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Objective Mutations in the colony‐stimulating factor 1 receptor gene (CSF1R) were identified as a cause of adult‐onset inherited leukoencephalopathy. The present study aims at investigating the frequency, clinical characteristics, and functional effects of CSF1R mutations in Taiwanese patients with adult‐onset leukoencephalopathy. Methods Mutational analysis of CSF1R was performed in 149 unrelated individuals with leukoencephalopathy by a targeted resequencing panel covering the entire coding regions of CSF1R. In vitro analysis of the CSF1‐induced autophosphorylation activities of mutant CSF1R proteins was conducted to assess the pathogenicity of the CSF1R mutations. Results Among the eight CSF1R variants identified in this study, five mutations led to a loss of CSF1‐induced autophosphorylation of CSF1R proteins. Four mutations (p.K586*, p.G589R, p.R777Q, and p.R782C) located within the tyrosine kinase domain of CSF1R, whereas the p.T79M mutation resided in the immunoglobulin‐like domain. The five patients carrying the CSF1R mutations developed cognitive decline at age 41, 43, 50, 79, and 86 years, respectively. Psychiatric symptoms and behavior changes were observed in four of the five patients. The executive function and processing speed were severely impaired at an early stage, and their cognitive function deteriorated rapidly within 3–4 years. Diffusion‐restricted lesions at the subcortical regions and bilateral corticospinal tracts were found in three patients. Interpretation CSF1R mutations account for 3.5% (5/149) of the adult‐onset leukoencephalopathy in Taiwan. CSF1R mutations outside the tyrosine kinase domain may also disturb the CSF1R function and lead to the clinical phenotype. Molecular functional validation is important to determine the pathogenicity of novel CSF1R variants.

Aim Chronic kidney disease (CKD) is associated with unfavorable outcomes in patients with ischemic stroke. One major metabolic derangement of CKD is dyslipidemia, which can be managed by statins. This study aimed to investigate whether the association of statins with post-stroke outcomes would be affected by renal function. Methods We evaluated the association of statin therapy at discharge with 3-month outcomes according to the estimated glomerular filtration rate (eGFR) of 50,092 patients with acute ischemic stroke from the Taiwan Stroke Registry from August 2006 to May 2016. The outcomes were mortality, functional outcome as modified Rankin Scale (mRS), and recurrent ischemic stroke at 3 months after index stroke. Results Statin therapy at discharge was associated with lower risks of mortality (adjusted hazard ratio [aHR], 0.41; 95% confidence interval [CI], 0.34 to 0.50) and unfavorable functional outcomes (mRS 3-5; aHR, 0.80; 95% CI, 0.76 to 0.84) in ischemic stroke patients. After stratification by eGFR, the lower risk of mortality associated with statins was limited to patients with an eGFR above 15 mL/min/1.73 m2. Using statins at discharge was correlated with a lower risk of unfavorable functional outcomes in patients with an eGFR of 60-89 mL/min/1.73 m2. Statin therapy in patients with an eGFR of 60-89 mL/min/1.73 m2 may be associated with a higher risk of recurrent ischemic stroke compared with nonusers (aHR, 1.29; 95% CI, 1.07 to 1.57). Conclusions In patients with acute ischemic stroke, the associations of statins with mortality and functional outcomes was dependent on eGFR.

Cryptogenic stroke comprises about one-quarter of ischemic strokes with high recurrence rate; however, studies specifically investigating the features and treatment of this stroke subtype are rare. The concept of ‘embolic stroke of undetermined source’ (ESUS) may facilitate the development of a standardized approach to diagnose cryptogenic stroke and improve clinical trials. Since recent large randomized control trials failed to demonstrate a reduction in stroke recurrence with anticoagulants, anti-platelet agents remain the first-line treatment for ESUS patients. Nevertheless, patients with high risk of stroke recurrence (e.g., those with repeated embolic infarcts despite aspirin treatment) require a more extensive survey of stroke etiology, including cardiac imaging and prolonged cardiac rhythm monitoring. Anticoagulant treatments may still benefit some subgroups of high-risk ESUS patients, such as those with multiple infarcts at different arterial territories without aortic atheroma, the elderly, or patients with high CHA2D2-VASc or HOVAC scores, atrial cardiopathy or patent foramen ovale. Several important ESUS clinical trials are ongoing, and the results are anticipated. With rapid progress in our understanding of ESUS pathophysiology, new subcategorizations of ESUS and assignment of optimal treatments for each ESUS subgroup are expected in the near future.

BACKGROUND AND PURPOSE The CHA2 DS2 -VASc score has immense prognostic value in patients with embolic stroke of undetermined source (ESUS). We aimed to determine the usefulness of advanced renal dysfunction and its addition to the CHA2 DS2 -VASc score in improving predictive accuracy. METHODS In total, 3775 ESUS patients were enrolled from a nationwide hospital-based prospective study. Advanced renal dysfunction was defined as estimated glomerular filtration rate 2 at first-, third-, and sixth-month post-stroke. The renal (R)-CHA2 DS2 -VASc score was derived by including advanced renal dysfunction in the CHA2 DS2 -VASc score. Risk stratification improvement after including advanced renal dysfunction was assessed using C statistic, integrated discrimination improvement (IDI), and category-free net reclassification index (NRI). RESULTS After adjusting for confounding factors and CHA2 DS2 -VASc score, advanced renal dysfunction showed significant associations with all-cause mortality (HR: 2.88, 95% CI: 1.92-4.34) and poor functional outcome at third- (OR: 2.69, 95% CI: 1.47-4.94) and sixth-month post-stroke (OR: 2.67, 95% CI: 1.47-4.83). IDI and NRI showed that incorporating advanced renal dysfunction significantly improved risk discrimination over the original CHA2 DS2 -VASc score. R-CHA2 DS2 -VASc score ≥2 increased risk by 1.94-fold (95% CI: 1.15-3.27) for all-cause mortality, and ≥4 increased risk by 1.62-fold (95% CI: 1.05-2.50) of poor functional outcome at third-month post-stroke and by 1.81-fold (95% CI: 1.19-2.75) at sixth-month post-stroke. CONCLUSIONS Advanced renal dysfunction was significantly associated with clinical and functional outcomes in ESUS patients and may improve prognostic impact of the CHA2 DS2 -VASc score.

Background and Aim Previous studies indicated that the HDAC3 and HDAC9 genes play critical roles in atherosclerosis and ischemic stroke (IS). The purpose of this study was to investigate the association of combined single-nucleotide polymorphisms in the HDAC3 and HDAC9 genes with the susceptibility to IS. Methods A case–control study was conducted including 863 IS patients and 863 age- and gender-matched healthy participants. A polygenic score was developed to estimate the contribution of a combination of the HDAC3 and HDAC9 genes to the risk of IS. The interactive effects of traditional risk factors of stroke and the polygenic score on the risk of IS were explored. Additionally, the association between the polygenic score and the progression of atherosclerosis, a potential risk factor of IS, was examined in our healthy controls. Results Subjects with a higher polygenic score had an increased risk of IS (odds ratio: 1.83; 95% confidence interval: 1.38–2.43) after adjusting for covariates compared with individuals with a lower polygenic score. An interactive effect of diabetes mellitus and the polygenic score on the risk of IS was observed. A significant positive correlation between the polygenic score and a change in the plaque score (standardized β = 0.42, p = 0.0235) in healthy controls with diabetes mellitus was found. Conclusion Our results suggested that the combination of the HDAC3 and HDAC9 genes with a history of diabetes mellitus could exacerbate the deterioration of atherosclerosis, thereby increasing the risk of IS. Further studies are warranted to explore our results in other populations.

