not on treatment
(untreated hypertensive); SBPX140 mm
Hg on treatment (uncontrolled hypertensive)
Cognitive function and hypertension
J Birns and L Kalra
Study
Cognitive function and hypertension
J Birns and L Kalra
Abbreviations: DBP, diastolic blood pressure; MMSE, mini-mental state examination; NA, not applicable; SBP, systolic blood pressure; SPMSQ, short portable mental status questionnaire.
J- and U-shaped relationships between tests of
perceptuomotor speed, executive function and
confrontation naming and DBP; negative association
between working memory and DBP; negative
association between non-verbal memory and SBP
Digit span, verbal learning, Benton
visual retention, trail making, letter
fluency, category fluency, Boston
naming tests
NA
847 subjects; mean age 71 years;
free from cerebrovascular disease,
renal failure, dementia
Waldstein et al.45
Increased SBP significantly associated with impaired
trail-making test B performance; no other significant
relationships between BP and cognitive performance
Verbal memory, visual memory, trail
making, word fluency tests
NA
70 subjects; mean age 72 years;
free from cardiac disease,
peripheral vascular disease,
carotid stenosis, diabetes, stroke,
dementia, chronic lung disease,
Parkinson’s disease, severe
hypertension (SBP4200 mm Hg or
DBP4110 mm Hg)
Kuo et al.44
Significant negative association between cognitive
performance and DBP
MMSE
BP4160/95 mm Hg (hypertension)
Kähönen-Väre et al.43 650 subjects; (239 aged 75 years,
212 aged 80 years and 199 aged
85 years)
Subjects
Study
Table 1 Continued
Classification of hypertension
Neuropsychological test(s)
Results/conclusions
91
9.1% of the treatment group and 11.0% of the
placebo group (relative risk reduction of 19%,
P ¼ 0.01).73 In contrast to these results, the other
three large randomized trials (SHEP (Systolic Hypertension in the Elderly Program), MRC (Medical
Research Council) and SCOPE (Study on Cognition
and Prognosis in the Elderly)), involving 7582
individuals over a mean follow-up period of 4.4
years, reported no positive effects on cognitive
function with antihypertensive therapy.69,70,74 Three
small trials (np69) with short follow-up duration
(p7 months) added to the heterogeneity of demonstrated effects of BP lowering on cognition with both
better and worse performance on different cognitive
tests being shown in addition to an absence of
significant effect.67,68,72 We have previously undertaken a meta-analysis of the randomized controlled
trials of BP reduction on cognitive function and
demonstrated a heterogeneous effect of BP lowering
on different aspects of cognitive function, with
improvement in global cerebral function and memory tasks but impaired performance on perceptual
processing and learning capacity tasks.66
Many of the existing controversies on the cognitive consequences of BP lowering, especially in
older people, arise from the design limitations of
studies. Most studies did not quantify the level of
cerebrovascular disease load in included subjects
nor consider this a relevant prognostic determinant.
Although only patients with previous strokes were
included in the PROGRESS study, aetiological
subtyping was not undertaken. Studies differed in
subjects’ age, BP, comorbidity, level of BP control,
antihypertensive treatment, methods of neuropsychological assessment and trial duration, and many
studies were not designed to address cognitive
issues. Indeed, cognitive assessments were secondary outcome measures in most studies. Differences
among studies in patient inclusion criteria and
treatment protocols also confound interpretation of
the literature. Furthermore, many studies allowed
the use of b-blocker or centrally acting antihypertensive agents, despite such drugs having the
potential to affect cognitive performance adversely.75
Summary
The results of cross-sectional studies investigating
the relationship between BP and cognition showed
conflicting relationships with positive, negative and
J- and U-shaped associations. The majority of longitudinal studies demonstrated elevated BP to be
associated with cognitive decline and a small
number of randomized controlled trials demonstrated heterogeneous effects of BP lowering on
cognitive function. These findings suggest a complex relationship between BP and cognitive function
consistent with the biological mechanisms that
exist. A variety of disease processes that are affected
Journal of Human Hypertension
Cognitive function and hypertension
J Birns and L Kalra
92
Table 2 Longitudinal studies assessing the effect of BP on cognitive function
Study
Wilkie and Eisdorfer46
47
Elias et al.
