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Abstract The effect of arterial tortuosity on intracranial atherosclerosis (ICAS) is not well understood. This study aimed to evaluate the effect of global intracranial arterial tortuosity on intracranial atherosclerotic burden in patients with ischemic stroke. We included patients with acute ischemic stroke who underwent magnetic resonance angiography (MRA) and classified them into three groups according to the ICAS burden. Global tortuosity index (GTI) was defined as the standardized mean curvature of the entire intracranial arteries, measured by in-house vessel analysis software. Of the 516 patients included, 274 patients had no ICAS, 140 patients had a low ICAS burden, and 102 patients had a high ICAS burden. GTI increased with higher ICAS burden. After adjustment for age, sex, vascular risk factors, and standardized mean arterial area, GTI was independently associated with ICAS burden (adjusted odds ratio [adjusted OR] 1.33; 95% confidence interval [CI] 1.09–1.62). The degree of association increased when the arterial tortuosity was analyzed limited to the basal arteries (adjusted OR 1.48; 95% CI 1.22–1.81). We demonstrated that GTI is associated with ICAS burden in patients with ischemic stroke, suggesting a role for global arterial tortuosity in ICAS.

Aging manifests as many phenotypes, among which age-related changes in brain vessels are important, but underexplored. Thus, in the present study, we constructed a model to predict age using cerebrovascular morphological features, further assessing their clinical relevance using a novel pipeline.Age prediction models were first developed using data from a normal cohort (n = 1181), after which their relevance was tested in two stroke cohorts (n = 564 and n = 455). Our novel pipeline adapted an existing framework to compute generic vessel features for brain vessels, resulting in 126 morphological features. We further built various machine learning models to predict age using only clinical factors, only brain vessel features, and a combination of both. We further assessed deviation from healthy aging using the age gap and explored its clinical relevance by correlating the predicted age and age gap with various risk factors.The models constructed using only brain vessel features and those combining clinical factors with vessel features were better predictors of age than the clinical factor-only model (r = 0.37, 0.48, and 0.26, respectively). Predicted age was associated with many known clinical factors, and the associations were stronger for the age gap in the normal cohort. The age gap was also associated with important factors in the pooled cohort atherosclerotic cardiovascular disease risk score and white matter hyperintensity measurements.Cerebrovascular age, computed using the morphological features of brain vessels, could serve as a potential individualized marker for the early detection of various cerebrovascular diseases.

Abstract Introduction Visual field defects (VFDs) represent a debilitating poststroke complication, characterized by unseen parts of the visual field. Visual perceptual learning (VPL), involving repetitive visual training in blind visual fields, may effectively restore visual field sensitivity in cortical blindness. This current multicenter, double‐blind, randomized, controlled clinical trial investigated the efficacy and safety of VPL‐based digital therapeutics (Nunap Vision [NV]) for treating poststroke VFDs. Methods Stroke outpatients with VFDs (>6 months after stroke onset) were randomized into NV (defective field training) or Nunap Vision‐Control (NV‐C, central field training) groups. Both interventions provided visual perceptual training, consisting of orientation, rotation, and depth discrimination, through a virtual reality head‐mounted display device 5 days a week for 12 weeks. The two groups received VFD assessments using Humphrey visual field (HVF) tests at baseline and 12‐week follow‐up. The final analysis included those completed the study (NV, n = 40; NV‐C, n = 35). Efficacy measures included improved visual area (sensitivity ≥6 dB) and changes in the HVF scores during the 12‐week period. Results With a high compliance rate, NV and NV‐C training improved the visual areas in the defective hemifield (>72 degrees2) and the whole field (>108 degrees2), which are clinically meaningful improvements despite no significant between‐group differences. According to within‐group analyses, mean total deviation scores in the defective hemifield improved after NV training (p = .03) but not after NV‐C training (p = .12). Conclusions The current trial suggests that VPL‐based digital therapeutics may induce clinically meaningful visual improvements in patients with poststroke VFDs. Yet, between‐group differences in therapeutic efficacy were not found as NV‐C training exhibited unexpected improvement comparable to NV training, possibly due to learning transfer effects.

Background and Purpose This study aimed to evaluate whether extracellular-vesicle-incorporated microRNAs (miRNAs) are potential biomarkers for cancer-related stroke. Methods This cohort study compared patients with active cancer who had embolic stroke of unknown sources (cancer-stroke group) with patients with only cancer, patients with only stroke, and healthy individuals (control groups). The expression profiles of miRNAs encapsulated in plasma exosomes and microvesicles were evaluated using microarray and validated using quantitative real-time polymerase chain reaction. The XENO-QTM miRNA assay technology was used to determine the absolute copy numbers of individual miRNAs in an external validation cohort. Results This study recruited 220 patients, of which 45 had cancer-stroke, 76 were healthy controls, 39 were cancer controls, and 60 were stroke controls. Three miRNAs (miR-205-5p, miR-645, and miR-646) were specifically incorporated into microvesicles in patients with cancer-related stroke, cancer controls, and stroke controls. The area under the receiver operating characteristic curves of these three miRNAs were 0.7692–0.8510 for the differentiation of patients with cancer-stroke from cancer-controls and 0.8077–0.8846 for the differentiation of patients with cancer-stroke from stroke controls. The levels of several miRNAs were elevated in the plasma exosomes of patients with cancer, but were lower than those in plasma microvesicles. An in vivo study showed that systemic injection of miR-205-5p promoted the development of arterial thrombosis and elevation of D-dimer levels Conclusion Stroke due to cancer-related coagulopathy was associated with deregulated expression of miRNAs, particularly microvesicle-incorporated miR-205-5p, miR-645, and miR-646. Further prospective studies of extracellular-vesicle-incorporated miRNAs are required to confirm the diagnostic role of miRNAs in patients with stroke and to screen the roles of miRNAs in patients with cancer.

