Risk Factors and Clinical Characteristics of First-ever Ischemic Stroke Caused by ICAS with Leukoaraiosis.

Background: Previous studies have mostly investigated the risk factors affecting the occurrence of leukoaraiosis and the risk factors affecting the severity of leukoaraiosis in patients with ischemic stroke, but there are relatively few studies on the risk factors and clinical characteristics affecting the severity of leukoaraiosis in the population with the most common type of first-episode ischemic stroke caused by intracranial atherosclerotic stenosis in China. Methods: We retrospectively studied patients with first-ever ischemic stroke due to intracranial atherosclerotic stenosis. All patients underwent diffusion weight magnetic resonance imaging and adjunctive examinations such as magnetic resonance angiography and/or computed tomography angiography and/or digital subtraction angiography. The characteristics and clinical data were also statistically analyzed. Results: Of the 504 patients enrolled, 176 (34.92%), 202 (40.08%), and 126 (25.00%) patients were in the mild, moderate, and severe groups, respectively, and the patients were older in the severe group compared with the moderate and mild groups (p < 0.05). Hypertension was more severe in the severe group compared with the severe and mild groups (p < 0.05). The time to hospital admission was shorter in the severe group compared with the moderate and mild groups (p < 0.05). The admission National Institutes of Health stroke scale was higher in the severe group than in the moderate and mild groups (p < 0.05). homocysteine, glucose, glycohemoglobin A1c, neutrophil-lymphocyte ratio, and ultrasensitive C-reactive protein to albumin ratio levels were significantly different between the three groups (p < 0.05). There was no significant correlation between the distribution of infarct foci in the anterior and posterior circulation in the three groups (p > 0.05). Conclusion: Age and homocysteine were independent risk factors for leukoaraiosis severity in patients with acute ischemic stroke, and all were positively associated with leukoaraiosis severity. Hypertension, glucose, glycohemoglobin A1c, neutrophil-lymphocyte ratio and ultrasensitive C-reactive protein to albumin ratio levels were highly significant in evaluating the prognosis of patients.

Precision Medicine for Blood Glutamate Grabbing in Ischemic Stroke.

Glutamate grabbers, such as glutamate oxaloacetate transaminase (GOT), have been proposed to prevent excitotoxicity secondary to high glutamate levels in stroke patients. However, the efficacy of blood glutamate grabbing by GOT could be dependent on the extent and severity of the disruption of the blood-brain barrier (BBB). Our purpose was to analyze the relationship between GOT and glutamate concentration with the patient's functional status differentially according to BBB serum markers (soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and leukoaraiosis based on neuroimaging). This retrospective observational study includes 906 ischemic stroke patients. We studied the presence of leukoaraiosis and the serum levels of glutamate, GOT, and sTWEAK in blood samples. Functional outcome was assessed using the modified Rankin Scale (mRS) at 3 months. A significant negative correlation between GOT and glutamate levels at admission was shown in those patients with sTWEAK levels > 2900 pg/mL (Pearson's correlation coefficient: -0.249; p < 0.0001). This correlation was also observed in patients with and without leukoaraiosis (Pearson's correlation coefficients: -0.299; p < 0.001 vs. -0.116; p = 0.024). The logistic regression model confirmed the association of higher levels of GOT with lower odds of poor outcome at 3 months when sTWEAK levels were >2900 pg/mL (OR: 0.41; CI 95%: 0.28-0.68; p < 0.0001) or with leukoaraiosis (OR: 0.75; CI 95%: 0.69-0.82; p < 0.0001). GOT levels are associated with glutamate levels and functional outcomes at 3 months, but only in those patients with leukoaraiosis and elevated sTWEAK levels. Consequently, therapies targeting glutamate grabbing might be more effective in patients with BBB dysfunction.

sTWEAK is a leukoaraiosis biomarker associated with neurovascular angiopathy.