Summary Objective This study used the Taiwan Stroke Registry data to evaluate the efficacy and safety of intravenous tissue plasminogen activator (tPA) in treating acute ischemic stroke in patients with renal dysfunction. Design We identified 3525 ischemic stroke patients and classified them into two groups according to the estimated glomerular filtration rate (eGFR) at the emergency department: ≥60, and Results Among patients with eGFR levels of Conclusions tPA for acute ischemic stroke could improve functional outcomes without increasing the risks of upper gastrointestinal bleeding for patients with or without renal dysfunction. The low eGFR was not a significant risk factor for intracerebral hemorrhage among patients receiving tPA treatment.

Objective: Stroke in young adults is uncommon, and the etiologies and risk factors of stroke in young adults differ from those in older populations. Smoker's paradox is an unexpected favorable outcome, and age difference is used to explain the association between smoking and the favorable functional outcome. This study aimed to investigate the existence of this phenomenon in young stroke patients.Methods: We analyzed a total of 9,087 young stroke cases registered in the nationwide stroke registry system of Taiwan between 2006 and 2016. Smoking criteria included having a current history of smoking more than one cigarette per day for more than 6 months. After matching for sex and age, a Cox model was used to compare mortality and function outcomes between smokers and non-smokers.Results: Compared with the non-smoker group, smoking was associated with older age, higher comorbidities, and higher alcohol consumption. Patients who report smoking with National Institutes of Health Stroke Scale scores of 11–15 had a worse functional outcome (adjusted odds ratio, 0.81; 95% confidence interval, 0.76 – 0.87).Conclusion: Smokers had a higher risk of unfavorable functional outcomes at 3 months after stroke, and therefore, we continue to strongly advocate the importance of smoking cessation.

Highlights • More patients with chronic hepatitis B (CHB) are surviving into old age. • The late-life health-related quality of life (HRQoL) they might experience remains unclear. • We repeatedly assessed HRQoL in a cohort of older adults with CHB over five years. • The HRQoL changes older CHB patients might experience were delineated. • Extrahepatic organ/system abnormalities were associated with changes in HRQoL., Despite the increasing health burden of chronic hepatitis B (CHB) in aging populations, little is known about the course of health-related quality of life (HRQoL) changes. We aimed to assess individual-level longitudinal HRQoL changes in elderly patients with CHB and to examine their correlates. A prospective 5.1 years-cohort study was conducted in community-dwelling adults aged 55 years with hepatitis B surface antigen-positive. Participants underwent serial measurement of HRQoL using the short-form (12) health survey version 2. Of 503 participants, 82.7% remained in good physical health throughout the study period, whereas 9.1% had declining physical health and 8.2% were in poor physical health. We likewise identified three trajectories of mental health changes (“good mental health” [86.9%], “declining mental health” [6.8%], and “poor mental health” [6.4%]). Three baseline characteristics were independently associated with a lower likelihood of remaining physically or mentally healthy: sarcopenic obesity (odds ratio [OR] with 95% confidence interval [95% CI] of 7.5 [2.8–20.5] for poor physical health, 3.1 [1.1–8.4] for declining physical health, 4.3 [1.4–13.0] for poor mental health), a higher number of metabolic abnormalities (OR [95% CI] of 3.6 [1.6–8.0] for poor physical health) and depressed mood (OR [95% CI] of 21.7 [5.8–81.0] for poor physical health, 5.3 [1.4–19.9] for declining physical health, 83.1 [19.7–350.2] for poor mental health, 13.6 [2.9–64.8] for declining mental health). In conclusion, in a cohort of elderly patients with CHB, we demonstrated the heterogeneity and nonlinearity of HRQoL changes and their associations with variations in specific extrahepatic organs/systems.

Vincristine is a clinically used antimicrotubule drug for treating patients with lymphoma. Due to its property of increasing platelet counts, vincristine is also used to treat patients with immune thrombocytopenia. Moreover, antiplatelet agents were reported to be beneficial in thrombotic thrombocytopenic purpura (TTP). Therefore, we investigated the detailed mechanisms underlying the antiplatelet effect of vincristine. Our results revealed that vincristine inhibited platelet aggregation induced by collagen, but not by thrombin, arachidonic acid, and the thromboxane A2 analog U46619, suggesting that vincristine exerts higher inhibitory effects on collagen-mediated platelet aggregation. Vincristine also reduced collagen-mediated platelet granule release and calcium mobilization. In addition, vincristine inhibited glycoprotein VI (GPVI) signaling, including Syk, phospholipase Cγ2, protein kinase C, Akt, and mitogen-activated protein kinases. In addition, the in vitro PFA-100 assay revealed that vincristine did not prolong the closure time, and the in vivo study tail bleeding assay showed that vincristine did not prolong the tail bleeding time, both findings suggested that vincristine may not affect normal hemostasis. In conclusion, we demonstrated that vincristine exerts antiplatelet effects at least in part through the suppression of GPVI signaling. Moreover, this property of antiplatelet activity of vincristine may provide additional benefits in the treatment of TTP.

OBJECTIVES Studies on the association of estimated glomerular filtration rate (eGFR) levels with hospital discharge disposition after stroke are limited with inconsistent results. This study investigated the odds of home discharge with eGFR levels at admission for patients with stroke using the Taiwan Stroke Registry (TSR) data. METHODS From the TSR database, a total of 51,338 stroke patients from 2006 to 2015 were categorized into five groups based on eGFR levels at admission. The proportion of home discharge by the eGFR levels was calculated and logistic regression analysis was used to estimate the related odds ratio (OR) and 95% confidence interval. RESULTS Near 85% of stroke patients were discharged to home. The proportion of home discharges decreased as the eGFR level declined. Compared to patients with eGFR ≥90 mL/min/1.73 m2, the adjusted ORs of home discharge were 0.91, 0.85, 0.63, 0.56 for patients with eGFR 60-89, eGFR 30-59, eGFR 15-29, and eGFR < 15 mL/min/1.73 m2 or on dialysis, respectively, in a graded relationship. The trends were consistent in the ischemic stroke and hemorrhagic stroke patients. The areas under the receiver operating characteristic curve for all stroke patients, ischemic stroke patients, and hemorrhagic stroke patients were 0.801, 0799, 0.815, respectively. CONCLUSION The odds of home discharge for stroke patients decreased with a significant independent graded association with declining eGFR levels. Renal function could predict home discharge after stroke.

Background Growing evidence shows links between septicaemia and non-multiple sclerosis demyelinating syndromes (NMSDS); nevertheless, epidemiological data are still very limited. This study aimed to explore the relationship between septicaemia and NMSDS in a general population. Methods The study included 482 781 individuals diagnosed with septicaemia and 1 892 825 age/sex-matched non-septicaemia patients for the comparison. Data were drawn from a population-based nationwide National Health Insurance Research Database Taiwan, from 1 January 2002 to 31 December 2011. The two cohorts of patients with and without septicaemia were followed up for the occurrence of NMSDS. The Cox-proportional hazard regression model was performed to estimate adjusted HR after multivariate adjustment. Results Individuals with septicaemia had a 4.17-fold (95% CI 3.21 to 5.4, p < 0.001) higher risk to develop NMSDS compared with those without septicaemia. Patients aged Conclusions Our results indicated that patients with septicaemia were likely to develop NMSDS. A possible contributing role of septicaemia in increasing the hazard of NMSDS is proposed, based on the outcome that individuals with higher severity of septicaemia carried elevated threat of encountering NMSDS.

