Jong-Won Chung

Branch atheromatous plaque: a major cause of lacunar infarction (high-resolution MRI study).

Background: Lacunar infarctions account for up to 25% of all ischemic strokes and, thus, constitute a numerically important subgroup. It is important that the two pathogeneses of lacunar infarction, that is, small-vessel occlusion and branch atheromatous disease, be differentiated because prognoses and treatment strategies differ. The authors evaluated the presence of branch atheromatous plaque in parent arteries that supply lacunar infarcts by high-resolution magnetic resonance imaging (HR-MRI). Methods: HR-MRI was performed in 15 patients with (1) a clinical presentation consistent with classical lacunar syndromes; (2) an acute lacunar infarction by diffusion-weighted imaging, measuring ≤20 mm in maximal diameter; (3) a magnetic resonance angiography showing a normal middle cerebral artery or basilar artery supplying the ischemic lesion, and (4) no other obvious etiology for small-vessel distribution ischemic stroke. Results: The median time of vessel wall imaging after index events was 4 days (range, 2–15 days). Six of the 15 patients had a lacunar infarction in the middle cerebral artery territory, and 9 had a lesion in the basilar artery territory. HR-MRI detected underlying atheromatous plaques in 9 patients (60%) with a lacunar infarction. In these 9 patients, asymptomatic intracranial atherosclerotic stenosis was more frequent compared to patients without branch atheromatous plaque (55.6 vs. 16.7%). In pontine infarctions, ischemic lesions that extended to the pial base of the pons were more frequent in patients with branch atheromatous plaques (83.3 vs. 33.3%), and all the ischemic lesions and atheromatous plaques were on the same side (right, n = 2; left, n = 4). All plaques responsible for acute symptomatic lacunar infarction were enhanced in contrast-enhanced T1-weighted HR-MR images. Conclusions: HR-MRI results enabled underlying symptomatic branch atheromatous disease to be detected in lacunar infarction patients. The experience gained during this study indicates that HR-MRI better delineates intracranial arterial lesions, suggesting that its use will lead to a further understanding of the mechanisms involved in stroke.

A Polymorphism in RNF213 Is a Susceptibility Gene for Intracranial Atherosclerosis

Background Both intracranial atherosclerotic stenosis (ICAS) and moyamoya disease (MMD) are prevalent in Asians. We hypothesized that the Ring Finger protein 213 gene polymorphism (RNF213), a susceptibility locus for MMD in East Asians, is also a susceptibility gene for ICAS in patients whose diagnosis had been confirmed by conventional angiography (absence of basal collaterals) and high-resolution MRI (HR-MRI, presence of plaque). Methods We analyzed 532 consecutive patients with ischemic events in the middle cerebral artery (MCA) distribution and relevant stenotic lesion on the distal internal carotid artery or proximal MCA, but no demonstrable carotid or cardiac embolism sources. Additional angiography was performed on 370 (69.5%) patients and HR-MRI on 283 (53.2%) patients. Results Based on angiographic and HR-MRI findings, 234 patients were diagnosed with ICAS and 288 with MMD. The RNF213 variant was observed in 50 (21.4%) ICAS patients and in 119 (69.1%) MMD patients. The variant was observed in 25.2% of patients with HR-MRI-confirmed ICAS. Similarly, 15.8% of ICAS patients in whom MMD was excluded by angiography had this variant. Among the ICAS patients, RNF213 variant carriers were younger and more likely to have a family history of MMD than non-carriers were. Multivariate testing showed that only the age of ICAS onset was independently associated with the RNF213 variant (odds ratio, 0.97; 95% CI, 0.944–0.99). Conclusions RNF213 is a susceptibility gene not only for MMD but also for ICAS in East Asians. Further studies are needed on RNF213 variants in ICAS patients outside East Asian populations.

Hypercoagulability and Mortality of Patients with Stroke and Active Cancer: The OASIS-CANCER Study

