From the Institute of Clinical Neuroscience, Department of Psychiatry,
Sahlgrenska University Hospital (I.S.), the Department of Geriatric Medicine,
Vasa Hospital (S.L., B.L.), Göteborg University, and the Department of
Radiology, Östra Hospital (L.-A.A.), Göteborg, Sweden.
Correspondence to Ingmar Skoog, MD, PhD, Department of Psychiatry, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. E-mail Ingmar.Skoog{at}psychiat.gu.se
Nonparticipants and participants were compared with regard to gender,
marital status, 3-year mortality rate, and registration as psychiatric
outpatient or inpatient in Gothenburg. No significant differences were
found with regard to these factors.13 Ten
individuals (3 nondemented, 7 demented) had no blood pressure
recordings, leaving 344 nondemented and 140 demented (61 with
Alzheimer's disease, 65 with vascular dementia, and 14 with
other types of dementia).13
Informed consent was obtained from all subjects and/or their relatives,
and the study was approved by the Ethics Committee for Medical Research
at Göteborg University. All procedures were in accordance with
institutional guidelines.
Examinations
Casual blood pressure was measured in the right arm with the subject in
the seated position after 5 minutes of rest using a mercury manometer.
Systolic and diastolic blood pressures were
registered to the nearest 5 mm Hg. Diastolic blood
pressure was defined as Korotkoff phase V. Orthostatic
hypotension was defined as a decline of
During a house call, a registered nurse interviewed the subjects
regarding their social and living conditions, their need for social and
medical care, and their drug consumption. The prescribed and actually
taken drug doses were registered and classified according to the
Anatomical Therapeutic Chemical (ATC) classification system recommended
by the World Health Organization.19 20
Diagnostic Procedures
CT Evaluations
All CT scans were performed without contrast enhancement and with 10-mm
continuous slices on a Philips Tomoscan 310 and on a General Electric
8800. The scans were examined by 2 radiologists without knowledge of
the results of the blood pressure readings and the neuropsychiatric
examinations.
The occipital, parietal, frontal, and temporal lobes were categorized
using a 4-point scale according to the estimated extent of brain
atrophy (normal, mild, moderate, and
severe).25
Measures of central atrophy were determined using a transparent metric
ruler as described by deLeon et al.25 The
following linear distances were measured: (a) the bifrontal span of the
lateral ventricle, (b) the width of the lateral ventricles at the head
of the caudate nucleus, (c) the sum of the separate widths of the left
and right sylvian fissures, (d) the minimum width of the bodies of the
lateral ventricles at the waist, and (e) the width of the third
ventricle. Ratios for a to d were determined by dividing the obtained
values by the width of the brain at the level of the measurement,
giving the following ratios: bifrontal ratio, bicaudate ratio, sylvian
fissure ratio, and sella media ratio. The rating procedure was carried
out separately for the cortical and ventricular
studies.
Statistical Analyses
Antihypertensive Treatment
Among nondemented individuals, the strength of the correlations between
blood pressure and cerebral atrophy did not differ between those
treated and not treated with antihypertensives, except for the
correlation between systolic blood pressure and bifrontal ratio
(not treated with antihypertensives, r=-0.30,
P=0.008; treated, r=-0.08,
P=0.532).
In the demented group, there were correlations only between cortical
atrophy and blood pressure in those not treated with antihypertensive
drugs. In this group, lower diastolic blood pressure was
correlated to frontal (not treated with antihypertensives,
r=-0.31, P=0.011; treated, r=0.01,
P=0.964), parietal (not treated, r=-0.29,
P=0.017; treated, r=0.05, P=0.814),
and occipital cortical atrophy (not treated, r=-0.31,
P=0.012; treated, r=0.12, P=0.541),
and lower systolic blood pressure was correlated with occipital
cortical atrophy (not treated, r=-0.23; treated,
r=-0.04). There was a similar difference between treated
and not-treated demented individuals for the correlation between
systolic blood pressure and cortical atrophy, but none of the
associations reached significance.