OBJECTIVE: Leukoaraiosis (LA) refers to white matter lesions of undetermined etiology associated with the appearance and worsening of vascular pathologies. The aim is to confirm an increased frequency and intensity of LA in symptomatic patients with neurovascular pathology compared with asymptomatic subjects, and its association with circulating serum levels of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK). METHODS: An observational study was conducted in which two groups of patients were compared. Group I (N = 242) comprised of asymptomatic subjects with arterial hypertension and/or diabetes or with a history of transient ischemic attacks, and Group II (N = 382) comprised patients with lacunar stroke or deep hemispheric intracerebral hemorrhage (ICH) of hypertensive origin. Serum levels of sTWEAK were analyzed and correlated with prevalence and intensity of LA according to the Fazekas scale. RESULTS: The prevalence of LA was higher in symptomatic (85.1%) versus asymptomatic patients (62.0%). Logistic regression model showed a significant relation of LA with neurovascular pathologies (OR: 2.69, IC 95%: 1.10-6.59, p = 0.003). When stratified according to the Fazekas scale, LA of grade II (OR: 3.53, IC 95%: 1.10-6.59, p = 0.003) and specially grade III (OR: 4.66, 95% CI: 1.09-19.84, p = 0.037) showed correlation with neurovascular pathologies. Increased sTWEAK levels were found in the symptomatic group in all LA grades (p < 0.0001), and associated with 5.06 times more risk of presenting clinical symptoms (OR: 5.06, 95% CI: 2.66-9.75, p < 0.0001). INTERPRETATION: LA showed a higher prevalence in patients with symptomatic lacunar stroke or deep hemispheric ICH. There is an association between sTWEAK levels and LA degree.

High-dose atorvastatin improves vascular endothelial function in patients with leukoaraiosis.

OBJECTIVE: Leukoaraiosis (LA), as an age-related white matter degeneration, is mainly caused by chronic ischemia. Our study aims to explore the efficacy of different doses of atorvastatin (ATV) in the vascular endothelial function in patients with LA. METHODS: Our study enrolled 402 LA patients who were then randomly included as control or treated with ATV (10 mg), ATV (20 mg), or ATV (30 mg). The total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were detected by enzyme colorimetric assay. The high-sensitivity C-reactive protein (hs-CRP) level, reactive hyperemia index (RHI), endothelin-1 (ET-1) content, and nitric oxide (NO) level were tested by latex agglutination test, peripheral arterial tonometry technology, radioimmunoassay, and nitrate reductase assay, respectively. RESULTS: After 8 weeks of ATV treatment, the levels of TC, LDL-C, and HS-CRP decreased significantly, and the trends were demonstrated in a more significant way with the increases of dose of ATV. The treatment with ATV at different doses elevated NO level and RHI and declined ET-1 content. Gastrointestinal reaction, muscular pain, and increased aminopherase were observed after treatment with the ATV at different doses with more obvious symptoms detected accompanied by the increase of the dose. The RHI was in negative correlation with the ET-1 and HS-CRP while in positive correlation with NO. CONCLUSION: Our study demonstrates that ATV can significantly improve the vascular endothelial function in LA patients with a dose-dependent effect.

Circulating ceramide ratios and risk of vascular brain aging and dementia.

BACKGROUND: We determined the association between ratios of plasma ceramide species of differing fatty-acyl chain lengths and incident dementia and Alzheimer's disease (AD) dementia in a large, community-based sample. METHODS: We measured plasma ceramide levels in 1892 [54% women, mean age 70.1 (SD 6.9) yr.] dementia-free Framingham Offspring Study cohort participants between 2005 and 2008. We related ratios of very long-chain (C24:0, C22:0) to long-chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Structural MRI brain measures were included as secondary outcomes. RESULTS: During a median 6.5 year follow-up, 81 participants developed dementia, of whom 60 were diagnosed with AD dementia. In multivariable Cox-proportional hazards analyses, each standard deviation (SD) increment in the ratio of ceramides C24:0/C16:0 was associated with a 27% reduction in the risk of dementia (HR 0.73, 95% CI 0.56-0.96) and AD dementia (HR 0.73, 95% CI 0.53-1.00). The ratio of ceramides C22:0/C16:0 was also inversely associated with incident dementia (HR per SD 0.75, 95% CI 0.57-0.98), and approached statistical significance for AD (HR 0.73, 95% CI 0.53-1.01, P = 0.056). Higher ratios of ceramides C24:0/C16:0 and C22:0/C16:0 were also cross-sectionally associated with lower white matter hyperintensity burden on MRI (-0.05 ± 0.02, P = 0.02; -0.06 ± 0.02, P = 0.003; respectively per SD increase), but not with other MRI brain measures. CONCLUSIONS: Higher plasma ratios of very long-chain to long-chain ceramides are associated with a reduced risk of incident dementia and AD dementia in our community-based sample. Circulating ceramide ratios may serve as potential biomarkers for predicting dementia risk in cognitively healthy adults.