Background and Purpose Patients with active cancer are at an increased risk for stroke. Hypercoagulability plays an important role in cancer-related stroke. We aimed to test whether 1) hypercoagulability is a predictor of survival, and 2) correction of the hypercoagulable state leads to better survival in patients with stroke and active cancer. Methods We recruited consecutive patients with acute ischemic stroke and active systemic cancer between January 2006 and July 2015. Hypercoagulability was assessed using plasma D-dimer levels before and after 7 days of anticoagulation treatment. The study outcomes included overall and 1-year survival. Plasma D-dimer levels before and after treatment were tested in univariate and multivariate Cox regression models. We controlled for systemic metastasis, stroke mechanism, age, stroke severity, primary cancer type, histology, and atrial fibrillation using the forward stepwise method. Results A total of 268 patients were included in the analysis. Patients with high (3rd–4th quartiles) pre-treatment plasma D-dimer levels showed decreased overall and 1-year survival (adjusted HR, 2.19 [95% CI, 1.46–3.31] and 2.70 [1.68–4.35], respectively). After anticoagulation treatment, post-treatment D-dimer level was significantly reduced and independently associated with poor 1-year survival (adjusted HR, 1.03 [95% CI, 1.01–1.05] per 1 μg/mL increase, P=0.015). The successful correction of hypercoagulability was a protective factor for 1-year survival (adjusted HR 0.26 [CI 0.10–0.68], P=0.006). Conclusions Hypercoagulability is associated with poor survival after stroke in patients with active cancer. Effective correction of hypercoagulability may play a protective role for survival in these patients.

Caveolin-1, Ring finger protein 213, and endothelial function in Moyamoya disease.

Background Moyamoya disease is a unique cerebrovascular occlusive disease of unknown etiology. Ring finger protein 213 (RNF213) was identified as a susceptibility gene for Moyamoya disease in East Asian countries. However, the pathogenesis of Moyamoya disease remains unclear. Methods We prospectively analyzed clinical data for 139 patients with Moyamoya disease (108 bilateral Moyamoya disease, 31 unilateral Moyamoya disease), 61 patients with intracranial atherosclerotic stroke, and 68 healthy subjects. We compared the genetic (RNF213 variant) and protein biomarkers for caveolae (caveolin-1), angiogenesis (vascular endothelial growth factor (VEGF) and receptor (VEGFR2), and antagonizing cytokine (endostatin)) and endothelial dysfunction (asymmetric dimethylarginine (ADMA), and nitric oxide and its metabolites (nitrite and nitrate)) between patients with Moyamoya disease and intracranial atherosclerotic stroke. We then performed path analysis to evaluate whether a certain protein biomarker mediates the association between genes and Moyamoya disease. Results Caveolin-1 level was decreased in patients with Moyamoya disease and markedly decreased in RNF213 variant carriers. Circulating factors such as VEGF and VEGFR2 did not differ among the groups. Markers for endothelial dysfunction were significantly higher in patients with intracranial atherosclerotic stroke but normal in those with Moyamoya disease. Path analysis showed that the presence of the RNF213 variant was associated with caveolin-1 levels that could lead to Moyamoya disease. The level of combined marker of Moyamoya disease (caveolin-1) and intracranial atherosclerotic stroke (ADMA, an endothelial dysfunction marker) predicted Moyamoya disease with good sensitivity and specificity. Conclusion Our results suggest that Moyamoya disease is a caveolae disorder but is not related to endothelial dysfunction or dysregulation of circulating cytokines.

Previous Statin Use and High-Resolution Magnetic Resonance Imaging Characteristics of Intracranial Atherosclerotic Plaque: The Intensive Statin Treatment in Acute Ischemic Stroke Patients With Intracranial Atherosclerosis Study

Background and Purpose— Although statin use has been linked to the stabilization of systemic atherosclerosis, its effect on symptomatic intracranial atherosclerotic plaques has yet to be explored. We hypothesized that premorbid statin use is associated with plaque instability in intracranial arteries and may lead to differential patterns (size and distribution) of ischemic lesions in patients with acute intracranial atherosclerotic stroke. Methods— One hundred and thirty-six patients with acute infarcts caused by intracranial atherosclerotic stroke underwent high-resolution magnetic resonance imaging. Patients were categorized into 3 groups based on their premorbid statin use: nonuser, low-dose user, and high-dose user, according to the 2013 American College of Cardiology/American Heart Association guidelines on blood cholesterol. Symptomatic lesions in intracranial arteries were analyzed using high-resolution magnetic resonance imaging for vascular morphology (degree of stenosis, remodeling index, and wall index) and plaque activation (pattern and volume of enhancement). The cortical distribution and volume of ischemic brain lesions were measured using diffusion-weighted imaging. Results— Among the enrolled patients, 38 (27.94%) were taking statins before the index stroke (22 low-dose statins and 16 high-dose statins). The degree of stenosis, remodeling index, and wall index did not differ between the 3 groups. However, the volume of plaque enhancement was significantly lower in statin users (nonuser, 33.26±40.72; low-dose user, 13.15±17.53; high-dose user, 3.13±5.26; P=0.002). Premorbid statin use was associated with a higher prevalence of nonembolic stroke and a decrease in large cortical infarcts (P=0.012). Conclusions— Premorbid statin usage is independently associated with reduced plaque enhancement and a decrease in large cortical lesions in patients with intracranial atherosclerotic stroke.

