Research Letters

Cerebral Ischemia Mediates the Effect of Serum Uric Acid

on Cognitive Function
Tracy D. Vannorsdall, PhD; H.A. Jinnah, MD, PhD; Barry Gordon, MD, PhD;
Michael Kraut, MD, PhD; David J. Schretlen, PhD
Background and PurposeHigh normal concentrations of serum uric acid (UA) are associated with mild cognitive
dysfunction and increased cerebral ischemia as indexed by white matter hyperintensity volumes. We hypothesized that
individual differences in white matter hyperintensities mediate the association between UA and mild cognitive
dysfunction.
MethodsOne hundred eighty community-dwelling adults aged 20 to 96 years completed neuropsychological testing,
laboratory blood studies, and a brain MRI scan.
ResultsSerum UA was associated (P0.05) with greater white matter hyperintensities and poorer working memory,
processing speed, fluency, and verbal memory. Associations remained after controlling for age, sex, race, education,
hypertension, diabetes, alcohol abuse, smoking, and body mass. Adding a term for white matter hyperintensity
attenuated these associations such that UA no longer predicted cognitive performance.
ConclusionsSeverity of cerebral ischemia might mediate the association between UA and cognitive dysfunction. Even
mild elevations in UA appear to contribute to structural and functional brain changes. (Stroke. 2008;39:3418-3420.)
Key Words: brain ischemia neuropsychology uric acid cognitive impairment white matter disease aging

erebral white matter hyperintensities (WMH) frequently

represent cerebral ischemia and are associated with
cerebrovascular risk factors and mild cognitive dysfunction.1
Although serum uric acid (UA) is an antioxidant and might
have neuroprotective properties, elevated UA also accompanies conditions that increase the risk of cognitive dysfunction.2 We recently found that older adults with high normal
concentrations of serum UA are 2.7 to 5.9 times more likely
to score in the bottom quartile on measures of processing
speed, verbal memory, and working memory.3 We also found
that adults with high normal serum UA levels are 2.8 times
more likely to show greater than average WMH burden.4
We assessed whether cerebral ischemic burden mediates
the association between serum UA and mild cognitive
dysfunction.

Materials and Methods

Participants
Participants (n301) were drawn from a community sample of
adults recruited for a study of normal aging. Subjects provided
written informed consent and the study was approved by the Johns
Hopkins Medicine Institutional Review Board. We excluded 121
who did not complete or produce useable MRI or blood laboratory
results, were taking antihyperuricemic medication, or did not com-

plete cognitive testing. Table 1 presents demographic characteristics

of the final sample (n180).

Procedure
Participants completed the evaluation on a single day. MRI parameters and WMH assessment methods are described elsewhere.4
Blinded to participant characteristics and using a region-of-interest
approach, all observable WMH were manually traced.4 WMH
volumes were calculated and are expressed as the proportion of
WMH to total brain volume. Serum UA was measured from a
nonfasting blood sample with an Olympus chemistry analyzer
(Olympus America, Melville, NY). Participants completed an
extensive neuropsychological test battery yielding 28 cognitive
test scores (see supplemental data, available online at
http://stroke.ahajournals.org).

Statistical Analysis
Each test score was z-transformed and assigned to one of 8 cognitive
domains (see Table 2). Coefficients alpha ranged from 0.76 to 0.93.
Pearson correlations explored zero-order relationships among WMH
burden, serum UA, and cognition.
To test for mediation, we conducted 2 series of hierarchical
multiple regressions using the 4 cognitive factors that correlated with
both serum UA and WMH. In both series, we regressed each
cognitive domain score on demographic and health variables (age,
sex, race, education, hypertension, diabetes, history of alcohol
abuse/dependence, tobacco use, and body mass index) en bloc at
Step 1. We then added terms for serum UA and total WMH volume

Received March 27, 2008; accepted April 11, 2008.

From the Department of Psychiatry and Behavioral Sciences (T.D.V., D.J.S.), the Russell H. Morgan Department of Radiology and Radiological
Sciences (M.K., D.J.S.), and the Department of Neurology (H.A..J., B.G.), Johns Hopkins University School of Medicine, Baltimore, Md; and the
Cognitive Science Department (B.G.), Johns Hopkins University, Baltimore, Md.
Correspondence to David J. Schretlen, PhD, Johns Hopkins Hospital, 600 N Wolfe Street, Meyer 218, Baltimore, MD 21287-7218. E-mail
dschret@jhmi.edu
2008 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org

DOI: 10.1161/STROKEAHA.108.521591

3418
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Vannorsdall et al
Table 1.

Demographic and Clinical Characteristics

MeanSD or n (%)

Age, years

59.918.9

Education, years

13.53.5

Female sex

94 (52.2)

White race

144 (80.0)

Hypertension

61 (33.9)

Diabetes mellitus

24 (13.3)

Current smoker

44 (24.4)

Alcohol abuse/dependence

13 (7.2)

Body mass index

27.25.1

Serum UA, mg/dL

4.51.4

Total WMH, % of TBV

Ischemia, Uric Acid, and Cognition

3419

Table 3. Hierarchical Multiple Regression Analyses

Demonstrating That WMH Volume Mediates the Association
Between Serum UA and Cognitive Functioning
R 2
Working
Memory

Processing
Speed

Ideational
Fluency

Verbal
Memory

Step 1 demographics and

health

0.39

0.60

0.37

0.32

Step 2 serum UA

0.03

0.01

0.02*

0.03*

Step 3 WMH volume

0.03

0.02

0.04

0.01

0.39

0.60

0.37

0.32

Model 1

Model 2

0.00230.0057

TBV indicates total brain volume.

in Steps 2 and 3, varying their order of entry across models to test for
mediation.

