Hypertension Is Related to Cognitive Impairment : A 20-Year Follow-up of 999 Men

Lena Kilander, Hkan Nyman, Merike Boberg, Lennart Hansson and Hans Lithell
Hypertension. 1998;31:780-786
doi: 10.1161/01.HYP.31.3.780
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 1998 American Heart Association, Inc. All rights reserved.
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Hypertension Is Related to Cognitive Impairment

A 20-Year Follow-up of 999 Men
Lena Kilander, Hkan Nyman, Merike Boberg, Lennart Hansson, Hans Lithell
AbstractRecent findings of a linkage between high blood pressure (BP) and later development of dementia have given new
prospects on cerebral target-organ damage in hypertension and have added substance to the concept of preventable
senility. The aim of this study was to analyze the impact of hypertension, circadian BP profile, and disturbed glucose
metabolism on cognitive function. The study population consisted of 999 seventy-year-old men from a population-based
cohort study in Uppsala, Sweden, followed with respect to cardiovascular risk factors since the age of 50 years. At the age
of 70, 24-hour ambulatory BP was monitored together with measurements of insulin sensitivity, glucose tolerance, serum
lipids, and lipoproteins. Cognitive function was assessed by the Mini-Mental State Examination and the Trail-Making Test.
High diastolic BP at baseline predicted later impaired cognitive performance, even after excluding men with a previous
stroke (n570). Cross-sectional measurements at age 70 showed that high 24-hour BP, nondipping, insulin resistance, and
diabetes all were related to low cognitive function. The relationships between hypertension and cognitive impairment
were strongest in untreated men. These data from a general population of healthy elderly men indicate that hypertension
and associated metabolic disturbances might be susceptibility factors for cognitive disorders. The findings add support to
possibilities of intervention in early stages in cognitive decline, ie, before manifest dementia. (Hypertension.
1998;31:780-786.)
Key Words: cognition n blood pressure monitoring, ambulatory n diabetes n insulin resistance

he question of whether some degree of cognitive deterioration is an inevitable part of aging or should be considered
as a pathological prestage of dementia is currently debated.
This is a field in need of research1 because further decline in
cognition might be preventable in the early stages of cognitive impairment nondementia. Vascular dementia is a common form of dementia; in the oldest elderly patients it is as
frequent as Alzheimers disease.2 Recently, a 15-year follow-up
study showed that high BP predicted dementia in the oldest
elderly patients, irrespective of subtype.3 Little is known about
how cognitive function is affected by vascular risk factors in the
general population. The aim of the present study was to
analyze the associations between BP, diurnal BP variation,
disturbances in glucose and lipid metabolism, and cognition.
We examined cognitive functions in a population-based cohort of 70-year-old men in which longitudinal measurements
of vascular risk factors were available.

Methods
The study population consisted of 999 men. They were participants in
a health survey focusing on cardiovascular risk factors that was started
in the beginning of the 1970s in Uppsala, Sweden. The original cohort
was defined as all men born in 1920 to 1924, who resided in the
municipality of Uppsala in 1970 to 1973 (n52841). A total of 2322
(81.7%) men participated in the baseline examination at 50 years of
age.4 As a result of this first survey, medical and/or dietary treatment
were offered to 126 men with hypertension, to 363 men with
hyperlipidemia, and to 112 men with impaired glucose tolerance.5 A

new examination was carried out when they were 60 years of age, in
which 1860 of the 2130 remaining men from the original study cohort
participated. In January of 1991, 422 subjects from the 50-year study
had died. Of the 1900 men still alive, those who lived in Uppsala
county (n51681) were invited to a more extensive health examination, in which 1221 men (72.6%) took part. These men were also
invited to a psychometric testing, in which 999 men (82%) took part.
Their mean age was 72.4 years (range, 69 to 75 years).