Body Mass Index
Blood Pressure in Relation to Dementia
Reduced Ambulatory Capacity and Spontaneous Activity
Reduced spontaneous activity was found in 5 of 340 (1.5%) nondemented
individuals and in 49 of 140 (35.0%) demented individuals. Among
nondemented individuals, those with reduced spontaneous activity had
lower systolic blood pressure than other individuals
(136.0±18.2 versus 162.5±23.6; P=0.013), while
diastolic blood pressure did not differ between the groups
(72.0±4.5 versus 79.5±12.8; P=0.190). Among demented
individuals, those with reduced spontaneous activity had lower
systolic blood pressure than other individuals (139.9±26.2
versus 153.1±22.7; P=0.002), while diastolic
blood pressure did not differ between the groups (76.5±13.0 versus
77.1±12.0; P=0.770).
At least 1 of these symptoms was found in 17 of 344 (4.9%)
nondemented, in 2 of 41 (4.9%) mildly demented, in 21 of 49 (42.9%)
moderately demented, and in 39 of 50 (78.0%) severely demented
individuals. Adjustment also for spontaneous activity and ambulatory
capacity did not change the correlations between blood pressure and
brain atrophy. After the adjustment, low systolic blood
pressure was associated with dementia (P=0.006), severity of
dementia (r=-0.11, P=0.019),
Alzheimer's disease (P=0.006), and other dementias
(P=0.045) but not with vascular dementia
(P=0.732). Diastolic blood pressure was not
associated with dementia, dementia severity, or type of dementia after
the adjustment for spontaneous activity and ambulatory capacity.
Blood Pressure in Relation to MMSE Score in Nondemented
Individuals
Orthostatic Hypotension
The relationship between blood pressure and cognitive function/dementia
may be age dependent. Although most cross-sectional studies in groups
of younger and middle-aged individuals31 32 33 34 35 36
report a lower cognitive performance in hypertensives compared
with normotensives, studies in the elderly report less conclusive
results.34 37 38 39 40 In line with this, the
Rotterdam Elderly Study41 reported that blood
pressure was negatively correlated to cognitive performance
before age 75 years, whereas there was a positive correlation above
that age. The latter was similar to our finding in nondemented
85-year-olds. This may explain why 2 previous brain imaging
studies,42 43 performed in clinical samples of
elderly persons who were younger than those in our study, reported an
association between hypertension and indices of brain atrophy.
The relationship may also be time dependent. The Honolulu-Asia Aging
Study44 reported that low performance in
psychometric tests in the population was correlated to higher
systolic blood pressure 25 years before the measurement of
cognitive function, and the Framingham Study45
reported that low cognitive performance was correlated to
higher blood pressure measured 12 to 14 years before testing. At the
time of testing, cognitive performance was not correlated to
blood pressure levels, and in the very elderly there was even a
tendency for low blood pressure to be associated with low cognitive
performance. In line with these results, a recent study
reported that both systolic and diastolic blood
pressures were increased 10 to 15 years before the onset of both
Alzheimer's disease and vascular
dementia.11 However, blood pressure declined in
the years before dementia onset. Thus, although previously high blood
pressure seems to precede the onset of dementia and cognitive decline
by many years, low blood pressure is often associated with already
manifest dementia, at least in the very elderly. It is possible that
the subtle cognitive impairment and the brain atrophy reported in
middle-aged and younger elderly hypertensives are early subclinical
manifestations of a dementia process, before the brain lesions reach a
threshold causing dementia and low blood pressure.
