Associations Between Biomarkers of Renal Function With Cerebral Microbleeds in Hypertensive Patients
American Journal of Hypertension
Associations Between Biomarkers of Renal Function With Cerebral Microbleeds in Hypertensive Patients
Jin-biao Zhang 1
Li-feng Liu 0
Zhen-guang Li 1
Hai-rong Sun 1
Xiao-hua Jü 1
0 Department of Neurology, Liaocheng People's Hospital and Liaocheng Clinical School of Taishan Medical University , Liaocheng , PR China
1 Department of Neurology, Weihai Municipal Hospital, The Affiliated Hospital of Binzhou Medical College , Weihai , PR China
BACKGROUND Cerebral microbleeds (CMBs) have been observed in the elderly and have been regarded as a manifestation of small vessel disease (SVD). Cerebral and glomerular SVD may have a common source of pathogenesis because these organs are closely connected through anatomic and hemodynamic similarities. The purpose of this study was to clarify the associations between kidney biomarker levels and CMBs in hypertensive patients.
blood pressure; cerebral microbleeds; chronic kidney disease; cystatin C; hypertension; small vessel disease
UACR and CysC levels were higher in the patients with CMBs than those
without, and the eGFR was lower in the patients with CMBs than those
Cerebral microbleeds (CMBs) are focal accumulations of
hemosiderin-containing macrophages in the perivascular
space of small blood vessels in the brain that indicate prev-i
ous extravasation of blood1. CMBs may be located in
various regions of the brain and persist indefinitely after initial
detection, and they are commonly observed not only in
patients with ischemic and hemorrhagic stroke but also in
normal elderly individuals. More importantly, CMBs may
predict future risk of stroke, especially hemorrhagic stroke
under antithrombotic therapy.2
Cerebral and glomerular small vessel disease (SVD) may
have a common pathogenesis source because these organs
are closely connected by anatomic and hemodynamic
similarities.3 Chronic kidney disease is emerging as an
independent risk factor for not only cardiovascular events but also
for stroke and cerebral SVDs, such as silent lacunar infarcts
(SLIs) and white matter lesions.4–6 Chronic kidney disease is
commonly defined by a reduction in the glomerular filtration
rate (GFR) or the presence of proteinuria. Recent studies have
indicated that low GFR levels and the presence of proteinuria
are associated with the presence of CMBs in TIA or stroke7.,8
Cystatin C (CysC) has been studied as an endogenous marker
Kidney biomarker levels are associated with the presence of CMB in
hypertensive patients without a history of transient ischemic attack
(TIA) or stroke, independent of conventional risk factors, and CysC was
a better marker for CMBs than eGFR and UACR.
Subjects were prospectively enrolled from consecutive
hypertensive outpatients aged ≥50 years who visited the
Department of Neurology at Weihai Municipal Hospital, an
affiliate of Binzhou Medical College, with neurological
complaints (i.e., headache or dizziness, vertigo, numbness,
syncope, or subjective memory impairment) between June 2011
and June 2013. Hypertension was defined as≥140/90 mm
Hg at three different times or the use of antihypertensive
medications. Carotid intima-media thickness was
measured to reflect the severity of atherosclerosis, and magnetic
resonance (MR) imaging was performed to evaluate susp-i
cious neurological symptoms. When neither neurological
symptoms nor a history of stroke or TIA were identified, the
patient was considered eligible for the study.
During the study period, 964 patients were identified as
candidates (Figure 1). We then excluded 51 patients whose
MR imaging examinations were not completed. Patients
with a history of stroke or TIA (n = 298), severe dementia
(n = 11), or brain surgery (n = 5) and those receiving
hemodialysis (n = 6) were excluded to eliminate any effects of
clinically evident diseases on CMBs. Patients with infective and
inflammatory disorders (n = 7), serious heart diseases (such
as recent acute coronary syndrome, life-threatening
arrhythmias, and heart failure) n( = 5), liver diseases (e.g., cirrhosis)
(n = 3), or cancer (n = 7) and disorders of the hematological
system ( n = 3) exhibit increased CysC levels and were thus
The final study population consisted of 568 hypertensive
patients. We recorded demographics and medical history in
detail. The ethical committee of Weihai Municipal Hospital
approved this study, and all participants provided informed
consent. In addition, this study was conducted in accordance
with the principles of the Declaration of Helsinki.
