Serum Uric Acid Is Associated with Cerebral White Matter

Hyperintensities in Patients with Acute Lacunar Infarction

Sang Won Han, Tae Jin Song, Cheryl D. Bushnell, Sung-Soo Lee, Seo Hyun Kim, Jun Hong Lee, Gyu Sik Kim,
Ok-Joon Kim, Im-Seok Koh, Jong Yun Lee, Seung-Han Suk, Sung Ik Lee, Hyo Suk Nam, Kyung-Yul Lee,
Jae Hyeon Park
From the Department of Neurology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea (SWH, JHP); Department of Neurology, Ewha Womans University
School of Medicine, Seoul, Korea (TJS); Department of Neurology, Wake Forest School of Medicine, Winston-Salem, NC (CDB); Department of Neurology, Yonsei University
Wonju College of Medicine, Wonju, Korea (SL, SHK); Department of Neurology, National Health Insurance Corporation Ilsan Hospital, Ilsan, Korea (JHL, GSK); Department of
Neurology, CHA University College of Medicine, Bundang, Korea (OK); Department of Neurology, National Medical Center, Seoul, Korea (IK, JYL); Department of Neurology,
Sanbon Hospital, Wonkwang University College of Medicine, Sanbon, Korea (SS, SIL); and Department of Neurology, Yonsei University College of Medicine, Seoul, Korea
(HSN, KL).

ABSTRACT
BACKGROUND AND PURPOSE: The Effect of Cilostazol in Acute Lacunar Infarction Based on Pulsatility Index of Transcranial
Doppler (ECLIPse) study showed a significant decrease in transcranial Doppler pulsatility index (PI) with cilostazol treatment
after 90 days of acute lacunar infarction. The aim of this analysis was to perform a subgroup analysis of the ECLIPse study to
explore the relationship between serum uric acid (UA) and the volume of white matter hyperintensities (WMH) in patients with
acute lacunar infarction.
METHODS: The ECLIPse was a multicenter, randomized, double-blind, placebo-controlled study conducted in Korea. For this
subgroup analysis, WMH volume was measured for those subjects for whom FLAIR or T2-weighted images were available using
semiautomated computerized software.
RESULTS: Of the 203 patients in 8 hospitals in the ECLIPse study, 130 in 6 hospitals were entered for this subgroup analysis.
The mean age was 64.7 ± 9.95 years, and 20.8% were women. The mean WMH volume was 11.57 cm3 (.13 to 68.45, median 4.86)
and mean serum UA was 5.2 mg/dL (1.5 to 8.9). Multiple linear regression analysis revealed that age (P < .001) and serum UA
(P = .013) were significantly associated with WMH volume. Age-adjusted scatterplots showed that serum UA level was positively
related to WMH volume in patients with acute lacunar infarction (r = 0.275, P = .003).
CONCLUSIONS: This study showed that serum UA was associated with cerebral WMH in patients with acute lacunar infarction.

Keywords: Lacunar infarcts, uric acid, white matter hyperintensities.

Acceptance: Received July 14, 2015, and in revised form August 17, 2015. Accepted for publication September 1, 2015.

Correspondence: Address correspondence to Kyung-Yul Lee, Department of Neurology, Gangnam Severance Hospital, Yonsei University College of
Medicine, 211 Eonjuro, Gangnam-gu, 135-720, Seoul, Korea. E-mail: kylee@yuhs.ac.
Conflicts of interest: None.

