Vascular Medicine

15(2) 91–97
Ankle–brachial index predicts level of, but not © The Author(s) 2010
Reprints and permission: http://www.
change in, cognitive function:The Edinburgh sagepub.co.uk/journalsPermission.nav
DOI: 10.1177/1358863X09356321

Artery Study at the 15-year follow-up http://vmj.sagepub.com

Wendy Johnson1,2, Jacqueline F Price3, Snorri B Rafnsson3,

Ian J Deary1 and F Gerald R Fowkes3

Abstract
The ankle–brachial index (ABI), a marker of generalized atherosclerosis, is related to cognitive impairment in older adults.
We investigated whether ABI is associated specifically with age-related cognitive decline. We measured ABI at recruit-
ment and 5 and 12 years later in a sample of individuals aged 55–74 years. Cognition was measured in 717 of these
participants 10 years after recruitment and 5 years later. It was found that ABI was associated with the level of cognitive
function, even after adjustment for estimated premorbid function and concurrently measured anxiety and depression
(standardized coefficient of 0.07), but this was attenuated by anxiety and depression. ABI was not associated with change
in cognitive function. In conclusion, over long time periods, low ABI may be associated with reduced cognitive function in
older adults, at least partly because the associated poor health creates anxiety and depression.

Keywords
ankle–brachial index; change in cognitive function; late-life cognitive function

