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1.  Effects of apolipoprotein E genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage 
Rodent models of acute ischaemic stroke and head injury suggest that apolipoprotein E (APOE) genotype influences neuronal repair, regeneration and survival after brain injury. Possession of an APOE ε4 allele is associated with poor outcome after head injury in clinical studies. APOE might therefore influence outcome after acute stroke in humans.
Objective and methods
To comprehensively search, identify, assess and carry out meta‐analyses of studies reporting on the association between APOE and the combined outcome of death or dependency, or death alone, several months after ischaemic stroke, intracerebral haemorrhage (ICH) or subarachnoid haemorrhage (SAH).
Main analyses included data from nine studies on 2262 patients (1453 with ischaemic stroke, 199 with ICH and 610 with SAH). Overall, ε4+ genotypes were not significantly associated with risk of death or dependency several months after stroke. However, there was significant heterogeneity between studies, and between the three pathological types of stroke. ε4+ genotypes were associated with increased death or dependency after SAH (relative risk (RR) 1.40, 95% confidence interval (CI) 1.06 to 1.84), with a trend towards a similar association with ICH (RR 1.38, 95% CI 0.99 to 1.92), but not with ischaemic stroke (RR 0.98, 95% CI 0.85 to 1.12). Results were similar for death alone.
APOE may differentially affect outcome after the three main pathological types of stroke. Further, large studies are needed to confirm or refute these findings, and to assess the possibility of an interaction between the effects of APOE and age.
PMCID: PMC2077401  PMID: 16926234
2.  Effects of apolipoprotein E genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage 
Rodent models of acute ischaemic stroke and head injury suggest that apolipoprotein E genotype (APOE) influences neuronal repair, regeneration and survival after brain injury. Possession of an APOE ε4 allele is associated with poor outcome after head injury in clinical studies. APOE might therefore influence outcome after acute stroke in humans.
We comprehensively sought, identified, assessed and performed meta-analyses of studies reporting on the association between APOE and the combined outcome of death or dependency, or death alone, several months after ischaemic stroke (IS), intracerebral haemorrhage (ICH) or subarachnoid haemorrhage (SAH).
Our main analyses included data from 9 studies in a total of 2262 patients (1453 IS, 199 ICH, 610 SAH). Overall, ε4+ genotypes were not significantly associated with risk of death or dependency several months after stroke. However, there was significant heterogeneity between studies, and between the three pathological types of stroke. ε4+ genotypes were associated with increased death or dependency after SAH (RR 1.40, 95% CI 1.06 to 1.84), with a trend toward a similar association with ICH (RR 1.38, 95% CI 0.99 to 1.92), but not IS (RR 0.98, 95% CI 0.85 to 1.12). Results were similar for death alone.
APOE may differentially affect outcome after the three main pathological types of stroke. Further, large studies are needed to confirm or refute these findings, and to assess the possibility of an interaction between the effects of APOE and age.
PMCID: PMC2077401  PMID: 16926234
3.  Update in Intracerebral Hemorrhage 
The Neurohospitalist  2011;1(3):148-159.
Spontaneous, nontraumatic intracerebral hemorrhage (ICH) is defined as bleeding within the brain parenchyma. Intracranial hemorrhage includes bleeding within the cranial vault and encompasses ICH, subdural hematoma, epidural bleeds, and subarachnoid hemorrhage (SAH). This review will focus only on ICH. This stroke subtype accounts for about 10% of all strokes. The hematoma locations are deep or ganglionic, lobar, cerebellar, and brain stem in descending order of frequency. Intracerebral hemorrhage occurs twice as common as SAH and is equally as deadly. Risk factors for ICH include hypertension, cerebral amyloid angiopathy, advanced age, antithrombotic therapy and history of cerebrovascular disease. The clinical presentation is “stroke like” with sudden onset of focal neurological deficits. Noncontrast head computerized tomography (CT) scan is the standard diagnostic tool. However, newer neuroimaging techniques have improved the diagnostic yield in terms of underlying pathophysiology and may aid in prognosis. Intracerebral hemorrhage is a neurological emergency. Medical care begins with stabilization of airway, breathing function, and circulation (ABCs), followed by specific measures aimed to decrease secondary neurological damage and to prevent both medical and neurological complications. Reversal of coagulopathy when present is of the essence. Blood pressure management can be key and continues as an area of debate and ongoing research. Surgical evacuation of ICH is of unproven benefit though a subset of well-selected patients may have improved outcomes. Ventriculostomy and intracranial pressure (ICP) monitoring are interventions also used in this patient population. To date, hemostatic medications and neuroprotectants have failed to result in clinical improvement. A multidisciplinary approach is recommended, with participation of vascular neurology, vascular neurosurgery, critical care, and rehabilitation medicine as the main players.