Background: The natural history of vertebrobasilar artery (VBA) stenosis or occlusion remains understudied. Methods: Patients with diagnosis of ischemic stroke or transient ischemic attack (TIA) who were noted to have VBA stenosis based on computed tomography or magnetic resonance imaging or catheter-based angiogram were selected from Taiwan Stroke Registry. Cox proportional hazards model was used to determine the hazards ratio (HR) of recurrent stroke and death within 1 year of index event in various groups based on severity of VBA stenosis (none to mild: 0–49%; moderate to severe: 50–99%: occlusion: 100%) after adjusting for differences in demographic and clinical characteristics between groups at baseline evaluation. Results: None to mild or moderate to severe VBA stenosis was diagnosed in 6972 (66%) and 3,137 (29.8%) among 10,515 patients, respectively, and occlusion was identified in 406 (3.8%) patients. Comparing with patients who showed none to mild stenosis of VBA, there was a significantly higher risk of recurrent stroke (HR 1.21, 95% CI 1.01–1.45) among patients with moderate to severe VBA stenosis. There was a nonsignificantly higher risk of recurrent stroke (HR 1.49, 95% CI 0.99–2.22) and significantly higher risk of death (HR 2.21, 95% CI 1.72–2.83), among patients with VBA occlusion after adjustment of potential confounders. Conclusions: VBA stenosis or occlusion was relatively prevalent among patients with TIA or ischemic stroke and associated with higher risk of recurrent stroke and death in patients with ischemic stroke or TIA who had large artery atherosclerosis.

Objective: Stroke in young adults is uncommon, and the etiologies and risk factors of stroke in young adults differ from those in the older populations. Smoker’s paradox is an unexpected favorable outcome, and age difference was used to explain the association between smoking and the favorable functional outcome. This study aimed to investigate the existence of this phenomenon in young stroke patients.Methods: We analyzed a total of 9,460 young stroke cases registered in the nationwide stroke registry system of Taiwan between 2006 and 2016. Smoking criteria included having a past or current history of smoking more than 1 cigarette per day for more than 6 months. After matching for sex and age, a Cox model was used to compare complications, mortality and outcomes between smokers and non-smokers.Results: Smoking was associated with older age, higher comorbidities, and higher alcohol consumption. Smoking patients with NIHSS scores of 11–15 had a worse functional outcome (adjusted OR, 0.81; 95% CI, 0.76–0.87), and smoking cessation would substantially reverse those effects.Conclusion: The smoker’s paradox definitely does not exist, and therefore we continue to strongly advocate the importance of smoking cessation.

Normal aging is associated with functional and structural alterations in the human brain. The effects of normal aging and gender on morphological changes in specific regions of the brain are unknown. The fractal dimension (FD) can be a quantitative measure of cerebral folding. In this study, we used 3D-FD analysis with the Desikan&ndash, Killiany (DK) atlas to assess subregional morphological changes in adulthood. A total of 258 participants (112 women and 146 men) aged 30&ndash, 85 years participated in this study. Participants in the middle-age group exhibited a decreased FD in the lateral frontal lobes, which then spread to the temporal and parietal lobes. Men exhibited an earlier and more significant decrease in FD values, mainly in the right frontal and left parietal lobes. Men exhibited more of a decrease in FD values in the subregions on the left than those in the right, whereas women exhibited more of a decrease in the lateral subregions. Older men were at a higher risk of developing mild cognitive impairment (MCI) and exhibited age-related memory decline earlier than women. Our FD analysis using the DK atlas-based prediagnosis may provide a suitable tool for assessing normal aging and neurodegeneration between groups or in individual patients.

Previously, we reported that phospholipase D1 (PLD1) and PLD2 inhibition by selective PLD1 and PLD2 inhibitors could prevent platelet aggregation in humans, but not in mice. Moreover, only the PLD1 inhibitor, but not PLD2 inhibitor, could effectively prevent thrombus formation in mice, indicating that PLD might play different roles in platelet function in humans and mice. Although PLD1 and PLD2 were reported to be implicated in thrombotic events, the role of PLD in mice remains not completely clear. Here, we investigated the role of PLD1 and PLD2 in acute pulmonary thrombosis and transient middle cerebral artery occlusion-induced brain injury in mice. The data revealed that inhibition of PLD1, but not of PLD2, could partially prevent pulmonary thrombosis-induced death. Moreover, concurrent PLD1 and PLD2 inhibition could considerably increase survival rate. Likewise, inhibition of PLD1, but not PLD2, partially improved ischemic stroke and concurrent inhibition of PLD1, and PLD2 exhibited a relatively better protection against ischemic stroke, as evidenced by the infarct size, brain edema, modified neurological severity score, rotarod test, and the open field test. In conclusion, PLD1 might play a more important role than PLD2, and both PLD1 and PLD2 could act synergistically or have partially redundant functions in regulating thrombosis-relevant events.

Activated microglia are crucial in the regulation of neuronal homeostasis and neuroinflammation. They also contribute to neuropathological processes after ischemic stroke. Thus, finding new approaches for reducing neuroinflammation has gained considerable attention. The metal ruthenium has gained notable attention because of its ability to form new complexes that can be used in disease treatment. [Ru(&eta, 6-cymene)2-(1H-benzoimidazol-2-yl)-quinoline Cl]BF4 (TQ-6), a potent ruthenium (II)-derived compound, was used in this study to investigate its neuroprotective action against microglia activation, middle cerebral artery occlusion (MCAO)-induced embolic stroke, and platelet activation, respectively. TQ-6 (2 &mu, M) potently diminished inflammatory mediators (nitric oxide/inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2)) expression, nuclear factor kappa B (NF-&kappa, B) p65 phosphorylation, nuclear translocation, and hydroxyl radical (OH&bull, ) formation in LPS-stimulated microglia. Conversely, TQ-6 increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Moreover, it significantly reduced brain infarct volume and edema in MCAO mice. Additionally, it drastically inhibited platelet aggregation and OH&bull, production in mice platelets. This study confirmed that TQ-6 exerts an anti-neuroinflammatory effect on microglia activation through neuroprotection, antiplatelet activation, and free radical scavenging. The authors propose that TQ-6 might mitigate neurodegenerative pathology by inhibiting the NF-&kappa, B-mediated downstream pathway (iNOS and COX-2) and enhancing Nrf2/HO-1 signaling molecules in microglia.