Introduction
Cognitive function varies widely among individuals, yet
almost everyone experiences declines with age. Though peo-
ple can maintain an independent life with a wide range of
cognitive function, there is some essentially threshold level
of cognitive function below which cognitive function limits
the ability to live independently and must be considered a
disability. In youth, cognitive function below this threshold
level is associated with mental retardation. Among people
over perhaps the age of 55 years, because declines with age
are often observed, cognitive function below this threshold
level is generally considered impairment from a prior higher
level and is commonly associated with dementia or an inter-
mediate state such as mild cognitive impairment (MCI).
Cognitive impairment has prevalence rates of about 8%
for frank dementia1 and can range to 20% for MCI.2 It
affects both care costs and quality of life for older peo-
ple.3 A major public health challenge is thus to identify
older people at risk of and suffering from cognitive
impairment who may benefit from preventive, supportive
and/or therapeutic measures to minimize future decline.
Identification of simple and accurate measures that are
acceptable to patients and can serve as indicators of cur-
rent cognitive impairment or risk of cognitive decline
could be helpful in developing long-term preventive and
treatment programmes.
The ankle–brachial index (ABI; the ratio of systolic
blood pressure in the ankle to that in the arm) has been pro-
posed as one such measure.4 Originally developed to aid in
the diagnosis of peripheral arterial disease, it is both a reli-
able indicator of generalized atherosclerosis5 and a predic-
tor of fatal cardiovascular event, myocardial infarction and
stroke.6–7 It has been associated with cognitive function in
several cross-sectional studies.8–13 In the Edinburgh Artery
Study (EAS4), it was shown to predict performance in non-
verbal reasoning, verbal fluency and processing speed 10
1
 entre for Cognitive Ageing and Cognitive Epidemiology, Department
C
of Psychology, University of Edinburgh, Edinburgh, UK
2
Department of Psychology, University of Minnesota – Twin Cities,
Minneapolis, MN, USA
3
Centre for Population Health Sciences, Division of Community Health
Sciences, University of Edinburgh, Edinburgh, UK
Corresponding author:
Wendy Johnson
Centre for Cognitive Ageing and Cognitive Epidemiology,
Department of Psychology
University of Edinburgh
7 George Square
Edinburgh EH8 9JZ, UK
Email: wendy.johnson@ed.ac.uk
92 Vascular Medicine 15(2)
years later. For processing speed, the association remained
significant after adjustment for premorbid cognitive func-
tion, suggesting that ABI may also predict cognitive
decline.
The purpose of this study was to explore this association
further in the same study population, augmenting the origi-
nal data by including new cognitive data collected 15 years
after the study’s inception, 5 years after the initial report.4
This made it possible to estimate associations with the
directly measured late life level of, and change in, cognitive
function.
Methods
Participants
The EAS began in 1987. Its purpose was to study the inci-
dence, prevalence and natural history of peripheral arterial
disease. Participants aged 55–74 years were randomly
recruited from the registers of 10 general medical practices
located in diverse geographic and sociodemographic areas
throughout the city of Edinburgh. At study inception, the
sample included 809 men and 783 women, a 65% response
rate to the initial invitations. Full details of study recruit-
ment and procedures have been described previously.14
The study was approved by the Lothian Health Board eth-
ics committee. Each participant provided informed con-
sent. The EAS is longitudinal, with clinical assessments at
5 and 12 years after inception.
In 1998, 10 years after study inception, the EAS obtained
consent to recruit study participants for cognitive testing.4
Invitations were issued by mail, and participants could elect
to be tested at home or at the University of Edinburgh. As
previously reported,4 at that time, 1103 of the original par-
ticipants were available; 461 were no longer participating.
Of these 1103, 740 initially agreed to be tested and 717 actu-
ally completed cognitive testing (65% response). Cognitive
testing was repeated in 2003, 15 years after study inception.
At that time, 601 (84%) of the 717 were still alive, but 23
were excluded by their general practitioners and four could
not be located. Of the remaining 574 invited, 460 agreed:
101 refused and 13 did not reply. Of those who agreed, 452
actually completed testing (79% response): seven withdrew
from the study and one could not be contacted. All partici-
pants who completed cognitive testing were included in this
study.
Measures
Study participants attended initial clinical examinations at uni-
versity or hospital clinics in 1988. They completed a written
questionnaire providing data on age, sex, lifetime smoking
history and history of cardiovascular disease. Participants also
underwent clinical examination by specially trained nurses.
Systolic blood pressure was measured in the right arm after 10
minutes of rest using a random zero sphygmomanometer.
Ankle systolic pressure was measured in the posterior tibial
artery of the right leg and then the left leg using a Doppler
ultrasound and a random zero sphygmomanometer with the
cuff position proximal to the malleoli. Because arterial disease
can occur unilaterally, we calculated the ABI by dividing the
lower of the indices obtained for the two legs by the brachial
pressure. All participants who were alive were invited to return
for the same examinations in 1993 and 2000, at intervals of 5
and 12 years since baseline. Cognitive testing, which took
about 50 minutes, was carried out by a specially trained nurse
and a research psychologist. The National Adult Reading Test
(NART),15 Logical Memory,16 Raven’s Progressive Matrices,17
Verbal Fluency,18 and Digit Symbol19 were administered in this
order. Scores on the NART show little decline with age, so it is
often used to estimate peak lifetime or premorbid cognitive
function.
As part of each cognitive assessment, participants
responded to the Hospital Anxiety and Depression Scale
(HADS),20 a well-validated measure of these mood states.
Because anxiety and depression are associated with both
hypertension21 and cognitive function,22 we carried out
analyses both with and without adjustment for these scale
scores at the first cognitive assessment and for change in
scores from first to second assessment. We used standard-
ized residuals created by regressing scores at the second
assessment on those at the first assessment to estimate
change in anxiety and depression over the 5-year period
between cognitive assessments.
We adjusted our analyses for smoking history. In the
first clinical assessment, participants reported current
smoking status, average numbers of cigarettes smoked per
day and numbers of years smoked. We converted this to
pack-years of smoking, entering zeros for life-long non-
smokers. At each follow-up, participants again reported
current smoking status and average numbers of cigarettes
smoked, as well as time since quitting if applicable. We
adjusted pack-years of smoking from the first assessment
by adding average pack-years since the first clinical assess-
ment and subtracting half of pack-years of smoking since
quitting when relevant. We adjusted our analyses for the
resulting 5-year smoking variable and change in smoking
from 5 to 12 years. We used the standardized residuals cre-
ated by regressing scores at the 12-year assessment on
those at the 5-year assessment to estimate change in smok-
ing over the 7-year period between clinical assessments.
We did not adjust for risk factors for atherosclerotic dis-
ease such as hypertension, presence of diabetes, body mass
index, or levels of triglycerides and cholesterol. Because
we hypothesized that ABI could be a marker of future cog-
nitive decline through development of atherosclerotic dis-
ease, to do so would have been to remove variance related
to atherosclerosis and thus possibly inappropriately fail to
observe the association in which we were interested.
Similarly, we did not adjust for demographic factors such
as education and income that are generally associated with
lifetime peak cognitive function as well as level of
cognitive function at any particular point in later life.
Statistical analysis
We used a latent variable growth curve model (ref. 23 for
methodology) to estimate level of and change in cognitive
Johnson W et al. 93