Subjects/follow-up
Neuropsychological test(s)
Results/conclusions
177 subjects; age 60–79 years; strokefree; 10 year follow-up
1702 subjects; age 55–88 years;
stroke-free; 12- to 14-year follow-up
Wechsler Adult Intelligence Scale
DBP inversely associated with cognitive
performance
SBP, DBP and duration of hypertension
inversely associated with cognitive performance
Logical memory, visual reproduction,
paired associate learning, digit span,
word fluency, similarities tests
Cognitive abilities screening
instrument
Launer et al.25
3735 subjects; mean age 78 years;
25-year follow-up
Okumiya et al.59
155 subjects; age 70–91 years; 3-year
follow-up
MMSE
J-curve relationship between SBP and decline in
cognitive performance
Guo et al.27
1022 subjects; ageX75 years; 3.5-year
follow-up
MMSE
SBP positively associated with cognitive
performance; no significant relationship
between DBP and cognitive performance
Swan et al.48
317 subjects; age 69–79 years; 25-year
follow-up
MMSE, digit symbol substitution,
Benton visual retention, verbal
fluency tests
SBP inversely associated with cognitive
performance
Swan et al.49
717 subjects; age 39–59 years; free of
cardiac disease; 30-year follow-up
SBP inversely associated with verbal learning
and memory, SBP decline inversely associated
with speeded performance
Kilander et al.31
999 subjects; age 69–75 years; 20-year
follow-up
MMSE, Iowa screening battery for
mental decline, digit symbol
substitution, colour trail making,
colour word interference, California
verbal learning tests
MMSE
Glynn et al.33
3576 subjects; ageX65 years; 6-year
follow-up
East Boston memory test, Pfeiffer
SPSMQ
U-shaped relationship between SBP and DBP
and SPSMQ performance
Sacktor et al.50
158 subjects; treated hypertensives;
ageX60 years; free of dementia; 1.5to 9-year follow-up
MMSE, blessed information memoryconcentration, cued selective
reminding, trail-making tests
SBP and DBP positively associated with decline
in cued selective reminding test total free recall;
SBP negatively associated with decline in cued
selective reminding test delayed free recall; no
other significant relationships between BP and
cognitive performance
Haan et al.51
3622 subjects; ageX65 years; 7-year
follow-up
1373 subjects; age 59–71 years; 4-year
follow-up
463 subjects; age 69–74 years; strokefree; 20-year follow-up
Modified MMSE, digit symbol
substitution test
MMSE
SBP inversely associated with cognitive
performance
BP and duration of hypertension inversely
associated with cognitive performance
DBP inversely associated with digit span, trailmaking and verbal fluency test performance
Tzourio et al.
52
Kilander et al.53
Knopman et al.54
Bohannon et al.60
10 963 subjects; age 47–70 years;
6-year follow-up
3202 subjects; ageX65 years; 3-year
follow-up
MMSE, vocabulary, digit span,
Claeson-Dahl, block span, trail
making, Rey-Osterrieth, verbal
fluency tests
Delayed word recall, digit symbol,
verbal fluency tests
SPSMQ
SBP inversely associated with cognitive
performance; no significant relationship
between DBP and cognitive performance
DBP inversely associated with cognitive
performance
BP inversely associated with digit symbol and
verbal fluency test performance
U-shaped relationship between SBP (but not
DBP) and SPSMQ performance in white
subjects; no significant relationships between
BP and cognitive performance in black subjects
DBP and SBP inversely associated with
visuospatial performance
Reinprecht et al.55
186 subjects; age 68 years; 13-year
follow-up
MMSE, synonyms, block design,
paired associates, digit symbol
substitution, Benton visual retention
tests
Elias et al.56
1423 subjects; age 55–88 years; free
from stroke, dementia,
cardiovascular disease; 5-year
follow-up
Logical memory, visual reproduction,
paired associate learning, digit span,
word fluency, similarities tests
BP inversely associated with cognitive
performance in men but not in women
Piguet et al.57
228 subjects; ageX75 years; 6-year
follow-up
4284 subjects; ageX65 years; 6-year
follow-up
MMSE
BP inversely associated with cognitive
performance
Quadratic relationship between DBP and change
in cognitive performance; no other significant
relationships between BP and cognitive
performance
529 subjects; age 18–83 years; free
from stroke, dementia, alcoholism,
drug abuse; 20-year follow-up
160 subjects; age 75–85 years; 10-year
follow-up
847 subjects; age 39–96 years; free
from cerebrovascular disease, renal
failure, dementia 11-year follow-up
Wechsler Adult Intelligence Scale
SBP and DBP inversely associated with
visualization/fluid cognitive performance
MMSE
BP positively associated with cognitive
performance
Quadratic relationship between SBP and nonverbal memory and confrontation naming
Hebert et al.61
Elias et al.58
Kähönen-Väre et al.43
Waldstein et al.45
MMSE, immediate and delayed
recall, symbol digit modalities tests
Digit span, verbal learning, Benton
visual retention, trail making, letter
fluency, category fluency, Boston
naming tests
Abbreviations: DBP, diastolic blood pressure; MMSE, mini-mental state examination; SBP, systolic blood pressure; SPMSQ, short portable mental
status questionnaire.