Supplemental Digital Content is available in the text., Background and Purpose: Among patients with a transient ischemic attack or minor ischemic strokes, those with ipsilateral atherosclerotic stenosis of cervicocranial vasculature have the highest risk of recurrent vascular events. Methods: In the double-blind THALES (The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death) trial, we randomized patients with a noncardioembolic, nonsevere ischemic stroke, or high-risk transient ischemic attack to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2–30) or placebo added to aspirin (300–325 mg on day 1 followed by 75–100 mg daily for days 2–30) within 24 hours of symptom onset. The present paper reports a prespecified analysis in patients with and without ipsilateral, potentially causal atherosclerotic stenosis ≥30% of cervicocranial vasculature. The primary end point was time to the occurrence of stroke or death within 30 days. Results: Of 11 016 randomized patients, 2351 (21.3%) patients had an ipsilateral atherosclerotic stenosis. After 30 days, a primary end point occurred in 92/1136 (8.1%) patients with ipsilateral stenosis randomized to ticagrelor and in 132/1215 (10.9%) randomized to placebo (hazard ratio 0.73 [95% CI, 0.56–0.96], P=0.023) resulting in a number needed to treat of 34 (95% CI, 19–171). In patients without ipsilateral stenosis, the corresponding event rate was 211/4387 (4.8%) and 230/4278 (5.4%), respectively (hazard ratio, 0.89 [95% CI, 0.74–1.08]; P=0.23, Pinteraction=0.245). Severe bleeding occurred in 4 (0.4%) and 3 (0.2%) patients with ipsilateral atherosclerotic stenosis on ticagrelor and on placebo, respectively (P=NS), and in 24 (0.5%) and 4 (0.1%), respectively, in 8665 patients without ipsilateral stenosis (hazard ratio=5.87 [95% CI, 2.04–16.9], P=0.001). Conclusions: In this exploratory analysis comparing ticagrelor added to aspirin to aspirin alone, we found no treatment by ipsilateral atherosclerosis stenosis subgroup interaction but did identify a higher absolute risk and a greater absolute risk reduction of stroke or death at 30 days in patients with ipsilateral atherosclerosis stenosis than in those without. In this easily identified population, ticagrelor added to aspirin provided a clinically meaningful benefit with a number needed to treat of 34 (95% CI, 19–171). Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03354429.

Objective Overweight and hyperlipidemia, the two established risk factors for acute ischemic stroke, are paradoxically associated with favorable outcomes. The paradox may be resolved by the concept of protein energy wasting (PEW), in which total cholesterol level and body mass index are used as nutritional indexes for predicting outcomes of chronic kidney disease. Methods Among 12 271 people with acute ischemic stroke and chronic kidney disease, 2086 were defined as being at risk of PEW—with a body mass index Results Based on the propensity score, 2081 PEW participants were matched to the same number of non-PEW control participants. PEW was associated with a higher mortality risk at 3 mo (adjusted hazard ratio, 1.19; 95% confidence interval [CI], 1.02–1.42) and 1 y (adjusted hazard ratio, 1.33; 95% CI1.13–1.52). PEW was also associated with poor functional outcomes (modified Rankin Scale score >2) at 1 mo (adjusted odds ratio, 1.32; 95% CI, 1.08–1.61) and 3 mo (adjusted odds ratio, 1.27; 95% CI, 1.03–1.56). Conclusions According to the PEW-based assessment system, a modest decrease in body mass index and total cholesterol levels suggests malnutrition and is associated with adverse outcomes of acute ischemic stroke.

Objective Features of cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy ( CADASIL) caused by NOTCH3 mutations vary between ethnicities and regions. In Taiwan, more than 70% of CADASIL patients carry the mutation hot spot of p.R544C. We investigated the prevalence of NOTCH3 p.R544C mutation in stroke patients in Taiwan. Methods This prospective, multicenter study recruited acute stroke patients within 10 days of symptom onset. The p.R544C mutation was identified by polymerase chain reaction with confronting two‐pair primers and sequencing. Clinical parameters, vascular risk factors, stroke subtypes, and stroke outcomes were analyzed. Results Of the 1970 stroke patients (mean age 61.1 ± 13.6 years, male 69.5%) included, 1705 (86.5%) had ischemic stroke and 265 (13.5%) had intracerebral hemorrhage. The prevalence of p.R544C in the study population was 2.8% (95% confidence interval [CI] = 2.1–3.5%). The prevalence was highest in patients with small vessel occlusion type of ischemic stroke (5.6%), followed by intracerebral hemorrhage (5.3%), and infarct of undetermined etiology (2.7%), and was low in patients with cardioembolism (0.8%) and large artery atherosclerosis (0.7%). All p.R544C patients with intracerebral hemorrhage were nonlobar hemorrhage. Sibling history of stroke (odds ratio [OR] = 4.50, 95% CI = 1.67–12.14 in ischemic stroke; OR = 6.03, 95% CI = 1.03–35.47 in intracerebral hemorrhage, respectively) and small vessel occlusion (OR, 4.03, 95% CI, 1.26–12.92) were significantly associated with p.R544C. Interpretation p.R544C NOTCH3 mutation is underdiagnosed in stroke patients in Taiwan, especially in those with small vessel occlusion and sibling history of stroke.

Background and aims This study investigated risks of short-term (1 and 3 months) and long-term (1-year) recurrent stroke associated with glomerular filtration rate (eGFR) in patients with acute ischemic stroke. Methods From the Taiwan Stroke Registry data, we identified 45,876 acute ischemic stroke patients from April 2006 to April 2014 and classified them into 4 groups based on the eGFR at admission: ≥ 90, 60–89, 30–59, and Results Both the risks of short-term and long-term recurrent stroke increased as the eGFR levels declined. The 1-month recurrent incidence rates increased steadily from 0.54 to 0.59, 0.84 and 0.89 per 1000 person-days, as the eGFR declined from ≥90 to 60–89, 30–59, and Conclusions There is an independent graded association between an increased risk of recurrent stroke and declining eGFR levels in patients with acute ischemic stroke.

Under the time-based criteria, patients with unknown onset stroke (UOS) are ineligible for reperfusion therapies. However, previous studies suggest that some patients with UOS may benefit from reperfusion. Several imaging modalities have been suggested to select patients for intervention, but the optimal imaging criteria are still controversial. Herein we present a series of four cases using 10-point CT-ASPECTS to support our decision of reperfusion therapy. We decided based on history, symptoms, and the 10-point CT-ASPECTS alone. Each patient's history suggested that the stroke just took place. All four patients had apparent clinical symptoms, with 10-point CT-ASPECTS. All of them had a reduction in their NIHSS after the reperfusion therapy. 10-point CT-ASPECTS could be used to support the presumption that the stroke just happens in patients with UOS. Further study is warranted to elucidate the value of CT-ASPECTS for UOS patients. Keywords: ASPECTS, Unknown onset stroke, Intravenous thrombolysis, Mechanical thrombectomy, Reperfusion therapy

Background Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system. Few studies focused on the relationship between septicemia and MS. Aim To evaluate the potential impact of septicemia on risk for MS. Design Two cohorts of patients with septicemia and without septicemia were followed up for the occurrence of MS. Methods Patients of 482 790 with septicemia was enrolled from the National Health Insurance Research Database between 2001 and 2011 as the study group to match the 1 892 820 individuals, as the control group, by age and gender. Incidence of MS in both groups was calculated. Cox proportional-hazards regressions were performed for investigating hazard ratios (HR) for MS between groups. Results Septicemia patients had a 3.06-fold (95% CI: 2.16-4.32, P

The effect of RA on recurrent stroke is unknown. Therefore, we examined effects of rheumatoid arthritis (RA) on risk of stroke recurrence and investigated the interaction between RA and traditional cardiovascular risk factors on recurrence risk after ischemic stroke (IS) or transient ischemic attack (TIA). Of 3190 patients with IS or TIA recruited in this cohort study, 638 were comorbid with RA and 2552 without RA. Stroke recurrence, RA, lifestyle, lipid variables and other comorbidities were identified through linkage between a nationwide stroke database in Taiwan and the National Health Insurance claims database. Cox proportional hazard models with competing risk adjustment were used to evaluate the relationship between RA and recurrent stroke. Patients with RA showed a significantly increased risk of recurrent stroke, particular in recurrent IS/TIA. The increased risk of recurrent IS/TIA in RA patients may through the changes of triglycerides (TG)/high-density lipoprotein cholesterol (HDL-C) ratio. A positive additive interaction was observed between RA and current smoking on the risk of recurrent IS/TIA. Significantly increased risks for recurrent IS/TIA were observed among RA patients who smoked > 40 years or those who smoked > 20 cigarettes/day. This study provides the first evidence that RA significantly increased recurrence IS/TIA risk. The changes of TG/HDL-C ratio may play some roles in the recurrence IS/TIA risk in RA patients. In addition, our results suggest that smoking increases the risk of recurrent IS/TIA in RA patients and reinforces the need for aggressive smoking cessation efforts in RA patients.