Table 1.  Descriptive statistics for the total cohort and the cognitively tested subgroup at baseline

Characteristic Total cohort Cognitively tested p-value of

difference
Mean SD Mean SD

Age   64.9   5.7   63.6   5.4 < 0.001

Symptomatic cardiovascular disease (%)   16.0 N/A   12.4 N/A < 0.001
Ankle–brachial index    1.03   0.18    1.06   0.16 < 0.001
Systolic blood pressure 144.5 24.1 140.9 22.8 < 0.001
Serum cholesterol, mmol/l    7.03   1.33    7.07   1.27 0.35
Pack-years of cigarette smoking   16.81 21.87   14.19 18.66 < 0.001
Symptomatic heart disease was history of myocardial infarction, angina pectoris, stroke, or intermittent claudication.

function over the 5-year period. A key aspect of the growth
curve model was its simultaneous incorporation of assess-
ments of latent variable measures of level of, and change
in, cognitive function. This eliminated the potential for
bias due to variance in individual tests. In addition, it was
possible to measure separately the effects of age, sex,
smoking, anxiety, depression and ABI on level of cognitive
ability at the first assessment and change in cognitive
ability from the first to the second assessment. We could
also measure the correlation between level of cognitive
ability and its change. Probably most importantly, we could
include the participants who were present at the first cogni-
tive assessment, but not at the second, using full informa-
tion maximum likelihood estimation.
We fit several models of potential interest in explain-
ing associations between ABI and level of, and change in,
cognitive function. The baseline model considered only
age, sex and prior smoking (at year 5) as covariates in
order to assess the total effects of pre-existing ABI
(reflected by baseline assessment) on level of cognitive
function at year 10. It also considered the effects of the
same variables on change in cognitive function between
years 10 and 15, as well as the effects of change in smok-
ing (years 5–12) and change in ABI (years 5–12) on
change in cognitive function. These time points of assess-
ment of ABI did not tie optimally with the time points of
assessment of cognitive function, but our approach did
make possible a look at the effects of level of, and change
in, ABI over an extended time period. To evaluate the
extent to which the ABI’s association with cognitive
function might be mediated by anxiety and depression,
we also estimated a second model using the HADS (at
year 10) as covariates of level of cognitive function, and
change in these scales between year 10 and year 15 as
covariates on change in cognitive function. Finally, to
provide some idea of the extent to which lifetime peak
cognitive function might be associated with that decline,
we estimated a third model including the NART as a
covariate. To avoid possible distortion of results due to
the presence of a few individuals with very high values of
ABI possibly associated with cardiovascular disease, we
ran our analyses both including all data at the values
reported and limiting ABI values to 1.4. As results were
essentially identical, we present only those based on the
reported data.
Results
The participants who completed initial cognitive testing
were slightly younger and had lower prevalence rates of
cardiovascular disease, cardiovascular risk factors and
higher mean ABI than the full EAS sample. Because all of
these factors also tend to be associated with cognitive abil-
ity, the participants also likely had higher cognitive test
scores than those who were not tested would have received.
Comparison data are shown in Table 1. As we were inter-
ested in cognitive function as an outcome, we made use
only of participants who completed at least the initial cog-
nitive testing. The resulting restriction of range acted to
attenuate the associations of interest.
All cognitive test scores were positively correlated with
the ABI measures taken nearest to their time of completion,
though correlations were low (0.03–0.20). Only the corre-
lations between ABI and Verbal Fluency were not signifi-
cant, and the correlation between ABI at year 5 and Verbal
Fluency at year 15 was negative (–0.01). Hospital Anxiety
and Depression were similarly correlated with ABI at the
respective time periods. Individual differences in ABI itself
were not particularly stable: the correlation between assess-
ments at years 5 and 12 was 0.39. The strongest correla-
tions were between assessments of the same test measures.
The average correlation between assessments of the same
cognitive tests was 0.79, and the average correlation
between assessments of the HADS scales was 0.67. The
full correlation table for the sample that completed cogni-
tive testing is shown in the Appendix.
The columns entitled ‘Excluding HADS and NART’ in
Table 2 show the estimated model effects on cognitive func-
tion before consideration of Anxiety and Depression. The
model fit quite well by all fit statistics compiled (specific
details on fit statistics are available from the first author upon
request). There was a moderate effect of –0.46 of age on level
of function. This indicates that a younger age at baseline was
associated with a later higher level of cognitive function.
Smoking also had a small but significant effect (–0.12), and
there was a marginally significant (p = 0.09) tendency for
men to have better cognitive function than women (coeffi-
cient = –0.08). ABI also had a small but significant effect on
level of function (coefficient = 0.15, p = 0.001). The mean
cognitive change parameter was –0.04, which indicated that,
after adjustment for covariates, cognitive function declined
 94