MR imaging assessment
All 568 hypertensive participants underwent MR
examination with susceptibility-weighted imaging (SWI). In
addition, all patients received conventional T1- and T2-weighted,
fluid-attenuated inversion recovery sequence, and
diffusionweighted imaging scans. MR imaging examinations were
performed with a Magnetom Trio whole-body 3.0-T MR
scanner (Siemens, Erlangen, Germany) with a 40 mT/m
gradient. A receiver-only eight-channel phased array head
coil was used in all acquisitions with an integrated parallel
acquisition technique. SWI was obtained as a fully
velocitycompensated, three-dimensional gradient echo sequence
using the following parameters: repetition time, 27 ms; time
of echo, 20 ms; flip angle, 15°; matrix, 350× 445; field of
view, 192 × 220 mm; and slice thickness, 1.2 mm. Minimal
intensity projection images were reconstructed on a console
by overlaying the six adjacent slices from the original SWI,
with a slice thickness of 7.2mm. 13–15 The presence and
number of CMBs on SWI were independently interpreted by two
experienced neuroradiologists and determined by
consensus. CMBs were defined as focal areas with very low signal
intensity, smaller than 10mm. 16 Hypointense lesions were
excluded if they appeared to be vascular flow voids (based on
sulcal location or linear shape), basal ganglia mineralization,
or artifacts from an adjacent bone or sinus. SLIs were defined
as focal lesions >3mm and <15 mm, with a hyperintense rim
on fluid-attenuated inversion recovery images,
corresponding hyperintensity on T2-weighted images and
corresponding hypointensity on T1-weighted images. Furthermore, a
white matter lesion was defined as at least one focal lesion
in the cerebral white matter with a corresponding
hyperintensity on fluid-attenuated inversion recovery images. The
Fazekas scale was used to score the white matter lesions.
Scores of 0–6 were given for a deep WMH (DWMH) in
the temporal, frontal, parietal, and occipital lobe (DWMH;
range: 0–24), and scores of 0–2 were given for three
periventricular hyperintensities (PVH; range: 0–6)1.7
The interrater reliability for the whole group for the
presence of CMBs was k = 0.876, and the intraclass correlation
coefficient for the number of CMBs was k = 0.869, which
indicates good agreement.
Evaluation of baseline risk factors
The diagnosis of diabetes mellitus was based on the use
of antidiabetic treatment or repeated pathologic blood
tests indicating fasting values ≥7 mmol/l (126 mg/dl) or
values load≥11.1 mmol/l (200 mg/dl) 2 h after an oral
glucose. A history of smoking was coded if the subject smoked
during the 3 months prior to the most recent stroke event.
Alcohol was accepted as a risk factor if current consumption
Blood samples were obtained from patients between 6:00
and 8:00 am after overnight fasting. Total protein, serum
albumin, total cholesterol, triglyceride, low-density
lipoprotein cholesterol, blood urea nitrogen, and hemoglobin
levels were measured by standard laboratory methods.
Hyperlipidemia was determined when total cholesterol was
≥200 mg/dl or when low-density lipoprotein cholesterol was
≥130 mg/dl. High-sensitivity C-reactive protein (hs-CRP)
levels were determined using a latex-enhanced
immunonephelometric method on a Hitachi 7600 autoanalyzer
(Hitachi, Tokyo, Japan).
The carotid intima-media thickness was measured by
Color Doppler ultrasound. The intima-media thickness was
calculated by averaging the thickness at 12 sites: the near and
far walls of both left and right distal common carotid artery,
internal carotid artery, and carotid bifurcation.