J Neuroimaging 2016;26:351-354.
DOI: 10.1111/jon.12308

Introduction hemodynamics and WMH.6 WMH is closely related with

The Effect of Cilostazol in Acute Lacunar Infarction Based on
Pulsatility Index of Transcranial Doppler (ECLIPse) study was
a multicenter, randomized, double-blind, placebo-controlled
trial that evaluated the difference between the propensities of
cilostazol and placebo to reduce the pulsatility index (PI) in pa-
tients with acute lacunar infarction using the serial transcranial
Doppler (TCD) examinations. The main finding of the ECLIPse
study was that cilostazol further decreased TCD PIs at 90 days
compared to placebo in patients with acute lacunar infarction.1
White matter hyperintensities (WMH) characterized by bi-
lateral, mostly symmetrical hyperintensities on T2-weighted
MRI are common in older individuals. These lesions are en-
titled as leukoaraiosis, white matter lesions, leukoencephalopa-
thy, and white matter disease.2,3 WMH are more common
and more extensive in patients with acute lacunar infarction
than in patients with other stroke subtypes, and they are as-
sociated with lacunes, perivascular spaces, cerebral microb-
leeds, and brain atrophy.3–5 A number of studies have shown
a strong relationship between impairments in cerebrovascular
cerebral arterial pulsatility, which is strongly dependent on
large artery stiffness. Arterial stiffening results in increased
aortic pulsatility and its transmission to the cerebral circula-
tion plays a pathophysiological role in the development of
WMH.7
Uric acid (UA) is the end product of the metabolism of
purine nucleotides. Serum UA had been linked to oxidative
stress and atherosclerosis, which were regarded as the contribu-
tors to the development of brain ischemic change.8 Several stud-
ies reported the association between hyperuricemia with other
cardiovascular risk factors such as hypertension, diabetes mel-
litus, systemic inflammation, and lipid abnormalities.9 Recent
data also suggest that serum UA is positively associated with
increased cerebral ischemia as indexed by WMH volume.9–11
Even mildly elevated serum UA is associated with increased
WMH volume, particularly in older adults.10 However, there
is limited information on the relationship between serum UA
and cerebral WMH in acute lacunar infarction. The aim of this
analysis was to perform a subgroup analysis of ECLIPse study

Copyright ◦ 2015 by the American Society of Neuroimaging

C 351
Table 1. Baseline Characteristics of Enrolled Patients.

N = 130 Men (n = 103) Women (n = 27) P-Value

Age, years 64.7 ± 9.95 64.06 ± 10.42 67.33 ± 7.51 .128

BMI, kg/m2 24.3 ± 3.06 24.3 ± 3.02 23.8 ± 3.21 .366
Waist circumference, cm 87.3 ± 8.48 87.9 ± 8.10 85.0 ± 9.51 .152
Hypertension, n 71 (54.6) 59 (57.3) 12 (44.4) .233
Diabetes mellitus, n 41 (31.5) 31 (30.1) 10 (37.0) .490
Hypercholesterolemia, n 17 (13.1) 13 (12.6) 4 (14.8) .763
Coronary artery disease, n 0 (0) 0 (0) 0 (0)
Current smoking, n 43 (33.1) 43 (41.7) 0 (0)
Systolic blood pressure, mmHg 137.9 ± 19.27 139.2 ± 20.46 133.1 ± 13.00 .147
Diastolic blood pressure, mmHg 83.8 ± 10.16 84.5 ± 10.86 81.1 ± 6.41) .128
Fasting glucose, mg/dL 121.4 ± 43.06 122.3 ± 40.24 118.4 ± 53.21 .689
Total cholesterol, mg/dL 185.1 ± 33.59 183.1 ± 33.65 192.4 ± 32.97 .201
LDL-cholesterol, mg/dL 117.9 ± 28.42 116.8 ± 29.11 122.0 ± 25.75 .399
HDL-cholesterol, mg/dL 43.5 ± 9.45 42.7 ± 8.94 46.7 ± 10.77 .045*
Triglyceride, mg/dL 157.9 ± 93.35 162.0 ± 88.73 142.7 ± 109.74 .340
Plasma fibrinogen, mg/dL 306.2 ± 84.81 306.1 ± 72.64 306.7 ± 57.23 .971
Serum uric acid, mg/dL 5.2 ± 1.43 5.3 ± 1.40 4.8 ± 1.52 .131
Serum BUN, mg/dL 15.0 ± 4.50 15.2 ± 4.71 14.4 ± 3.57 .396
Serum creatine, mg/dL .97 ± 0.23 1.01 ± 0.22 .84 ± 0.19 <.001*
WMH volume, cm3 11.73 ± 15.69 12.3 ± 16.27 8.8 ± 14.41 .319