Table 2.  Estimated associations between variables of interest and level of cognitive function at year 10, and change in cognitive function between years 10 and 15, including and excluding
adjustment for anxiety, depression and pre-existing cognitive function

Excluding HADS and NART Excluding only NART Including all

Coefficient Standard error p-value Coefficient Standard error p-value Coefficient Standard error p-value

Effects on level of cognitive function

   Age -0.46 0.04 < 0.001 -0.44 0.04 < 0.001 -0.44 0.04 < 0.001
   Sex -0.08 0.05 0.09 -0.03 0.05 0.52 -0.05 0.04 0.27
   Smoking at year 5 -0.12 0.05 0.015 -0.10 0.05 0.046 -0.08 0.04 0.01
   ABI at baseline   0.15 0.05 0.001   0.14 0.05 0.002   0.07 0.04 0.03
   Hospital anxiety at year 10 N/A N/A N/A -0.14 0.05 0.002 -0.08 0.04 0.024
   Hospital depression at year 10 N/A N/A N/A -0.11 0.04 0.011 -0.06 0.05 0.07
   NART at year 10 N/A N/A N/A N/A N/A N/A   0.57 0.03 < 0.001
Effects on change in cognitive function
   Sex   0.05 0.08 0.57   0.02 0.08 0.77   0.03 0.08 0.73
   Smoking at year 5 -0.04 0.31 0.91 -0.13 0.31 0.67 -0.15 0.31 0.62
   ABI at baseline -0.04 0.12 0.71 -0.09 0.12 0.45 -0.07 0.12 0.56
   Change in smoking, years 5–12 -0.08 0.34 0.81   0.06 0.34 0.87   0.07 0.34 0.83
   Change in ABI, years 5–12   0.13 0.10 0.20   0.14 0.10 0.14   0.14 0.10 0.15
   Hospital anxiety at year 10 N/A N/A N/A   0.11 0.09 0.21   0.11 0.09 0.24
   Hospital depression at year 10 N/A N/A N/A -0.08 0.10 0.41 -0.09 0.10 0.35
   Change in hospital anxiety, years 10–15 N/A N/A N/A -0.22 0.08 0.006 -0.22 0.08 0.099
   Change in hospital depression, years 10–15 N/A N/A N/A -0.19 0.09 0.033 -0.19 0.09 0.039
   NART at year 10 N/A N/A N/A N/A N/A N/A -0.08 0.08 0.31
HADS, Hospital Anxiety and Depression Scale; NART, National Adult Reading Test (which represents pre-existing cognitive function);  ABI, ankle–brachial index.
Vascular Medicine 15(2)
Johnson W et al. 95
at 0.04 standard deviation per year over the period between
cognitive assessments. Its standard deviation, however, was
only 0.05, indicating that most participants experienced
about the same rate of cognitive decline, again after adjust-
ment for covariates. Consistent with this, there was no sub-
stantial correlation between level of and change in cognitive
function, and none of the change covariates had any signifi-
cant effect on cognitive change.
The columns entitled ‘Excluding only NART’ in Table 2
show results adjusting for HADS scores at first cognitive
assessment as contributors to level of cognitive function and
changes in these scores as contributors to change in cognitive
function. The model fit indicators improved with addition of
these variables (specific details on fit statistics are available
from the first author upon request). The effects of year 10
Anxiety on level of cognitive function and change in Anxiety
on change in cognitive function were particularly significant
(–0.14, p = 0.002; –0.22, p = 0.006, respectively), but
Depression’s effects were also significant. They did not
account for the effect of ABI, however, as its coefficient
remained significant (0.14, p = 0.002). The addition of the
NART, however, reduced this effect to marginal significance
(0.07, p = 0.052). The addition of the NART also reduced the
effects of year 10 Anxiety and Depression on level of cogni-
tive function to non-significance, though they did not sub-
stantially alter the effects of change in Anxiety and change in
Depression on change in cognitive function.
Discussion
In this study, we used a second cognitive assessment from
EAS to refine and extend initial observations4 of the effects
of ABI on cognitive function. In doing so, we considered
the effects of estimated lifetime peak cognitive ability as
measured by the NART, ABI measured earlier in the study,
and anxiety and depression as measured concurrently with
cognitive function by the HADS. Our results indicated
modest but important effects of pre-existing ABI on initial
level of assessed cognitive function. These effects were
diminished but not completely eliminated by consideration
of anxiety and depression. There was also some suggestion
that baseline ABI might be associated with change in cog-
nitive function since peak cognitive function, but there was
no evidence for direct effects of change in ABI on mea-