Measurement of kidney biomarkers
Serum CysC was measured with the automated
particleenhanced turbidimetric immunoassay using a Hitachi 7600
autoanalyzer. The intra-assay and interassay coefficients of
variation for CysC were 0.52–0.84% and 0.46–1.25%,
respectively. Serum creatinine was measured by the Jaffe kinetic
method on a Hitachi 7600 autoanalyzer. The estimated GFR
(eGFR) of each participant was calculated from the serum
creatinine (Cr) value and the patient’s age using the abbre-vi
ated Modification of Diet in Renal Disease equatio1n8 modi
fied by the Chinese coefficient.19 Spot urine samples were
collected early in the morning. The urinary albumin
concentration was measured using an immunoturbidimetric assay,
and urine creatinine was analyzed using the Jaffe reaction.
The urine albumin-creatinine ratio (in mg/g) was calculated
by dividing the urinary albumin value by the urinary creat-i
Continuous variables are expressed as the mean ± SE;
categorical variables are expressed as constituent ratios. All
of the statistical analyses were performed using SPSS 13.0
for Windows (SPSS, Chicago, IL). Continuous data were
compared between groups using a Student’s t-test, and
categorical data were compared using a chi-squared test. We
used the multivariate cumulative logistic model to quantify
the effects of risk factors on the CMBs. We also performed
a multilinear regression analysis of kidney biomarker levels
and the number of CMBs. Receiver operating characteristic
analysis was performed to evaluate the diagnostic potential
of kidney biomarkers. The threshold for statistical signif-i
cance wasP < 0.05.
CMBs were observed in 106 of 568 hypertensive patients
(18.7%). Of the 545 identified CMBs, 145 (26.6%) were
located in the basal ganglia, 83 (15.2%) in the thalamus,
59 (10.8%) in the cerebellum, 90 (16.5%) in the brainstem
(mostly in the pons), 109 (20.0%) in the subcortical white
matter, and 59 (10.8%) in the cortex. In the univariate anal-y
sis, age, prevalence of SLI, degrees of PVH and DWMH,
hsCRP, urinary albumin/creatinine ratio (UACR), and CysC
levels were higher in patients with CMBs than those without
CMBs, and the eGFR was lower in patients with CMBs than
those without (Table 1).
We assessed the use of medications by all enrolled patients.
The results indicate no significant differences in medication
use between the groups.
Adjusted relationship between the presence of CMBs and kidney biomarker levels
Multivariate logistic regression analyses were used to
determine the association between age, sex, baseline risk
factors, serum hs-CRP levels, and kidney biomarker levels in
patients with CMBs. Table 2 shows that each 1 SD decrease
in eGFR and 1 SD increase in UACR and CysC levels were
significantly associated with the presence of CMBs after
adjustment for age and sex (Model 1), and after additional
adjustments for diabetes, hyperlipidemia, current smoker
designation, current drinker designation, the levels of blood
pressure, the presence of SLI, WMH (PVH, DWMH) grade,
and hs-CRP level (Model 2). The odds ratio (OR) of each
kidney biomarker (eGFR, UACR, CysC) for the presence
of CMBs was 1.38 (0.85–2.77), 2.03 (1.41–4.31), and 2.46
(1.44–5.93), respectively (Model 2).
Furthermore, eGFR and UACR were only associated with
the presence of deep or infratentorial CMBs (OR: 1.95, 95%
confidence interval (CI): 1.37–3.27, P < 0.05; OR: 2.25, 95%
CI: 1.66–4.46, P < 0.01 (Model 2)). No significant differences
were found between eGFR and UACR levels and the
presence of pure lobar CMBs in the multivariate logistic analysis
(Table 2). The associations between CysC levels and deep
or infratentorial CMBs or lobar CMBs remained significant
after adjustment for age and sex (Model 1) and after ad-di
tional adjustments for diabetes, hyperlipidemia, current
drinker designation, the levels of blood pressure, the
presence of SLI, WMH (PVH, DWMH) grade, and hs-CRP level
(OR: 2.59, 95% CI: 1.57–6.22, P < 0.05; OR: 1.57, 95% CI:
1.15–4.85, P < 0.05 (Model 2)).