Association between serum carbohydrate antigen 19-9 levels and leukoaraiosis in middle-aged and older adults: A cross-sectional study.

BACKGROUND AND AIMS: Leukoaraiosis refers to lesions with high signal intensity on magnetic resonance imaging (MRI) in periventricular and subcortical white matter that results from chronic microvascular ischemic brain damage. Increasing evidence suggests that serum CA 19-9 is associated with non-malignant conditions including type 2 diabetes, dyslipidemia, and metabolic syndrome, which are closely related to microangiopathy. Thus, we hypothesized that serum CA 19-9 levels would be associated with cerebrovascular microangiopathy measured by leukoaraiosis among middle-aged and older adults. METHODS: This cross-sectional study included 1833 Korean adults aged ≥45 years who participated in a health examination program between 2010 and 2011. Serum CA 19-9 levels were quantified by chemiluminescence immunoassay and categorized as quartiles: Q1: ≤4.5, Q2: 4.6-7.5, Q2: 7.6-12.2, and Q4: ≥12.3 ng/mL. Odds ratios (ORs) and 95% confidence intervals (CIs) for leukoaraiosis based on brain MRI scans were calculated across serum CA19-9 quartiles using multiple logistic regression analysis. RESULTS: The overall prevalence of leukoaraiosis was 4.6% and increased with serum CA 19-9 quartiles. Compared to the lowest quartile, the OR (95% CI) of the highest CA 19-9 quartile for leukoaraiosis was 2.20 (1.10-4.42) after adjusting for age, sex, BMI, regular exercise, hypertension, type 2 diabetes, dyslipidemia, smoking status, and alcohol drinking. CONCLUSIONS: Serum CA 19-9 levels were positively and independently associated with leukoaraiosis. Our findings indicate that serum CA 19-9 level might be a useful additional measure for assessing cerebrovascular microangiopathy in clinical settings.

Association of serum cystatin C with white matter abnormalities in patients with amnestic mild cognitive impairment.

AIM: White matter hyperintensities (WMH) on MRI have been reported to be a risk factor for the conversion from mild cognitive impairment (MCI) to Alzheimer's disease, although the reason remains unclear. In the present study, we hence investigated the associations between WMH volumes and cognitive function, blood levels of various molecules, and the presence of lifestyle-associated diseases in patients with amnestic MCI. METHODS: The initial data of 38 patients with amnestic MCI and 10 normal control individuals were analyzed. The volumes of periventricular hyperintensities (PVH) and deep WMH (DWMH) were measured on T2 fluid-attenuated inversion recovery using the imaging software, 3D Slicer; and the association between PVH/DWMH volumes and cognitive function, blood levels of molecules (such as cystatin C [CysC], 25-hydroxyvitamin D and homocysteine) and the presence of lifestyle-associated diseases (such as hypertension, hyperlipidemia and diabetes mellitus) were analyzed. RESULTS: In the MCI group, the PVH volume : intracranial volume ratio significantly correlated with Trail Making Test-A/B scores and CysC level by Pearson's analysis, and the PVH volume : intracranial volume ratio significantly correlated with only CysC levels, whereas the DWMH volume : intracranial volume ratio did not correlate with any items at all by linear multiple regression analysis. CONCLUSIONS: PVH volume was closely associated with frontal lobe dysfunction, particularly with attention and executive dysfunction. Serum CysC level was associated with PVH volume, which suggests that CysC might be a useful marker for determining treatment strategies for white matter abnormalities in amnestic MCI. Geriatr Gerontol Int 2019; 19: 1036-1040.

Association between serum carcinoembryonic antigen (CEA) levels and leukoaraiosis in middle-aged and older adults: A cross-sectional study.