sured change in cognitive function between years 10 and 15
of the study.
Study limitations
The primary limitations of this study were that the clinical
and cognitive assessments were not optimally timed to pro-
vide maximum power to measure the associations of inter-
est, and the sample that completed cognitive testing was in
better health than the whole sample assessed by the EAS. In
addition, though the NART is generally considered a good
estimate of peak life cognitive function, measured later in
life it cannot completely substitute for a cognitive assess-
ment at some earlier age. ABI measurements did not include
blood pressure measurements in the left arm, which could
be an issue in participants with subclinical subclavian ste-
nosis. Moreover, our measures of smoking habits, anxiety
and depression were based on self reports and thus are sub-
ject to the inaccuracies of long-term recall and bias, and we
made our adjustments for the effects of having smoked but
quit judgementally.
How is ABI associated with cognitive function?
Our results were consistent with previous studies suggest-
ing an association between low ABI and poor cognitive
function.4,8–13,24–26 Price et al.4 proposed that this association
may indicate that ABI is a marker of coming cognitive
decline. The current results, extending the initial findings in
the same sample, provide tentative support for this sugges-
tion, in that baseline ABI was a significant predictor of later
cognitive function even after adjustments for the HADS
scales and, marginally, the NART were considered.
However, they more strongly support the hypothesis that
low ABI and low cognitive function are associated over
very long time spans primarily because low ABI is a good
indicator of poor general vascular health and poor cognitive
function is a weak indicator of poor general health. All
findings should be considered in the context of the 5-year
period between the relevant assessments of ABI and cogni-
tive function, and the fact that anxiety and depression
explained part of the association we observed.
The involvement of anxiety and depression in the
association between ABI and cognitive function is
intriguing from two perspectives. First, changes in anxi-
ety and depression from years 10 to 15 were associated
with changes in cognitive function during the same
period. It is unusual to be able to pick up variables asso-
ciated with rates of change in cognitive function because
in many studies participants appear to decline in function
at very similar rates. This is partly an issue of statistical
power, but it is also an indication that individual differ-
ences in change in cognitive function are much smaller
than individual differences in level of cognitive function
at any age. Thus, simply our ability to detect associations
with changes in anxiety and depression warrants atten-
tion. Second, the involvement of changes in anxiety and
depression speaks to the psychological processes
involved in aging. It is at least as likely that observed
decline in cognitive function brought on increased anxi-
ety and depression as increased anxiety and depression
reduced ABI which in turn impaired cognitive function.
Still, the association suggests the participants’ awareness
of, and emotional responses to, the difficulties encoun-
tered in aging.
ABI is simple to collect. It provides reliable information
about atherosclerotic conditions that are associated with
poor cognitive function. It thus provides a cheap and effec-
tive means of collecting a general indicator of overall cog-
nitive and physical health. Our results add to the growing
evidence that measures of physical health also pick up
information about cognitive health, and suggest that pre-
ventive and therapeutic interventions should be evaluated
for effects on cognitive as well as physical function.
96 Vascular Medicine 15(2)
Acknowledgements
Wendy Johnson holds a RCUK Fellowship. The Edinburgh
Artery Study is supported by the British Heart Foundation.
Wendy Johnson, Jacqueline Price and Ian Deary are members
of the University of Edinburgh Centre for Cognitive Ageing and
Cognitive Epidemiology, which is supported by the BBSRC,
EPSRC, ESRC and MRC as part of the Lifelong Health and Well-
being Initiative.
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Appendix.
Johnson W et al.