Journal of Human Hypertension
Table 3 Randomized placebo-controlled clinical trials assessing the effect of BP-lowering agents on cognitive function
Mean BP reduction
Neuropsychological test(s)
Conclusions
Lasser et al.67
69 subjects; age 25–55 years; DBP 90–
104 mm Hg; randomized to prazosin,
hydrochlorothiazide, propranolol or
placebo; 7-month follow-up
69% of patients on prazosin, 69%
of patients on hydrochlorothiazide,
58% of patients on propranolol and
22% of patients on placebo achieved
target DBPo90 mm Hg
Russell revision of Wechsler memory scale,
digit span, digit symbol substitution, block
design, simple reaction time, combination
reaction time and signal detection tests
No significant differences in changes in
neuropsychological test scores other than
impaired block design performance in
hydrochlorothiazide group
McCorvey et al.68
16 patients with asymptomatic
essential hypertension; ageX55
years; no BP criteria; randomized
to hydrochlorothiazide, propranolol,
enalapril or placebo; 4-week
follow-up
Compared with placebo: 12/5 mm Hg
(hydrochlorothiazide); 5/2 mm Hg
(propranolol); 3/0 mm Hg
(enalapril) (negative BP reductions
equate to BP increases)
Finger tapping, stimulus reaction time, trail
making, discriminant reaction, continuous
performance, selective reminding tests
No significant difference in changes in
neuropsychological test scores between
groups other than fewer incorrect responses
in trail-making tests and greater discriminant
reaction time response rate in
hydrochlorothiazide group
SHEP (Systolic Hypertension
in the Elderly Program)69
2034 subjects; ageX60 years; SBP
160–219 mm Hg; DBPo90 mm Hg;
randomized to chlorthalidone in step
1 and atenolol or reserpine in step 2
versus placebo; 5-year follow-up
27/9 mm Hg (treatment group);
15/5 mm Hg (placebo)
Digit symbol substitution, addition, finding
A’s, Boston naming, delayed recognition,
letter set tests
No significant difference in changes in
neuropsychological test scores between
groups
MRC (Medical Research
Council)70
2584 subjects; age 65–74 years; SBP
160–209 mm Hg; DBPo115 mm Hg;
randomized to diuretic, b-blocker or
placebo; 54-month follow-up
33.5 mm Hg SBP (diuretic);
30.9 mm Hg SBP (b-blocker);
16.4 mm Hg SBP (placebo)
Paired associate learning, trai-making tests
No significant difference in
neuropsychological test scores among three
groups
Syst-Eur (Systolic
hypertension in Europe)71
2418 subjects; ageX60 years; SBP
160–219 mm Hg; DBPo95 mm Hg;
randomized to nitrendipine±
enalapril, hydrochlorothiazide or
both versus placebo; 2-year follow-up
21.7/6.4 mm Hg (treatment group);
13.4/2.6 mm Hg (placebo)
MMSE; DSM-IIIR dementia criteria
diagnostic tests
Reduction in decline in MMSE score and
decreased incidence of dementia from 7.7
to 3.8 cases per 1000 patient-years
Denolle et al.72
15 subjects; age 50–75 years; SBP
160–180 mm Hg; DBP 95–105 mm Hg;
randomized to nicardipine, clonidine
or placebo; 2-week follow-up
13/6 mm Hg (nicardipine);
9/12 mm Hg (clonidine);
0/1 mm Hg (placebo)
Simple reaction, finger tapping, CFF,
continuous performance, digit symbol
substitution, body sway, dual coding,
Syndrom Kurz Test, learning memory tests
Increase in CFF in nicardipine group;
increase in length of body sway and decrease
in CFF in clonidine group
PROGRESS (Perindopril
Protection against Recurrent
Stroke Study)73
6105 patients with previous stroke or
TIA; no age or BP inclusion criteria;
mean age 64 years; mean BP 147/86;