BMI = body mass index; LDL = low-density lipoprotein; HDL = high-density lipoprotein; BUN = blood urea nitrogen; WMH = white matter hyperintensities. Data
are mean ± SD or numbers (%). Significant P is marked with* .

to explore the relationship between serum UA and cerebral
WMH volume in patients with acute lacunar infarction.
Materials and Methods
Patient Selection
The design and results of the ECLIPse study have been
published.1 In brief, the study was a multicenter, randomized,
double-blind, placebo-controlled study conducted at multiple
trial sites in Korea. The primary outcomes were changes in the
middle cerebral artery and basilar artery PIs at 14 and 90 days
from the baseline TCD study. Patients were eligible for the trial
if they experienced their first lacunar infarction within the pre-
ceding 7 days and were 45 years of age or older. Patients with
chronic liver disease (aspartate aminotransferase >100 IU/L or
alanine aminotransferase >100 IU/L) or chronic renal disease
(creatinine >3.0 mg/dL) were excluded during the screening
period for study enrollment.1 Between November 2006 and
October 2008, 203 patients were consecutively enrolled from
8 tertiary-care hospitals. All patients were given 100 mg as-
pirin once a day during the 90-day trial. In addition, patients
were randomly assigned to receive either placebo or 100 mg
cilostazol twice a day. The systemic investigations performed in
every patient included 12-lead EKG, lipid profiles, and standard
blood and urine tests. The patients’ demographics, vascular risk
factors, biomarkers, and neurologic examination were collected
at baseline.
Patients with brain MRI scans, performed on a 1.5-T scan-
ner with axial T1-weighed, T2-weighed, and fluid-attenuated
inversion recovery images, were selected for this subgroup
analysis. WMH volumes were measured in patients for
whom 2-dimensional fluid attenuated inversion recovery or
T2-weighted images were available by using semiautomated
computerized software (Xelis, Infinitt, Korea). A single trained
neurologist (T.J.S.) blinded to study group measured the WMH
volume. WMH volume was checked twice, and the mean
value was entered for statistical analysis. Intraclass correlation
was excellent (.93; 95% confidence interval, .83-.97).
All patients provided written informed consent. The study
protocol was approved by institutional review boards of each
of the participating hospitals.
Statistical Analysis
Categorical data were examined by χ 2 statistics. The Mann-
Whitney U test was used to compare the non-normally dis-
tributed data, and Student’s t-test was used to compare normally
distributed data. Univariate relationships between continuous
variables were assessed by linear regression. Multivariate lin-
ear regression models were used to analyze the association of
significant univariate variables. Two-sided null hypotheses of
no difference were rejected if P-values were less than .05. SPSS
version 20.0 for Windows was used for statistical analysis.
Results
Of the 203 patients in 8 hospitals in the ECLIPse study, 130 in
6 hospitals were entered for this subgroup analysis. Cilostazol
was given to 63 patients (48.5%) and placebo to 67 patients
(51.5%). There were no patients with history of gout or taking
an antihyperuricemic medication. The mean age was 64.7 ±
9.95 years, and 20.8% were women. Of these, 54.6% had a his-
tory of hypertension, 31.5% of diabetes, 13.1% of dyslipidemia,
and 33.1% of current smoking. The mean WMH volume was
11.57 cm3 (.13 to 68.45, median 4.86) and mean serum UA
was 5.2 mg/dL (1.5 to 8.9; Table 1). Serum UA concentrations
ranged from 2.7 to 7.5 mg/dL for women and 1.5 to 8.9 mg/dL
for men. There were no significant differences in these base-
line characteristics except current smoking status, serum cre-
atine, and high-density lipoprotein cholesterol levels between
men and women (Table 1). Serum UA was positively corre-
lated with WMH volume (r = .243, P = .009), body mass index
(r = .243, P = .011), waist circumference (r = .242, P = .024),