Although we believe that the low blood pressure found in individuals
with dementia and cerebral atrophy is secondary to the brain lesions,
one should not exclude the possibility that low blood pressure may
cause lesions in the brain. Systemic hypotension associated with
reduced cerebral blood flow may give rise to a spectrum of
ischemic neuronal lesions in vulnerable areas of the
brain.46 Although the frequency of
orthostatic hypotension was similar in demented and
nondemented individuals in our study, we cannot exclude the possibility
that delayed orthostatic hypotension might have contributed
to or caused dementia or reduced ambulatory capacity. Delayed
orthostatic hypotension, starting after >10 minutes of
standing, is common in individuals with
dementia.28 However, it is not clear whether the
frequency differs from that in normal elderly persons. Overtreatment
with antihypertensive drugs has thus been suggested to increase the
risk of brain damage and dementia in the very
old.47 In our study, however, individuals with
dementia used antihypertensive medications less often than did
nondemented individuals. Although this may be due to recall bias in
demented individuals, the registration of drug consumption was based on
both subjective and objective information obtained by a registered
nurse during the house call.19 The findings are
also supported by our longitudinal data,48 which
showed that during an observational period from age 70 to 85 years,
those who developed dementia after age 80 were given antihypertensives
to a lesser extent before this age than those not developing dementia.
Overtreatment with antihypertensives was thus not the cause of the low
blood pressure in demented individuals.
Some limitations of the study have to be considered. It has to be
emphasized that linear measurements and subjective ratings are rather
crude ratings of cortical atrophy. However, if anything, this should
decrease the possibility of finding differences between the groups. A
second limitation is that only about half of those invited to have a CT
scan accepted. However, this is not a low response rate for such an
examination in a population study. Furthermore, those who participated
did not differ from those not participating regarding a number of
factors, including mean blood pressure levels. Third, it has to be
emphasized that differential survival may be of importance in
cross-sectional studies at these high ages. If the combination of high
blood pressure and cerebral atrophy is lethal, it may contribute to the
relationships reported here. Fourth, there is a possibility that
unrecognized confounders may account for the observed relationships.
One such possibility is difference in BMI. Although this was not
relevant in the nondemented group, we cannot exclude that this
possibility may partly explain the results in the demented group, due
to insufficient information regarding BMI in this group.
In summary, we found that cerebral atrophy was associated with lower
blood pressure in a population-based sample of nondemented 85-year-old
persons. Lower blood pressure was also associated with increasing
severity of dementia. Our findings emphasize the intriguing
relationship between the brain and blood pressure and suggest that low
blood pressure is mainly a secondary phenomenon in dementia
disorders.
Received December 15, 1997;
first decision January 14, 1998;
accepted May 4, 1998.
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© 1998 American Heart Association, Inc.
Scientific Contributions
A Population-Based Study on Blood Pressure and Brain Atrophy in 85-Year-Olds
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Abstract—In the general population,
mean systolic and diastolic blood pressure
increases up to age 75 years but decreases thereafter. The brain has a
role in blood pressure regulation; it is not clear whether the cerebral
changes that occur with aging contribute to the decline in blood
pressure in the very elderly. We examined a population-based sample of
484 85-year-old persons (344 nondemented and 140 demented, 61 with
Alzheimer's disease, 65 with vascular dementia, and 14 with
other types of dementia) with a neuropsychiatric examination and blood
pressure measurements. Dementia was diagnosed according to the criteria
proposed in the Diagnostic and Statistical Manual of
Mental Disorders, edition 3, revised. Brain atrophy was
measured by CT of the brain. In the nondemented group, frontal
(r=-0.18, P=0.037) and parietal
(r=-0.23, P=0.008) cortical atrophy and
bifrontal ratio (r=-0.20, P=0.013) were
associated with lower systolic blood pressure, and frontal
(r=-0.23, P=0.010) and parietal
(r=-0.24, P=0.008) cortical atrophy and
bifrontal ratio (r=-0.23, P=0.006) with
lower diastolic blood pressure. Systolic blood
pressure was lower in subjects with Alzheimer's disease and
vascular dementia, and diastolic blood pressure was lower
in those with vascular dementia compared with the nondemented.