Background and aims Renal dysfunction is a potent risk factor for cardiovascular diseases, including stroke. This study aimed to evaluate the impact of admission estimated glomerular filtration rate (eGFR) levels on short-term (1-month) and long-term (1-year) mortality in patients with acute ischemic stroke. Methods From the Taiwan Stroke Registry data, we classified ischemic stroke patients, identified from April 2006 to December 2015, into 5 groups by eGFR at admission: ≥ 90, 60–89, 30–59, 15–29, and Results Among 52,732 ischemic stroke patients, 1480 died within one month. The 1-month mortality rate was over 5-fold greater in patients with eGFR Conclusions After acute ischemic stroke, patients with reduced eGFR are at elevated risks of short-term and long-term deaths in a graded relationship.

A 61-year-old man with myasthenia gravis who previously underwent post-thymectomy radiotherapy for a metastatic thymoma presented with altered mental status. Examination revealed papilledema and frontoexecutive dysfunction.

Background: Stroke is one of the leading causes of mortality and neurologic deficits. Management measures to improve neurologic outcomes are in great need. Our previous intervention trial in elderly subjects successfully used salt as a carrier for potassium, demonstrating a 41% reduction in cardiovascular mortality by switching to potassium-enriched salt. Dietary magnesium has been associated with lowered diabetes and/or stroke risk in humans and with neuroprotection in animals.Objective: Because a large proportion of Taiwanese individuals are in marginal deficiency states for potassium and for magnesium and salt is a good carrier for minerals, it is justifiable to study whether further enriching salt with magnesium at an amount near the Dietary Reference Intake (DRI) amount may provide additional benefit for stroke recovery.Design: This was a double-blind, randomized controlled trial comprising 291 discharged stroke patients with modified Rankin scale (mRS) ≤4. There were 3 arms: 1) regular salt (Na salt) (n = 99), 2) potassium-enriched salt (K salt) (n = 97), and 3) potassium- and magnesium-enriched salt (K/Mg salt) (n = 95). The NIH Stroke Scale (NIHSS), Barthel Index (BI), and mRS were evaluated at discharge, at 3 mo, and at 6 mo. A good neurologic performance was defined by NIHSS = 0, BI = 100, and mRS ≤1.Results: After the 6-mo intervention, the proportion of patients with good neurologic performance increased in a greater magnitude in the K/Mg salt group than in the K salt group and the Na salt group, in that order. The K/Mg salt group had a significantly increased OR (2.25; 95% CI: 1.09, 4.67) of achieving good neurologic performance compared with the Na salt group. But the effect of K salt alone (OR: 1.58; 95% CI: 0.77, 3.22) was not significant.Conclusions: This study suggests that providing the DRI amount of magnesium and potassium together long term is beneficial for stroke patient recovery from neurologic deficits. This trial was registered at clinicaltrials.gov as NCT02910427.

The CT angiography (CTA) spot sign is a strong predictor of hematoma expansion in intracerebral hemorrhage (ICH). However, CTA parameters vary widely across centers and may negatively impact spot sign accuracy in predicting ICH expansion. We developed a CT iodine calibration phantom that was scanned at different institutions in a large multicenter ICH clinical trial to determine the effect of image standardization on spot sign detection and performance. A custom phantom containing known concentrations of iodine was designed and scanned using the stroke CT protocol at each institution. Custom software was developed to read the CT volume datasets and calculate the Hounsfield unit as a function of iodine concentration for each phantom scan. CTA images obtained within 8 h from symptom onset were analyzed by two trained readers comparing the calibrated vs. uncalibrated density cutoffs for spot sign identification. ICH expansion was defined as hematoma volume growth >33%. A total of 90 subjects qualified for the study, of whom 17/83 (20.5%) experienced ICH expansion. The number of spot sign positive scans was higher in the calibrated analysis (67.8 vs 38.9% p

We investigated the impact of serum cholesterol levels on 30-day mortality after ischemic stroke in dialysis patients.From the Taiwan Stroke Registry data, we identified 46,770 ischemic stroke cases, including 1101 dialysis patients and 45,669 nondialysis patients from 2006 to 2013.Overall, the 30-day mortality was 1.46-fold greater in the dialysis group than in the nondialysis group (1.75 versus 1.20 per 1000 person-days). The mortality rates were 1.64, .62, 2.82, and 2.23 per 1000 person-days in dialysis patients with serum total cholesterol levels of 120 mg/dL, 120-159 mg/dL, 160-199 mg/dL, and ≥200 mg/dL, respectively. Compared to dialysis patients with serum total cholesterol levels of 120-159 mg/dL, the corresponding adjusted hazard ratios of mortality were 4.20 (95% confidence interval [CI] = 1.01-17.4), 8.06 (95% CI = 2.02-32.2), and 6.89 (95% CI = 1.59-29.8) for those with cholesterol levels of 120 mg/dL, 160-199 mg/dL, and ≥200 mg/dL, respectively.Dialysis patients with serum total cholesterol levels of ≥160 mg/dL or 120 mg/dL on admission are at an elevated hazard of 30-day mortality after ischemic stroke.

Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) caused by mutations of the 33-exon NOTCH3 gene is the most common single gene disorder of stroke.1 To date, more than 200 different NOTCH3 mutations have been reported worldwide, while R544C in exon 11 was the most prevalent hot spot mutation in East Asia and accounted for more than 70% of the patients in their CADASIL cohorts.2 3 Patients with CADASIL may suffer from ischaemic stroke (IS) and intracerebral haemorrhage (ICH), especially among Asians. Therefore, we aimed to compare the clinical features of acute ICH vs IS events in patients with CADASIL and focused on the effects of ICH on stroke recurrence and long-term outcome. The patients enrolled in this study were prospectively recruited from a multicentre stroke registry established since 2006 with at least 12 hospitals in Taiwan. We screened R544C mutation from participants who provided their blood sample and those whose harbouring R544C mutation were then included in the present study. Preadmission, inpatient and discharge data were collected by trained personnel. The responsible neurologist on each study site will examine the medical record or interview the patients to acquire follow-up information. All patients received at least one neuroimaging examination to document the locations of acute stroke. Abnormal white matter hyperintensity (WMH) lesion was scored by the Fazekas scale. The number and …

Ischemic stroke (IS) is multifactorial causation combining with traditional cardiovascular disease (CVD) and genetic risk factors. Combined effects of MMP-7, MMP-8 and MMP-26 on the risk of IS remain incompletely understood. We aimed to assess individual and joint effects for IS risk by weighted genetic risk score (wGRS) from these three genes and traditional CVD risk factors. A case-control study including 500 cases with IS and 500 stroke-free healthy controls frequency-matched with cases by age and sex was conducted. The wGRS was a weighted average of the number of risk genotype across selected SNPs from MMP-7, MMP-8 and MMP-26. Multivariate logistic regression models were used to analyze the relationship between wGRS and risk of IS. A wGRS in the second tertile was associated with a 1.5-fold increased risk of IS compared with the lowest tertile after adjusting for traditional CVD risk factors. Compared to subjects with low genetic and low modifiable CVD risk, those with high genetic and high modifiable CVD risk had the highest risk of IS (adjusted-OR = 5.75). In conclusion, higher wGRS was significantly associated with an increased risk for IS. A significant interaction between genetic and traditional CVD risk factors was also found on the risk of IS.