Step 1 demographics and

health
Step 2 WMH volume

0.05

0.03

0.05

0.02*

Step 3 serum UA

0.01

0.00

0.00

0.01

*P0.05.
P0.01.
P0.05.

Results
As seen in Table 2, higher serum UA correlated with
increased WMH volume and worse performance on tests of
working memory, processing speed, fluency, and verbal
memory. WMH volume correlated inversely with performance in 7 of 8 cognitive domains.
Table 3 (Model 1) shows that, after adjusting for demographic and health variables (Step 1), higher serum UA
concentrations accounted for additional variance in performance on tests of working memory, fluency, and verbal
learning/memory. Beta weights for serum UA at Step 2 were
0.20, 0.17, and 0.21 (all Ps0.05), respectively, for
these 3 models. UAs association with processing speed
failed to reach statistical significance (0.12, P0.053).
Thereafter, adding a term for WMH volume (Step 3) improved the models for working memory, processing speed,
and ideational fluency, but not verbal learning/memory, and
attenuated the initial beta weights for serum UA to nonsignificant levels (all Ps0.05).
Table 2. Pearson Correlations Among Cognitive Domains,
Serum UA, and WMH Volume
Serum UA
Serum UA

0.232

0.002

Working memory

0.245

0.001

WMH volume*

In Model 2, after adjusting for demographic and health

variables (Step 1), adding a term for WMH volume (Step
2) explained additional variance in test performance in all
4 cognitive domains (s0.17 to 0.25, Ps0.05). In
these analyses, however, adding a term for serum UA (Step
3) did not improve the statistical models for any cognitive
factor. Nor did it significantly reduce the beta weights
obtained for WMH at Step 2 for working memory, processing speed, or ideational fluency (s0.18 to 0.23;
all Ps0.01).
In sum, both higher UA levels and greater WMH burden
were associated with worse performance on tests of working memory, processing speed, ideational fluency, and
verbal memory even after controlling for health and
demographic variables. However, WMH burden appears to
mediate the relationships between UA and performance on
tests of working memory, processing speed, and ideational
fluency, whereas UA does not appear to mediate the
relationships between WMH burden and cognitive performance. There is no mediation apparent with respect to
verbal learning/memory, UA, and WMH.

Discussion

0.367

0.001

These findings suggest that severity of cerebral ischemia

mediates the previously reported association between serum UA and mild cognitive dysfunction. This effect was
present even after controlling for health conditions that are
known to be associated with both cerebral ischemia and
elevated UA. Furthermore, the observed associations were
present in relation to performance on tests of working
memory, processing speed, and ideational fluency. These
processes are particularly sensitive to cerebral ischemic
burden both in healthy adults and those with various
illnesses.1
Even mild elevations of serum UA are associated with
cerebral ischemia.4 Impaired vascular tone and endothelial
dysfunction likely contribute to the development of some

WMH Volume

Processing speed

0.118

0.011

0.409

0.001

Ideational fluency

0.204

0.006

0.353

0.001

Crystallized intelligence

0.060

0.427

0.073

0.333

Fluid intelligence

0.128

0.087

0.348

0.001

Verbal learning/memory

0.257

0.001

0.307

0.001

Visual learning/memory

0.118

0.115

0.367

0.001

Executive functioning

0.047

0.533

0.190

0.011

*WMH expressed as percentage of total brain volume.

See supplementary online material for details regarding the cognitive test
battery.

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3420

Stroke

December 2008

ischemic changes, because they permit cerebrospinal fluid to

cross the blood brain barrier and allow interstitial water to
accumulate, resulting in areas of edema identified as WMH
on brain MRI.5 The association of UA with nitric oxide
represents one possible pathway by which mildly elevated
UA could contribute to cerebral ischemia. Nitric oxide is a
potent vasodilator that mediates vascular tone in the
endothelium, fluctuates inversely with UA in healthy
adults,6 and is inhibited by UA in those with cerebrovascular risk factors.7,8 Decreased endothelial-dependent vasodilation, as assessed by brachial flow-mediated dilation
(a noninvasive measure of endothelium-derived nitric oxide activity), is associated with both mild hyperuremia9
and increased WMH.10 These findings support the idea that
mechanisms contributing to impaired endothelial functioning and vascular tone play a role in the development of
cerebral ischemic burden. It also appears plausible that
increased UA could reduce nitric oxide availability in the
brain, contributing to endothelial dysfunction and the
subsequent development of WMH. However, this potential
mechanism is speculative, and many other factors affect
cerebrovascular tone and endothelial integrity. There are
also other potential means by which UA could contribute
to endothelial dysfunction such as through the acquisition
of pro-oxidant properties.11
Extending these cross-sectional findings with longitudinal
studies would be helpful to determine whether elevated UA
increases the risk or rate of cognitive decline in elderly adults.
A clinical trial may also be useful in determining whether the
administration of medications aimed at reducing the production of serum UA would reduce the incidence of ischemic
brain disease and associated cognitive dysfunction.

Acknowledgments
We thank Susan Stern for her contribution to the study and the
measurement of WMH.

Sources of Funding
Financial support for this research was provided by National Institutes of Health/National Institute of Mental Health Grant MH60504,

the Therapeutic Cognitive Neuroscience Fund, and the Benjamin &

Adith Miller Family Endowment on Aging, Alzheimers and Autism
Research.

Disclosures
D.J.S. receives royalties from the sale of the Brief Test of Attention.

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Cerebral Ischemia Mediates the Effect of Serum Uric Acid on Cognitive Function
Tracy D. Vannorsdall, H.A. Jinnah, Barry Gordon, Michael Kraut and David J. Schretlen
Stroke. 2008;39:3418-3420; originally published online September 4, 2008;
doi: 10.1161/STROKEAHA.108.521591
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2008 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

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