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Blood Pressure, Cognitive Functions, and Prevention of Dementias in Older Patients With Hypertension
Willem H. Birkenhäger, MD, PhD;
Françoise Forette, MD, PhD;
Marie-Laure Seux, MD;
Ji-Guang Wang, MD;
Jan A. Staessen, MD, PhD
Arch Intern Med. 2001;161:152-156.
ABSTRACT
The prevalence and incidence of degenerative and vascular dementias
increase exponentially with age, from 70 years onward. In view of the increasing
longevity of humans, both varieties are bound to evolve into a major problem
worldwide. According to several longitudinal studies, hypertension appears
to predispose individuals to the development of cognitive impairment and ensuing
dementia, after a period varying from a few years to several decades. Antihypertensive
drug treatment, according to preliminary evidence, may serve to reduce the
rates of such events. Such findings await to be confirmed by formal therapeutic
trials against a backdrop of "historical" observational sources.
INTRODUCTION
Dementia is characterized by the development of a range of intellectual
and other mental defects, such as a progressive loss of memory, disorientation
in space and time, loss of autonomy, and emotional depersonalization. The
most dominant types of dementia are Alzheimer disease and vascular dementia,
in proportions of roughly 2:1. The prevalence and incidence of both disorders
increase exponentially with age, from 70 years onward. Both varieties are
evolving into a major health problem worldwide, as a natural consequence of
increasing longevity.
Among various factors supposedly predisposing to the incidence and prevalence
of cognitive impairment and the development of different forms of dementia,
a history of hypertension has become increasingly discernable in observational
studies.
COGNITIVE PERFORMANCE AND DEMENTIA IN RELATION TO BLOOD PRESSURE
Hypertension, through its well-recognized contribution to the development
of macroscopic cerebrovascular lesions, might equally well be expected to
predispose to the development of more subtle cerebral processes, based on
arteriolar narrowing, allied microvascular pathological features, or both,
in due time leading to cognitive impairment and finally overt dementia.
The results from cross-sectional observational studies on the relation
between hypertension and cognitive function seem to support such a notion,
although the evidence is far from uniform, according to an overview by Seux
and Forette.1 These researchers collected data
from a dozen studies including older patients with normotension and hypertension
and came up with the following findings. In 4 studies,2, 3, 4, 5
no correlation between cognitive function and blood pressure was observed.
By contrast, other studies revealed a negative correlation between cognition
and systolic blood pressure (SBP),6 diastolic
blood pressure (DBP),7, 8, 9
or SBP and DBP.10, 11 One series12 exhibited a positive correlation between SBP or DBP
and cognitive function. Such variability is likely to depend, at least in
part, on the selection of populations investigated and differences between
neuropsychological detection methods.1 Perhaps
more important, a concurrent examination of blood pressure and cognition starts
from a possibly misleading concept of synchronicity in the development of
both features.
A more realistic approach by longitudinal long-term investigations has
allowed the possibility of discerning more distant associations between high
blood pressure and cognitive dysfunction chronologically.
In this regard, Elias et al13 have broken
ground by reviewing cognitive function and memory performance in the Framingham
cohort, 12 to 14 years after recruitment, in relation to initial blood pressure
measurement. Most hypertensive subjects (88%) had received no treatment in
the interim. After correction for demographic variables and cardiovascular
risk factors other than high blood pressure, cognitive performance was found
to be negatively correlated with the initial SBP and DBP readings.
A similar pattern, focused on SBP and subsequent cognitive function,
has been observed during the Honolulu-Asia Aging Study14:
a significant relation was established between SBP at enrollment and the risk
of cognitive impairment 25 years later.
Skoog et al15 conducted a 15-year follow-up
study of blood pressure and dementia in Gothenburg, Sweden. They analyzed
the relation between blood pressure and dementia starting with patients without
dementia at the age of 70 years, and observing them up to the age intervals
of 70 to 75, 75 to 79, and 79 to 85 years. Participants who developed dementia
at age 79 to 85 years had a higher SBP and DBP at the age of 70 years, compared
with those who did not. An additional remarkable finding in this study was
that blood pressure in the years just preceding the onset of dementia paradoxically
tended to become lower than in individuals without dementia. This applied
in particular to those developing Alzheimer disease and in those with white
matter lesions on computed tomography.
Another follow-up study,16 of 40 months'
duration in very elderly patients (aged 75-101 years), likewise demonstrated
that the lower the SBP, the worse the cognitive performance.
Tentative explanations for these paradoxical findings may be as follows.