Background and Objectives: Intravenous recombinant tissue plasminogen activator (rt-PA) has been approved for acute ischemic stroke (AIS) within 3 h after onset and the treatment was then extended to 4.5 h. However, the Food and Drug Administration did not approve the indication in the expanded time window. This retrospective, matched cohort study aims to investigate the effectiveness and safety of rt-PA in AIS at 3–4.5 h after onset. Materials and Methods: The treatment group included AIS patients receiving rt-PA at 3–4.5 h after onset, otherwise complying with the regulation, in the stroke registries in 16 hospitals between 2008 and 2017. The control group included age- and sex-matched patients not receiving intravenous thrombolysis from the same registries, excluding those with contraindications. The primary outcome was modified Rankin Scale (mRS) 0–1 at day 90. The safety outcomes were any intracerebral hemorrhage (ICH), early neurological deterioration and 3-month mortality. Results: Each group had 374 patients. There were 34.0% of patients with 3-month mRS 0-1 in the treatment group vs. 22.7% in the control group with an odds ratio of 1.75 (95% confidence intervals, 1.27 to 2.42, P = 0.001). There was no difference in symptomatic ICH, early neurological deterioration and 3-month mortality rates between two groups. The 3-month mRS and symptomatic ICH did not differ significantly in patients receiving standard dose or low dose of rt-PA. Conclusions: Our results support the prescription of rt-PA in AIS patients 3–4.5 h after onset as an effective and tolerable treatment in their functional recovery.

BACKGROUND AND PURPOSE Studies on using antiplatelet agents for secondary prevention in ischaemic stroke patients with renal dysfunction are limited. The Taiwan Stroke Registry database was used to compare the efficacy of antiplatelet agents. METHODS From the Taiwan Stroke Registry data, 39 174 acute ischaemic stroke patients were identified and were classified into three groups by antiplatelet agent: aspirin, clopidogrel and dual antiplatelet therapy (DAPT) with a combination of aspirin and clopidogrel. The re-stroke incidence and 1-year mortality were stratified by estimated glomerular filtration rate (eGFR) levels at admission: ≥90, 60-89 and

The time to initiate intravenous thrombolysis for acute ischemic stroke is generally limited to within 4.5 hours after the onset of symptoms. Some trials have suggested that the treatment window may be extended in patients who are shown to have ischemic but not yet infarcted brain tissue on imaging.We conducted a multicenter, randomized, placebo-controlled trial involving patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging. The patients were randomly assigned to receive intravenous alteplase or placebo between 4.5 and 9.0 hours after the onset of stroke or on awakening with stroke (if within 9 hours from the midpoint of sleep). The primary outcome was a score of 0 or 1 on the modified Rankin scale, on which scores range from 0 (no symptoms) to 6 (death), at 90 days. The risk ratio for the primary outcome was adjusted for age and clinical severity at baseline.After 225 of the planned 310 patients had been enrolled, the trial was terminated because of a loss of equipoise after the publication of positive results from a previous trial. A total of 113 patients were randomly assigned to the alteplase group and 112 to the placebo group. The primary outcome occurred in 40 patients (35.4%) in the alteplase group and in 33 patients (29.5%) in the placebo group (adjusted risk ratio, 1.44; 95% confidence interval [CI], 1.01 to 2.06; P = 0.04). Symptomatic intracerebral hemorrhage occurred in 7 patients (6.2%) in the alteplase group and in 1 patient (0.9%) in the placebo group (adjusted risk ratio, 7.22; 95% CI, 0.97 to 53.5; P = 0.05). A secondary ordinal analysis of the distribution of scores on the modified Rankin scale did not show a significant between-group difference in functional improvement at 90 days.Among the patients in this trial who had ischemic stroke and salvageable brain tissue, the use of alteplase between 4.5 and 9.0 hours after stroke onset or at the time the patient awoke with stroke symptoms resulted in a higher percentage of patients with no or minor neurologic deficits than the use of placebo. There were more cases of symptomatic cerebral hemorrhage in the alteplase group than in the placebo group. (Funded by the Australian National Health and Medical Research Council and others; EXTEND ClinicalTrials.gov numbers, NCT00887328 and NCT01580839.).

Phospholipase D (PLD) is involved in many biological processes. PLD1 plays a crucial role in regulating the platelet activity of mice, however, the role of PLD in the platelet activation of humans remains unclear. Therefore, we investigated whether PLD is involved in the platelet activation of humans. Our data revealed that inhibition of PLD1 or PLD2 using pharmacological inhibitors effectively inhibits platelet aggregation in humans. However, previous studies have showed that PLD1 or PLD2 deletion did not affect mouse platelet aggregation in vitro, whereas only PLD1 deletion inhibited thrombus formation in vivo. Intriguingly, our data also showed that the pharmacological inhibition of PLD1 or PLD2 does not affect mouse platelet aggregation in vitro, whereas the inhibition of only PLD1 delayed thrombus formation in vivo. These findings indicate that PLD may play differential roles in humans and mice. In humans, PLD inhibition attenuates platelet activation, adhesion, spreading, and clot retraction. For the first time, we demonstrated that PLD1 and PLD2 are essential for platelet activation in humans, and PLD plays different roles in platelet function in humans and mice. Our findings also indicate that targeting PLD may provide a safe and alternative therapeutic approach for preventing thromboembolic disorders.

Background Clopidogrel was thought to be superior to aspirin for secondary prevention of vascular diseases in clinical trials. In this study we assessed the safety and efficacy of clopidogrel versus aspirin in real‐world practice by using the Taiwan Stroke Registry. Methods and Results Patients with ischemic stroke (2006–2016) on aspirin or clopidogrel for secondary stroke prevention were identified in the Taiwan Stroke Registry. Stroke recurrence and mortality rates in patients receiving aspirin (N=34 679) were compared with those receiving clopidogrel (N=7611) during a 12‐month follow‐up period. Propensity score matching and conditional Cox proportional hazards regression model were applied to control confounding factors with 6443 patients in each group. After propensity score matching, stroke recurrence rates were comparable between groups, with 223 patients in the aspirin (3.46%) and 244 in the clopidogrel group (3.79%) (hazard ratio=1.13, 95% confidence interval=0.89–1.43, P =0.311). However, the mortality rate was significantly higher in the clopidogrel group (362 patients, 5.62%) than in the aspirin group (302 patients, 4.69%) (hazard ratio=1.30, 95% confidence interval=1.07–1.58, P =0.008). Results were consistent before and after propensity score matching. Conclusions Clopidogrel was as effective as aspirin for prevention of recurrent stroke in real‐world practice. However, the mortality rate was significantly higher in the clopidogrel than in the aspirin group.

