Oral anticoagulant use and the development of new cerebral microbleeds in cardioembolic stroke patients with atrial fibrillation.

OBJECTIVE: Cerebral microbleeds (CMBs) are a magnetic resonance imaging (MRI) marker for cerebral small vessel disease. Existing CMBs and those that newly develop are associated with the risks of stroke incidence and recurrence. The purpose of the present study was to investigate the association of oral anticoagulant (OAC) use and the development of new CMBs in cardioembolic stroke patients with atrial fibrillation. SUBJECTS AND METHODS: We prospectively followed cardioembolic stroke patients with atrial fibrillation who had been hospitalized in the stroke center of our hospital, had been prescribed anticoagulants at discharge, and underwent repeated brain MRI with an interval of at least one year from the baseline MRI. Assessing the presence, number and location of CMBs using T2*-weighted gradient-recalled echo MRI, we used logistic regression models to investigate the associations between OAC use and the incidence of new CMBs. We also examined associations of subsequent stroke with OACs and CMBs during the follow-up. RESULTS: A total of 81 patients, consisting of 45 patients receiving direct oral anticoagulants (DOACs) and 36 patients receiving warfarin (WF), were analyzed in the present study. Baseline CMBs were observed in 19/81 patients (23.5%) and new CMBs in 18/81 patients (22.2%) on follow-up MRI (median interval, 34 months). Of the 31 new CMBs, 25 (80.6%) developed in the lobar location and 6 (19.4%) in the deep or infratentorial location. New CMBs occurred in 4 patients (10.0%) taking DOACs　alone, in 10 patients (35.7%) taking WF alone, in 3 patients (37.5%) taking WF plus antiplatelet agents and in 1 patient (20.0%) taking DOAC plus antiplatelet agent. Regarding location, the new CMBs were the lobar type in 7 of the 10 patients taking WF alone, as well as in 3 of the 4 patients taking DOACs alone. In multivariate analysis, the presence of CMBs at baseline and WF use (vs. DOAC use) were associated with new CMBs (CMB presence at baseline: OR 4.16, 95% CI 1.19-14.44; WF use: OR 3.38, 95% CI 1.02-11.42). The presence of ≥ 2 CMBs at baseline was related to a higher risk of subsequent stroke (OR 7.25, 95% CI 1.01-52.35, P = 0.048). CONCLUSION: Our findings suggest that DOAC compared with WF use at discharge is associated with a lower incidence of new CMBs in cardioembolic stroke patients with atrial fibrillation. Further prospective studies in the clinical setting are needed to confirm our exploratory data.

Higher Levels of Cystatin C Are Associated with Extracranial Carotid Artery Steno-Occlusive Disease in Patients with Noncardioembolic Ischemic Stroke.

BACKGROUND: Large artery atherosclerosis is a major cause of ischemic stroke worldwide. Differential biomarker profiles associated with extra- and intracranial atherosclerosis are a topic of considerable interest. Cystatin C (CysC), a marker of renal function, is a risk factor for cardiovascular disease. AIM: We sought to determine whether CysC levels were associated with extra- and intracranial large artery stenosis (LAS) in patients with acute ischemic stroke. METHODS: We retrospectively analyzed data of acute noncardioembolic ischemic stroke patients who were admitted to our stroke center within 5 days from symptom onset. Serum CysC levels were measured using latex agglutination turbidimetric immunoassay. Extra- and intracranial LAS were defined as ≥ 50% diameter stenosis or occlusion of the relevant internal carotid artery (ICA) and/or middle cerebral artery (MCA) using carotid echography and volume rendering on magnetic resonance angiography. Multivariate logistic analyses were used to assess the association between CysC levels and LAS after adjustment for potential confounders. RESULTS: Of 205 patients (mean age 70.2 years), 76 (37.1%) had LAS. The distribution of LAS was 29 extracranial ICA, 34 intracranial ICA/MCA (8 ICA only, 25 MCA only, 1 ICA+MCA) and 13 tandem stenosis (both extracranial ICA and intracranial ICA/MCA). Levels of CysC were higher in patients with extracranial ICA stenosis than in those with intracranial ICA/MCA stenosis (1.23 ± 0.33 vs. 0.97 ± 0.21 mg/l, p < 0.001). In multivariate analysis, the highest CysC tertile (>1.04 mg/l) was significantly associated with extracranial ICA stenosis (adjusted odds ratio [OR] 5.01, 95% confidence interval [CI] 1.51-16.63, p = 0.009) after adjustment for age, sex, diabetes, chronic kidney disease, current smoking, systolic blood pressure, HDL cholesterol, high-sensitivity C-reactive protein (hs-CRP) and premorbid lipid-lowering drugs use. When CysC was considered as a continuous variable, 1 SD increase in CysC was significantly associated with extracranial ICA stenosis (adjusted OR 3.01, 95% CI 1.58-5.72, p = 0.001). However, there were no significant associations between CysC levels and intracranial ICA/MCA stenosis. In addition, CysC levels showed a weak but statistically significant correlation with hs-CRP levels (r = 0.195, p = 0.021). Using receiver operating characteristic curve analysis, CysC value displayed good performance in discriminating extracranial ICA stenosis (c-statistic 0.79, 95% CI 0.69-0.89, p < 0.001). CONCLUSIONS: This preliminary study suggests that higher levels of CysC were independently associated with symptomatic extracranial ICA stenosis, but not with intracranial ICA/MCA stenosis in patients with noncardioembolic stroke. Our findings provide new insights into the link between serum CysC and carotid atherosclerosis.