352 Journal of Neuroimaging Vol 26 No 3 May/June 2016

Table 2. Univariate Linear Regression Analyses of the Baseline Char- Table 3. Multiple Linear Regression Analysis to Predict WMH
acteristics According to WMH Volume. Volume from Demographic, Vascular Risk Factors, and
Biomarkers.
WMH Volume
B (SE) Standardized β P-Value
B (SE) Standardized β P-Value
Age .588 (0.147) .356 <.001*
Demographics Uric acid 2.557 (1.013) .223 .013*
Age .621 (0.130) .388 <.001* Fibrinogen .035 (0.021) .146 .102
BMI −.805 (0.444) −.163 .072 Hypertension 3.362 (2.898) .103 .249
Waist circumference .022 (0.194) .011 .911
Systolic blood pressure .084 (0.073) .101 .252 WMH = white matter hyperintensities; SE = standard error. Significant P is
Diastolic blood pressure .003 (0.138) .138 .985 marked with* .
Vascular risk factors
Hypertension 5.140 (2.777) .161 .067
Diabetes mellitus .657 (3.014) .019 .828 matory responses and UA, white blood cells, and C-reactive
Hypercholesterolemia 2.385 (4.150) .051 .567 protein is significantly related with subclinical atherosclerosis.15
Current smoking −1.496 (1.536) −.086 .332 In addition, serum UA causes arteriolar disease and impairs the
Laboratory findings autoregulatory response. Impaired autoregulatory response of
Total cholesterol .008 (0.042) .018 .842 the cerebral arterioles is strongly associated with increased risk
LDL-cholesterol .008 (0.050) .015 .869
for cerebral small vessel disease (SVD).16,17 Impaired vascular
HDL-cholesterol .082 (0.149) .049 .582
Triglyceride −.006 (0.015) −.034 .702
tone, oxidative stress, endothelial dysfunction, and systemic in-
Fasting glucose −.038 (0.032) −.109 .239 flammation may contribute to ischemic changes because they
Plasma fibrinogen .044 (0.022) .191 .045* permit cerebrospinal fluid to cross the blood-brain barrier and
Serum uric acid 2.781 (1.045) .243 .009* cause areas of edema, identified as WMH.3,4
Serum BUN .009 (0.313) .002 .978 One recent study showed that allopurinol treatment im-
Serum creatine 10.234 (6.180) .145 .100 proved the 3-month functional status of acute ischemic stroke
WMH = white matter hyperintensities; BMI = body mass index; LDL = low-
patients who had high levels of serum UA without consid-
density lipoprotein; HDL = high-density lipoprotein. ering the decreased effect of allopurinol on serum UA.18 A
Significant P is marked with* . low serum UA is modestly associated with a very good short-
term outcome as well.19 Though descriptive studies show that
higher concentrations of serum UA are beneficial in patients
serum blood urea nitrogen (r = .202, P = .03), and serum crea-
with acute stroke and are associated with better outcome af-
tine (r = .266, P = .004).
ter thrombolytic treatment,20,21 recent study reveals that the
Table 2 shows the univariate linear regression analyses of
addition of UA to thrombolytic therapy did not increase the
the baseline characteristics according to WMH volume. WMH
proportion of patients who achieved excellent outcome after
volume was significantly related with age (P < .001), plasma
stroke compared with placebo.22,23 More studies may be needed
fibrinogen (P = .045), and serum UA (P = .009; Table 2). Old
to define the role of UA in the pathogenesis of stroke and
age and increased plasma fibrinogen and serum UA levels were
WMH.
significantly associated with increased WMH volume. Multiple
linear regression analysis revealed that age (P < .001) and serum
UA (P = .013) were significantly associated with WMH volume
(Table 3). Figure 1 showed the age-adjusted scatterplots of the
relationship between serum UA and WMH volume. Serum UA
level was positively related to WMH volume in patients with
acute lacunar infarction (r = .275, P = .003).