randomized to
perindopril±indapamide versus
placebo; 3.9-mean year follow-up
Compared with placebo: 9/4 mm Hg
(treatment group)
MMSE
19% relative risk reduction in cognitive
decline in treatment group
SCOPE (Study on Cognition
and Prognosis in the
Elderly)74
4964 subjects; age 70–89 years; SBP
160–179 mm Hg; DBP 90–99 mm Hg;
MMSE424; randomized to
candesartan or placebo with open
label active antihypertensive therapy
added as needed; 3.7-year mean
follow-up
21.7/10.8 mm Hg (candesartan);
18.5/9.2 mm Hg (control group)
MMSE
No difference in cognitive decline between
groups
Cognitive function and hypertension
J Birns and L Kalra
Study design
Abbreviations: CFF, critical flicker fusion threshold determination; DBP, diastolic blood pressure; DSM-IIIR, Diagnostic and Statistical Manual of Mental Disorders, third edition revised; MMSE,
mini-mental state examination; SBP, systolic blood pressure; TIA, transient ischaemic attack.
93
Journal of Human Hypertension
Trial
Cognitive function and hypertension
J Birns and L Kalra
94
by hypertension may result in cognitive impairment
and the aetiology of cognitive impairment may
influence specific domains of cognitive deficit.
The need for different cognitive assessments for
evaluating cognitive impairments of differing aetiology has been previously documented14 and the
different results shown in both epidemiological and
intervention studies may in part be explained by use
of a variety of cognitive instruments. Neuropsychological studies to date argue for comprehensive
measurement of cognitive domains76 and future
studies investigating the relationships between
cognitive function and hypertension will benefit
from outcome measures that allow detection of
deficits in specific cognitive domains.
BP lowering is beneficial in the vast majority of
patients with vascular risk factors but the effect of
BP reduction on cognition can only be assessed by
randomized controlled trials including appropriate
cognitive end points. The occurrence of lacunes and
white matter changes increases exponentially after
the age of 65 years77 and as the baby boomer
generation reaches the age of 65–70 years by 2015,
we will experience the predicted upswing in
cognitive impairment. Now is the time for randomized clinical trials to examine the relationship
between cognitive function and hypertension.
Disclosure
The authors report no conflict of interest.
References
1 Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH,
Eberlein KA et al. Blood pressure, stroke and coronary
heart disease. Part 2, short-term reduction in blood
pressure: overview of randomised drug trials in their
epidemiological context. Lancet 1990; 335: 827–838.
2 Lewington S, Clarke R, Qizilbash N, Peto R, Collins R,
Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality:
a meta-analysis of individual data for one million
adults in 61 prospective studies. Lancet 2002; 360:
1903–1913.
3 PROGRESS Collaborative Group. Randomised trial of a
perindopril-based blood pressure-lowering regimen
among 6105 individuals with previous stroke
or transient ischaemic attack. Lancet 2001; 358:
1033–1041.
4 Dufouil C, Chalmers C, Coskun O, Besancon V, Bousser
M-G, Guillon P et al. Effects of blood pressure lowering
on cerebral white matter hyperintensities in patients
with stroke. The PROGRESS (Perindopril Protection
against Recurrent Stroke Study) magnetic resonance
imaging substudy. Circulation 2005; 112: 1644–1650.