BackgroundConstipation symptoms are highly prevalent in acute ischemic stroke, but the clinical and neuroimaging predictors are unknown. This study aimed to identify lesions and clinical features associated with acute constipation.MethodsData from patients with acute ischemic stroke registered in a hospital-based stroke registry between January 2018 and December 2019 were analyzed. Clinical, laboratory, and imaging features were examined for associations with acute constipation. Using the topographic lesion on diffusion-weighted images, multivariate support vector regression-based lesion-symptom mapping (SVR-LSM) was conducted and compared between the non-constipation and acute constipation groups.ResultsA total of 256 patients (mean age 67 years, men: 64%) were included. Acute constipation was noted in 81 patients (32%). Initial stroke severity, represented by initial National Institutes of Health and Stroke Scale (NIHSS) scores, was associated with acute constipation. Laboratory parameters, including fibrin degradation products (FDP), fibrinogen, D-dimer, lipoprotein (a), and free fatty acid levels, also showed statistically significant differences between the non-constipation and constipation groups. FDP, D-dimer, and free fatty acid levels were independently associated with acute constipation in the logistic regression model after adjusting for initial NIHSS scores and potassium levels. SVR-LSM revealed that bilateral lesions in the precentral gyrus, insula, opercular part of the inferior frontal gyrus, the inferior parietal lobule, and lesions in the right middle frontal gyrus were significantly associated with acute constipation. The results were consistent after controlling for the initial NIHSS scores and poststroke potassium levels. When cardioembolic stroke subjects were excluded, the right insular and prefrontal cortex lesions lost their association with acute constipation.ConclusionAcute constipation symptoms after acute ischemic stroke are mainly related to bilateral lesions in the insula, precentral gyrus, postcentral gyrus, and inferior parietal lobule. Clinically important predictors of acute constipation include initial neurological severity and thromboembolic markers of stroke.

Abstract Identifying the cerebral arterial branches is essential for undertaking a computational approach to cerebrovascular imaging. However, the complexity and inter-individual differences involved in this process have not been thoroughly studied. We used machine learning to examine the anatomical profile of the cerebral arterial tree. The method is less sensitive to inter-subject and cohort-wise anatomical variations and exhibits robust performance with an unprecedented in-depth vessel range. We applied machine learning algorithms to disease-free healthy control subjects (n = 42), patients with stroke with intracranial atherosclerosis (ICAS) (n = 46), and patients with stroke mixed with the existing controls (n = 69). We trained and tested 70% and 30% of each study cohort, respectively, incorporating spatial coordinates and geometric vessel feature vectors. Cerebral arterial images were analyzed based on the ‘segmentation-stacking’ method using magnetic resonance angiography. We precisely classified the cerebral arteries across the exhaustive scope of vessel components using advanced geometric characterization, redefinition of vessel unit conception, and post-processing algorithms. We verified that the neural network ensemble, with multiple joint models as the combined predictor, classified all vessel component types independent of inter-subject variations in cerebral arterial anatomy. The validity of the categorization performance of the model was tested, considering the control, ICAS, and control-blended stroke cohorts, using the area under the receiver operating characteristic (ROC) curve and precision-recall curve. The classification accuracy rarely fell outside each image’s 90–99% scope, independent of cohort-dependent cerebrovascular structural variations. The classification ensemble was calibrated with high overall area rates under the ROC curve of 0.99–1.00 [0.97–1.00] in the test set across various study cohorts. Identifying an all-inclusive range of vessel components across controls, ICAS, and stroke patients, the accuracy rates of the prediction were: internal carotid arteries, 91–100%; middle cerebral arteries, 82–98%; anterior cerebral arteries, 88–100%; posterior cerebral arteries, 87–100%; and collections of superior, anterior inferior, and posterior inferior cerebellar arteries, 90–99% in the chunk-level classification. Using a voting algorithm on the queued classified vessel factors and anatomically post-processing the automatically classified results intensified quantitative prediction performance. We employed stochastic clustering and deep neural network ensembles. Ma-chine intelligence-assisted prediction of vessel structure allowed us to personalize quantitative predictions of various types of cerebral arterial structures, contributing to precise and efficient decisions regarding the cerebrovascular disease.

Background Although it is well known that the disordered brain provokes cardiac autonomic dysfunction, the detailed location of brain lesions related to cardiac function warrants further investigation. We aimed to elucidate the brain lesions topographically associated with left ventricular (LV) systolic function measured by myocardial strain in patients with acute ischemic stroke without preexisting primary cardiac dysfunction by using support vector regression lesion‐symptom mapping. Methods and Results Subjects were those with LV ejection fraction of 50% or more among patients with acute ischemic stroke registered in the Samsung Medical Center stroke registry between 2016 and 2017. To evaluate LV systolic performance and contractility, we measured LV ejection fraction and LV global and regional longitudinal strain using 2‐dimensional speckle‐tracking echocardiography. The association between stroke lesion location and cardiac strain was assessed using support vector regression lesion‐symptom mapping. Of a total of 776 patients, 286 subjects (mean age of 67.0 years, 65.4% men) were finally enrolled in this study. The mean global longitudinal strain was −17.0±3.4%, and the mean LV ejection fraction was 64.7±5.7%. The support vector regression lesion‐symptom mapping analysis revealed that the right insula and peri‐insular regions and left parietal cortex were associated with impaired LV global longitudinal strain in patients with acute ischemic stroke. In addition, impaired regional longitudinal strain showed topographical associations with these regions. Conclusions This study suggests that brain lesions in the right insula and peri‐insular regions and left parietal cortex are topographically associated with impaired LV strain in patients with acute ischemic stroke without preexisting cardiac dysfunction.