Vascular Risk Factors

From the baseline examination at age 50 years, data for the following
measurements were collected: office SBP and DBP measured in the
supine position after 10 minutes rest with a mercury manometer to the
nearest 0 or 5 mm Hg; BMI calculated as weight (in kilograms)
divided by the height squared (in meters); and fasting concentrations
of blood glucose, serum insulin (n5815), HDL cholesterol (n5801),
and serum triglycerides. The study protocol has previously been
described in detail.6 Values of serum lipids and lipoproteins were later
standardized to correspond to the methods used for the 70-year
survey. From the 60-year survey, data on office BP, measured as
described above, and antihypertensive treatment from a questionnaire
were collected. At the 70-year survey, the investigations included
office SBP and DBP in the supine position, measured with a
sphygmomanometer to the nearest 2 mm Hg (mean of two measurements), calculation of BMI, analyses of fasting plasma concentrations
of insulin and glucose, and serum lipids and lipoproteins.7 Twentyfour-hour ABPMs were completed in 950 of the participants in the
cognitive study, using the Accutracker 2 equipment (Suntech Medical
Instruments Inc). BP recordings were made every 20 minutes during
daytime (6:00 AM to 11:00 PM) and every 20 or 60 minutes during
nighttime (11:00 PM to 6:00 AM). The following variables were used

Received May 20, 1997; first decision June 30, 1997; revision accepted October 6, 1997.
From the Department of Geriatrics (L.K., M.B., L.H., H.L.), Uppsala, and the Department of Clinical Neurosciences (H.N.), Karolinska Hospital,
Stockholm, Sweden.
Correspondence to Dr Lena Kilander, Department of Geriatrics, Klsangsgrand 10 D, PO Box 609, S-751 25 Uppsala, Sweden.
1998 American Heart Association, Inc.

780
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Kilander et al

781

TABLE 1.
ABPM
BMI
BP
DBP
DDBP
DSBP
HR
ICD
MAP
M/I
MMSE
NBP
NDBP
NSBP
OGTT
SBP
TMT

Selected Abbreviations and Acronyms

5 ambulatory blood pressure measurement
5 body mass index
5 blood pressure
5 office diastolic blood pressure
5 mean daytime diastolic blood pressure
5 mean daytime systolic blood pressure
5 heart rate
5 International Classification of Diseases
5 mean arterial pressure
5 insulin sensitivity index
5 Mini-Mental State Examination
5 nocturnal blood pressure
5 mean nocturnal diastolic blood pressure
5 mean nocturnal systolic blood pressure
5 oral glucose tolerance test
5 office systolic diastolic blood pressure
5 Trail-Making Test

in the analyses: MAP, SBP, DBP, and HR during 24 hours; DSBP and
DDBP; and NSBP and NDBP. The difference between mean DSBP
and mean NSBP was calculated. Nondipping was defined as
D(DSBP2NSBP) of #0 mm Hg. SBP variability was estimated as the
quotient between the mean standard deviation SBP divided by the
mean SBP. An OGTT was carried out (n5976), and subjects were
classified as having normal or impaired glucose tolerance or diabetes
according to the criteria of the National Diabetes Data Group.8 A
hyperinsulinemic euglycemic clamp7 was performed (n5965) and the
M/I was calculated as glucose uptake per minute divided by mean
insulin concentration during the clamp, 60 to 120 minutes. Reproducibility was tested in 21 subjects. The coefficients of variation were
24-hour DBP, 5%; plasma glucose, 6%; M/I, 14%; serum triglycerides,
15%; and plasma insulin, 20%.

Cognitive Function
The psychometric testing included the MMSE9 (n5891) (MMSE was
added to the protocol after the start) and the TMT-A (n5998) and
TMT-B (n5996).10 Standardized procedures from published manuals
were used in the administration and evaluation. The maximal time set
for TMT-B was 240 seconds. MMSE is a widely used instrument in
the screening for cognitive disorders, and the TMT was selected to
assess psychomotor speed and shifting capacity. The testing was
performed in connection with the ABPM in some cases, but in others
the time interval was longer (mean, 18 months). After a logarithmic
transformation of the test results, a z transformation was applied, and
a composite cognitive score was calculated for each subject as the
mean sum of the test scores. Cognitive score was treated both as a
continuous outcome variable and as a dichotomous variable, setting
the cutoff level for low results at the lowest quintile.