5 Spence JD. Cerebral consequences of hypertension:
where do they lead? J Hypertens Suppl 1996; 14:
S139–S145.
6 Skoog I. A review on blood pressure and ischaemic
white matter lesions. Dement Geriatr Cogn Disord
1998; 9(Suppl 1): 13–19.
Journal of Human Hypertension
7 O’Sullivan M, Morris RG, Huckstep B, Jones DK,
Williams SC, Markus HS. Diffusion tensor MRI
correlates with executive dysfunction in patients with
ischaemic leukoaraiosis. J Neurol Neurosurg Psychiatry 2004; 75: 441–447.
8 de la Torre JC, Fortin T. A chronic physiological rat
model of Alzheimer’s disease. Behav Brain Res 1994;
63: 35–40.
9 Sparks DL, Scheff SW, Liu H, Landers TM, Coyne CM,
Hunsaker III JC. Increased incidence of neurofibrillary
tangles (NFT) in non-demented individuals with
hypertension. J Neurol Sci 1995; 131: 162–169.
10 Kalaria RN, Kenny RA, Ballard CG, Perry R, Ince P,
Polvikoski T. Towards defining the neuropathological
substrates of vascular dementia. J Neurol Sci 2004; 226:
75–80.
11 O’Brien JT, Erkinjuntii E, Reisberg B, Roman G,
Sawada T, Pantoni L et al. Vascular cognitive impairment. Lancet Neurol 2003; 2: 89–93.
12 Qiu C, Winblad B, Fratiglioni L. The age-dependent
relation of blood pressure to cognitive function and
dementia. Lancet Neurol 2005; 4: 487–499.
13 Cummings JL. Frontal–subcortical circuits and human
behavior. J Psychosom Res 1998; 44: 627–628.
14 Birns J, Markus H, Kalra L. Blood pressure reduction
for vascular risk: is there a price to be paid? Stroke
2005; 36: 1308–1313.
15 Shi J, Yang SH, Stubley L, Day AL, Simpkins JW.
Hypoperfusion induces overexpression of beta-amyloid precursor protein mRNA in a focal ischemic
rodent model. Brain Res 2000; 853: 1–4.
16 Tanaka M, Fukuyama H, Yamauchi H, Narita M,
Nabatame H, Yokode M et al. Regional cerebral
blood flow abnormalities in nondemented patients
with memory impairment. J Neuroimag 2002; 12:
112–118.
17 Verghese J, Lipton RB, Hall CB, Kuslansky G, Katz MJ.
Low blood pressure and the risk of dementia in very
old individuals. Neurology 2003; 61: 1667–1672.
18 Wallace RB, Lemke JH, Morris MC, Goodenberger M,
Kohout F, Hinrichs JV. Relationship of free-recall
memory to hypertension in the elderly: the Iowa 65+
Rural Health Study. J Chronic Dis 1985; 38: 475–481.
19 Farmer ME, White LR, Abbott RD, Wolz MM, Wolf PA.
Blood pressure and cognitive performance: the
Framingham Study. Am J Epidemiol 1987; 126:
1103–1114.
20 Elias MF, Robbins MA, Schultz Jr NR, Pierce TW. Is
blood pressure an important variable in research on
aging and neuropsychological test performance?
J Gerontol 1990; 45: P128–P135.
21 Scherr PA, Hebert LE, Smith IA, Evans DA. Relation of
blood pressure to cognitive functions in the elderly.
Am J Epidemiol 1991; 134: 1303–1315.
22 Starr JM, Whalley LJ, Inch S, Schering PA. Blood
pressure and cognitive function in healthy old people.
J Am Geriatr Soc 1993; 41: 753–756.
23 Desmond DW, Tatemichi TK, Paik M, Stern Y. Risk
factors for cerebrovascular disease as correlates of
cognitive function in a stroke-free cohort. Arch Neurol
1993; 50: 162–166.
24 Kuusisto J, Koivisto K, Mykkanen L, Helkala EL,
Vanhanen M, Hänninen T et al. Essential hypertension
and cognitive function: the role of hyperinsulinemia.
Hypertension 1993; 22: 771–779.