Systolic (r=-0.27, P<0.0001)
and diastolic (r=-0.10,
P=0.020) blood pressure was negatively correlated to
dementia severity. In the demented subjects, frontal cortical atrophy
was correlated to lower diastolic blood pressure
(r=-0.21, P=0.043). Our findings suggest
that age-related changes in brain structure may contribute to the
decrease in blood pressure in the very elderly and that low blood
pressure in dementia disorders is mainly a secondary phenomenon.
Key Words: blood pressure • cerebral atrophy • epidemiological methods • Alzheimer's disease • dementia, vascular
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
In western
populations, mean systolic blood pressure rises with advancing
age, at least up to age 75 years, while mean diastolic
blood pressure rises until the ages of approximately 55 to 65 years.
After the age of 75 to 80 years, a decrease in mean blood pressure
levels has been observed.1 2 3 The reason for the
decrease in blood pressure in the highest age groups has not been fully
clarified, but it has been suggested that selective mortality in
individuals with high blood pressure, age-related impairment of left
ventricular function, and changes in body mass, body
composition, and endocrine and metabolic function may play
a role. With increasing age, the prevalence of cerebral disorders such
as Alzheimer's disease and vascular dementia
increases,4 but cerebral changes also occur in
normal aging.5 Several brain areas suggested to
have a role in blood pressure regulation6 7 8 are
affected in Alzheimer's disease9 and in
normal aging.5 Brain disorders may thus also
contribute to the decrease in blood pressure observed in the very
elderly.10 In line with this hypothesis, we
recently reported from a 15-year longitudinal population study that a
decline in blood pressure occurred in the years before dementia
onset,11 and Guo et al12
reported that blood pressure was lower in individuals aged >75 years
with Alzheimer's disease or vascular dementia compared with
the nondemented. Whether the decline in blood pressure observed in the
very elderly is related to organic brain changes in the nondemented
elderly as well is unclear. To further elucidate this relationship, we
studied blood pressure in relation to brain atrophy measurements
determined by CT of the brain and in relation to Alzheimer's
disease and vascular dementia in a representative
sample of 85-year-old persons as part of the Longitudinal
Gerontological and Geriatric Population Studies in
Gothenburg.11 13 14 15
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Subjects
All 85-year-old persons born between July 1, 1901, and June 30,
1902, and registered for census purposes in Gothenburg, Sweden, were
invited to take part in a health survey. Persons living in both the
community and at institutions were included. A systematic subsample,
comprising every second person from the sample, was examined by a
psychiatrist in the subject's home (n=494). The sample has been
described in detail previously.13
The examinations included medical history and a physical
examination performed by a geriatrician, a neuropsychiatric examination
and a telephone interview with a close informant performed by a
psychiatrist, an ECG, a chest x-ray, a battery of blood tests, and CT
of the brain.13 The examinations were
semistructured.13 Cognitive function in
nondemented individuals was measured with the Mini-Mental State
Examination (MMSE),16 a simple instrument
measuring global cognitive function with a maximum score of 30.
Spontaneous activity and ambulatory capacity were rated according to
the Gottfries-Bråne-Steen Scale.17 Medical
records from psychiatric and geriatric institutions and outpatient
departments in Gothenburg were examined by a psychiatrist. 
20 mm Hg in
systolic blood pressure or 10 mm Hg in
diastolic blood pressure within 3 minutes of standing after
5 minutes of rest in the supine position.18 All
the blood pressure measurements were made without knowledge of the
results from the neuropsychiatric and CT examinations and vice
versa.
Dementia and its severity were determined according to the
criteria proposed in the Diagnostic and Statistical
Manual of Mental Disorders, edition 3,
revised,21 using information from the
psychiatric examination and the close informant interview, as described
in more detail previously.13 Subjects with
dementia were classified into etiological subgroups:
Alzheimer's disease according to the criteria of the National
Institute of Neurological and Communicative Disorders and Stroke and
the Alzheimer's Disease and Related Disorders
Association,22 and vascular dementia and other
causes of dementia according to criteria proposed by Erkinjuntti et
al.23 In the etiological diagnosis of dementia,
information from the physical and psychiatric examinations, close
informant interview, laboratory tests, ECG, head CT, cerebrospinal
fluid analysis, and case records was
used.13
All demented persons (n=140) and a systematic subsample of 266
nondemented individuals were invited to undergo CT of the head.