Diagnostic value of kidney biomarkers for CMBs in hypertensive patients
Receiver operating characteristic curve analysis was pe-r
formed to verify the diagnostic accuracy of kidney
biomarkers for CMBs in hypertensive patients. CysC levels exhibited
fair diagnostic value for CMBs, with an area under the curve
of 0.80 (95% CI: 0.76–0.86), whereas the area under the curve
for UACR and eGFR were only 0.69 (95% CI: 0.65–0.74) and
0.63 (95% CI: 0.58–0.67), respectively (Figure 2).
Logistic regression analysis indicated that the comb-i
nation of CysC and UACR levels (B = 2.583, SE = 0.457,
P < 0.001) significantly discriminated the patients with
CMBs from those without, even after adjustment for age
and sex, diabetes, hyperlipidemia, current drinker
designation, the levels of blood pressure, the presence of SLI, WMH
(PVH, DWMH) grade, and hs-CRP level.
Correlation between the number of CMBs and kidney biomarker levels
To strengthen the association of kidney biomarker levels
with CMBs, multivariate regression analysis confirmed the
association of serum kidney biomarker levels and number
of CMBs after adjustments for age, sex, hypertension,
diabetes, hyperlipidemia, current smoker designation, current
drinker designation, the levels of blood pressure, the
presence of SLI, WMH (PVH, DWMH) grade, and hs-CRP. In
the patients with deep or infratentorial CMBs, the
number of CMB increased as eGFR decreased and UACR and
CysC levels increased (P = 0.041, adjusted R2 total = 0.190;
P = 0.037, adjusted R2 total = 0.222; P = 0.021, adjusted
R2 total = 0.263). In the patients with pure lobar CMBs,
the number of CMBs increased as CysC levels increased
(P = 0.032; adjusted R2 total = 0.233). No correlation was
observed between eGFR or UACR levels and the number of
American Journal of Hypertension 28(
) June 2015 741
n (%), number of subjects (percentage); P values were obtained by chi-squared test for categorical variables, by independent t-test (two sided)
for continuous variables. Abbreviations: ARB, angiotensin receptor blocker; ACEI, angiotensin-converting enzyme inhibition; BMI, body mass index;
BUN, blood urea nitrogen; CMB, cerebral microbleed; DBP, diastolic blood pressure; DM, diabetes mellitus; DWMH, deep white matter
hyperintensities; eGFR, estimated glomerular filtration rate; FBG, fasting blood glucose; hs-CRP, high-sensitivity C-reactive protein; IMT, intima-media
thickness; IQR, interquartile range; LDL, low-density lipoprotein cholesterol; NIHSS, The National Institutes of Health Stroke Scale; PVH, periventricular
hyperintensities; SBP, systolic blood pressure; SLI, silent lacunar infarction; TC, total cholesterol; UACR, urine albumin/creatinine ratio.
This cross-sectional hospital-based study demonstrated
that in hypertensive patients without a history of stroke or
TIA, eGFR, and UACR are independently associated with the
prevalence of deep or infratentorial CMBs but not pure lobar
CMBs. Our findings are in agreement with the
populationbased Rotterdam Scan Study, which showed that risk factors
for CMBs differed with their location.20,21 CysC is
independently associated with CMBs in both deep or infratentorial
and lobar locations. Furthermore, CysC exhibited fair dia-g
nostic value of CMBs, with an area under the curve of 0.80.