PMCID: PMC3726132  PMID: 23983850
intracerebral hemorrhage; diagnosis; treatment; prognosis; surgery
4.  Influence of stroke subtype on quality of care in the Get With The Guidelines–Stroke Program 
Neurology  2009;73(9):709-716.
Little is known about in-hospital care for hemorrhagic stroke. We examined quality of care in intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) admissions in the national Get With The Guidelines–Stroke (GWTG-Stroke) database, and compared them to ischemic stroke (IS) or TIA admissions.
Between April 1, 2003, and December 30, 2007, 905 hospitals contributed 479,284 consecutive stroke and TIA admissions. The proportions receiving each quality of care measure were calculated by dividing the total number of patients receiving the intervention by the total number of patients eligible for the intervention, excluding ineligible patients or those with contraindications to treatment. Logistic regression models were used to determine associations between measure compliance and stroke subtype, controlling for patient and hospital characteristics.
Stroke subtypes were 61.7% IS, 23.8% TIA, 11.1% ICH, and 3.5% SAH. Performance on care measures was generally lower in ICH and SAH compared to IS/TIA, including guideline-recommended measures for deep venous thrombosis (DVT) prevention (for ICH) and smoking cessation (for SAH) (multivariable-adjusted p < 0.001 for all comparisons). Exceptions were that ICH patients were more likely than IS/TIA to have door-to-CT times <25 minutes (multivariable-adjusted p < 0.001) and to undergo dysphagia screening (multivariable-adjusted p < 0.001). Time spent in the GWTG-Stroke program was associated with improvements in many measures of care for ICH and SAH patients, including DVT prevention and smoking cessation therapy (multivariable-adjusted p < 0.001).
Many hospital-based acute care and prevention measures are underutilized in intracerebral hemorrhage and subarachnoid hemorrhage compared to ischemic stroke /TIA. Duration of Get With The Guidelines–Stroke participation is associated with improving quality of care for hemorrhagic stroke.
= American Heart Association;
= deep venous thrombosis;
= generalized estimating equation;
= Get With The Guidelines–Stroke;
= intracerebral hemorrhage;
= ischemic stroke;
= Patient Management Tool;
= subarachnoid hemorrhage.
PMCID: PMC2734292  PMID: 19720978
5.  APOE Genotype and Functional Outcome Following Aneurysmal Subarachnoid Hemorrhage 
Biological research for nursing  2008;10(3):205-212.
Apolipoprotein E (apoE), the major apolipoprotein in the central nervous system, has been shown to influence neurologic disease progression and response to neurologic injury in a gene-specific manner. Presence of the APOE4 allele is associated with poorer response to traumatic brain injury and ischemic stroke, but the association between APOE genotype and outcome following aneurysmal subarachnoid hemorrhage (SAH) remains unclear. The purpose of this project was to investigate the association between APOE genotype and outcome after SAH. We also explored the association of APOE4 genotype and cerebral vasospasm (CV) presence in a subsample of our population with available angiographic data. A sample of 206 aneurysmal SAH participants had APOE genotyping performed, Glasgow outcome scores (GOS) and modified Rankin scores (MRS) collected at 3 and 6 months after aneurysm rupture. No significant association was found between the presence of the APOE4 genotype and functional outcomes controlling for age, race, size of hemorrhage (Fisher grade), and severity of injury (Hunt & Hess grade). However when controlling for CV and the covariates listed above, individuals with the APOE4 allele had worse functional outcomes at both time points. The presence of the APOE2 allele was not associated with functional outcomes even when considering presence of CV. There was no difference in mortality associated with APOE4 presence, APOE2 presence, or presence of CV. These findings suggest APOE4 allele is associated with poor outcome after aneurysmal SAH.