25 Launer LJ, Masaki K, Petrovitch H, Foley D, Havlik RJ.
The association between midlife blood pressure levels
Cognitive function and hypertension
J Birns and L Kalra
95
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
and late-life cognitive function. The Honolulu-Asia
Aging Study. JAMA 1995; 274: 1846–1851.
Gale CR, Martyn CN, Cooper C. Cognitive impairment
and mortality in a cohort of elderly people. Br Med J
1996; 312: 608–611.
Guo Z, Fratiglioni L, Winblad B, Viitanen M. Blood
pressure and performance on the Mini-Mental State
Examination in the very old: cross-sectional and
longitudinal data from the Kungsholmen Project. Am
J Epidemiol 1997; 145: 1106–1113.
Cacciatore F, Abete P, Ferrera N, Paolisso G, Amato L,
Canonico S et al. The role of blood pressure in
cognitive impairment in an elderly population.
J Hypertens 1997; 15: 135–142.
van Boxtel MPJ, Gaillard C, Houx PJ, Buntinx F, de
Leeuw PW, Jolles J. Can the blood pressure predict task
performance in a healthy population sample?
J Hypertens 1997; 15: 1069–1076.
Cerhan JR, Folsom AR, Mortimer JA, Shahar E,
Knopman DS, McGovern PG et al. Correlates of cognitive
function in middle-aged adults. Atherosclerosis Risk
in Communities (ARIC) Study Investigators. Gerontology 1998; 44: 95–105.
Kilander L, Nyman H, Boberg M, Hansson L, Lithell H.
Hypertension is related to cognitive impairment: a 20year follow-up of 999 men. Hypertension 1998; 31:
780–786.
Seux M-L, Thijs L, Forette F, Staessen JA, Birkenhäger
WH, Bulpitt CJ et al. Correlates of cognitive status of
old patients with isolated systolic hypertension: the
Syst-Eur Vascular Dementia Project. J Hypertens 1998;
16: 963–969.
Glynn RJ, Beckett LA, Hebert LE, Morris MC,
Scherr PA, Evans DA. Current and remote blood
pressure and cognitive decline. JAMA 1999; 281:
438–445.
Harrington F, Saxby BK, McKeith IG, Wesnes K, Ford
GA. Cognitive performance in hypertensive and normotensive older subjects. Hypertension 2000; 36:
1079–1082.
Di Carlo A, Baldereschi M, Amaducci L, Maggi S,
Grigoletto F, Scarlato G et al. Cognitive impairment
without dementia in older people: prevalence, vascular risk factors, impact on disability. The Italian
Longitudinal Study on Aging. J Am Geriatr Soc 2000;
48: 775–782.
Stewart R, Richards M, Brayne C, Mann A. Vascular
risk and cognitive impairment in an older, British,
African-Caribbean population. J Am Geriatr Soc 2001;
49: 263–269.
André-Petersson L, Hagberg B, Janzon L, Steen G. A
comparison of cognitive ability in normotensive and
hypertensive 68-year-old men: results from population
study ‘men born in 1914’, in Malmö, Sweden. Exp
Aging Res 2001; 27: 319–340.
Izquierdo-Porrera AM, Waldstein SR. Cardiovascular
risk factors and cognitive function in African
Americans. J Gerontol B Psychol Sci Soc Sci 2002;
57: P377–P380.
Morris MC, Scherr PA, Hebert LE, Bennett DA, Wilson
RS, Glynn RJ et al. Association between blood pressure
and cognitive function in a biracial community
population of older persons. Neuroepidemiology 2002;
21: 123–130.
Budge MM, de Jager C, Hogervorst E, Smith AD,
Oxford Project To Investigate Memory and Ageing
(OPTIMA). Total plasma homocysteine, age, systolic
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
blood pressure, and cognitive performance in older
people. J Am Geriatr Soc 2002; 50: 2014–2018.
Paran E, Anson O, Reuveni H. Blood pressure and
cognitive functioning among independent elderly. Am
J Hypertens 2003; 16: 818–826.
Pandav R, Dodge HH, DeKosky ST, Ganguli M. Blood
pressure and cognitive impairment in India and the
United States: a cross-national epidemiological study.