Potential Confounders
All pharmacological treatment with agents affecting BP, irrespective of
indication (ie, b-blockers, calcium antagonists, angiotensin-converting enzyme inhibitors, diuretics, and a-blockers), was recorded in a
questionnaire at age 70 years. Educational level was stratified as low
(elementary school only, 6 to 7 years, n5530), medium (secondary
school, n5309), or high (university studies, n5160). Main previous
occupational level was divided into three categories: low (manual
workers, n5406), medium (foremen, clerks, salesmen, n5388), and
high (major professionals, business managers, n5193). The following
are diagnoses of stroke according to the ICD-8 or ICD-9 before the
cognitive testing results were collected from the Swedish National
Inpatient Register and cover all diagnoses in hospitalized patients from
1970 and onward: intracerebral hemorrhage (431), thromboembolic
stroke (433 to 434), transient ischemic attack (435), and acute
ill-defined cerebrovascular disease (436). Informed consent was
obtained from the participants after the nature of the procedures had

Description of Participants (n5999)

Characteristic

Percentage/Mean (SD)

Education #7 y

53.1%

Low occupational level

41.2%

50-Year survey
Office DBP, mm Hg

82 (10)

s-Glucose, mmol/L

5.0 (0.6)

s-Insulin (mU/L)

12.4 (6.8)

70-Year Survey
24-h DBP, mm Hg

76 (8)

Nondippers*

6.8%

p-Glucose, mmol/L

5.8 (1.5)

p-Insulin, mU/L

12.8 (8.4)

M/I

5.1 (2.5)

s-Triglycerides, mmol/L

1.43 (0.78)

BMI, kg/m2

26.3 (3.3)

Diabetes (OGTT)

14.2%

Antihypertensive treatment

34.2%

Previous stroke

7.0%

*Nondippers indicate SBP daytime minus SBP nighttime #0 mm Hg.

Any pharmacological treatment affecting BP.

been fully explained. The study was approved by the Ethics Committee at Uppsala University.

Statistics
A logarithmic transformation was applied to all variables not normally
distributed. Students unpaired t test was applied for comparisons
between independent groups, the x2 test was used for analysis of
relationships between categorical variables, and linear relationships
were examined with Pearsons correlation coefficient. In the analyses
of determinants of cognitive function, adjustment was made for
potential confounders, ie, socioeconomic factors (educational and
occupational levels) and age. ANCOVA was applied in multivariate
models with continuous dependent variables, and logistic regression
was used when the outcome variable was binary. The odds ratio for
continuous explaining variables was calculated per increase with 1 SD
within a 95% confidence interval or per year (age). Testing for trend
was performed according to Spearman.

Results
Description of the Population
Characteristics of the participants (n5999) are shown in Table
1. Diabetes according to the OGTT was present in 139
subjects (14.2%), and a total of 5.3% were treated with peroral
antidiabetic agents or insulin. Thirty-four percent were treated
with drugs affecting BP, irrespective of indication, mainly
b-blockers and/or diuretics (26%), and the rate of treatment
with lipid-lowering agents was 9.4%. The correlation coefficient between MMSE and TMT-A was r5.32; between
MMSE and TMT-B it was r5.40; and between TMT-A and
TMT-B it was r5.66. Seventy men had had a previous stroke,
and they were excluded from the main part of the analyses.
Excluding stroke patients, a large majority had high scores in
the MMSE: 462 men scored 29 to 30 points; 287 men scored
27 to 28 points, and 77 men scored 26 points or below. The
nonparticipants in the cognitive testing (n5222) differed from
the participants (n5999) with regard to a higher rate of low

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Hypertension and Cognitive Impairment

782
TABLE 2.

DBP at Age 50 Years in Relation to Cognitive Function at Age 70 Years

Cognitive score,
Mean (SD)

P*

Treatment at 60 y

DBP at 60 y

Treatment at 70 y

DBP at 70 y

#70 mm Hg (n5147)

10.17 (0.71)

...