Background and aimsPleiotropic effects of statins result in the stabilization of symptomatic intracranial arterial plaque. However, little is known about the effect of statins in non-symptomatic cerebral arteries. We hypothesized that intensive statin therapy could produce a change in the non-symptomatic cerebral arteries.MethodsThis is a sub-study of a prospective observational study under the title of “Intensive Statin Treatment in Acute Ischemic Stroke Patients with Intracranial Atherosclerosis: a High-Resolution Magnetic Resonance Imaging (HR-MRI) study.” Patients with statin-naive acute ischemic stroke who had symptomatic intracranial artery stenosis (above 50%) were recruited for this study. HR-MRI was performed to assess the patients’ cerebral arterial status before and 6 months after the statin therapy. To demonstrate the effect of statins in the non-symptomatic segment of intracranial cerebral arteries, we excluded symptomatic segments from the data to be analyzed. We compared the morphological changes using cerebrovascular morphometry.ResultsA total of 54 patients (mean age: 62.9 ± 14.4 years, 59.3% women) were included in this study. Intensive statin therapy produced significant morphological changes of overall cerebral arteries. Among the morphological features, the arterial luminal area showed the highest number of significant changes with a range from 5.7 and 6.7%. Systolic blood pressure (SBP) was an independent factor associated with relative changes in posterior circulation bed maximal diameter percentage change (beta −0.21, 95% confidence interval −0.36 to −0.07, p = 0.005).ConclusionIntensive statin therapy produced a favorable morphological change in cerebral arteries of not only the target arterial segment but also non-symptomatic arterial segments. The change in cerebral arterial luminal diameter was influenced by the baseline SBP and was dependent on the topographic distribution of the cerebral arteries.Clinical Trial Registration: ClinicalTrials.gov, identifier NCT02458755.

Background and Purpose Previous studies have assessed the relationship between cerebral vessel tortuosity and intracranial aneurysm (IA) based on two-dimensional brain image analysis. We evaluated the relationship between cerebral vessel tortuosity and IA according to the hemodynamic location using three-dimensional (3D) analysis and studied the effect of tortuosity on the recurrence of treated IA. Methods We collected clinical and imaging data from patients with IA and disease-free controls. IAs were categorized into outer curvature and bifurcation types. Computerized analysis of the images provided information on the length of the arterial segment and tortuosity of the cerebral arteries in 3D space. Results Data from 95 patients with IA and 95 controls were analyzed. Regarding parent vessel tortuosity index (TI; P

Background Unlike patients with stroke caused by other mechanisms, the effect of elevated plasma total homocysteine (tHcy) on the prognosis of patients with both ischemic stroke and atrial fibrillation (AF) is unknown. This study aimed to evaluate the association between tHcy level and the functional outcome of patients with AF‐related stroke. Methods and Results We included consecutive patients with AF‐related stroke between 2013 and 2015 from the registry of a real‐world prospective cohort from 11 large centers in South Korea. A 3‐month modified Rankin Scale score ≥3 was considered an unfavorable outcome. Since tHcy is strongly affected by renal function, we performed a subgroup analysis according to the presence of renal dysfunction. A total of 910 patients with AF‐related stroke were evaluated (mean age, 73 years; male sex, 56.0%). The mean tHcy level was 11.98±8.81 μmol/L. In multivariable analysis, the tHcy level (adjusted odds ratio, 1.04; 95% CI, 1.01–1.07, per 1 μmol/L) remained significantly associated with unfavorable outcomes. In the subgroup analysis based on renal function, tHcy values above the cutoff point (≥14.60 μmol/L) showed a close association with the unfavorable outcome only in the normal renal function group (adjusted odds ratio, 3.10; 95% CI, 1.60–6.01). In patients with renal dysfunction, tHcy was not significantly associated with the prognosis of AF‐related stroke. Conclusions A higher plasma tHcy level was associated with unfavorable outcomes in patients with AF‐related stroke. This positive association may vary according to renal function but needs to be verified in further studies.

Background and PurposeCollateral flow in acute ischemic stroke is known as a predictor of treatment outcome and long-term prognosis. However, factors determining the initial collateral flow remain unclear. We investigated factors related to collateral flow in patients with acute ischemic stroke caused by large vessel occlusion (AIS-LVO) and further analyzed the results according to stroke etiology.MethodsThis was a retrospective study using prospective stroke registry data from a single university hospital from October 2014 to May 2021. AIS-LVO with middle cerebral artery M1 occlusion identified by pre-treatment multiphasic computed tomography angiography was included. Collateral flow score was graded on a 6-point ordinal scale according to pial arterial filling.ResultsA total of 74 patients [cardioembolism (CE): 57; large artery atherosclerosis (LAA): 17] was included. The mean age of all patients was 72.2 ± 11.7 years, and 37.8 % (n = 28) were men. Multivariate regression analysis showed that initial SBP [odds ratio (OR): 0.994; 95% confidence interval (CI): 0.990–0.998; p = 0.002] and stroke etiology (OR: 0.718; 95% CI: 0.548–0.940; p = 0.019) were independent factors of the collateral flow grade. Collateral flow grade was independently associated with initial SBP in the CE group (OR: 0.993; 95% CI: 0.989–0.998; p = 0.004) but not in the LAA group (OR: 0.992; 95% CI: 0.980–1.004; p = 0.218). Initial SBP was significantly correlated with NIHSS score in the CE group but not in the LAA group (r2= 0.091, p = 0.023; r2 = 0.043, p = 0.426, respectively).ConclusionsElevated initial SBP was associated with poor cerebral collateral flow and more severe symptoms in the CE group, but not in the LAA group in patients with AIS-LVO. These findings suggest differential effects of initial SBP elevation on collateral flow by stroke subtypes.