First, the decline in blood pressure shortly preceding dementia may be due
to loss of physical activity. In addition, a failure of maintaining blood
pressure at this stage may be an expression of brain lesions accompanying
Alzheimer disease in prefrontal autonomic centers, resulting in central dysregulation
of blood pressure.17 Conversely, the decrement
in blood pressure, presumably exaggerated during orthostasis, through periods
of cerebral ischemia, to a certain extent may have furthered the pathogenesis
of Alzheimer disease.
A recently finished investigation18 dealt
with a study population of 999 men, aged 50 years at enrollment and followed
up for 20 years. At the age of 70 years, cognitive function was highest in
those with an initial DBP lower than 70 mm Hg and lowest in subjects with
a DBP higher than 105 mm Hg. The end point age herein was identical with the
starting age in Gothenburg,15 so that this
study agewise may have fallen short of the possibility of detecting a biphasic
phenomenon, as previously referred to.
Another recently published report19 dealt
with 2068 inhabitants of the East Boston, Mass, area. These subjects had participated
in 2 successive studies, the Hypertension Detection and Follow-up Program,
organized from 1973 to 1974, and the Established Populations for the Epidemiologic
Study of the Elderly, organized from 1982 to 1983. In the latter part of this
serially combined evaluation, subjects were aged 65 to 102 years at baseline.
Blood pressure, mental status, and memory were assessed at baseline and 3
and 6 years later. In analyses adjusted for age, sex, and educational level,
there was no strong linear association between blood pressure and cognition.
The only suggestive finding was that an SBP of 160 mm Hg or higher 9 years
before (ie, at randomization for the Hypertension Detection and Follow-up
Program trial) was associated with a (statistically significant) 14% higher
rate of test errors in the Established Populations for the Epidemiologic Study
of the Elderly phase, compared with a reference group with an SBP of 130 to
139 mm Hg. The weakness of this association could be caused by interference
of secondary factors in the highest age range, as indicated earlier. Moreover,
the analysis of the combined Hypertension Detection and Follow-up Program–Established
Populations for the Epidemiologic Study of the Elderly data is fraught with
the lack of a proper discrimination between antihypertensive treatment and
nontreatment.
In summary, longitudinal cohort studies appear to support the notion
that hypertension predisposes to cognitive decline and development of dementia,
although with a considerable time lag that may amount to several decades.
In the late interval shortly preceding dementia, the original negative relation
between blood pressure and cognitive function may become unrecognizable due
to a terminal decline in blood pressure. This phenomenon would seem to require
extremely careful vigilance in the practical management of the very elderly
patient with hypertension, including monitoring of blood pressure and cognition.
EFFECTS OF ANTIHYPERTENSIVE TREATMENT ON COGNITIVE FUNCTION AND PREVENTION
OF DEMENTIA
Guided by the successful effects of antihypertensive medication in containing
stroke rates in elderly patients, particularly those with systolic hypertension,20, 21, 22, 23, 24
one could reasonably hope to see rather similar effects for the prevention
of dementia given the latter's association with hypertension.
In several observational studies relating hypertension with cognitive
function, the influence of concurrent antihypertensive medication use has
been taken into consideration as well.
In the Kungsholmen (Sweden) Project,23
1301 subjects aged 75 years and older were followed up for an average of 3
years. Cognitive functions were assessed using the Mini-Mental State Examination
and other psychometric tests, and Diagnostic and Statistical
Manual of Mental Disorders, Third Edition,25
criteria when needed for establishing dementia (more information about these
methods is available from the authors). At the end of the follow-up period,
987 subjects were still alive. In the subpopulation with an SBP higher than
160 mm Hg, a DBP higher than 95 mm Hg, or both (n = 458), 122 received diuretic
therapy. Compared with untreated patients, the subjects thus treated showed
an adjusted relative risk for dementia of 0.6 (95% confidence interval, 0.3-1.2).
This trend was tentatively interpreted by the authors as a potential benefit
from diuretic treatment. But they fully recognized the limitations of the
results, in that information of drug use was only available at baseline, the
duration of treatment being unknown. Moreover, the group using antihypertensive
medication in this cohort differed inherently from the untreated group due
to the presence of heart disease and stroke in the latter, another example
of confounding by indication. Therefore, these authors, like the previous
ones, admitted the need for clinical trials.
The recently finished Epidemiology of Vascular Aging Study24
recruited 1389 subjects aged 59 to 74 years, including 167 hypertensive subjects
who were reexamined 2 and 4 years later. After 4 years, 81 hypertensive individuals
had received antihypertensive treatment with various drugs (ß-blockers,
calcium channel blockers [CCBs], angiotensin-converting enzyme inhibitors,
and diuretics). In untreated hypertensive participants, a correlation was
observed between the level of blood pressure and a subsequent decline in cognitive
function (a decrement of >4 points on the 30-point Mini-Mental State Examination
scale). The relative risk amounted to 4.3 (95% confidence interval, 2.3-8.0)
compared with normotensive enrollees. In the treated group, the relative risk
appeared to be reduced to 1.3 (95% confidence interval, 0.3-3.9).