2.7%

78 (7)

8.2%

79 (10)

7580 mm Hg (n5392)

60.00 (0.82)

.0065

2.8%

85 (8)

23.2%

82 (9)

8590 mm Hg (n5268)

10.04 (0.70)

.0018

17.2%

90 (8)

39.9%

86 (9)

95100 mm Hg (n586)

60.00 (0.89)

.032

51.2%

95 (9)

70.9%

89 (9)

$105 mm Hg (n536)

20.33 (0.82)

.0016

88.9%

96 (8)

91.7%

89 (9)

DBP at Age 50 y

Treatment and DBP indicate rates of antihypertensive treatment and DBP at 60 and 70 years, respectively.
*Comparisons with DBP #70 mm Hg, adjusted for age and educational and occupational levels. Test for trend: P5.0040; P5.034, including serum insulin at age 50.

education (72%, P,.0001 compared with participants). In

addition, they had higher office DBP at age 50 and higher
plasma concentrations of insulin at age 70 (both P,.05). The
distributions of 24-hour DBP were equal in participants and
nonparticipants.

Interrelationships Between Risk Factors

The correlation coefficients between office and 24-hour measurements were r5.58 for SBP and r5.62 for DBP. There were only
weak linear relationships between BP and metabolic measurements. The correlation coefficients between metabolic measurements and 24-hour DBP were as follows: plasma glucose, r5.12
(P5.003); plasma insulin, r5.08 (P5.05); M/I, r52.12
(P5.003); and BMI, r5.13 (P5.0007). Serum lipids were not
significantly related to 24-hour DBP. Concentrations of serum
triglycerides were closely related to M/I (r52.39) and to plasma
glucose (r5.27). Plasma glucose was significantly higher in nondippers (6.3 mmol/L) than in dippers (5.7 mmol/L), independent
of 24-hour DBP (P5.008, logistic regression).

Vascular Risk Factors and Cognitive Function

The mean cognitive z score in the entire cohort was 60.00

(SD 0.82; range, 25.19 to 12.00). Cognitive score was equal
in men with missing results from the ABPM, the clamp, or the
OGTT compared with the others. Stroke patients (n570)
were excluded from the analyses of determinants of cognitive
function. Their results are shown separately. In all analyses,
adjustment was made for age and educational and occupational
levels. The relationships with the composite cognitive score
described below were unchanged when separate analyses
between risk factors and the single test results (MMSE,
TMT-A, TMT-B) were performed.

tertile; the difference was, however, not significant when DBP

was adjusted for. High systolic BP, BMI, or high levels of
blood glucose or serum lipids at baseline were not associated
with later impaired performance.

Cross-sectional Measurements
Blood Pressure
There was an inverse relationship between 24-hour ambulatory SBP and DBP at age 70 years and cognitive score, NDBP
showing the strongest linear relationship (r52.15, P,.0001).
Mean HR during 24 hours was also inversely related to
cognitive z score (r52.12, P5.0015). Cognitive score by
tertiles of 24-hour DBP are shown in Fig 2, with separate
analyses for untreated men (n5594) and treated men (n5289).
The inverse relationship between BP and cognitive score was
similar in both categories but significant for untreated men
only (P5.014 for trend). Mean cognitive score did not differ
between men with and without treatment (10.03 versus
10.02, respectively, P5.941), despite higher mean 24-hour
DBP in the latter group (75 versus 78 mm Hg, respectively,
P,.0001). This finding is discussed further in the following
sections. Isolated systolic hypertension was not related to
impaired cognitive function.

Nondipping and BP Variability

Mean cognitive score was lower in nondippers (n559, 20.22,

SD 0.95), than in dippers (n5824, 10.04 [0.77], P5.04). In
multivariate analyses with cognitive score as a continuous
outcome variable, nondipping, mean 24-hour DBP, and mean
24-hour HR were all significantly and inversely related to

Longitudinal Measurements
Office DBP at baseline (age 50) was inversely related to
cognitive function 20 years later. In the analysis, participants
were split into five DBP categories. Cognitive performance at
age 70 was highest in men with the lowest baseline BP,
DBP#70 mm Hg (n5147), and lowest in men with
DBP$105 mm Hg (n536), adjusted value for trend P5.0040
(Table 2). Rates of antihypertensive treatment and office DBP
at age 60 and 70 years in each BP category are also shown in
Table 2. Only 3 men with DBP$105 mm Hg were not treated
20 years later; their mean cognitive score was 21.24. Serum
concentrations of insulin at age 50 were also inversely related
to cognitive results at follow-up (Fig 1). Men within the lowest
tertile of s-insulin had higher results than those in the highest

Figure 1. Tertiles of serum insulin at age 50 years relative to

cognitive score 20 years later. Cognitive score in tertile 1 versus
tertile 3, ANCOVA: P1 (adjusted for age, education, occupation)5.031; P2 (as P11DBP at age 50)5.145.