BackgroundThis study aimed to investigate clinical outcome predictors of acute stroke patients with large vessel occlusion and active cancer and validate the significance of D-dimer levels for endovascular thrombectomy decisions.MethodsWe analyzed a prospectively collected hospital-based stroke registry to determine clinical EVT outcomes of acute stroke patients within 24 h with following criteria: age ≥18 years, NIHSS ≥6, and internal carotid artery or middle cerebral artery lesion. All patients were classified into EVT and non-EVT groups. Patients were divided into two groups by initial D-dimer level. We explored variables potentially associated with successful recanalization as well as 3-month functional outcomes and mortality rates.ResultsAmong 68 patients, 36 were treated with EVT, with successful recanalization in 55.6%. The low D-dimer group showed a higher rate of successful recanalization and favorable outcome than the high D-dimer group. The mortality rate was higher in the high D-dimer group. No EVT and high D-dimer level were independent predictors of mortality, whereas lesion volume and low D-dimer level were independently associated with favorable outcomes.ConclusionsD-dimer level is a prognostic factor in acute LVO stroke patients with active cancer, and its high value for EVT decisions provisionally supports its testing in this patient population.

Systemic cancer and ischemic stroke are common conditions and two of the most frequent causes of death among the elderly. The association between cancer and stroke has been reported worldwide. Stroke causes severe disability for cancer patients, while cancer increases the risk of stroke. Moreover, cancer-related stroke is expected to increase due to advances in cancer treatment and an aging population worldwide. Because cancer and stroke share risk factors (such as smoking and obesity) and treatment of cancer can increase the risk of stroke (e.g., accelerated atherosclerosis after radiation therapy), cancer may accelerate conventional stroke mechanisms (i.e., atherosclerosis, small vessel disease, and cardiac thrombus). In addition, active cancer and chemotherapy may enhance thrombin generation causing stroke related to coagulopathy. Patients with stroke due to cancer-related coagulopathy showed the characteristics findings of etiologic work ups, D-dimer levels, and infarct patterns. In this review, we summarized the frequency of cancer-related stroke among patients with ischemic stroke, mechanisms of stroke with in cancer patients, and evaluation and treatment of cancer-related stroke. We discussed the possibility of cancer-related stroke as a stroke subtype, and presented the most recent discoveries in the pathomechanisms and treatment of stroke due to cancer-related coagulopathy.

Background: Ischemic stroke with atrial fibrillation (AF) may recur despite appropriate treatment. It may be AF-related or AF-unrelated. We compared the factors associated with AF-related and AF-unrelated recurrences among ischemic stroke patients with AF.Methods: Patients with ischemic stroke and AF were enrolled from 11 centers in Korea. Ischemic stroke recurrence was classified as AF-related if the lesion pattern was compatible with cardioembolism without significant stenosis or as AF-unrelated if the lesion was more likely due to small vessel disease or arterial stenosis. Factors associated with stroke recurrence (AF-related and AF-unrelated) were investigated.Results: Among the 2,239 patients, 115 (5.1%) experienced recurrence (75 AF-related and 40 AF-unrelated). Factors independently associated with any stroke recurrence included AF diagnosed before stroke, small subcortical infarctions, and small scattered lesions in a single vascular territory. Type of AF was associated with the type of stroke recurrence, with persistent AF being associated with AF-related stroke [hazard ratio (HR) = 2.94, 95% confidence interval (CI) 1.69–5.26; p < 0.001]. By contrast, paroxysmal AF (HR = 3.76, 95% CI 1.56–9.04; p = 0.003), AF diagnosed before stroke (HR = 2.38, 95% CI 1.19–4.55; p = 0.014), small scattered lesions in a single vascular territory (reference: corticosubcortical lesion, HR = 3.19, 95% CI 1.18–8.63; p = 0.022), and the use of antiplatelet agents (HR = 2.11, 95% CI 1.11–4.03; p = 0.024) were independently associated with AF-unrelated stroke.Conclusion: Persistent AF was more associated with AF-related stroke recurrence, whereas paroxysmal AF was more associated with AF-unrelated stroke recurrence. A scattered lesion in a single vascular territory may predict AF-unrelated stroke recurrence.

Background and Purpose To investigate the number and characteristics of patients eligible for endovascular treatment (EVT) determined using three different selection methods: clinical-core mismatch, target mismatch, and collateral status. Methods Using the data of consecutive patients from two prospectively maintained registries of university medical centers, the number and characteristics of patients according to the three selection methods were investigated and their correlation was analyzed. Patients with anterior circulation stroke due to occlusion of the middle cerebral and/or internal carotid artery and a National Institute of Health Stroke Scale (NIHSS) score of ≥6 points, who arrived within 8 hours or between 6 and 12 hours of symptom onset and underwent magnetic resonance imaging prior to EVT, were included. Collateral status was assessed using magnetic resonance perfusion-derived collateral flow maps. Results Three hundred thirty-five patients were investigated; the proportions of patients who were eligible and ineligible for EVT in all three selection methods were both small (n=85, 25.4%; n=54, 16.1%, respectively). The intercorrelation among the three selection methods was low (κ=0.235). The baseline NIHSS score and onset-to-selection time interval were associated with the presence of clinical-core mismatch, while the penumbra/core volume ratio and onset-to-selection time interval were related to target mismatch; none of these variables were associated with collateral status. The infarct core volume was associated with favorable profiles in all three selection methods. Conclusions Although the application of individual selection methods resulted in favorable outcomes after EVT in clinical trials, there is a significant discrepancy in EVT eligibility depending on the selection method used.

Background Although antiplatelet agents are frequently prescribed in moyamoya disease in routine clinical practice, there are no large‐scale epidemiologic trials or randomized trial evidence to support their use in patients with moyamoya disease. Methods and Results Using the Korean National Health Insurance Service database, patients diagnosed with moyamoya disease between 2002 and 2016 were followed up for up to 14 years to assess, using time‐dependent Cox regression in all patients and in a propensity score–matched cohort, the association of antiplatelet therapy and individual antiplatelet agents with survival. Among 25 978 patients with newly diagnosed moyamoya disease, mean age was 37.6±19.9 years, 61.6% were women, and total follow‐up was 163 347 person‐years. Among 9154 patients who were prescribed antiplatelet agents at least once during the follow‐up period, the proportion prescribed cilostazol gradually increased from 5.5% in 2002 to 56.0% in 2016. Any antiplatelet use was associated with reduced risk of death (hazard ratio, 0.77; 95% CI, 0.70–0.84) in a multivariate model. Among individual antiplatelet agents, cilostazol was associated with greater reduction in mortality than the 5 other antiplatelet regimens. Subgroup analysis, according to the age group and history of ischemic stroke, and sensitivity analysis, using propensity score–matched analysis, revealed consistent results. Conclusions Antiplatelet therapy is associated with substantial improvement in survival in patients with moyamoya disease, and cilostazol is associated with greater survival benefit compared with other antiplatelet regimens. These results provisionally support the use of antiplatelet therapy in patients with moyamoya disease and the conduct of confirmatory randomized controlled trials.