PMCID: PMC2744368  PMID: 19017669
apolipoprotein E; subarachnoid hemorrhage; cerebral vasospasm; Modified Rankin Score; Glasgow Outcome Score
6.  A Risk Score for In‐Hospital Death in Patients Admitted With Ischemic or Hemorrhagic Stroke 
We aimed to derive and validate a single risk score for predicting death from ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH).
Methods and Results
Data from 333 865 stroke patients (IS, 82.4%; ICH, 11.2%; SAH, 2.6%; uncertain type, 3.8%) in the Get With The Guidelines—Stroke database were used. In‐hospital mortality varied greatly according to stroke type (IS, 5.5%; ICH, 27.2%; SAH, 25.1%; unknown type, 6.0%; P<0.001). The patients were randomly divided into derivation (60%) and validation (40%) samples. Logistic regression was used to determine the independent predictors of mortality and to assign point scores for a prediction model in the overall population and in the subset with the National Institutes of Health Stroke Scale (NIHSS) recorded (37.1%). The c statistic, a measure of how well the models discriminate the risk of death, was 0.78 in the overall validation sample and 0.86 in the model including NIHSS. The model with NIHSS performed nearly as well in each stroke type as in the overall model including all types (c statistics for IS alone, 0.85; for ICH alone, 0.83; for SAH alone, 0.83; uncertain type alone, 0.86). The calibration of the model was excellent, as demonstrated by plots of observed versus predicted mortality.
A single prediction score for all stroke types can be used to predict risk of in‐hospital death following stroke admission. Incorporation of NIHSS information substantially improves this predictive accuracy.
PMCID: PMC3603253  PMID: 23525444
intracerebral hemorrhage; ischemic stroke; mortality; subarachnoid hemorrhage
7.  30-Day Mortality and Readmission after Hemorrhagic Stroke among Medicare Beneficiaries in Joint Commission Primary Stroke Center Certified and Non-Certified Hospitals 
Background and Purpose
Ischemic stroke patients treated at Joint Commission Primary Stroke Center (JC-PSC) certified hospitals have better outcomes. Data reflecting the impact of JC-PSC status on outcomes after hemorrhagic stroke are limited. We determined whether 30-day mortality and readmission rates after hemorrhagic stroke differed for patients treated at JC-PSC certified versus non-certified hospitals.
The study included all fee-for-service Medicare beneficiaries ≥65 years old with a primary discharge diagnosis of subarachnoid hemorrhage (SAH) or intracerebral hemorrhage (ICH) in 2006. Covariate-adjusted logistic and Cox proportional hazards regression assessed the effect of care at a JC-PSC certified hospital on 30-day mortality and readmission.
There were 2,305 SAH and 8,708 ICH discharges from JC-PSC certified hospitals and 3,892 SAH and 22,564 ICH discharges from non-certified hospitals. Unadjusted in-hospital mortality (SAH: 27.5% vs. 33.2%, p<0.0001; ICH: 27.9% vs. 29.6%, p=0.003) and 30-day mortality (SAH: 35.1% vs. 44.0%, p<0.0001; ICH: 39.8% vs. 42.4%, p<0.0001) were lower in JC-PSC hospitals, but 30-day readmission rates were similar (SAH: 17.0% vs. 17.0%, p=0.97; ICH: 16.0% vs. 15.5%; p=0.29). Risk-adjusted 30-day mortality was 34% lower (OR 0.66, 95% CI 0.58–0.76) after SAH and 14% lower (OR 0.86, 95% CI 0.80–0.92) after ICH for patients discharged from JC-PSC certified hospitals. There was no difference in 30-day risk-adjusted readmission rates for SAH or ICH based on JC-PSC status.