Arch Neurol 2003; 60: 1123–1128.
Kähönen-Väre M, Brunni-Hakala S, Lindroos M,
Pitkala K, Strandberg T, Tilvis R. Left ventricular
hypertrophy and blood pressure as predictors of
cognitive decline in old age. Aging Clin Exp Res
2004; 16: 147–152.
Kuo HK, Sorond F, Iloputaife I, Gagnon M, Milberg W,
Lipsitz LA. Effect of blood pressure on cognitive
functions in elderly persons. J Gerontol A Biol Sci
Med Sci 2004; 59: 1191–1194.
Waldstein SR, Giggey PP, Thayer JF, Zonderman AB.
Nonlinear relations of blood pressure to cognitive
function: the Baltimore Longitudinal Study of Aging.
Hypertension 2005; 45: 374–379.
Wilkie F, Eisdorfer C. Intelligence and blood pressure
in the aged. Science 1971; 172: 959–962.
Elias MF, Wolf PA, D’Agostino RB, Cobb J, White LR.
Untreated blood pressure level is inversely related to
cognitive functioning: the Framingham Study. Am J
Epidemiol 1993; 138: 353–364.
Swan GE, DeCarli C, Miller BL, Reed T, Wolf PA, Jack
LM et al. Association of midlife blood pressure to latelife cognitive decline and brain morphology. Neurology 1998; 51: 986–993.
Swan GE, Carmelli D, Larue A. Systolic blood pressure
tracking over 25 to 30 years and cognitive performance
in older adults. Stroke 1998; 29: 2334–2340.
Sacktor N, Gray S, Kawas C, Herbst J, Costa P,
Fleg J. Systolic blood pressure within an intermediate
range may reduce memory loss in an elderly
hypertensive cohort. J Geriatr Psychiatry Neurol
1999; 12: 1–6.
Haan MN, Shemanski L, Jagust WJ, Manolio TA, Kuller
L. The role of APOE epsilon4 in modulating effects of
other risk factors for cognitive decline in elderly
persons. JAMA 1999; 282: 40–46.
Tzourio C, Dufouil C, Ducimetière P, Alpérovitch A.
Cognitive decline in individuals with high blood
pressure: a longitudinal study in the elderly. EVA
Study Group. Epidemiology of Vascular Aging.
Neurology 1999; 53: 1948–1952.
Kilander L, Nyman H, Boberg M, Lithell H. The
association between low diastolic blood pressure in
middle age and cognitive function in old age.
A population-based study. Age Ageing 2000; 29:
243–248.
Knopman D, Boland LL, Mosley T, Howard G, Liao D,
Szklo M et al. Cardiovascular risk factors and cognitive
decline in middle-aged adults. Neurology 2001; 56:
42–48.
Reinprecht F, Elmståhl S, Janzon L, André-Petersson L.
Hypertension and changes of cognitive function in 81year-old men: a 13-year follow-up of the population
study ‘men born in 1914’, Sweden. J Hypertens 2003;
21: 57–66.
Elias MF, Elias PK, Sullivan LM, Wolf PA, D’Agostino RB.
Lower cognitive function in the presence of obesity and
hypertension: the Framingham Heart Study. Int J Obes
Relat Metab Disord 2003; 27: 260–268.
Journal of Human Hypertension
Cognitive function and hypertension
J Birns and L Kalra
96
57 Piguet O, Grayson DA, Creasey H, Bennett HP, Brooks
WS, Waite LM et al. Vascular risk factors, cognition
and dementia incidence over 6 years in the Sydney
Older Persons Study. Neuroepidemiology 2003; 22:
165–171.
58 Elias PK, Elias MF, Robbins MA, Budge MM. Blood
pressure-related cognitive decline: does age make a
difference? Hypertension 2004; 44: 631–636.
59 Okumiya K, Matsubayashi K, Wada T, Osaki Y, Doi Y,
Ozawa T. J-curve relation between blood pressure and
decline in cognitive function in older people living
in community, Japan. J Am Geriatr Soc 1997; 45:
1032–1033.