Background: The risk of recurrent stroke in patients with ischemic stroke with vertebral/basilar artery stenosis remains to be systematically studied. Methods: We analyzed data from Taiwan Stroke Registry (TSR), with stroke registries provided by 59 hospitals. Patients who had diagnosis of ischemic stroke and were categorized into the “large artery atherosclerosis” group by TOAST who underwent CTA, MRA, or catheter- based angiography were identified for the present study. The patients were divided into 3 groups based on the extent of vertebral (VA) and/or basilar artery (BA) stenosis as follows: 0-49%, 50-99%, and 100% (total occlusion). Cox proportional hazards model was used to determine the hazard ratios (HRs) of recurrent stroke within 1 year of index event after adjusting for all relevant risk factors by univariable Cox model. Results: In the TSR data base, 84,831patients were in the ischemic stroke group. Based on TOAST, 20,220 patients were in the large-artery atherosclerosis group. Among these patients, a total of 10,515 were of age 18 or greater who had CTA, MRA or angiographic studies that included VA/BA. There were 6,972 subjects with VA/BA stenosis in the 0-49%, 3,137 in the 50-99% and 406 in the 100% (total occlusion) groups respectively. With VA/BA stenosis in the 0-49% range as the reference, HRs of recurrent stroke in one year by multivariable modeling with adjustment of all relevant risk factors by univariable Cox model was 1. 29 (95% CI, 1.05 - 1.58, p Conclusions: Vertebral or basilar artery stenosis or occlusion was relatively prevalent among patients with ischemic stroke categorized in the large artery artherosclerosis group by TOAST with greater extent of VA/BA stenosis carrying greater risk of recurrent stroke within 1 year after stroke.

Translocator protein 18 kDa (TSPO) has been used as a biomarker of brain injury and inflammation in various neurological diseases. In this study, we measured the level of TSPO in acute ischemic stroke patients and determined its association with the degree of stroke severity and its ability to predict stroke functional outcomes. In total, 38 patients with moderate to severe acute ischemic stroke were enrolled. Demographic information, cerebral risk factors, and stroke severity were examined at the baseline. The National Institutes of Health Stroke Scale, modified Rankin Scale, and Barthal Index were assessed at discharge as measures of poor functional outcomes and severe disability. The baseline fasting plasma TSPO level was assessed within 24 h after the incident stroke and during hospitalization (on days 8–10). The proportion of patients with poor functional outcomes was significantly higher in the higher-TSPO group (compared to the lower group) in terms of clinical worsening (odds ratio (OR) = 11.69, 95% confidence interval (CI) = 2.08–65.6), poor functional outcomes (OR = 10.5, 95% CI = 1.14–96.57), and severe disability (OR = 4.8, 95% CI = 1.20–19.13). Plasma TSPO may be intimately linked with disease progression and worse functional outcomes in acute ischemic stroke patients.

To investigate the expression patterns of 2 soluble isoforms of receptor for advanced glycation end-product (RAGE), including endogenous secretory RAGE (esRAGE) and cleaved RAGE (cRAGE), and their associations with outcome in acute ischemic stroke (IS).Acute IS patients (n = 106) and age- and sex-matched controls (n = 150) were recruited. Plasma levels of total soluble RAGE (sRAGE) and esRAGE in patients at48 hours and 48-72 hours after IS and in controls were measured by ELISA. The level of cRAGE was calculated by subtracting the level of sRAGE from that of esRAGE. Poor outcome was defined as modified Rankin Scale score2 at 3 months after stroke.The plasma levels of cRAGE were significantly higher and correlated to those of esRAGE (p0.001). The plasma levels of esRAGE and cRAGE were both significantly higher in IS patients48 hours and 48-72 hours after onset than in controls, but only level of cRAGE at48 hours was independently associated with poor outcome after adjusting for clinical variables (odds ratio 2.44; 95% confidence interval 1.16-5.16; p = 0.019).The plasma level of cRAGE at48 hours after IS, rather than esRAGE, is a significant predictor of acute IS outcome.

Background Pulse pressure (PP) is related to cardiac function, arterial stiffness, fluid status, and vascular events. This study aimed to explore the prognostic role of PP upon admission in patients with acute ischemic stroke (AIS) based on a nation‐wide stroke registry. Methods and Results We evaluated the association between PP upon admission and outcomes 3 months after a stroke in patients who had an AIS registered in the Taiwan Stroke Registry, including 56 academic and community hospitals between 2006 and 2013. Three months after the stroke, unfavorable outcomes were defined using a modified Rankin scale of 3 to 6. Of 33 530 patients (female, 40.6%; mean age, 68.8±13.3 years) who had an AIS, PP upon admission had a reverse J‐curve association with an unfavorable outcome. After adjusting for clinical variables, including AIS subtypes, initial National Institutes of Health Stroke Scale, and systolic and diastolic blood pressure upon admission, a PP of P Conclusions Low PP upon admission was associated with unfavorable patient outcomes in AIS.

Background Cumulative evidence has shown that low mitochondrial DNA (mt DNA ) content is related to elevated oxidative stress and atherosclerosis, which play important roles in ischemic stroke. The objective of this study was to explore the association between mt DNA content in peripheral blood leukocytes and ischemic stroke. Methods and Results A total of 350 patients with first‐ever ischemic stroke and 350 healthy controls were recruited in this case‐control study. The mt DNA content in peripheral blood leukocytes was determined by quantitative real‐time polymerase chain reaction. The levels of oxidized glutathione, reduced glutathione, and 8‐hydroxy‐2′‐deoxyguanosine were measured by ELISA kits. Multivariate logistic regression models were used to analyze the relationship between mt DNA content in peripheral blood leukocytes and ischemic stroke. Our results show that mt DNA content of patients with ischemic stroke was notably lower compared with controls. A significant association was found between low mt DNA content and ischemic stroke. Furthermore, significant interactions were identified between low mt DNA and proven risk factors in patients with ischemic stroke. The levels of oxidized glutathione and 8‐hydroxy‐2′‐deoxyguanosine were significantly greater in patients with ischemic stroke compared with controls. Conclusions Our results demonstrate that low mt DNA content in peripheral blood leukocytes is associated with ischemic stroke. The relationship of low mt DNA content and ischemic stroke was particularly notable in individuals who had low mt DNA content combined with diabetes mellitus, metabolic syndrome, or cigarette smoking. Oxidative stress may be one of the contributory factors to decreased mt DNA content in patients with ischemic stroke.

Background: Patients with minor acute ischemic stroke or transient ischemic attack are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was the first trial with ticagrelor in patients with acute ischemic stroke or transient ischemic attack in which the efficacy and safety of ticagrelor were compared with those of aspirin. The main safety objective was assessment of PLATO (Platelet Inhibition and Patient Outcomes)–defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH). Methods: An independent adjudication committee blinded to study treatment classified bleeds according to the PLATO, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions. The definitions of ICrH and major bleeding excluded cerebral microbleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population. Results: A total of 13 130 of 13 199 randomized patients received at least 1 dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (hazard ratio, 0.83; 95% confidence interval, 0.52–1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (4 on ticagrelor and 9 on aspirin) were hemorrhagic strokes, and 4 (2 in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in 6 and 13, traumatic in 3 and 3, and procedural in 3 and 2 patients on ticagrelor and aspirin, respectively. In total, 9 fatal bleeds occurred on ticagrelor and 4 on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independently of bleeding classification, PLATO, TIMI, or GUSTO, the relative difference between treatments for major/severe bleeds was similar. Nonmajor bleeds were more common on ticagrelor. Conclusions: Antiplatelet therapy with ticagrelor in patients with acute ischemic stroke or transient ischemic attack showed a bleeding profile similar to that of aspirin for major bleeds. There were few ICrHs. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01994720.