Impact of albuminuria on early neurological deterioration and lesion volume expansion in lenticulostriate small infarcts.

BACKGROUND AND PURPOSE: Albuminuria, a marker of chronic kidney disease, is associated with an increased risk of incident stroke and unfavorable long-term outcomes. However, the association of albuminuria with short-term outcomes and change in infarct volume in patients with acute small subcortical infarction remains unknown. METHODS: We retrospectively reviewed 85 consecutive patients with acute small subcortical infarcts in the lenticulostriate artery territory who were admitted to our stroke center within 24 hours of symptom onset and underwent serial diffusion-weighted imaging (DWI). Albuminuria was determined based on the urinary albumin-to-creatinine ratio obtained from a first morning spot urine after admission. Infarct volume was measured on axial sections of the initial and follow-up DWI. Early neurological deterioration (END) was defined as an increase of ≥2 points in the National Institutes of Health Stroke Scale score during the first 5 days after admission. RESULTS: Albuminuria (UACR ≥30 mg/g creatinine) was observed in 14 of 18 patients with END (77.8%) and in 25 of 67 patients without END (37.3%), P=0.002. Multivariate logistic regression analysis revealed that albuminuria was associated with END after adjustment for age, low estimated glomerular filtration rate (<60 mL/min per 1.73 m2), and infarct volume on initial DWI (odds ratio, 6.64; 95% confidence interval, 1.62-27.21; P=0.009). In addition, albuminuria was an independent predictor of increase in infarct volume using multivariate linear regression analysis (ß coefficient=0.217; P=0.038). CONCLUSIONS: Our findings suggest that albuminuria is associated with END and infarct volume expansion in patients with small subcortical infarcts in the lenticulostriate artery territory.

Association of chronic kidney disease and cerebral small vessel disease with cognitive impairment in elderly patients with type 2 diabetes.

BACKGROUND/AIMS: In recent years, the relationship between chronic kidney disease (CKD) and cognitive impairment has been attracting attention. Cerebral small vessel disease (SVD) is also associated with an increased risk of cognitive impairment. However, it is still unknown whether CKD markers are associated with cognitive impairment independently of SVD in elderly diabetic patients. METHODS: Seventy-nine type 2 diabetic patients (mean age, 76.0 years) were enrolled in the present study. CKD was defined as the presence of albuminuria and/or a low estimated glomerular filtration rate (eGFR <60 ml/min/1.73 m(2)). SVD was evaluated by the presence and severity of silent brain infarcts (SBIs) and white matter lesions (WMLs) on brain magnetic resonance imaging. Neuropsychological tests were assessed using four validated cognitive instruments. RESULTS: In multiple linear regression analyses, albuminuria was associated with worse modified Stroop Color Word scores (ß = 0.284, p = 0.017) and low eGFR was associated with reduced Digit Symbol Substitution scores (ß = -0.224, p = 0.026) after adjustment for age, sex, education years, diabetes duration, hypertension, multiple SBIs, and advanced WMLs. In contrast, there were no significant associations between CKD markers and Mini-Mental State Examination or Word Recall scores. CONCLUSION: Our findings suggest that albuminuria and low eGFR are associated with frontal lobe dysfunction independently of SVD in elderly type 2 diabetic patients.

Microalbuminuria is independently associated with deep or infratentorial brain microbleeds in hypertensive adults.

BACKGROUND: Brain microbleeds (BMBs) detected on gradient echo T2*-weighted magnetic resonance imaging (GE-MRI) may be pathophysiologically linked to ischemic cerebral small-vessel disease (SVD) and increased risk of future hemorrhagic stroke. Chronic kidney disease (CKD) has been associated with the presence of BMBs in stroke patients. However, the relationship between CKD markers and BMBs in stroke-free populations is unknown. METHODS: Two hundred and eighty-five hypertensive subjects (mean age 68.6 years) without neurological symptoms were enrolled from a hospital-based outpatient clinic and all participants underwent GE-MRI. We calculated urinary albumin/creatinine ratio (UACR) from morning spot urine and the estimated glomerular filtration rate (eGFR) in serum samples. Multivariate logistic regression analysis was used to evaluate the association between these kidney biomarkers and the presence and location of BMBs, controlling for age, sex, use of antihypertensive or antithrombotic drugs, and MRI findings. RESULTS: BMBs were observed in 48 (16.8%) patients. Median UACRs were significantly higher in patients with deep or infratentorial BMBs than in patients with pure lobar BMBs (54 vs. 17 mg/g creatinine, P = 0.04). No significant differences were found between eGFR levels and the location of BMBs. Microalbuminuria (UACR >30- ≤300 mg/g creatinine), but not low eGFR level was significantly associated with higher prevalence of deep or infratentorial BMBs (odds ratio (OR): 3.16, 95% confidence interval (CI): 1.34-7.44, P = 0.009) even after adjustment for potential confounding factors. CONCLUSIONS: Microalbuminuria is closely associated with the prevalence of deep or infratentorial BMBs in hypertensive patients. Our findings provide new insights into the association between risk factors and the distribution of BMBs.