Discussion
In this study, we explored the relationship between serum UA
and WMH volume in patients with acute lacunar infarction.
Our study showed that WMH volume was positively associated
with age and serum UA in patients with acute lacunar infarction.
Serum UA is one of the most important endogenous antiox-
idants products to scavenge free radicals in the human brain.
The capacity of UA accounts for more than one-half of the
free radical scavenging capacity in serum. However, there have
been significant questions whether UA is neuroprotective as an
antioxidant or neurotoxic as a pro-oxidant.8–10 When serum UA
levels are elevated to ࣙ4 mg/dL, this former antioxidant may
become a pro-oxidant.12 Serum UA may have harmful effects
Fig 1. Age-adjusted scatterplots of the relationship between serum
on platelet function and cause endothelial dysfunction.13,14 Ev- UA and WMH volume. r = Pearson’s partial correlation coefficient.
idence from clinical and experimental studies has also shown X-axes are based on calculated residuals from regressing serum UA
that serum UA is significantly correlated with inflammatory on age. Y-axes are based on calculated residuals from regressing
markers.15 Lower serum UA is associated with systemic inflam- WMH volume on age.

Han et al: Uric Acid and White Matter Hyperintensities 353

 While there was no significant relationship between plasma
fibrinogen and WMH volume in this study, a trend toward
higher plasma fibrinogen level was observed in increased
WMH volume (P = .102). Previous studies have demonstrated
that plasma fibrinogen levels are elevated in patients with
WMH.11,24 Fibrinogen influences hemorheology in the micro-
circulation, a mechanism proposed to explain the pathophys-
iology of WMH.24 Though WMH are strongly associated with
cerebrovascular disease and vascular risk factors, the pathogen-
esis of WMH is not well understood and could be multifactorial.
The strengths of this study were quantitative measurement
for WMH volume and the collection of many types of clinical
data and relevant biomarkers. Our study had limitations. First,
in the ECLIPse study, only Korean patients with acute first-
ever lacunar infarction and 45 years of age or older were en-
rolled for the study, limiting the generalizability to other stroke
types and geographic regions. Second, the sample size for this
subgroup analysis was small and was not determined a priori.
Third, serum UA levels fluctuate considerably even in nor-
mal individuals and are affected by very many factors, includ-
ing diet, hydration, alcoholism, diabetic control, level of exer-
cise, and nasogastric feeding over 7 days. Though the baseline
National Institutes of Health Stroke Scale (NIHSS) score was
2.4 ± 1.7 and the median time from symptom onset to ran-
domization was 5 days in our study, these confounders may
influence study outcome. These limitations should be consid-
ered when interpreting our data.
In conclusion, this study showed that serum UA was
associated with cerebral WMH in patients with acute lacunar
infarction. Prevention of WMH progression by treating the
underlying causes may reduce the risk of stroke, dementia, and
other consequences of SVD. Further clinical trials are required
to establish whether the treatment aimed at reducing the serum
UA would decrease the incidence of ischemic stroke and
WMH.
This work was supported by the Inje Research and Scholarship Foun-
dation in 2013.
References
1. Han SW, Lee SS, Kim SH, et al. Effect of cilostazol in acute lacu-
nar infarction based on pulsatility index of transcranial Doppler
(ECLIPse): a multicenter, randomized, double-blind, placebo-
controlled trial. Eur Neurol 2012;69:33-40.
2. Hopkins RO, Beck CJ, Burnett DL, et al. Prevalence of white matter