Platelet activation is involved in cardiovascular diseases, such as atherosclerosis and ischemic stroke. Licochalcone A (LA), an active ingredient of licorice, exhibits multiple biological activities such as anti-oxidation and anti-inflammation. However, its role in platelet activation remains unclear. Therefore, the study investigated the antiplatelet mechanism of LA. Our data revealed that LA (2-10 μM) concentration dependently inhibited platelet aggregation induced by collagen, but not thrombin and U46619. LA markedly attenuated collagen-stimulated ATP release, P-selectin secretion, calcium mobilization, and GPIIbIIIa activation, but did not interfere with the collagen binding to platelets. Moreover, LA significantly reduced the activation of PLCγ2, PKC, Akt and MAPKs. Thus, LA attenuates platelet activation, possibly by inhibiting collagen receptor downstream signaling but not by blocking the collagen receptors. In addition, LA prevented adenosine diphosphate (ADP)-induced acute pulmonary thrombosis, fluorescein sodium-induced platelet thrombus formation, and middle cerebral artery occlusion/reperfusion-induced brain injury in mice, but did not affect normal hemostasis. This study demonstrated that LA effectively reduced platelet activation and thrombus formation, in part, through the inhibition of PLCγ2-PKC, Akt, and MAPK pathways, without the side effect of bleeding. These findings also indicate that LA may provide a safe and alternative therapeutic approach for preventing thromboembolic disorders such as stroke.

Background and purpose Physical activity is associated with a reduced incidence of first-time stroke. However, few studies have examined the effect of pre-stroke physical activity on post-stroke complications and clinical outcomes. Methods A total of 39 835 cases of stroke registered in the nationwide stroke registry system of Taiwan between 2006 and 2009 were analyzed according to five levels of severity as determined by National Institutes of Health Stroke Scale score upon hospital admission. Pre-stroke physical activity was defined in the Taiwan Stroke Registry as dedicated leisure-time physical activity for at least 30 min/day for 3 days/week for more than 6 months. A Cox model was used to compare complications and outcomes between active and inactive groups. Results The active and inactive groups were similar in age distribution and stroke type distribution, but the active group had better National Institutes of Health Stroke Scale scores upon admission. The active group also had significantly fewer post-stroke complications. Active patients had lower hospital mortality and better functional outcomes upon discharge as per the modified Rankin Scale. Improved functional status in the active group was significant at 1, 3 and 6 months post-stroke. Conclusion Dedicated leisure-time physical activity for at least 30 min/day, at least three times per week for more than 6 months was associated with decreased stroke severity, fewer post-stroke complications, lower mortality and better outcomes.

Background Estrogen plays an important role as an anti-inflammatory and neuroprotective agent in ischemic stroke. In this study, we analyzed the effect of a polygenic risk score (PRS) constructed using inflammatory genes and estradiol levels on the risk of ischemic stroke. Methods This case-control study was conducted with 624 ischemic stroke patients and 624 age- and gender-matched controls. The PRS estimated the polygenic contribution of inflammatory genes from ischemic stroke susceptibility loci. Estradiol levels were measured using a radioimmunoassay. High and low estradiol levels were defined according to the log-transformed median estradiol levels in female and male controls. Results Subjects in the fourth quartile of the PRS had a significant 1.57-fold risk of ischemic stroke (95% confidence interval [CI], 1.12 ~ 2.19), after adjusting for covariates compared to individuals in the lowest quartile. Compared to individuals with high estradiol levels and a low PRS as the reference group, those exposed to low estradiol levels and a high PRS had an increased risk of ischemic stroke (odds ratio, 3.35; 95% CI, 1.79 ~ 6.28). Similar results were also observed in males when the analysis was stratified by gender. Conclusions Our data suggest that the PRS can be useful in evaluating a high risk of ischemic stroke among patients, especially those exposed to low estradiol levels.

Background Asians have higher frequency of intracranial arterial stenosis. The present study aimed to compare the clinical features and outcomes of ischemic stroke patients with and without middle cerebral artery (MCA) stenosis, assessed by transcranial sonography (TCS), based on the Taiwan Stroke Registry (TSR). Methods Patients with acute ischemic stroke or transient ischemic attack registered in the TSR, and received both carotid duplex and TCS assessment were categorized into those with stenosis (≥50%) and without (

Rationale It is not uncommon for patients with ischemic stroke to have peripheral arterial disease (PAD). Patients with polyvascular diseases carry greater burden of atherosclerosis and higher risks of developing vascular events and death. More effective regimens, such as dual antiplatelet agents, may be more effective for controlling progression of atherosclerosis in secondary prevention. Aim This study aims to evaluate whether cilostazol plus aspirin is more efficacious than aspirin alone for preventing progression of atherosclerosis in patients with ischemic stroke or transient ischemic attack (TIA) who also have peripheral arterial disease. Design The Safety and Efficacy of Cilostazol in Ischemic Stroke Patients with Peripheral Arterial Disease (SPAD) study is a randomized double-blinded placebo-controlled trial. Patients with previous ischemic stroke or TIA who had been taking aspirin (100 mg per day), aged 50 years or older, with PAD in the lower limbs based on ankle-brachial index (ABI) Study outcomes Patients will be evaluated at 1, 3, 6, 9 and 12 months after randomization. The primary endpoint is difference in change in ABI between groups. The secondary and tertiary endpoints are the difference between groups in change in carotid intima-media thickness (IMT) and incidence rate of major cardiovascular events, including recurrent stroke, myocardial infarction, unstable angina, other vascular events, and death; and the safety measures, including major bleeding events, hemorrhagic stroke and death of any cause. Conclusion The SPAD trial is the first study to evaluate the safety and efficacy of dual antiplatelet agents, aspirin plus cilostazol, in comparison with aspirin alone in patients with both ischemic stroke or TIA and PAD. Results from this trial will provide important information on the merit of adding cilostazol to aspirin for slowing down progression of atherosclerosis in patients with ischemic stroke and PAD.

Volume 120, issue 3 (2011) pp. 121–129 Following an investigation of Professor Kou-Gi Shyu by the Academic Ethical Issue Committee of Shin-Kong Wu Ho-Su Memorial Hospital and by Taipei Medical University, it has been …

Resistin may play a major potential role in vascular remodelling and may contribute to atherogenesis. However, the role of VSMC (vascular smooth muscle cell)-derived resistin in neointimal formation is not well understood. We hypothesize that endogenous resistin derived from VSMCs may contribute to neointimal formation after vascular injury. VSMCs from thoracic aorta of adult Wistar rats were cultured. The carotid artery from adult Wistar rats was injured by balloon catheter. Resistin significantly increased migration and proliferation of VSMCs. Resistin siRNA (small interfering RNA) and resistin antibody significantly inhibited migration and proliferation of VSMCs induced by conditioned medium from stretched VSMCs. Resistin protein and mRNA expression significantly increased at 14 days after carotid injury. Resistin siRNA and NAC (N-acetylcysteine) significantly reduced resistin protein and mRNA expression induced by balloon injury. Carotid artery injury increased ROS (reactive oxygen species) production. Treatment with NAC and resistin siRNA decreased ROS production. The neointimal area was significantly increased after carotid injury and was significantly reduced by resistin siRNA and NAC. In conclusion, resistin increases migration and proliferation of VSMCs, and expression of resistin in carotid artery significantly increases after injury. Resistin siRNA attenuates neointimal formation after carotid injury partly through an antioxidative mechanism. Resistin may play a pivotal role in the pathogenesis of neointimal thickening after mechanical injury.