Patients treated at JC-PSC certified hospitals had lower risk-adjusted mortality rates for both SAH and ICH but similar 30-day readmission rates as compared with non-certified hospitals.
PMCID: PMC3292255  PMID: 22033986
hemorrhagic stroke; certified stroke center; outcomes
8.  Subarachnoid hemorrhage: tests of association with apolipoprotein E and elastin genes 
BMC Medical Genetics  2007;8:49.
Apolipoprotein E (APOE) and elastin (ELN) are plausible candidate genes involved in the pathogenesis of stroke. We tested for association of variants in APOE and ELN with subarachnoid hemorrhage (SAH) in a population-based study. We genotyped 12 single nucleotide polymorphisms (SNPs) on APOE and 10 SNPs on ELN in a sample of 309 Caucasian individuals, of whom 107 are SAH cases and 202 are age-, race-, and gender-matched controls from the Greater Cincinnati/Northern Kentucky region. Associations were tested at genotype, allele, and haplotype levels. A genomic control analysis was performed to check for spurious associations resulting from population substructure.
At the APOE locus, no individual SNP was associated with SAH after correction for multiple comparisons. Haplotype analysis revealed significant association of the major haplotype (Hap1) in APOE with SAH (p = 0.001). The association stemmed from both the 5' promoter and the 3' region of the APOE gene. APOE ε2 and ε 4 were not significantly associated with SAH. No association was observed for ELN at genotype, allele, or haplotype level and our study failed to confirm previous reports of ELN association with aneurysmal SAH.
This study suggests a role of the APOE gene in the etiology of aneurysmal SAH.
PMCID: PMC1950089  PMID: 17672902
9.  Systematic Review and Meta-Analysis of Randomized Controlled Trials of Xingnaojing Treatment for Stroke 
Objective. Xingnaojing injection (XNJ) is a well-known traditional Chinese patent medicine (TCPM) for stroke. The aim of this study is to assess the efficacy of XNJ for stroke including ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). Methods. An extensive search was performed within using eight databases up to November 2013. Randomized controlled trials (RCTs) on XNJ for treatment of stroke were collected. Study selection, data extraction, quality assessment, and meta-analysis were conducted according to the Cochrane standards, and RevMan5.0 was used for meta-analysis. Results. This review included 13 RCTs and a total of 1,514 subjects. The overall methodological quality was poor. The meta-analysis showed that XNJ combined with conventional treatment was more effective for total efficacy, neurological deficit improvement, and reduction of TNF-α levels compared with those of conventional treatment alone. Three trials reported adverse events, of these one trial reported mild impairment of kidney and liver function, whereas the other two studies failed to report specific adverse events. Conclusion. Despite the limitations of this review, we suggest that XNJ in combination with conventional medicines might be beneficial for the treatment of stroke. Currently there are various methodological problems in the studies. Therefore, high-quality, large-scale RCTs are urgently needed.
PMCID: PMC3953647
10.  Copeptin as a Marker for Severity and Prognosis of Aneurysmal Subarachnoid Hemorrhage 
PLoS ONE  2013;8(1):e53191.
Grading of patients with aneurysmal subarachnoid hemorrhage (aSAH) is often confounded by seizure, hydrocephalus or sedation and the prediction of prognosis remains difficult. Recently, copeptin has been identified as a serum marker for outcomes in acute ischemic stroke and intracerebral hemorrhage (ICH). We investigated whether copeptin might serve as a marker for severity and prognosis in aSAH.
Eighteen consecutive patients with aSAH had plasma copeptin levels measured with a validated chemiluminescence sandwich immunoassay. The primary endpoint was the association of copeptin levels at admission with the World Federation of Neurological Surgeons (WFNS) grade score after resuscitation. Levels of copeptin were compared across clinical and radiological scores as well as between patients with ICH, intraventricular hemorrhage, hydrocephalus, vasospasm and ischemia.