60 Bohannon AD, Fillenbaum GG, Pieper CF, Hanlon JT,
Blazer DG. Relationship of race/ethnicity and blood
pressure to change in cognitive function. J Am Geriatr
Soc 2002; 50: 424–429.
61 Hebert LE, Scherr PA, Bennett DA, Bienias JL, Wilson
RS, Morris MC et al. Blood pressure and late-life
cognitive function change: a biracial longitudinal
population study. Neurology 2004; 62: 2021–2024.
62 Gorelick PB. Risk factors for vascular dementia
and Alzheimer disease. Stroke 2004; 35(11 Suppl 1):
2620–2622.
63 Birns J, Morris R, Jarosz J, Markus H, Kalra L. Ethnic
differences in the cerebrovascular impact of hypertension. Cerebrovasc Dis 2008; 25: 408–416.
64 Luchsinger JA, Tang MX, Shea S, Mayeux R. Hyperinsulinemia and risk of Alzheimer disease. Neurology
2004; 63: 1187–1192.
65 Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg
IH, D’Agostino RB et al. Plasma homocysteine as a risk
factor for dementia and Alzheimer’s disease. N Engl J
Med 2002; 346: 476–483.
66 Birns J, Morris R, Donaldson N, Kalra L. The effects of
blood pressure reduction on cognitive function: a
review of effects based on pooled data from clinical
trials. J Hypertens 2006; 24: 1907–1914.
67 Lasser NL, Nash J, Lasser VI, Hamill SJ, Batey DM.
Effects of antihypertensive therapy on blood pressure
control, cognition, and reactivity. A placebo-controlled
comparison of prazosin, propranolol, and hydrochlorothiazide. Am J Med 1989; 86: 98–103.
68 McCorvey Jr E, Wright Jr JT, Culbert JP, McKenney JM,
Proctor JD, Annett MP. Effect of hydrochlorothiazide,
Journal of Human Hypertension
69
70
71
72
73
74
75
76
77
enalapril, and propranolol on quality of life and
cognitive and motor function in hypertensive patients.
Clin Pharm 1993; 12: 300–305.
Applegate WB, Pressels S, Wittes J, Luhr J,
Shekelle RB, Camel GH et al. Impact of the treatment
of isolated systolic hypertension on behavioural
variables: results from the Systolic Hypertension
in the Elderly Program. Arch Intern Med 1994; 154:
2154–2160.
Prince M, Bird AS, Blizard RA, Mann AH. Is the
cognitive function of older patients affected by antihypertensive treatment? Results from 54 months of the
Medical Research Council’s trial of hypertension in
older adults. Br Med J 1996; 312: 801–805.
Forette F, Seux ML, Staessen JA, Thijs L, Birkenhager
WH, Babarskiene MR et al. Prevention of dementia in
randomised double-blind placebo-controlled Systolic
Hypertension in Europe (Syst-Eur) trial. Lancet 1998;
352: 2046–2052.
Denolle T, Sassano P, Allain H, Bentue-Ferrer D,
Breton S, Cimarosti I et al. Effects of nicardipine and
clonidine on cognitive functions and electroencephalography in hypertensive patients. Fundam Clin
Pharmacol 2002; 16: 527–535.
Tzourio C, Anderson C, Chapman N, Woodward M,
Neal B, MacMahon S et al. Effects of blood pressure
lowering with perindopril and indapamide therapy on
dementia and cognitive decline in patients with
cerebrovascular disease. Arch Inter Med 2003; 163:
1069–1075.
Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A,
Olofsson B et al. The Study on Cognition and
Prognosis in the Elderly (SCOPE): principal results of
a randomized double-blind intervention trial. J Hypertens 2003; 21: 875–886.
Dimsdale JE, Newton RP, Joist T. Neuropsychological
side-effects of beta blockers. Arch Intern Med 1989;
149: 514–525.
Twamley EW, Ropacki SA, Bondi MW. Neuropsychological and neuroimaging changes in preclinical
Alzheimer’s disease. J Int Neuropsychol Soc 2006; 12:
707–735.
Roman GC, Erkinjuntti T, Wallin A, Pantoni L,
Chui HC. Subcortical ischaemic vascular dementia.
Lancet Neurol 2002; 1: 426–436.