The results described seem to carry a promise for routine antihypertensive
treatment in reducing the incidence of cognitive impairment. Nevertheless,
such achievements would need to be confirmed by formally administered prospective
therapeutic trials.
Three major randomized placebo-controlled hypertension trials have encompassed
substudies focusing on the course of cognitive function and the incidence
of dementia: the Systolic Hypertension in the Elderly Program,20
the Medical Research Council trial,21 and the
Systolic Hypertension in Europe (Syst-Eur) trial.22
The Systolic Hypertension in the Elderly Program20
involved a group of 2034 subjects aged 60 years and older recruited because
of isolated systolic hypertension (SBP,  160 mm Hg; and DBP, <90 mm
Hg) for active and placebo treatment with the diuretic chlorthalidone as the
primary drug. These patients underwent an elaborate battery of psychometric
tests at baseline, repeated at intervals of 6 months up to an average observation
period of 5 years. The outcome was that neither the evolution of cognitive
function nor the incidence of dementia was significantly different between
the active treatment and placebo groups. The incidence of dementia was 1.6%
and 1.9%, respectively.
In a subset of 2584 participants in the Medical Research Council trial21 of treatment in older patients with hypertension
randomized to a diuretic, ß-blocker, or placebo, psychometric tests were
performed covering a period of 54 months. Again, no significant difference
in test scores was detected between the active treatment and placebo groups.
The Syst-Eur trial,22 dealing with older
(60 years) patients with isolated systolic hypertension (SBP, 160
mm Hg; and DBP, <95 mm Hg) included a side project investigating 2418 subjects
in whom cognitive function and incidence of vascular and degenerative dementias
were assessed comparing outcome while taking active treatment (with nitrendipine
as the primary drug) vs a matching placebo.22
Methods used were the Mini-Mental State Examination, followed by more specific
approaches in case of scores less than 23 (Diagnostic and
Statistical Manual of Mental Disorders, Third Edition; Hachinski scoring;
and imaging techniques). The median follow-up period lasted only 2 years because
of the necessity of termination of the trial, due to the statistical attainment
of preset stroke rate differences between the active and placebo treatment
groups as the predeclared primary end point. According to the intention-to-treat
analysis, 21 cases of dementia were seen in the placebo group vs 11 in the
actively treated group. A breakdown according to the type of dementia is presented
in Figure 1. Active treatment reduced
the rate of dementia by 50%, from 7.7 to 3.8 per 1000 patient-observation
years (P = .05).
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Number of incident cases of dementia by cause in the Vascular Dementia
Project of the Systolic Hypertension in Europe trial.22
The median observation period in the placebo-treated and actively treated
(the dihydropyridine calcium channel blocker nitrendipine being the primary
drug) groups covered 2 years, after which the trial had to be stopped due
to the attainment of a predeclared statistically significant difference between
stroke rates in both groups. Except for one case in the placebo group (intention-to-treat
analysis), patients exhibiting dementia had remained free from stroke. The
dominance of Alzheimer disease in association with systolic hypertension was
still unpresaged when the Vascular Dementia Project was conceived (1989).
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Thus, when overviewing the results of these 3 randomized placebo-controlled
trials, the dihydropyridine CCB nitrendipine so far has emerged as the only
first-line antihypertensive drug exhibiting a statistically valid potential
of preventing dementia, reducing its incidence by half.
Such a preventive action of a (lipid-soluble) dihydropyridine CCB could
be reconciled with views on the pathogenesis of dementia,22, 26, 27
in which intracellular neuronal surfeit of calcium with aging is considered
to be a prime mover in elaborating a veritable cascade of neurotoxic precursors
of degenerative and vascular dementias.
But, while the theoretical basis for such a pattern of pathogenesis
is being developed, its therapeutic corollary in terms of calcium channel
blockade should be examined in more detail, for various reasons. First, the
Syst-Eur substudy, although statistically significant, is based on relatively
few patients. Second, some studies28, 29
have indicated that CCBs might be far from ideal when compared with the incidence
of cognitive impairment during other antihypertensive drug regimens. However,
the latter studies lacked a well-founded trial plan and had the bias of confounding
by indication, a particular feature in the use of CCBs because they are a
treatment of choice in patients with exaggerated cardiovascular risk.30
We believe there is a compelling reason for initiating a new randomized
therapeutic hypertension trial focusing on cognitive function and the occurrence
of dementia and comparing the specific efficacies of the various main drug
classes in this regard. Such a trial is being prepared under the acronym DEPHY
(Dementia Prevention in Hypertension) by the European Working Party on High
Blood Pressure in the Elderly.