Copeptin levels were significantly associated with the severity of aSAH measured by WFNS grade (P = 0.006), the amount of subarachnoid blood (P = 0.03) and the occurrence of ICH (P = 0.02). There was also a trend between copeptin levels and functional clinical outcome at 6-months (P = 0.054). No other clinical outcomes showed any statistically significant association.
Copeptin may indicate clinical severity of the initial bleeding and may therefore help in guiding treatment decisions in the setting of aSAH. These initial results show that copeptin might also have prognostic value for clinical outcome in aSAH.
PMCID: PMC3543451  PMID: 23326397
11.  Initial Troponin Level as a Predictor of Prognosis in Patients with Intracerebral Hemorrhage 
It has been suggested that elevated cardiac troponin T (cTnT) level is a marker of increased risk of mortality in acute ischemic stroke and subarachnoid hemorrhage (SAH). However, the association of serum cTnT level and prognosis of intracerebral hemorrhage (ICH) has been sparsely investigated. The aim of this study was to identify the relationship between cTnT level and the outcome in patients with spontaneous ICH.
We retrospectively investigated 253 patients identified by a database search from records of patients admitted in our department for ICH between January 1, 2003 and December 31, 2007. The patients were divided into 2 groups; the patients in group 1 (n=225) with serum cTnT values of 0.01 ng/mL or less, and those in group 2 (n=28) with serum cTnT values greater than 0.01 ng/mL.
The serum cTnT level was elevated in 28 patients. There were significant differences in sex, hypertension, creatine kinase-myocardial band, midline shift, side of hematoma, and presence of intraventricular hemorrhage between the 2 groups. Logistic regression analysis identified the level of consciousness on admission, cTnT and midline shift as independent predictors of hospital mortality.
Theses results suggest that increased serum cTnT level at admission is associated with in-hospital mortality and the addition of a serum cTnT assay to routine admission testing should be considered in patients with ICH.
PMCID: PMC2711233  PMID: 19609419
Cardiac troponin T; Intracerebral hemorrhage; Outcome
12.  APOE Genotype Predicts Extent of Bleeding and Outcome in Lobar Intracerebral Hemorrhage 
Lancet neurology  2011;10(8):702-709.
APOE alleles ε2/ε4 increase risk of intracerebral hemorrhage (ICH) in the lobar regions, presumably through their influence on risk of cerebral amyloid angiopathy. We investigated whether these variants also associate with ICH severity, specifically larger ICH volume at presentation.
We initially investigated the association of ε2/ε4 with ICH volume and outcome in a Discovery sample of 865 individuals of European ancestry. Replication was completed in two samples, comprising 946 Europeans (Replication I) and 214 African-Americans (Replication II) respectively. Admission ICH volume was quantified on CT scan. Poor functional outcome (modified Rankin Scale: 3 – 6) and mortality were assessed at 90 days.
Among patients with lobar ICH, APOE ε2 was associated with larger ICH volume: each allele copy increased hematoma size by 5·3 cc (95% CI 4·1 – 6·2 cc, p = 0.004), with replication in Europeans (p = 0·008) and African Americans (p = 0·016). Consistent with this, ε2 was associated with both mortality (OR = 1·50, 1·23 – 1·82, p = 2·45 × 10−5) and poor functional outcome (OR = 1·52, 1·25 – 1·85, p = 1·74 × 10−5). We were not able to replicate published associations between ε4 and overall ICH mortality in a meta-analysis of all available data (n = 2202 ICH cases, OR = 1·08, 95% CI: 0·86 – 1·36, p = 0·52).
In lobar ICH, APOE ε2 is associated with larger ICH volume at presentation, and hence increased mortality and disability. These findings suggest a role for the vasculopathic changes associated with the ε2 allele in influencing the severity and clinical course of lobar ICH.
This study was funded by NIH-NINDS, the American Heart Association, government agencies in Spain, Poland and Austria, academic institutions in Sweden and Austria, and philanthropic organizations.
PMCID: PMC3153411  PMID: 21741316
13.  Impact of a Neurointensivist on Outcomes in Critically Ill Stroke Patients 
Neurocritical Care  2012;16(1):63-71.