Correlations among study variables in cognitively tested subgroup

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

  1. Age at baseline 1.00

  2. Sex -0.02 1.00
  3. Smoking, year 5 -0.02 -0.25 1.00
  4. ABI, year 5 -0.14 -0.17 -0.11 1.00
  5. NART,15 year 10 -0.03 -0.03 -0.05 0.08 1.00
  6. Anxiety, year 10 -0.06 0.24 -0.01 -0.08 -0.15 1.00
  7. Depression, year 10 0.12 0.08 0.10 -0.19 -0.13 0.46 1.00
  8. Logical Memory,16 -0.22 -0.04 -0.02 0.17 0.30 -0.12 -0.13 1.00
year 10
  9. Raven,17 year 10 -0.33 -0.15 -0.04 0.12 0.47 -0.16 -0.14 0.42 1.00
10. Verbal Fluency,18 -0.11 -0.02 -0.03 0.03 0.49 -0.10 -0.14 0.25 0.39 1.00
year 10
11. Digit Symbol,19 -0.40 0.04 -0.12 0.13 0.41 -0.10 -0.21 0.38 0.56 0.45 1.00
year 10
12. Smoking, year 12 0.00 -0.19 0.96 -0.13 -0.08 0.02 0.11 -0.04 -0.09 -0.06 -0.16 1.00
13. ABI, year 12 -0.21 -0.22 -0.13 0.39 0.16 -0.02 -0.10 0.13 0.19 0.08 0.20 -0.16 1.00
14. Anxiety, year 15 -0.04 0.19 0.09 -0.08 -0.21 0.68 0.41 -0.10 -0.21 -0.14 -0.15 0.14 -0.08 1.00
15. Depression, 0.19 0.09 0.07 -0.24 -0.12 0.35 0.65 -0.09 -0.11 -0.12 -0.26 0.10 -0.13 0.43 1.00
year 15
16. Logical Memory,16 -0.18 -0.04 -0.02 0.16 0.29 -0.11 -0.13 0.71 0.39 0.20 0.33 -0.05 0.13 -0.12 -0.14 1.00
year 15
17. Raven,17 year 15 -0.29 -0.17 0.00 0.20 0.46 -0.23 -0.15 0.37 0.77 0.34 0.56 -0.04 0.24 -0.26 -0.19 0.46 1.00
18. Verbal Fluency,18 -0.16 -0.03 0.01 -0.01 0.46 -0.11 -0.11 0.16 0.35 0.82 0.45 -0.02 0.02 -0.15 -0.17 0.22 0.38 1.00
year 15
19. Digit Symbol,19 -0.39 0.06 -0.12 0.15 0.33 -0.11 -0.20 0.30 0.54 0.39 0.85 -0.14 0.19 -0.20 -0.29 0.37 0.65 0.45 1.00
year 15
ABI, ankle–brachial index; NART, National Adult Reading Test.
Depending on the number of participants in each cell, correlations greater than about 0.08 were significant at p < 0.05, with no correction for multiple testing.
The ‘Anxiety’ and ‘Depression’ scores come from the HADS.
The column numbers refer to the variables numbered in the rows.
Correlations referred to in the text are shown in bold.
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