Brain microangiopathy and macroangiopathy share common risk factors and biomarkers.

AIMS Besides carotid or cardiac embolism, stroke can occur via microangiopathy (small arterial disease [SAD]) and macroangiopathy (intracranial atherosclerotic stroke [ICAS]) of the intracranial vasculature. There have been efforts to identify risk factors specific to microangiopathy and macroangiopathy, including vascular risk factors, and protein and genetic biomarkers. We hypothesized that despite the anatomic and pathophysiological differences between microvessels and macrovessels, microangiopathy and macroangiopathy share common risk factors during disease progression. METHODS Among 714 patients with acute infarctions within middle cerebral artery territory, 126 with SAD and 116 with ICAS were included in this study. Subclinical microangiopathy (degree of leukoaraiosis) and macroangiopathy (number of tandem stenosis) was graded in each patient. Inflammatory biomarkers (C-reactive protein, E-selectin, and LpPLA2), endothelial dysfunction (asymmetric dimethylarginine, urinary albumin-to-creatinine ratio, endostatin, and homocysteine), atherogenesis (lipoprotein(a), adiponectin, and resistin), and renal function (creatinine clearance and estimated glomerular filtration rate) were assessed. RESULTS Compared with the patients with isolated SAD, those with isolated ICAS were younger, were current smokers, and showed higher apoB levels (p < 0.05 in all cases). However, with the progression of subclinical microangiopathy, asymptomatic macroangiopathy worsened and vice versa. No significant differences in risk factors were observed between advanced SAD and ICAS. Decreased renal function was independently associated with progression of microangiopathy and macroangiopathy. Markers of endothelial dysfunction, but not the other markers, were significantly related to creatinine clearance level. CONCLUSIONS Mild to moderate loss of renal function is strongly associated with both intracranial microangiopathy and macroangiopathy. Endothelial dysfunction may be associated with this relationship.

Extents of white matter lesions and increased intraventricular extension of intracerebral hemorrhage.

Objectives:To determine whether the extent of white matter lesions on a CT scan of acute intracerebral hemorrhage patients is associated with the prevalence and severity of intraventricular extension of hemorrhage. Design and Setting:A post hoc analysis of Acute Brain Bleeding Analysis–IntraCerebral Hemorrhage cohort, a nationwide prospective cohort of acute intracerebral hemorrhage patients (total number of cohort subjects, 1,604). Patients:Spontaneous intracerebral hemorrhage patients (n = 1,262). Interventions:None. Measurements:The authors analyzed CT scan images taken within 48 hours after stroke onset. Extent of white matter lesions, volume of intracerebral hemorrhage, presence of intraventricular extension of hemorrhage, and intraventricular extension of hemorrhage score (approximation of intraventricular extension of hemorrhage volume) were measured using CT scans, and demographic, laboratory, clinical, and mortality data were also gathered through review of medical records and retrieval from the governmental statistical archive. Main Results:The frequency of intraventricular extension of hemorrhage in our population was 27.2% (343 subjects). The proportion of extensive white matter lesions in intraventricular extension of hemorrhage subjects (33.8%) was higher than that of non–intraventricular extension of hemorrhage cases (16.3%; p < 0.01). Multivariable analysis showed that mild (odds ratio, 1.48; 95% confidence interval 1.05– 0.09; p < 0.01) and extensive (odds ratio, 2.73; 95% confidence interval 1.88–3.98; p < 0.01) white matter lesions were significantly associated with the presence of intraventricular extension of hemorrhage in spontaneous intracerebral hemorrhage patients. The estimated mean of the intraventricular extension of hemorrhage score from the extensive white matter lesions group (9.09 ± 0.76) was significantly higher than that of the no white matter lesions group (6.72 ± 0.78; p < 0.01 from analyses of covariances) after adjustment for relevant covariates. Conclusions:We documented that the severity of white matter lesions is related to the occurrence and amount of intraventricular extension of hemorrhage in spontaneous intracerebral hemorrhage cases.