Background The RNF213 (ring finger protein 213 gene) variant R4810K is a susceptibility allele not only for Moyamoya disease (MMD) but also for intracranial atherosclerosis (ICAS) in East Asian populations. We hypothesized that this variant would affect the distribution of ICAS and recurrence of cerebrovascular events. Methods and Results We conducted a prospective study of patients with ICAS and MMD using high‐resolution magnetic resonance imaging and RNF213 R4810K genotyping. Patients were included in the ICAS group when relevant plaques existed on high‐resolution magnetic resonance imagingand in the MMD group when they carried the variant and high‐resolution magnetic resonance imaging showed no plaques but characteristic features of MMD. We compared clinical and neuroimaging features of patients with ICAS‐RNF213+ with patients with ICAS‐RNF213− and of patients with MMD. Of 477 patients, 238 patients were in the ICAS group and 239 were in the MMD group. Among patients with ICAS, 79 patients (33.2%) were in the ICAS‐RNF213+ group and 159 (66.8%) in the ICAS‐RNF213− group. Tandem lesions were significantly more common in the ICAS‐RNF213+ group than in the ICAS‐RNF213− group (40.3% versus 72.2%, P

Background and aims: The pathophysiology of hippocampal enlarged perivascular spaces (H-EPVS) and its relationship to cognitive impairment is largely unknown. This study aimed to investigate the relationship between H-EPVS and cognition in non-dementic elderly population.Methods: A total of 109 subjects were prospectively enrolled. The eligibilities for inclusion were age from 55 to 85 years and Mini-Mental Status Examination score of ≥26. The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Montreal Cognitive Assessment, transcranial Doppler (TCD), and brain magnetic resonance imaging results were evaluated. H-EPVS was categorized in a three-degree scale: degree 0 (no), degree 1 (1,2), and degree 2 (>2). The associations between H-EPVS and TCD parameters/cognitive test profiles were analyzed.Results: The mean age was 65.2 years, and 52.3% subjects were men. H-EPVS was found to be associated with age (degree 2 vs. degree 1 vs. degree 0, 69.20 ± 6.93 vs. 65.70 ± 5.75 vs. 63.80 ± 5.43; p = 0.030) and ADAS-Cog memory score (degree 2 vs. degree 1 vs. degree 0, 14.88 ± 4.27 vs. 12.49 ± 4.56 vs. 11.4 ± 4.23; p = 0.037). However, the pulsatility index was not related to the degree of H-EPVS. Multivariate analysis revealed medial temporal atrophy (MTA) scale score was independently associated with ADAS-Cog memory score (MTA scale sum ≥4, p = 0.011) but not with the degree of H-EPVS. MTA scale score showed correlation with H-EPVS (r = 0.273, p = 0.004).Conclusions: Aging was associated with the development of H-EPVS in non-dementic elderly population. Memory function was found to be associated with MTA but not with the degree of H-EPVS.

Background There is insufficient evidence on the effect of statins, particularly high‐intensity statins, in patients with acute ischemic stroke and atrial fibrillation. We investigated the impact of statins on the outcomes in these patients, including those who might be vulnerable to statin therapy and those without clinical atherosclerotic cardiovascular diseases. Methods and Results A total of 2153 patients with acute ischemic stroke and atrial fibrillation were enrolled in the present nationwide, multicenter, cohort study. The primary composite end point was the occurrence of net adverse clinical and cerebral events (NACCE; death from any cause, stroke, acute coronary syndrome, or major bleeding) over a 3‐year period based on statin intensity. NACCE rates were lower in patients receiving low‐ to moderate‐intensity (adjusted hazard ratio 0.64; 95% CI: 0.52‐0.78) and high‐intensity statins (hazard ratio 0.51; 95% CI 0.40‐0.66) than in those not receiving statin therapy. High‐intensity statins were associated with a lower risk for NACCE than low‐ to moderate‐intensity statins (hazard ratio 0.76; 95% CI 0.59‐0.96). Subgroup analyses showed that the differences in hazard ratio for 3‐year NACCE favored statin use across all subgroups, including older patients, those with low cholesterol levels, patients receiving anticoagulants, and patients without clinical atherosclerotic cardiovascular diseases. Magnified benefits of high‐intensity statins compared with low‐ to moderate‐intensity statins were observed in patients who underwent revascularization therapy and those under 75 years of age. Conclusions Statins, particularly high‐intensity statins, could reduce the risk for NACCE in patients with acute ischemic stroke and atrial fibrillation; this needs to be further explored in randomized controlled trials.

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.