BACKGROUND: Leukoaraiosis refers to lesions of high signal intensities in periventricular and subcortical white matter, which result from chronic microvascular ischemic damage of the brain. Emerging evidence suggests that serum carcinoembryonic antigen (CEA) is elevated in cardiometabolic diseases, which are closely related with microangiopathy. Thus, we hypothesized that serum CEA levels could be associated with leukoaraiosis and aimed to examine this association among middle-aged and older adults. METHODS: This cross-sectional study included 2164 Korean adults aged ≥ 45 years who underwent a health examination program at a single hospital between 2010 and 2015. Serum CEA levels were quantified by chemiluminescence immunoassay and categorized as quartiles: Q1: ≤ 1.1, Q2: 1.2-1.6, Q2: 1.7-2.4, and Q4: ≥ 2.5 µg/L. The odds ratios (ORs) and 95% confidence intervals (95% CIs) for leukoaraiosis based on brain MRI scans were calculated across serum CEA quartiles using multiple logistic regression analysis after adjusting for age, sex, body mass index, smoking status, fasting plasma glucose, triglyceride, HDL-cholesterol, hypertension, type 2 diabetes, and leukocyte count. RESULTS: The overall prevalence of leukoaraiosis was 5.4% and increased with serum CEA quartiles: 3.3% for Q1, 5.0% for Q2, 5.8% for Q3, and 7.6% for Q4 (P < 0.001). The OR (95% CI) of the highest CEA quartile, compared to the lowest quartile, for leukoaraiosis was 2.164 (1.169-4.006) after adjusting for confounding variables. CONCLUSIONS: Serum CEA levels were positively and independently associated with leukoaraiosis. Our findings indicate that serum CEA level might be useful additional measure in assessing leukoaraiosis in clinical settings.

Leukoaraiosis is an independent predictor of intracranial hemorrhage in patients with atrial fibrillation.

We evaluated the predictive value of several clinical, radiological and laboratory parameters on the risk of predict intracranial hemorrhage (ICH) in patients with atrial fibrillation (AF). We conducted a case-control study on a consecutive hospital based series of patients with AF and ICH. A random sample of subjects with AF without ischemic or hemorrhagic stroke was selected from the same hospital in the same period to perform as the control group, with a ratio of two controls per case. All patients underwent the same evaluation protocol. Patients without neuroimaging exams were excluded. During the study period we identified 37 subjects with AF and ICH. 74 subjects without stroke events were randomly chosen among subjects with AF. Among cases 56.8% were female; mean age was 83.1 years. Patients with ICH were more often on anticoagulant therapy (75.7%), compared with controls (45.9%; p = 0.0002). On CT scans, cases had a greater severity of leukoaraiosis at the Blennow scale (p < 0.0001) and a higher frequency of lacunar infarcts (p = 0.006). No significant association was found between MRI parameters or the HAS-BLED score and the occurrence of ICH. CT scan is more useful than MRI and HAS-BLED score to predict ICH in patients with AF on antithrombotic therapy.

Risk factors of pure leukoaraiosis and the association with preclinical carotid atherosclerosis.

BACKGROUND AND AIMS: The risk factors of cerebral large artery disease (carotid atherosclerosis) have been well recognized, but not of small artery disease, especially leukoaraiosis. In this study, we investigated the risk factors of pure leukoaraiosis (without stroke), and the association with preclinical carotid atherosclerosis. METHODS: Data from 384 subjects with leukoaraiosis and 379 controls with normal cerebral parenchyma were collected at the Beijing Tiantan Hospital from 1 January, 2009 to 31 December, 2015. Entry criteria: 1) age over 40 years; 2) not taking lipid lowering drugs and vitamin B; 3) normal cerebral parenchyma or leukoaraiosis on brain MRI scan; 4) intra- and extra-cranial large artery stenosis less than 50%. EXCLUSION CRITERIA: 1) any brain lesions except cerebral leukoaraiosis; 2) severe systemic diseases. Age, gender, well-known vascular risk factors, serum lipid profile, levels of total homocysteine, vitamin B12, folic acid were analyzed with multivariable logistic regression model. RESULTS: Age and hypertension, but not serum homocysteine, vitamin B12, folic acid, or serum lipid profile, were independently associated with leukoaraiosis. Furthermore, there was no significant association between pure leukoaraiosis and preclinical carotid atherosclerosis after adjusting for age. CONCLUSIONS: Only age and hypertension are independently related to pure leukoaraiosis, and there is no association between pure leukoaraiosis and preclinical carotid atherosclerosis.