Current guidelines for management of critically ill stroke patients suggest that treatment in a neurocritical care unit (NCCU) and/or by a neurointensivist (NI) may be beneficial, but the contribution of each to outcome is unknown. The relative impact of a NCCU vs. NI on short- and long-term outcomes in patients with acute ischemic stroke (AIS), intracerebral hemorrhage (ICH) and aneurysmal subarachnoid hemorrhage (SAH) was assessed.
2,096 stroke patients admitted to a NCCU or non-neuro ICU at a tertiary stroke center were analyzed before the appointment of a NI, during the NI’s tenure, and after the NI departed and was not replaced. Data included admission ICU type, availability of a NI, age, NIHSS, ICH score and 3 and 12 month outcome.
For AIS, compared to the time interval with a NI, departure of the NI predicted a worse rate of return to pre-stroke function at 3 months. For ICH, NCCU treatment predicted shorter ICU and hospital LOS but had no effect on short or long term outcomes. No effect of a NI was seen. For SAH, availability of an NI (but not an NCCU) predicted improved outcomes but longer ICU LOS. Disposition and in-hospital mortality improved when a NI was present, but continued improvement did not occur after the NI’s departure.
Presence of an NI was associated with improved clinical outcomes. This effect was more evident in patients with SAH. Patients with ICH tend to have poor outcomes regardless of the presence of a NCCU or a NI.
PMCID: PMC3265609  PMID: 21847702
ischemic stroke; intracerebral hemorrhage; subarachnoid hemorrhage; neurointensivist; neurocritical care; outcomes
14.  Subarachnoid haemorrhage in the elderly: a necropsy study of the association with cerebral amyloid angiopathy. 
To clarify the contribution of cerebral amyloid angiopathy (CAA) to subarachnoid haemorrhage (SAH) in the elderly, relationships between SAH and CAA were investigated in 997 necropsy cases aged 60 years or older. Primary SAH (bleeding from subarachnoid vessels) was found in 15 cases (1.5%). There was no case in which primary SAH was clearly attributed to CAA. Secondary SAH [secondary rupture of intracerebral haemorrhage (ICH) through the cortex to the subarachnoid space] was found in 23 patients (2.3%). In 11 (48%) of them, ICH with secondary SAH was associated with CAA. The results indicated that primary SAH is rarely related to CAA, however, CAA is the most frequent cause of ICH accompanying secondary SAH in the elderly.
PMCID: PMC1015016  PMID: 8505648
15.  Risk factors for intracerebral hemorrhage differ according to hemorrhage location 
Neurology  2012;79(23):2275-2282.
Risk factors have been described for spontaneous intracerebral hemorrhage (ICH); their relative contribution to lobar vs nonlobar hemorrhage location is less clear. Our purpose here was to investigate risk factors by hemorrhage location.
This case-control study prospectively enrolled subjects with first-ever spontaneous ICH and matched each with up to 3 controls by age, race, and gender. Conditional stepwise logistic regression modeling was used to determine significant independent risk factors for lobar and nonlobar ICH.
From December 1997 through December 2006, 597 cases and 1,548 controls qualified for the analysis. Hypertension, warfarin use, first-degree relative with ICH, personal history of ischemic stroke, less than a high school education, and APOE ε2 or ε4 genotype were more common in ICH cases. Hypercholesterolemia and moderate alcohol consumption (≤2 drinks per day) were less common in ICH cases. The associations of hypertension and hypercholesterolemia were specific for nonlobar ICH. Conversely, the association of APOE ε2 or ε4 genotype was specific for lobar ICH.
APOE ε2 or ε4 genotype was associated specifically with lobar ICH. Hypertension was associated specifically with nonlobar ICH. A protective association was seen between hypercholesterolemia and nonlobar ICH; no such association was identified for lobar ICH.