Impact of Slow Blood Filling via Collaterals on Infarct Growth: Comparison of Mismatch and Collateral Status

Background and Purpose Perfusion-diffusion mismatch has been evaluated to determine whether the presence of a target mismatch helps to identify patients who respond favorably to recanalization therapies. We compared the impact on infarct growth of collateral status and the presence of a penumbra, using magnetic resonance perfusion (MRP) techniques. Methods Consecutive patients who were candidates for recanalization therapy and underwent serial diffusion-weighted imaging (DWI) and MRP were enrolled. A collateral flow map derived from MRP source data was generated by automatic post-processing. The impact of a target mismatch (Tmax>6 s/apparent diffusion coefficient (ADC) volume≥1.8, ADC volume<70 mL; and Tmax>10 s for ADC volume<100 mL) on infarct growth was compared with MR-based collateral grading on day 7 DWI, using multivariate linear regression analysis. Results Among 73 patients, 55 (75%) showed a target mismatch, whereas collaterals were poor in 14 (19.2%), intermediate in 36 (49.3%), and good in 23 (31.5%) patients. After adjusting for initial severity of stroke, early recanalization (P<0.001) and the MR-based collateral grading (P=0.001), but not the presence of a target mismatch, were independently associated with infarct growth. Even in patients with a target mismatch and successful recanalization, the degree of infarct growth depended on the collateral status. Perfusion status at later Tmax time points (beyond the arterial phase) was more closely correlated with collateral status. Conclusions Patients with good collaterals show a favorable outcome in terms of infarct growth, regardless of the presence of a target mismatch pattern. The presence of slow blood filling predicts collateral status and infarct growth.

Frequency and significance of rare RNF213 variants in patients with adult moyamoya disease

Purpose Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by stenosis of the internal carotid arteries with compensatory development of collateral vessels. Although a founder variant of RNF213, p.Arg4810Lys (c.14429G>A, rs112735431), is a major genetic risk factor for MMD in East Asians, the frequency and disease susceptibility of other variants in this gene remain largely unknown. In the present study, we investigated the association of RNF213 variants with MMD in Korean patients and population controls. Methods For all RNF213 variants listed in the Human Gene Mutation Database (HGMD) as disease-causing or likely disease-causing mutations for MMD, genotyping was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Genetic data from 264 adult patients with MMD were analyzed and compared with two control populations comprised of 622 and 1,100 Korean individuals, respectively. Results Among the 30 RNF213 variants that were listed in the HGMD, p.Arg4810Lys was identified in 67.4% (178/264) of patients with MMD and showed a significantly higher allele frequency than in the controls, giving an odds ratio of 63.29 (95% confidence interval, 33.11–120.98) for the 622 controls and 48.55 (95% confidence interval, 31.00–76.03) for the 1100 controls. One additional variant, p.Ala5021Val (c.15062C>T, rs138130613), was identified in 0.8% (2/264) of patients; however, the allele frequencies were not significantly different from those in the controls. Conclusions These results suggest that, in our cohort of Korean patients, the p.Arg4810Lys is the only variant that is strongly associated with MMD among the 30 RNF213 variants listed in the HGMD.

CT Angiography of Collateral Vessels and Outcomes in Endovascular-Treated Acute Ischemic Stroke Patients

Background and Purpose Measuring the extent of the collateral blood vessels using computed tomography (CT) angiography source images may promote tissue survival and functional gain in acute ischemic stroke patients who are candidates for endovascular recanalization treatment. Methods Of 5,558 acute stroke patients registered in a prospective clinical stroke registry, 104 met the selection criteria of endovascular recanalization treatment for internal cerebral artery or middle cerebral artery main-stem (M1) occlusions and presented for treatment ≤4 hours after the event. Using CT angiography source images, two independent and blinded reviewers measured the extent of collateral circulations at four regions, with good interrater reliability. The functional recovery at 3 months after stroke was used as an outcome variable. Results Cases with a sufficient collateral circulation at the Sylvian fissure showed significantly increased likelihood of having a modified Rankin Scale score of ≤2 at 3 months after stroke (adjusted odds ratio=3.03, 95% confidence interval=1.19–7.73, p=0.02), but the association became nonsignificant after adding the infarct volume to the model (p=0.65). The association between leptomeningeal convexity collaterals and functional recovery was no longer significant after adjusting for the infarct volume (p=0.28). The natural indirect effect of infarct volume on functional recovery was significant for both the Sylvian fissure (p=0.03) and leptomeningeal convexity (p=0.02) collaterals. Conclusions The extent of collateral circulation at the Sylvian fissure was significantly associated with functional recovery, which may be mediated via the volume of the final infarction.