Ninety-nine (69%) demented and 136 (51%) nondemented individuals
accepted. Three CT scans were excluded from the present study for
technical reasons. The sample has been described in detail
previously.24 Within the demented and nondemented
groups, there were no differences with regard to gender, marital
status, psychiatric registration, mental disorders,
institutionalization, 3-year mortality, history of focal neurological
symptoms, cardiovascular disorders, hypertension, and
mean systolic and diastolic blood pressure between
participants and nonparticipants in the CT
examinations.24
Fisher's exact test and t test were used to test the
hypothesis of no difference between the groups.26
Pitman's permutation test was used to test
correlations.26 Adjustments for gender and
treatment with antihypertensive drugs were performed in all
analyses. Adjustments for gender, dementia, and treatment with
antihypertensive drugs were made in the analyses of the total
group. An ordinary stepwise multiple regression analysis was
used to adjust for gender and body mass index (BMI) in the nondemented
group.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Blood Pressure in Relation to Brain Atrophy
In the nondemented group, the presence of frontal and parietal
cortical atrophy and an increased bifrontal ratio was significantly
correlated to lower systolic and diastolic blood
pressure (Table 1
). In the
demented group, the presence of frontal atrophy was related to lower
diastolic blood pressure.
View this table:
[in a new window]
Table 1. Correlation (r) Between
Systolic and Diastolic Blood Pressure and Cerebral
Atrophy in 85-Year-Olds
Drugs classified as antihypertensive (diuretics,
ß-blockers, and other antihypertensive drugs) were prescribed less
often for demented individuals than nondemented (46 of 147 versus 164
of 347; odds ratio, 0.5; 95% confidence interval, 0.3 to 0.8;
P=0.001). Those given these drugs did not differ from other
individuals regarding mean systolic and diastolic
blood pressure either in the total group or when demented and
nondemented individuals or men and women were considered
separately.
BMI was determined in 338 individuals and was significantly
correlated to systolic (r=0.18, P=0.001)
and diastolic (r=0.14, P=0.013) blood
pressure. Among those who had a CT scan of the brain, BMI was measured
in 125 of 133 nondemented individuals but in only 44 of 99 demented
(and among demented, in only 11 of 62 with moderate to severe
dementia). It was thus not meaningful to use BMI as a background
variable in the demented group. When BMI was used as a background
variable in the nondemented group, frontal (r=-0.18,
P=0.043) and parietal (r=-0.25,
P=0.006) cortical atrophy was associated with lower
systolic blood pressure, and frontal (r=-0.22,
P=0.015) and parietal (r=-0.27,
P=0.003) cortical atrophy with lower diastolic
blood pressure.
Systolic and diastolic blood pressures were
lower in demented than in nondemented 85-year-olds and decreased with
dementia severity (Table 2). Blood
pressure was lower in both Alzheimer's disease and vascular
dementia groups than in the nondemented group. Dementia severity was
correlated to lower systolic blood pressure in
Alzheimer's disease (r=-0.22,
P<0.0001) and in vascular dementia (r=-0.19,
P<0.0001) and to lower diastolic blood pressure
in vascular dementia (r=-0.11, P=0.019) but not
in Alzheimer's disease (r=-0.05,
P=0.351).
View this table:
[in a new window]
Table 2. Blood Pressure in Relation to Dementia in
85-Year-Olds
Reduced ambulatory capacity (defined as an inability to move
independently) was found in 7 of 338 (2.1%) nondemented individuals
and in 33 of 139 (23.7%) demented individuals. Among nondemented
individuals, those with a reduced ambulatory capacity had lower
mean±SD systolic (132.9±22.9 versus 162.9±23.4;
P=0.0008) and diastolic (68.6±19.5 versus
79.6±12.5; P=0.023) blood pressure than other individuals.