Metabolically healthy obesity and risk of leukoaraiosis; a population based cross-sectional study.

Metabolically healthy obese (MHO) individual is known to be defended from the metabolic complications of obesity. Leukoaraiosis, which is commonly detected on brain magnetic resonance imaging (MRI), is now recognized as a risk of stroke, dementia and death. However, the association between MHO and the prevalence of leukoaraiosis is unclear. In this cross-sectional study of 796 participants who received a medical examination program, we investigated the association between MHO and the prevalence of leukoaraiosis. We used common clinical markers for definition of metabolic healthy status: blood pressure, fasting plasma glucose, triglycerides and high-density lipoprotein cholesterol concentrations. Obesity was defined by body mass index ≥25.0 kg/m2. We diagnosed leukoaraiosis by fluid-attenuated inversion recovery without hypointensity on T1-weighted images or the presence of a hyperintensity on T2-weighted images. The crude prevalence proportion of leukoaraiosis was 44.5% (case/n = 171/384) in metabolically healthy nonobese (MHNO) individual, 46.3% (44/95) in MHO individual, 62.3% (114/183) in metabolically unhealthy nonobese (MUNO) individual or 56.6% (77/136) in MUO individual. The odds ratios of prevalence of leukoaraiosis were 1.19 (95% CI 0.74-1.90, p = 0.471) for MHO, 1.79 (1.22-2.62, p = 0.003) for MUNO and 1.56 (1.03-2.37, p = 0.037) for MUO individuals after adjusting for sex, age, smoking statues, habit of exercise and alcohol, compared with MHNO individual. We revealed that MHO individuals were not related with the higher risk of leukoaraiosis, whereas MUNO and MUO individuals were.

High neutrophil to lymphocyte ratio is associated with white matter hyperintensity in a healthy population.

High neutrophil to lymphocyte ratio (NLR) is correlated with the occurrence, morbidity and mortality of cerebrovascular disease as a marker of systemic inflammation. However, its effect on cerebral white matter hyperintensity (WMH) is unclear. We investigated high NLR burden as a surrogate marker of WMH volume in a healthy population. Healthy subjects with voluntary health check-ups between January 2006 and December 2013, including brain MRI and laboratory examination, were collected. WMH volumes were rated quantitatively. A total of 2875 subjects were enrolled, and the mean volume of WMH was 2.63±6.26mL. In multivariate linear regression analysis, NLR [ß=0.191, 95% confidence interval (CI)=0.104 to 0.279, P<0.001] remained significant after adjusting for confounders. Age (ß=0.049, 95% CI=0.045 to 0.054, P<0.001), hypertension (ß=0.191, 95% CI=0.101 to 0.281, P<0.001), diabetes (ß=0.153, 95% CI=0.045 to 0.261, P=0.006), and extracranial atherosclerosis (ß=0.348, 95% CI=0.007 to 0.688, P=0.045) were also significant independently from NLR. Additionally, the high NLR group (NLR≥1.52) was related to male sex, hypertension, diabetes, current smoking, extracranial atherosclerosis, silent brain infarct, and high WMH volumes. In conclusion, high NLR is associated with larger WMH volumes in a healthy population. Assessment of NLR may be helpful in detecting cerebral WMH burdens in high risk groups.

Analysis of risk factors in patients with leukoaraiosis.

To investigate the risk factors for leukoaraiosis (LA) and the correlation between risk factors and LA.The study comprised 92 patients with diagnoses of LA (LA group) and 56 non-LA individuals (control group). Data were collected for the following: age, gender, fasting blood glucose, total cholesterol, triglyceride, high- and low-density lipoprotein cholesterol, uric acid, creatinine, and histories of smoking, hypertension, and diabetes. Levels of serum asymmetric dimethylarginine (ADMA) were detected by enzyme-linked immunosorbent assay.Univariate analysis showed statistical significance between the 2 groups in age, histories of hypertension and smoking, uric acid, creatinine, and levels of serum ADMA (P < 0.05). Binary logistic analysis showed that age (P < 0.0001), hypertension (P = 0.0101), and serum ADMA (P = 0.0206) were related to LA. Pearson correlation analysis showed that levels of serum ADMA correlated with uric acid (r = 0.184, P = 0.025) and creatinine (r = 0.169, P = 0.04).Age, hypertension, and levels of serum ADMA were independent risk factors for LA. Serum ADMA levels may be related to uric acid and creatinine.