CONCLUSIONS
The attempt to analyze a possible association between hypertension and
dementia has led into a maze and toward a challenge. A challenge, because
a causal relation might offer a unique opportunity to influence the catastrophic
process of dementia in elderly patients with hypertension, representing one
third of the population aged 70 years and older. And a maze, in view of the
confusing experience regarding the complicated nature of an entanglement,
if any, between the 2 disease entities. We had to help ourselves with historical
data, for the simple reason that on principle no hypertensive patient should
henceforth be left untreated, except through his or her own volition.
Fortunately, we have been able to sample plenty of relevant historical
data based on longitudinal observational studies, most of them reported in
recent years. Despite some inconsistencies between these studies, a common
picture seems to emerge, in that hypertension becoming manifest at a relatively
early age tends to presage the occurrence of cognitive impairment later. The
interval between the 2 developments appears to be extremely variable, extending
from a mere few years to a lag phase of some 2 decades or more. Such variations
apparently do not only depend on natural history but are also influenced by
the design of such follow-up studies, particularly for planned repeated-visit
intervals. Such arbitrary periods, taken together with different age cutoffs,
have thwarted our attempts to integrate the temporal relations among these
studies. The issue has been complicated further by a paradoxical decline in
blood pressure shortly preceding the onset of overt Alzheimer disease in very
elderly patients with hypertension. Nevertheless, our assessment still seems
to indicate a role for hypertension in a more or less distant elaboration
of impaired cognition and dementia, whether of vascular or degenerative origin.
This takes us to the question of whether antihypertensive treatment
may ameliorate the prospects of cognitive function in hypertensive patients
in the future. This could admittedly be a mere theoretical issue because of
the established need to treat hypertension anyway, with a view on the containment
of "organic" cardiovascular sequelae. We nevertheless believe that a positive
effect on dementia prevention would be a major step forward in the interest
of public health by creating a general awareness of the sheer possibility
of obviating dementia through antihypertensive drug treatment.
The evidence obtained so far must be judged as still being ambiguous.
Two longitudinal observational studies23, 24
encompassing a subgroup of routinely treated patients with hypertension by
nonspecified regimens have shown a reduced relative risk of 0.6 compared with
nontreated patients with hypertension in an aging population. This is a promising
result, but one that should be corroborated by properly conducted studies
in which antihypertensive medications have been properly apportioned in a
randomized fashion vs placebo-based "treatment." Unfortunately, a mere 3 properly
administered prospective therapeutic trials in hypertensive populations have
paid attention to cognitive function: the Systolic Hypertension in the Elderly
Program, the Medical Research Council trial, and the Syst-Eur trial. The first
2, using diuretics or ß-blockers as the first-line drug, failed to demonstrate
any substantial effect of treatment on cognition. By contrast, the third trial
(Syst-Eur) actually achieved a reduction of the number of patients exhibiting
dementia by half. The primary drug in that trial happened to be a dihydropyridine
CCB, nitrendipine. A particular protecting mechanism for prevention of mental
deterioration could possibly be tied in with prevalent concepts about the
genesis of degenerative dementia. Nevertheless, these findings may constitute
a rather slim basis for advocating a universal preventive policy.
The resulting ambiguity is simply intolerable from the viewpoint of
public health worldwide and should not be allowed to continue. Hence our call
for a broadly based comparative antihypertensive trial (the Dementia Prevention
in Hypertension trial) encompassing a focus on assessment of cognitive function
on top of registering somatic cardiovascular events.
In the meantime, general hypertension care physicians should be encouraged
to incorporate the Mini-Mental State Examination method into their diagnostic
arsenal.
AUTHOR INFORMATION
Accepted for publication July 20, 2000.
We thank J. I. S. Robertson, MD, PhD, for his lucid suggestions.
From the Faculty of Medicine, Erasmus University Rotterdam, Rotterdam,
the Netherlands (Dr Birkenhäger); the Department of Geriatrics, Broca
Hospital, Centre Hospitalier Universitaire Cochin, University of Paris V,
Paris, France (Drs Forette and Seux); and the Studiecoördinatiecentrum,
Hypertensie en Cardiovasculaire Revalidatie Eenheid, Departement Moleculair
en Cardiovasculair Onderzoek, Katholieke Universiteit Leuven, Leuven, Belgium
(Drs Wang and Staessen).
Corresponding author and reprints: Jan A. Staessen, MD, PhD, Studiecoördinatiecentrum,
Laboratorium Hypertensie, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven,
Belgium (e-mail: jan.staessen{at}med.kuleuven.ac.be).
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