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Kilander et al

783

Figure 3. Cognitive score by tertiles of M/I (insulin sensitivity

index) at age 70. P1 for trend (adjusted for age, education,
occupation)5.048. P2 for trend (as P1124-hour DBP and
treatment)5.055.

higher plasma glucose (Table 3). In a multivariate model that

included 24-hour DBP, p-glucose, p-insulin, M/I, s-triglycerides, BMI, HDL cholesterol, treatment, age, educational and
occupational levels, an increase of 24-hour DBP with 1 SD
was associated with an odds ratio of 1.45 (1.20 to 1.75) of
cognitive impairment. Despite higher DBP in treated men,
antihypertensive treatment was associated with a decreased
risk, ie, treatment was a negative confounder. As shown in
Table 4, the association between hypertension and cognitive
impairment was significant only in untreated men.
Figure 2. Cognitive score by tertiles of 24-hour DBP at age 70.
Tests for trend according to Spearman, adjusted for age, education, occupation, and M/I. P for trend5.014 in untreated men;
P for trend5.272 in treated men.

cognitive performance, independent of each other. Cognitive

performance in men with high NBP variability as measured by
the quotient between SD (of NSBP) divided by mean (of
NSBP), and in extreme dippers (D[DSBP2NSBP] of
$20 mm Hg), was equal to the rest of the cohort. There was
no relationship between the number of missing single measurements due to technical reasons and cognitive performance.

Insulin Resistance and Diabetes

As shown in Fig 3, measurements of M/I was negatively
related to cognitive results (P5.048 for trend). When adjustment was made for 24-hour DBP and treatment, the value for
trend was P5.055. Men with diabetes according to the OGTT
(n5130) performed worse than nondiabetic men (n5779,
20.16 [0.90] versus 10.06 [0.75]), independent of 24-hour
DBP (P5.005). In a multivariate model (n5868), diabetes,
nondipping, and 24-hour DBP were all independently and
inversely related to cognitive score as a continuous outcome
variable. In diabetic men, performance was equal in men with
and without pharmacological treatment. Stratifying for diabetes did not alter the relationship between high DBP and low
cognitive results.

Multivariate Analysis
In a logistic regression model, cognitive function was treated as
a dichotomous variable with the cutoff level for low performance set at the lowest quintile. In univariate analysis, men
with low cognitive function had higher 24-hour DBP and

Stroke Patients
Men with a previous stroke (n570) had lower cognitive
results; mean cognitive score (SD) was 20.43 (1.14) versus
10.02 (0.78) for nonstroke subjects (P5.0001), and they had
higher DBP at baseline. When stroke cases were included in
the analyses previously described, the relationships between
vascular risk factors and low cognitive performance remained
almost identical.

Discussion
High DBP at the baseline examination at age 50 years was
related to impaired cognitive performance 20 years later, even
after exclusion of men with a previous stroke. Elevated
concentrations of serum insulin also predicted later low cognitive function, but not independently of DBP. Cross-sectional measurements at age 70 showed that high 24-hour DBP,
a nondipping nocturnal BP pattern, insulin resistance, and
diabetes all were related to low cognitive function. The
relationships between hypertension and cognitive impairment
were strongest in men without antihypertensive treatment.
High BP and impaired glucose metabolism11 are both independent predictors of cerebrovascular disease. We conclude
that hypertension and factors linked to the syndrome of insulin
resistance12 might contribute to cognitive disturbances in the
elderly, mediated through functional changes, or by silent
cerebral large- and small-vessel lesions.
This group was a healthy cohort in which only a minority of
the participants scored below 27 points in the MMSE. It
consisted of approximately half of the survivors from the
baseline examination only, but nonresponse to health surveys
has, on the other hand, been shown to be associated both with

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Hypertension and Cognitive Impairment