hyperintensities in a young healthy population. J Neuroimaging
2006;16:243-51.
3. Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cere-
bral small vessel disease: insights from neuroimaging. Lancet Neu-
rol 2013;12:483-97.
4. Pantoni L. Cerebral small vessel disease: from pathogenesis and
clinical characteristics to therapeutic challenges. Lancet Neurol
2010;9:689-701.
354 Journal of Neuroimaging Vol 26 No 3 May/June 2016
5. Jouvent E, Viswanathan A, Chabriat H. Cerebral atrophy in cere-
brovascular disorders. J Neuroimaging 2010;20:213-8.
6. Purkayastha S, Fadar O, Mehregan A, et al. Impaired cerebrovascu-
lar hemodynamics are associated with cerebral white matter dam-
age. J Cereb Blood Flow Metab 2014;34:228-34.
7. Webb AJ, Simoni M, Mazzucco S, et al. Increased cerebral arterial
pulsatility in patients with leukoaraiosis: arterial stiffness enhances
transmission of aortic pulsatility. Stroke 2012;43:2631-6.
8. Warner DS, Sheng H, Batinic-Haberle I. Oxidants, antioxidants
and the ischemic brain. J Exp Biol 2004;207:3221-31.
9. Shih CY, Chen CY, Wen CJ, et al. Relationship between serum
uric acid and cerebral white matter lesions in the elderly. Nutr
Metab Cardiovasc Dis 2012;22:154-9.
10. Schretlen DJ, Inscore AB, Vannorsdall TD, et al. Serum uric
acid and brain ischemia in normal elderly adults. Neurology
2007;69:1418-23.
11. Tsuda Y, Satoh K, Kitadai M, et al. Hemorheologic profiles of
plasma fibrinogen and blood viscosity from silent to acute and
chronic cerebral infarctions. J Neurol Sci 1997;147:49-54.
12. Hayden MR, Tyagi SC. Uric acid: a new look at an old risk
marker for cardiovascular disease, metabolic syndrome, and type
2 diabetes mellitus: the urate redox shuttle. Nutr Metab (Lond)
2004;1:10.
13. Gustafsson D, Unwin R. The pathophysiology of hyperuricaemia
and its possible relationship to cardiovascular disease, morbidity
and mortality. BMC Nephrol 2013;14:164.
14. Storhaug HM, Norvik JV, Toft I, et al. Uric acid is a risk factor for
ischemic stroke and all-cause mortality in the general population: a
gender specific analysis from the Tromso Study. BMC Cardiovasc
Disord 2013;13:115.
15. Zhu A, Zou T, Xiong G, et al. Association of uric acid with tradi-
tional inflammatory factors in stroke. Int J Neurosci 2015;126:335-
41.
16. Kanbay M, Segal M, Afsar B, et al. The role of uric acid in the
pathogenesis of human cardiovascular disease. Heart 2013;99:759-
66.
17. Toyoda K. Cerebral small vessel disease and chronic kidney dis-
ease. J Stroke 2015;17:31-7.
18. Taheraghdam AA, Sharifipour E, Pashapour A, et al. Allopurinol
as a preventive contrivance after acute ischemic stroke in patients
with a high level of serum uric acid: a randomized, controlled trial.
Med Princ Pract 2014;23:134-9.
19. Chiquete E, Ruiz-Sandoval JL, Murillo-Bonilla LM, et al. Serum
uric acid and outcome after acute ischemic stroke: PREMIER
study. Cerebrovasc Dis 2013;35:168-74.
20. Chamorro A, Obach V, Cervera A, et al. Prognostic significance
of uric acid serum concentration in patients with acute ischemic
stroke. Stroke 2002;33:1048-52.
21. Amaro S, Urra X, Gomez-Choco M, et al. Uric acid levels are
relevant in patients with stroke treated with thrombolysis. Stroke
2011;42:S28-32.
22. Chamorro A, Amaro S, Castellanos M, et al. Safety and effi-
cacy of uric acid in patients with acute stroke (URICO-ICTUS):
a randomised, double-blind phase 2b/3 trial. Lancet Neurol
2014;13:453-60.
23. Campbell BC, Davis SM, Donnan GA. Uric acid for stroke: glim-
mer of hope or false dawn? Lancet Neurol 2014;13:440-1.
24. Marti-Fabregas J, Valencia C, Pujol J, et al. Fibrinogen and the
amount of leukoaraiosis in patients with symptomatic small-vessel
disease. Eur Neurol 2002;48:185-90.