These results were also supported by a recent study that
demonstrated an association between elevated CysC levels and
markers of SVD, such as white matter lesions and subclinical
lacunar infarction, in community-based elderly patients2.2
The kidney and brain are end organs that are vulnerable
to hypertensive damage because their vascular beds have
very low resistance and are passively perfused at high flow
throughout systole and diastole. Therefore, it is important
to consider the hemodynamic similarities of vascular beds
as a factor for the association between CMBs and chronic
kidney disease. Some studies have indicated that low GFR
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levels and the presence of proteinuria are associated with
the presence of CMBs in TIA or stroke.7,8 One recent study
from Umemura et al.23 showed that microalbuminuria but
not low eGFR levels was independently associated with deep
or infratentorial CMBs in hypertensive adults without a
history of stroke or TIA. Our study found that both eGFR
and microalbuminuria were independently associated with
the prevalence of deep or infratentorial CMBs in
hypertensive patients without a history of stroke or TIA. Compared
with Umemura et al., we detected CMBs by SWI sequences
that employ a high-resolution three-dimensional
gradientrecalled echo sequence with a long echo time, utilizing both
magnitude and phase information2,4 making these
modalities more sensitive at detecting CMBs than conventional
gradient-echo T2* sequences.13 The sample size of this study
was also relatively larger.
CysC is a cysteine proteinase inhibitor that is released
at a constant rate from all nucleated cells. The protein is
filtrated freely by the glomerulus and is almost completely
reabsorbed and catabolized in the renal tubule9s,.10 CysC
has been considered one of the more specific and
sensitive endogenous markers of kidney function.9,25 CysC is a
marker for impaired endothelial function, not just in the
glomerulus but also throughout the vascular tree. Hence, as a
novel marker of renal function, elevated CysC levels may be
associated with the presence of CMBs. Our previous study
also found that elevated levels of CysC are associated with
the presence of CMBs in acute stroke patients,
independent of conventional risk factors2.6 Elevated levels of CysC
and the presence of CMBs may be the end organ damage
that results from a hypertensive insult. No location-specific
association of CMBs with CysC was observed, indicating
that CMBs are a marker for the general severity of SVD and
can be seen as the common downstream product of two
separate pathways: hypertensive vasculopathy and cerebral
amyloid angiopathy. Our data raise the possibility that CysC
is important to the pathogenesis of any CMB. Some
largescale studies have shown that deep or infratentorial CMBs
are generally associated with atherosclerotic microangiop-a
thy and that pure lobar CMBs can commonly be attributed
to vascular β-amyloid (Aβ) deposition (cerebral amyloid
angiopathy)2.0,27 CysC plays a role in the different processes
and stages of atherosclerotic disease2.8,29 The pathogenesis
of atherosclerotic disease may be an imbalance between
the expression of cysteine cathepsins and their endogenous
inhibitor, CysC, in atherosclerotic lesions in humans.30 CysC
also plays an important role in the pathogenesis of cerebral
amyloid angiopathy3.1 CysC is also involved in many
pathological processes, including oxidative stress and
inflammation.31,32 In our study, the association between the number of
CMBs and serum CysC was also significant in patients with
pure lobar CMBs. However, the causality between serum
CysC levels and cerebral amyloid angiopathy or CMB path-o
genesis has not yet been established.
Our results have some limitations. First, the
cross-sectional design limits causal inferences, and further follow-up
is needed. Second, our results are limited to the cohort of
elderly individuals with hypertension, and therefore, they
cannot be generalized to the general population. Third, the
small sample size of the pure lobar CMBs creates limitations
in the multivariate analysis of associations between kidney
markers (especially CysC) and pure lobar CMBs.
In conclusion, in hypertensive patients without a history
of stroke or TIA, low eGFR and microalbuminuria are only
associated with an increased prevalence of deep or infrate-n
torial CMBs. Higher CysC levels were observed in subjects
with CMBs, regardless of their location. Furthermore, CysC
was a better marker for CMBs than eGFR and UACR, and
exhibited fair diagnostic value. Further prospective studies
are required to specifically define whether a causal relatio-n
ship between kidney markers and the development of CMBs
exists in hypertensive patients.
The authors declared no conflict of interest.
1. Fisher M , French S , Ji P , Kim RC . Cerebral microbleeds in the elderly: a pathological analysisS . troke 2010 ; 41 : 2782 - 2785 .