784

TABLE 3. Determinants of Low Cognitive Performance: Cross-sectional Data at

Age 70 Years
Cognitive Function
Characteristic
24-h DBP, mm Hg
fP-Glucose, mmol/L

Logistic Regression

Normal
(n5743)

Low
(n5186)

P1

OR (95% CI)

P2

76 (8)

78 (8)

.0002

1.45 (1.201.75)

.0001
.188

5.7 (1.4)

6.0 (1.8)

.034

1.13 (0.941.37)

12.7 (8.2)

13.3 (9.2)

.984

0.87 (0.691.09)

.223

5.2 (2.5)

4.8 (2.6)

.155

1.00 (0.771.29)

.983

1.39 (0.71)

1.57 (1.04)

.271

0.99 (0.791.23)

.911

BMI, kg/m

26.1 (3.2)

26.9 (3.9)

.089

1.12 (0.891.41)

.346

HDL cholesterol, mmol/L

1.30 (0.34)

1.25 (0.37)

.232

0.90 (0.721.13)

.349

Antihypertensive treatment, %

32.6

33.3

.775

0.64 (0.420.98)

.0418

Age, y

72.3

72.8

1.35 (1.141.58)

.0003

Education, L/M/H

46/35/19%

81/15/4%

0.42 (0.270.65)

.0001

Occupation, L/M/H

35/42/23%

66/30/4%

0.57 (0.390.83)

.0038

fP-Insulin, mU/L
M/I
fS-Triglycerides, mmol/L
2

Values are presented as mean (SD). Low function indicates cognitive score within the lowest quintile; OR, odds ratio;
CI, 95% confidence interval; and L/M/H, low/medium/high.
P 1 model includes age, educational, and occupational levels (ANCOVA). OR and CI for continuous variables are
calculated per 1 SD increase (per 1 year for age). All listed covariates are included in the logistic regression model.

a higher vascular risk and with cognitive impairment.13 Those

who declined to participate in the cognitive testing had a lower
level of education and higher office BP and serum insulin than
the participants, ie, factors with positive relationship to the
outcome. Furthermore, in our study cohort, the risk factor
pattern has been blunted not only by selection but also by the
effects of preventive treatment. Special efforts to prevent
cardiovascular disease were taken since the 50-year survey, in
which primary preventive measures were instituted in men
who were found to be hypertensive, hyperlipidemic, or had an
impaired glucose tolerance. Thus, we believe that the inference of the relationships to the general population of community-living elderly males might rather be underestimated.
The most convincing evidence of a relationship between
hypertension and cognitive deterioration is derived from a
prospective study in the 1960s, when antihypertensive
treatment was still infrequent.14 The authors suggested that
the basis for the cognitive decline associated with aging
TABLE 4.

should be considered secondary to some pathologic processes and not merely as a normal aging process. Results
from other studies assessing longitudinally measured BP
point in the same direction. In the Honolulu-Asia Aging
Study, high midlife SBP was a predictor of reduced cognitive function in later life, when stroke cases were included.15
Similarly, in the Framingham study, untreated BP levels and
chronicity of hypertension were inversely related to the
composite cognitive score.17
Diabetes in the elderly has been linked to cognitive impairment in cross-sectional case-control studies,18 and impaired
cognitive performance in diabetic subjects has been related to
poorer metabolic control.19 In a cohort study, diabetes and
impaired glucose tolerance were associated with lower results
in the MMSE; however, this relationship was independent of
other factors associated with insulin resistance.20 In other
studies, the combinations of hypertension and hyperinsulinemia,21 hypercholesterolemia, or diabetes, as defined by a

Determinants of Low Cognitive Performance Stratified for Antihypertensive Treatment

Untreated Men

Treated Men

Cognitive Performance

Cognitive Performance

Normal
(n5501)

Low
(n5124)

P*

Normal
(n5242)

Low
(n562)

P*

24-h DBP, mm Hg

75 (7)

78 (8)

,.0001

78 (9)

79 (8)

.430

fP-Glucose, mmol/L

5.6 (1.3)

5.8 (1.7)

.087

5.9 (1.6)

6.3 (2.1)

.229

12.4 (8.8)

11.9 (7.3)

.545

13.5 (6.8)

15.9 (11.8)

.584

5.6 (2.5)