The association of uric acid with leukoaraiosis.

Objective To explore the possible correlation between uric acid levels and leukoaraiosis (LA). Methods This cross-sectional study enrolled patients who presented with some neurological discomfort (e.g. dizziness, headache, mild cognitive impairment). Potential demographic and clinical risk factors associated with LA, including sex, age, hypertension, diabetes mellitus, smoking, alcohol consumption, dyslipidaemia, plasma fibrinogen, D-dimer, uric acid, and homocysteine, were investigated using univariate and multivariate logistic regression analyses. Results A total of 268 patients were enrolled in the study and divided into the LA group ( n = 164) and the non-LA group ( n = 104). Compared with the non-LA group, uric acid was significantly higher in the LA group (mean ± SD: 356.49 ± 121.85 µmol/l versus 289.96 ± 102.98 µmol/l). Multivariate logistic regression analyses showed that uric acid was an independent risk factor for LA (odds ratio 1.285; 95% confidence interval 1.062, 1.556). Conclusion Hyperuricaemia was an independent risk factor for leukoaraiosis in Chinese patients.

Red Blood Cell Distribution Width Is Associated with Severity of Leukoaraiosis.

Red blood cell distribution width (RDW) is one of the routine hematologic parameters reported in the complete blood count test, which has been recognized as strong prognostic marker for various medical conditions, especially cardiovascular disease. We evaluated that RDW was also associated with the leukoaraiosis; common radiological finding of brain and that has been strongly associated with risk of stroke and dementia. In the present study, we included 1006 non-stroke individuals who underwent brain MRI and routine complete blood count test including RDW. Fazekas scale was used to measure the severity of leukoaraiosis based on fluid-attenuated inversion recovery image, and the severity was dichotomized to mild-degree (Fazekas scale: 0-1) and severe-degree leukoaraiosis (Fazekas scale: 2-3). Univariate and multivariate logistic regression models were constructed to evaluate independent risk factor for severe-degree of leukoaraiosis. Mean age of 1006 subjects was 64.34 ± 9.11 year, and mean of RDW was 12.97 ± 0.86%. The severe-degree of leukoaraiosis (Fazekas scale ≥ 2) was found in 28.83%. In the multivariate logistic regression, 4th quartile of RDW (> 13.3%) were significantly associated with the presence of severe-degree of leukoaraiosis (adjusted odds ratio, 1.87; 95% confidence interval, 1.20-2.92) compared to the 1st quartile of RDW (< 12.5%). The significance was not changed after adjustments for hemoglobin and other hematologic indices. These findings suggest that RDW is independently associated with severity of leukoaraiosis.

C-reactive protein and cognition are unrelated to leukoaraiosis.

Elevated serum levels of C-reactive protein (CRP) have been associated with leukoaraiosis in elderly brain. However, several studies indicate that leukoaraiosis is associated with an increased risk of cognitive impairment. It is unknown how the effect of CRP on cognition is mediated by leukoaraiosis. The purpose of this study is to assess the relationship between serum levels of CRP, the presence of leukoaraiosis, and cognitive impairment in a population of coronary patients over 50 years old. CRP levels explained 7.18% (P: 0.002) of the variance of the MMSE. The adjustment for the presence of leukoaraiosis little changed this variance (5.98%, P: 0.005), indicating that only a small portion of the CRP influence on cognition was mediated via leukoaraiosis. Patients with CRP levels ≥ 5.0 had 2.9 (95% CI: 1.26-6.44) times more chance to present cognitive impairment (P: 0.012). We found that elevated serum levels of CRP were associated with increased risk of cognitive impairment in elderly and it was not mediated by presence of leukoaraiosis.

Association of rs2075575 and rs9951307 polymorphisms of AQP-4 gene with leukoaraiosis.