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 volume10 s for ADC volume

Background An increased risk of acute ischemic stroke is recognized among patients with cancer. However, the mechanism behind cancer‐related stroke is unclear. In this study, we determined the presence of associated venous thromboembolism and arterial thromboembolism and their clinical impact on patients with cancer‐related stroke. Methods and Results Patients with embolic stroke of undetermined source with or without cancer were evaluated for venous thromboembolism (deep vein thrombosis [DVT] and/or pulmonary embolism) and arterial thromboembolism by using Doppler sonography to determine the presence of lower‐extremity DVT and the microembolic signal of the symptomatic cerebral circulation, respectively. Infarct volume was determined by diffusion‐weighted magnetic resonance imaging. The multivariable linear regression and Cox proportional hazard analysis were used to investigate the effect of DVT and microembolic signal on infarct volume and 1‐year survival, respectively. Of 142 screened patients, 118 were included (37 with, 81 without cancer). Those with cancer had a higher prevalence of DVT or microembolic signal than did the noncancer group (62.2% versus 19.8%; P

Background and aims: Atrial fibrillation (AF) is a major cause of ischemic stroke; however, detailed clinical data and prognostic factors for stroke patients with AF are lacking in Korea. We aimed to investigate clinical information and factors associated with functional outcomes of stroke patients with AF from the Korean nationwide ATrial fibrillaTion EvaluatioN regisTry in Ischemic strOke patieNts (K-ATTENTION) database.Methods: From January 2013 to December 2015, consecutive clinical information from acute stroke patients with AF or history of AF was collected from 11 centers in Korea. Collected data included demographics, risk factors, pre-stroke medication, stroke severity, stroke subtypes, concomitant cerebral atherosclerosis, brain image findings, recanalization therapy, discharge medication, and functional outcome at 3 months after index stroke.Results: A total of 3,213 stroke patients (mean age, 73.6 ± 9.8 years; female, 48.6%) were included. The mean CHA2DS2-VASc score was 4.9. Among the 1,849 (57.5%) patients who had brain image and functional outcome data, poor outcome (modified Rankin scale > 2) was noted in 53.1% (981/1,849) of patients. After adjusting for age, sex, and variables that had a p < 0.05 in univariate analysis or well-known factors for functional outcome, presence of asymptomatic extracranial cerebral atherosclerosis [odd ratio (OR): 1.96, 95% confidence interval (CI): 1.36–2.82, p = 0.001] and less frequent prior stroke statin intake (OR: 0.69, 95% CI: 0.49–0.98, p = 0.038) were associated with poor functional outcome.Conclusion: Our results suggest that presence of non-relevant extracranial cerebral atherosclerosis may affect poor functional outcome and prior stroke statin therapy may be feasible in Korean stroke patients with AF.

Background Intracranial atherosclerotic stroke is prevalent in Asians. We hypothesized that patients with the ring finger protein 213 (RNF213) variant, a susceptibility locus for moyamoya disease in Asians, have different neuroimaging characteristics in terms of the vessel wall and hemodynamics. Methods and Results We analyzed consecutive patients with ischemic events in middle cerebral artery distribution and relevant plaques of the distal internal carotid artery or proximal middle cerebral artery on high‐resolution magnetic resonance imaging. Patients with carotid/cardiac sources of embolism or moyamoya disease were excluded. High‐resolution magnetic resonance imaging features (eg, outer vessel diameters and plaque characteristics) and fractional flow (as measured by adjusted signal intensity ratio on time‐of‐flight magnetic resonance angiography) were compared between RNF213 p.Arg4810Lys variant carriers and noncarriers. Among 144 patients included, 44 (29.9%) had the RNF213 variant. Clinical characteristics, including age, sex, body mass index, and vascular risk factors, were not significantly different between RNF213 variant carriers and noncarriers. However, the outer vessel diameter was smaller in RNF213 variant carriers than in noncarriers (P

Background: Risk stratification of asymptomatic carotid artery stenosis (ACAS) is still an issue for carotid revascularization. We sought to identify factors associated with symptomatic carotid artery stenosis (SCAS) using multimodal imaging techniques.Methods: We retrospectively collected data on patients who underwent carotid artery revascularization. Results from duplex sonography, computerized tomography angiography, brain magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), perfusion-weighted imaging, and demographic profiles were compared between ACAS and SCAS patients. Differences in baseline characteristics between the two groups were balanced by the propensity matching score method. Multivariable regression analysis was performed to identify factors associated with symptomaticity of carotid artery stenosis. We compared the strength of associations between significant imaging factors and symptomatic carotid stenosis using C statistics.Results: A total of 259 patients (asymptomatic 57.1%, symptomatic 42.9%) with carotid stenosis were included. After 1:1 propensity score matching, the multivariable regression analysis revealed that the absence of plaque calcification [Odds ratio 0.41, 95% confidence interval (CI) 0.182–0.870, p = 0.023], deep white matter hyperintensity (DWMH; Odds ratio 3.46, 95% CI 1.842–6.682, p < 0.001), susceptibility vessel sign seen on gradient-echo MRI (Odds ratio 2.35, 95% CI 1.113–5.107, p = 0.027), and increased cerebral blood volume (CBV) seen on perfusion-weighted MRI (CBV; Odds ratio 2.17, 95% CI 1.075–4.454, p = 0.032) were associated with SCAS. The combination of these variables had a fair accuracy to classify SCAS (Area under the curve 0.733, 95% CI 0.662–0.803).Conclusions: We identified several multimodal imaging markers independently associated with SCAS. These markers may provide information to identify ACAS patients with high risk of ischemic stroke. Future studies are needed to predict SCAS using our findings in other independent cohorts.

Background and Purpose: Despite the recent growing interest in the cancer–stroke association, the long-term effect, and organ-specific association with stroke incidence in subjects with cancer have not been clearly defined.Methods: Data were obtained from the Korean National Health Insurance Service National Sample Cohort database between 2002 and 2015. To investigate the effects of cancer on stroke incidence, subjects were classified into cancer and non-cancer groups based on the period after cancer diagnosis and origin organ of cancer. To minimize the effects of selection bias, we performed a propensity score matching analysis with covariates of demographic data, vascular risk factors, antithrombotics use and statin use. Incident stroke was diagnosed based on operational definition and classified into ischemic stroke and hemorrhagic stroke.Results: Data of 20,707 subjects with cancer and 675,594 without cancer were analyzed for 7 follow-up years. The subjects with cancer had higher risk of any stroke (subdistribution hazard ratio [SHR], 1.13; 95% confidence interval [CI], 1.02–1.26; p = 0.0181) than those without cancer. Similar trend was found for ischemic stroke (SHR, 1.17; 95% CI, 1.05–1.31; p = 0.0054), but not for hemorrhagic stroke. The risk of stroke was increased in subjects with cancer in the digestive organ, respiratory and intrathoracic organ, and “others (such as breast and female and male reproductive organs)” in 3 years; however, the association disappeared thereafter except those with “others” cancer. Chemotherapy increased the risk of ischemic stroke (SHR 1.21; 95% CI, 1.03–1.41).Conclusions: Cancer increases the risk of stroke at 3 years after the diagnosis of cancer, and the effect was maintained for 7 years. The association between cancer and stroke incidence depends on the organ from which the cancer originated and chemotherapy.