2. Biffi A , Halpin A , Towfighi A , Gilson A , Busl K , Rost N , Smith EE , Greenberg MS , Rosand J , Viswanathan A. Aspirin and recurrent intra-c erebral hemorrhage in cerebral amyloid angiopathy . Neurology 2010 ; 75 : 693 - 698 .
3. O 'Rourke MF , Safar ME . Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy . Hypertension 2005 ; 46 : 200 - 204 .
4. Koren-Morag N , Goldbourt U , Tanne D . Renal dysfunction and risk of ischemic stroke or TIA in patients with cardiovascular disease . Neurology 2006 ; 67 : 224 - 228 .
5. Khatri M , Wright CB , Nickolas TL , Yoshita M , Paik MC , Kranwinkel G , Sacco RL , DeCarli C. Chronic kidney disease is associated with white matter hyperintensity volume: the Northern Manhattan Study (NOMAS) . Stroke 2007 ; 38 : 3121 - 3126 .
6. Ikram MA , Vernooij MW , Hofman A , Niessen WJ , van der Lugt A , Breteler MM . Kidney function is related to cerebral small vessel disease . Stroke 2008 ; 39 : 55 - 61 .
7. Cho AH , Lee SB , Han SJ , Shon YM , Yang DW , Kim BS . Impaired kidney function and cerebral microbleeds in patients with acute ischemic stroke . Neurology 2009 ; 73 : 1645 - 1648 .
8. Ovbiagele B , Liebeskind DS , Pineda S , Saver JL . Strong independent correlation of proteinuria with cerebral microbleeds in patients with stroke and transient ischemic attack . Arch Neurol 2010 ; 67 : 45 - 50 .
9. Coll E , Botey A , Alvarez L , Poch E , Quintó L , Saurina A , Vera M , Piera C , Darnell A. Serum cystatin C as a new marker for noninvasive estimation of glomerular filtration rate and as a marker for early renal impa-ir ment . Am J Kidney Dis 2000 ; 36 : 29 - 34 .
10. Fliser D , Ritz E . Serum cystatin C concentration as a marker of renal dysfunction in the elderly . Am J Kidney Dis 2001 ; 37 : 79 - 83 .
11. Shlipak MG , Sarnak MJ , Katz R , Fried LF , Seliger SL , Newman AB , Siscovick DS , Stehman-Breen C . Cystatin C and the risk of death and cardiovascular events among elderly persons . N Engl J Med 2005 ; 352 : 2049 - 2060 .
12. Shlipak MG , Wassel Fyr CL , Chertow GM , Harris TB , Kritchevsky SB , Tylavsky FA , Satterfield S , Cummings SR , Newman AB , Fried LF . Cystatin C and mortality risk in the elderly: the health, aging, and body composition study . J Am Soc Nephrol 2006 ; 17 : 254 - 261 .
13. Nandigam RN , Viswanathan A , Delgado P , Skehan ME , Smith EE , Rosand J , Greenberg SM , Dickerson BC . MR imaging detection of cerebral microbleeds: effect of susceptibility-weighted imaging, section thickness, and field strength . AJNR Am J Neuroradiol 2009 ; 30 : 338 - 343 .
14. Haacke EM , Xu Y , Cheng YC , Reichenbach JR . Susceptibility weighted imaging (SWI) . Magn Reson Med 2004 ; 52 : 612 - 618 .
15. Reichenbach JR , Barth M , Haacke EM , Klarhöfer M , Kaiser WA , Moser E . High-resolution MR venography at 3.0 Tesla.J Comput Assist Tomogr 2000 ; 24 : 949 - 957 .
16. Greenberg SM , Eng JA , Ning M , Smith EE , Rosand J . Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemo-r rhage . Stroke 2004 ; 35 : 1415 - 1420 .
17. Scheltens P , Barkhof F , Leys D , Pruvo JP , Nauta JJ , Vermersch P , Steinling M , Valk J. A semiquantitative rating scale for the assessment of signal hyperi-n tensities on magnetic resonance imaging . J Neurol Sci 1993 ; 114 : 7 - 12 .