BACKGROUND: Leukoaraiosis (LA) is associated with structural and functional vascular changes that correlate with motor and gait disturbances, depressive symptoms, urinary disturbances, and dementia. The blood-brain barrier (BBB) plays a key role in development of lacunar stroke, leukoaraiosis, and other feature of cerebral small-vessel disease, and there are numerous studies examining changes in the BBB with normal aging and in dementia and LA. Aquaporin-4 (AQP-4), the primary water channel protein in the central nervous system, is involved in BBB development, function, and integrity, and its dysfunction induces several neurologic diseases. The aim of our study was to evaluate whether genetic variations in AQP-4 gene are associated with the development of LA. METHODS: DNA was amplified and the single-nucleotide polymorphisms in AQP-4 gene were investigated by melting curve analysis using real-time polymerase chain reaction. RESULTS: The frequency of both T allele and CT/TT genotypes of rs2075575 was significantly higher in LA group than in control group (C versus T, P = .0145; CC versus CT/TT, P = .038). However, no significant difference was observed between LA group and control group in rs9951307. Interestingly, the rs9951307 AG + GG genotype may confer a synergistic effect in odds ratio (OR) values when combined with the rs2075575 CT + TT genotypes (OR = 1.65 → 2.51). The C-A haplotype was significantly different between LA group and the control group (P = .005). By stratified analysis, rs2075575 and rs9951307 polymorphisms were statistically significant in the subjects with hypertension and hemoglobin A1c (P < .05), whereas the rs2075575 polymorphism was associated with high serum cholesterol (P < .05) and the rs9951307 polymorphism was associated with low serum homocysteine (P < .05). CONCLUSIONS: Our results indicate that AQP-4 genetic variations and haplotypes might contribute to the risk factors for LA.

Hyperhomocysteinemia associates with small vessel disease more closely than large vessel disease.

BACKGROUND: Hyperhomocysteinemia was believed to be an independent risk factor for stroke and associate with small vessel disease (SVD) related stroke and large vessel disease (LVD) related stroke differently. However it's still unclear which type of stroke associated with homocysteine (HCY) more strongly because the conclusions of previous studies were contradictory. In this study we focused on the subclinical angiopathies of stroke, i.e., SVD and LVD instead of stroke subtypes and sought to compare the associations between HCY level and different angiopathies. METHODS: 324 non-stroke patients were enrolled. Sex, age, HCY level and other vascular risk factors were collected. MRI and angiographies were used to determine the type of angiopathies and their severity, i.e., the scores of leukoaraiosis (LA), plaques and numbers of silent brain infarctions (SBI). LVD was defined as the presence of atherosclerotic plaques of cerebral arteries. SVD was defined as the presence of either LA or SBI. 230 patients were deemed to have LVD; 180 patients were deemed to have SVD. Spearman's correlation test and logistic regression were used to analyze the association between HCY level and different angiopathies. RESULTS: The correlation between HCY level and scores of plaques was weaker than that of the scores of LA and numbers of SBI. Hyperhomocysteinemia was an independent risk factor for SVD (OR = 1.315, P <0.001), whereas the association between HCY level and LVD was not that significant (OR = 1.058, P = 0.075). CONCLUSION: HCY level associated with SVD more strongly than LVD.

Association between serum total bilirubin level and leukoaraiosis in Korean adults.

OBJECTIVES: Leukoaraiosis is associated with cerebrovascular microangiopathy. Increasing evidence suggests that bilirubin is a potent cytoprotectant in the development of cardiovascular diseases. This study aimed to determine whether total bilirubin is related to leukoaraiosis. METHODS: We examined the relationship of total bilirubin with leukoaraiosis in 1005 Korean adults. The odds ratios for leukoaraiosis were calculated using multivariate logistic regression across serum total bilirubin tertiles. RESULTS: In comparison with the subjects in the reference group (total bilirubin: 15-26 µmol/L), the odds ratio (95% CI) for leukoaraiosis in the 3rd tertile (total bilirubin ≤10 µmol/L) was 5.50 (1.24-24.40) in women after adjusting for confounding variables. However, this inverse association between serum total bilirubin and the prevalence of leukoaraiosis was not found in men after adjusting for the same co-variables. CONCLUSION: Total bilirubin level was inversely associated with leukoaraiosis regardless of classical cardiovascular risk factors in Korean women.