ObjectiveIn vivo visualization of intracranial atherosclerotic plaque has been performed only with high-resolution magnetic resonance imaging (HRMR). We investigated whether atherosclerotic plaque of the basilar artery (BA) can be identified in conventional magnetic resonance imaging (MRI).MethodsPatients with acute ischemic stroke who had BA stenosis ("symptomatic BAA") were retrospectively recruited using the prospective stroke registry. In the HRMR databank, subjects without BA stenosis were recruited and classified as those with silent plaque ("silent BAA") and without any plaque ("normal controls"). Outer diameter of the BA and T2 plaque sign (an eccentric or complete obscuration of normal flow-void) within the BA were assessed by two blinded raters using conventional T2 MRI.ResultsSeventy-five patients with symptomatic BAA, 40 with asymptomatic BAA, and 36 normal controls were included in the study. Maximal BA diameter was significantly larger in symptomatic BAA patients with 70% stenosis (all pConclusionsOur data suggest that BA atherosclerosis can be detected by conventional MRI. When the use of HRMR is limited, conventional MR imaging may give additive information to clinicians.

Background and Purpose Left atrial dysfunction has been reported in patients with patent foramen ovale (PFO). Here we investigated the role of left atrial dysfunction in the development of embolic stroke in patients with PFO. Methods We identified consecutive patients with embolic stroke of undetermined sources except for PFO (PFO+ESUS). Healthy subjects with PFO served as controls (PFO+control). A stratified analysis by 10-year age group and an age- and sex- matching analysis were performed to compare echocardiographic markers between groups. In the PFO+ESUS group, infarct patterns of PFO-related stroke were determined (cortical vs. cortico-subcortical) and analyzed in correlation with left atrial function parameters. Results A total of 118 patients and 231 controls were included. The left atrial volume indices (LAVIs) of the PFO+ESUS patients were higher than those of the PFO+controls in age groups of 40–49, 50–59, and 60–69 years (P28 mL/m2) LAVI was more associated with the cortical infarct pattern (P=0.043 for an acute infarction and P=0.024 for a chronic infarction, both adjusted for age and shunt amount). The degree of right-to-left shunting was not associated with infarct patterns, but with the posterior location of acute infarcts (P=0.028). Conclusions Left atrial enlargement was associated with embolic stroke in subjects with PFO. Left atrial physiology might contribute to the development of PFO-related stroke and need to be taken into consideration for optimal prevention of PFO-related stroke.

Revascularization therapies have been established as the treatment mainstay for acute ischemic stroke. However, a substantial number of patients are either ineligible for revascularization therapy, or the treatment fails or is futile. At present, non-contrast computed tomography is the first-line neuroimaging modality for patients with acute stroke. The use of magnetic resonance imaging (MRI) to predict the response to early revascularization therapy and to identify patients for delayed treatment is desirable. MRI could provide information on stroke pathophysiologies, including the ischemic core, perfusion, collaterals, clot, and blood–brain barrier status. During the past 20 years, there have been significant advances in neuroimaging as well as in revascularization strategies for treating patients with acute ischemic stroke. In this review, we discuss the role of MRI and post-processing, including machine-learning techniques, and recent advances in MRI-based triage for revascularization therapies in acute ischemic stroke.

BackgroundFrom a therapeutic viewpoint, it is important to differentiate the underlying causes of embolism in patients with cryptogenic stroke, such as aortic arch atheroma, patent foramen ovale, and paroxysmal atrial fibrillation. We investigated the clinical and radiological characteristics of these 3 common causes of cryptogenic embolism to develop models for decision making in etiologic workups. Methods and ResultsA total of 321 consecutive patients with acute infarcts from cryptogenic embolism were included. Patients were divided into 3 groups—aortic arch atheroma (n=40), patent foramen ovale (n=153), and paroxysmal atrial fibrillation (n=128)—based on extensive cardiologic workups. We used a multinomial logistic regression analysis to detect the clinical and diffusion‐weighted imaging factors associated with the probability of aortic arch atheroma, patent foramen ovale, and paroxysmal atrial fibrillation. Clinical and radiological features differed among the groups. The patent foramen ovale group had a healthy vascular risk factor profile and showed posterior circulation involvement compared with other groups (P

Cancer and stroke, which are known to be associated with one another, are the most common causes of death in the elderly. However, the pathomechanisms that lead to stroke in cancer patients are not well known. Circulating extracellular vesicles (EVs) play a role in cancer-associated thrombosis and tumor progression. Therefore, we hypothesized that cancer cell-derived EVs cause cancer-related coagulopathy resulting in ischemic stroke.Serum levels of D-dimer and EVs expressing markers for cancer cells (epithelial cell adhesion molecule [CD326]), tissue factor (TF [CD142]), endothelial cells (CD31+CD42b-), and platelets (CD62P) were measured using flow cytometry in (a) 155 patients with ischemic stroke and active cancer (116 - cancer-related, 39 - conventional stroke mechanisms), (b) 25 patients with ischemic stroke without cancer, (c) 32 cancer patients without stroke, and (d) 101 healthy subjects.The levels of cancer cell-derived EVs correlated with the levels of D-dimer and TF+ EVs. The levels of cancer cell-derived EVs (CD326+ and CD326+CD142+) were higher in cancer-related stroke than in other groups (P