5.1 (2.7)

.231

4.3 (2.3)

4.1 (2.4)

.590

fS-Triglycerides (mmol/L)

1.33 (0.65)

1.46 (1.04)

.898

1.51 (0.80)

1.80 (1.02)

.069

BMI, kg/m2

25.6 (2.9)

26.5 (4.0)

.092

27.0 (3.4)

27.6 (3.7)

.544

HDL cholesterol, mmol/L

1.33 (0.35)

1.28 (0.36)

.410

1.23 (0.32)

1.18 (0.40)

.331

Characteristic

fP-Insulin, mU/L
M/I

Values are presented as mean (SD). Low function indicates cognitive score within the lowest quintile.
*Adjusted for age, education, and occupation (ANCOVA).

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Kilander et al
questionnaire,22 were related to impaired cognitive function.
To our knowledge, ours is the first cohort study showing that
cognitive impairment is related to metabolic disturbances
linked to the syndrome of insulin resistance, together with
hypertension.
The finding that diastolic BP in middle age predicts later
cognitive performance suggests a causal relationship. However,
the data from the ABPM are cross-sectional, and causal
mechanisms can only remain speculative. The causation might
be reverse, ie, cognitive impairment and altered BP regulation
may both be secondary to silent cerebrovascular lesions. In
cross-sectional studies, silent lacunar infarctions23 and vascular
dementia characterized by extensive white matter lesions or by
multiple lacunar infarctions24 have been related to the absence
of NBP decrements. Changes in BP circadian variability
indicate alterations of central nervous regulatory systems,
mediated by sympathetic activation. However, on the other
hand, sympathetic overreactivity could also be etiologically
linked to the syndrome of hypertension and insulin resistance25
and primarily affect cognitive function by vasoconstriction and
cerebral small-vessel lesions. The TMT reflects subcorticofrontal functions, among others, and impaired performance in the
TMT has previously been associated with subcortical smallvessel lesions.26,27
Is low BP always desirable, or is there a lower limit below
which too-aggressive antihypertensive treatment might be
hazardous? It has been hypothesized that low systemic BP
might primarily contribute to dementia via impaired cerebral perfusion and incomplete white matter infarctions in
areas supported by stenosed vessels.28 Extreme dipping, as
well as nondipping, was associated with silent cerebrovascular disease identified by magnetic resonance imaging.23
Moderate or severe dementia is accompanied by lower BP
levels, but in advanced stages, this is most likely a secondary
phenomenon.29 A previous study showed that cognitive
changes in hypertensive subjects, hypothetically mediated
through metabolic or hemodynamic mechanisms, could be
restored by treatment.30 In our cohort, there existed no
J-shaped relationship between BP and cognitive function,
and there were also indications of a positive effect of
treatment. This latter finding should be interpreted with
caution, because it may be due to selection.
To summarize, our results support the hypothesis that
cerebral target-organ damage in hypertension contributes to
cognitive impairment. Cognitive deterioration denotes an
impaired quality of life and is also a predictor of dementia and
mortality.31 Actions to prevent further decline must be considered as early in the course of the disease as possible, ie,
before clinical manifest dementia. Because a linkage with risk
factors for vascular disease has been established, it is urgent to
investigate whether further cognitive decline can be postponed
by a more intensive preventive treatment. There is convincing
evidence of the importance of adequate antihypertensive
treatment in primary prevention of cerebrovascular disease
even in higher ages,32 and there are no indications of treatment
causing cognitive deterioration.33 Our findings suggest that
treatment with pharmacological agents that maintain the normal 24-hour BP profile and have no metabolic side effects

785

should be preferred in the management of elderly persons with

hypertension.

Acknowledgments
The study was supported by grants from the Swedish Medical
Research Council (grant 5446), The King Gustav V and Queen
Victoria Foundation, The Foundation of Old Servants, The Alzheimer Foundation, The Dementia Foundation in Sweden, the Swedish
Stroke Foundation, and The Swedish Hypertension Society. We are
grateful to Paul McKeigue, Senior Lecturer, London School of
Hygiene & Tropical Medicine, for valuable comments on the manuscript and to Gun-Britt ngman for excellent coordination and care of
the study participants.

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