Among demented individuals, those with reduced ambulatory capacity had
lower systolic blood pressure than other individuals
(140.6±20.7 versus 151.0±25.5; P=0.035), while
diastolic blood pressure did not differ (75.7±13.2 versus
77.3±12.1; P=0.514).
In nondemented individuals (n=308), lower systolic blood
pressure was related to lower scores on the MMSE (r=0.12,
P=0.042). No relationship was found between MMSE scores and
diastolic blood pressure (r=0.02,
P=0.685) in nondemented individuals.
Orthostatic hypotension, defined as a systolic
blood pressure fall of 20 mm Hg within 3 minutes of standing
after 5 minutes in the supine position, was found in 67 of 333 (20.1%)
nondemented and in 19 of 86 (22.1%) demented subjects. A
diastolic blood pressure fall of 10 mm Hg or more was
found in 44 of 332 (13.3%) nondemented and in 14 of 86 (16.3%)
demented subjects. The frequency of orthostatic hypotension
did not differ among different severities or different types of
dementia.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
We found that cerebral atrophy (ie, neuronal degeneration) in
frontal and parietal cortical areas, and in central frontal areas, was
correlated to lower blood pressure in a representative
sample of nondemented 85-year-old persons; this suggests that
age-related changes in brain structure may contribute to the decrease
in blood pressure observed in the very
elderly,1 2 3 emphasizing the important role of
the central nervous system in blood pressure
regulation.6 7 We also confirmed previous
reports12 27 that systolic and
diastolic blood pressure is lower in individuals with
manifest Alzheimer's disease and vascular dementia than in
nondemented individuals and that blood pressure decreases with dementia
severity. These findings are supported by reports that blood pressure
declines in the years preceding dementia onset11
and further declines during the course of Alzheimer's
disease.10 28 The hypothalamus, the amygdala, the
insular cortex, the medial prefrontal cortex, the locus
coeruleus, the parabrachial nucleus, the pons, and the medulla
oblongata are involved in central blood pressure
regulation.8 10 Several of these areas are
affected in Alzheimer's disease9 and in
normal aging.5 Burke et
al10 reported a strong correlation between the
number of C1 neurons in the medulla oblongata and blood pressure in
Alzheimer patients. In our study, frontal atrophy was
associated with lower blood pressure in both nondemented and demented
individuals. Prefrontal areas are thought to be involved in blood
pressure regulation,8 but frontal convexity
lesions may also lead to a presentation of apathy and
inertia,29 a state that could be regarded as the
opposite to that of stress, which is correlated to increased blood
pressure.30 In our study, we found that reduced
spontaneity and ambulatory capacity were related to lower blood
pressure. It is thus possible that reduced activity in individuals with
brain atrophy may explain the association with low blood pressure.
However, although reduced activity influenced the correlation between
low blood pressure and severity of dementia and vascular dementia, it
did not explain the correlation between blood pressure and cerebral
atrophy.
Acknowledgments
The study was supported by grants from the Swedish Medical
Research Council (grant K97-21X-11267-03A, K97-27P-11337-03A), the
Delegation for Social Research of the Ministry of Health and Social
Affairs, the Göteborg Medical Services and Social Services
Administrations, Stiftelsen Söderström-Königska
Sjukhemmet, Konung Gustaf V:s och Drottning Victorias Stiftelse,
Stiftelsen för Gamla Tjänarinnor, Handlanden Hjalmar
Svenssons Forskningsfond, Stiftelsen Professor Bror Gadelius'
Minnesfond, The Swedish Society of Medicine, The Göteborg Medical
Society, Alzheimerfonden, Fredrik och Rosa Malmborgs Stiftelse,
and Alma och Anna Yhlen's Foundation.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Kannel B, Gordon T. Evaluation of
cardiovascular risk in the elderly: the Framingham
study. Bull N Y Acad Med. 1978;54:573–591.[Medline]
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