Both Moyamoya disease (MMD) and intracranial atherosclerotic stenosis (ICAS) are more prevalent in Asians than in Westerners. We hypothesized that a substantial proportion of patients with adult-onset MMD were misclassified as having ICAS, which may in part explain the high prevalence of intracranial atherosclerotic stroke in Asians.We analyzed 352 consecutive patients with ischemic events within the MCA distribution and relevant intracranial arterial stenosis, but no demonstrable carotid or cardiac embolism sources. Conventional angiography was performed in 249 (70.7%) patients, and the remains underwent MRA. The occurrence of the c.14429G>A (p.Arg4810Lys) variant in ring finger protein 213 (RNF213) was analyzed. This gene was recently identified as a susceptibility gene for MMD in East Asians.The p.Arg4810Lys variant was observed in half of patients with intracranial stenosis (176 of 352, 50.0%), in no healthy control subjects (n = 51), and in 3.2% of stroke control subjects (4 of 124 patients with other etiologies). The presence of basal collaterals, bilateral involvement on angiography, and absence of diabetes were independently associated with the presence of the RNF213 variant. Among 131 patients who met all three diagnostic criteria and were diagnosed with MMD, three-fourths (75.6%) had this variant. However, a significant proportion of patients who met two criteria (57.7%), one criterion (28.6%), or no criteria (20.0%) also had this variant. Some of them developed typical angiographic findings of MMD on follow-up angiography.Careful consideration of MMD is needed when diagnosing ICAS because differential therapeutic strategies are required for these diseases and due to the limitations of the current diagnostic criteria for MMD.

Growing evidence suggests that cells undergo apoptosis after spinal cord injury (SCI). However, little is known about the early events that trigger apoptosis in the contused cord. The BH3-only subfamily of pro-apoptotic regulators (e.g., bim, bad, and dp5) is recognized as initiators of the apoptotic cascade, and is subject to stringent control, both at the transcriptional and post-translational level. In the current study, we studied upstream events regulating trauma-induced apoptosis in the spinal cord. Within 1 h after SCI in rats, DP5 was induced, while Bim and Bad levels remained unchanged. In parallel, SCI also activated the stress-induced c-Jun N-terminal kinase (JNK), leading to the phosphorylation of c-Jun, with a similar temporal profile. Immunohistochemical analysis revealed that p-JNK and DP5 colocalized to neurons and oligodendrocytes undergoing apoptosis in the injured cord, but were absent in uninjured spinal cord. Furthermore, inhibition of JNK activity with in vivo delivery of SP600125 or a jnk1 antisense oligodeoxynucleotide (ODN) attenuated DP5 induction and caspase-3 activation. These results suggest that JNK activation contributes to trauma-induced DP5 expression and subsequent apoptosis in SCI.

BACKGROUND: Leukoaraiosis and cerebral microbleeds (CMB), which represent cerebral microangiopathy, commonly coexist in patients with acute lacunar stroke. Since they may have different impacts on stroke prognosis and treatment, it is important to know the factors associated with leukoaraiosis-predominant vs. CMB-predominant microangiopathies. METHODS: We prospectively recruited 226 patients with acute lacunar infarction and divided them into four groups according to the Fazekas' score and the presence of CMB: mild, red (predominant CMB), white (predominant leukoaraiosis) and severe microangiopathy groups. For comparison, we also evaluated 50 patients with intracerebral hemorrhage (ICH). We evaluated the clinical and laboratory findings of microangiopathy subtypes in patients with acute lacunar stroke and then compared them with those of primary ICH. RESULTS: The risk factor profile was different among the groups. Patients with acute lacunar infarct but mild microangiopathy were younger, predominantly male, less hypertensive, and more frequently had smoking and heavy alcohol habits than other groups. The risk factor profile of red microangiopathy was similar to that of ICH but differed from that of white microangiopathy. The subjects in the white microangiopathy group were older and more frequently had diabetes than those in the red microangiopathy or ICH group. After adjustments for other factors, age [odds ratio (OR) 1.13; 95% confidence interval (CI) 1.08-1.18; p

Background: Constipation symptoms are highly prevalent in acute ischemic stroke, but the clinical and neuroimaging predictors are unknown. This study aimed to identify lesions and clinical features associated with acute constipation. Methods: Data from patients with acute ischemic stroke registered in a hospitalbased stroke registry between January 2018 and December 2019 were analyzed. Clinical, laboratory, and imaging features were examined for associations with acute constipation. Using the topographic lesion on diffusion-weighted images, multivariate support vector regression-based lesion-symptom mapping (SVRLSM) was conducted and compared between the non-constipation and acute constipation groups. Results: A total of 256 patients (mean age 67 years, men: 64%) were included. Acute constipation was noted in 81 patients (32%). Initial stroke severity, represented by initial National Institutes of Health and Stroke Scale (NIHSS) scores, was associated with acute constipation. Laboratory parameters, including fibrin degradation products (FDP), fibrinogen, D-dimer, lipoprotein (a), and free fatty acid levels, also showed statistically significant differences between the nonconstipation and constipation groups. FDP, D-dimer, and free fatty acid levels were independently associated with acute constipation in the logistic regression model after adjusting for initial NIHSS scores and potassium levels. SVR-LSM revealed that bilateral lesions in the precentral gyrus, insula, opercular part of the inferior frontal gyrus, the inferior parietal lobule, and lesions in the right middle frontal gyrus were significantly associated with acute constipation. The results were consistent after controlling for the initial NIHSS scores and poststroke potassium levels. When cardioembolic stroke subjects were excluded, the right insular and prefrontal cortex lesions lost their association with acute constipation. Conclusion: Acute constipation symptoms after acute ischemic stroke are mainly related to bilateral lesions in the insula, precentral gyrus, postcentral gyrus, and inferior parietal lobule. Clinically important predictors of acute constipation include initial neurological severity and thromboembolic markers of stroke. [ABSTRACT FROM AUTHOR]