18. Levey AS , Coresh J , Greene T , Stevens LA , Zhang YL , Hendriksen S , Kusek JW , Van Lente F; Chronic Kidney Disease Epidemiology Collaboration . Using standardized serum creatinine values in the mo-d ification of diet in renal disease study equation for estimating glomerular filtration rate . Ann Intern Med 2006 ; 145 : 247 - 254 .
19. Ma YC , Zuo L , Chen JH , Luo Q , Yu XQ , Li Y , Xu JS , Huang SM , Wang LN , Huang W , Wang M , Xu GB , Wang HY . Modified glomerular filtr-a tion rate estimating equation for Chinese patients with chronic kidney disease . J Am Soc Nephrol 2006 ; 17 : 2937 - 2944 .
20. Vernooij MW , van der Lugt A , Ikram MA , Wielopolski PA , Niessen WJ , Hofman A , Krestin GP , Breteler MM . Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study . Neurology 2008 ; 70 : 1208 - 1214 .
21. Poels MM , Ikram MA , van der Lugt A , Hofman A , Krestin GP , Breteler MM , Vernooij MW . Incidence of cerebral microbleeds in the general population: the Rotterdam Scan Study . Stroke 2011 ; 42 : 656 - 661 .
22. Wada M , Nagasawa H , Kawanami T , Kurita K , Daimon M , Kubota I , Kayama T , Kato T . Cystatin C as an index of cerebral small vessel d-is ease: results of a cross-sectional study in community-based Japanese elderly . Eur J Neurol 2010 ; 17 : 383 - 390 .
23. Umemura T , Kawamura T , Sakakibara T , Mashita S , Hotta N , Sobue G . Microalbuminuria is independently associated with deep or infratentorial brain microbleeds in hypertensive adults . Am J Hypertens 2012 ; 25 : 430 - 436 .
24. Haacke EM , Mittal S , Wu Z , Neelavalli J , Cheng YC . Susceptibilityweighted imaging: technical aspects and clinical applications, part 1 . AJNR Am J Neuroradiol 2009 ; 30 : 19 - 30 .
25. Yaffe K , Lindquist K , Shlipak MG , Simonsick E , Fried L , Rosano C , Satterfield S , Atkinson H , Windham BG , Kurella-Tamura M. Cystatin C as a marker of cognitive function in elders: findings from the health ABC study . Ann Neurol 2008 ; 63 : 798 - 802 .
26. Zhang JB , Jü XH , Wang J , Sun HR , Li F . Serum cystatin C and cerebral microbleeds in patients with acute cerebral stroke . J Clin Neurosci 2014 ; 21 : 268 - 273 .
27. Greenberg SM , Vernooij MW , Cordonnier C , Viswanathan A , Al-Shahi Salman R , Warach S , Launer LJ , Van Buchem MA , Breteler MM . Cerebral microbleeds: a guide to detection and interpretation . Lancet Neurol 2009 ; 8 : 165 - 174 .
28. Ferraro S , Marano G , Biganzoli EM , Boracchi P , Bongo AS . Prognostic value of cystatin C in acute coronary syndromes: enhancer of ather-o sclerosis and promising therapeutic target . Clin Chem Lab Med 2011 ; 49 : 1397 - 1404 .
29. Urbonaviciene G , Shi GP , Urbonavicius S , Henneberg EW , Lindholt JS . Higher cystatin C level predicts long-term mortality in patients with peripheral arterial diseaseA . therosclerosis 2011 ; 216 : 440 - 445 .
30. Sjöberg S , Shi GP . Cysteine protease cathepsins in atherosclerosis and abdominal aortic aneurysm . Clin Rev Bone Miner Metab 2011 ; 9 : 138 - 147 .
31. Levy E , Jaskolski M , Grubb A . The role of cystatin C in cerebral amyloid angiopathy and stroke: cell biology and animal models . Brain Pathol 2006 ; 16 : 60 - 70 .
32. Mussap M , Plebani M. Biochemistry and clinical role of human cystatin C . Crit Rev Clin Lab Sci 2004 ; 41 : 467 - 550 .