PMCID: PMC3542348  PMID: 23175721
16.  Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke: Systematic review and meta-analysis of 14 015 stroke cases and pooled analysis of primary biomarker data from up to 60 883 individuals 
Background At the APOE gene, encoding apolipoprotein E, genotypes of the ε2/ε3/ε4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk of ischaemic stroke is less clear. We evaluated the association of APOE genotype with risk of ischaemic stroke and assessed whether the observed effect was consistent with the effects of APOE genotype on LDL-C or other lipids and biomarkers of cardiovascular risk.
Methods We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke. We pooled 41 studies (with a total of 9027 cases and 61 730 controls) using a Bayesian meta-analysis to calculate the odds ratios (ORs) for ischaemic stroke with APOE genotype. To better evaluate potential mechanisms for any observed effect, we also conducted a pooled analysis of primary data using 16 studies (up to 60 883 individuals) of European ancestry. We evaluated the association of APOE genotype with lipids, other circulating biomarkers of cardiovascular risk and carotid intima-media thickness (C-IMT).
Results The ORs for association of APOE genotypes with ischaemic stroke were: 1.09 (95% credible intervals (CrI): 0.84–1.43) for ε2/ε2; 0.85 (95% CrI: 0.78–0.92) for ε2/ε3; 1.05 (95% CrI: 0.89–1.24) for ε2/ε4; 1.05 (95% CrI: 0.99–1.12) for ε3/ε4; and 1.12 (95% CrI: 0.94–1.33) for ε4/ε4 using the ε3/ε3 genotype as the reference group. A regression analysis that investigated the effect of LDL-C (using APOE as the instrument) on ischaemic stroke showed a positive dose-response association with an OR of 1.33 (95% CrI: 1.17, 1.52) per 1 mmol/l increase in LDL-C. In the separate pooled analysis, APOE genotype was linearly and positively associated with levels of LDL-C (P-trend: 2 × 10−152), apolipoprotein B (P-trend: 8.7 × 10−06) and C-IMT (P-trend: 0.001), and negatively and linearly associated with apolipoprotein E (P-trend: 6 × 10−26) and HDL-C (P-trend: 1.6 × 10−12). Associations with lipoprotein(a), C-reactive protein and triglycerides were non-linear.
Conclusions In people of European ancestry, APOE genotype showed a positive dose-response association with LDL-C, C-IMT and ischaemic stroke. However, the association of APOE ε2/ε2 genotype with ischaemic stroke requires further investigation. This cross-domain concordance supports a causal role of LDL-C on ischaemic stroke.
PMCID: PMC3619955  PMID: 23569189
Stroke; lipids; apolipoprotein E; cardiovascular disease; systematic review; meta-analysis; biomarkers
17.  Association between the apolipoprotein E gene polymorphism and ischemic stroke in Chinese populations: New data and meta-analysis 
Ischemic stroke (IS) is a complex multifactorial inherited disease. Many studies have focused on the potential genetic effects of apolipoprotein E (ApoE) gene polymorphism on IS. However, inconsistencies still exist in the association of ApoE gene polymorphism with IS. The aim of this study was to investigate the ApoE gene polymorphism in relation to IS in the Guangxi Han populations and assess the risk of various ApoE genotypes associated with IS in Chinese populations. We conducted a case-control study involving a total of 166 IS cases and 192 healthy controls to investigate the association of ApoE gene polymorphism with IS in the Guangxi Han populations. Furthermore, we performed a meta-analysis to investigate whether the ApoE gene polymorphism is associated with IS in Chinese populations. There was no evidence for a significant association between ApoE gene polymorphism and IS in the Guangxi Han populations (ɛ2/ɛ2 vs. ɛ3/ɛ3: OR=1.25, 95% CI=0.08–20.17; ɛ2/ɛ3 vs. ɛ3/ɛ3: OR=1.49, 95% CI=0.79–2.79; ɛ2/ɛ4 vs. ɛ3/ɛ3: OR=1.25, 95% CI=0.17–9.00; ɛ3/ɛ4 vs. ɛ3/ɛ3: OR=1.10, 95% CI=0.60–2.04; ɛ4/ɛ4 vs. ɛ3/ɛ3: OR=2.50, 95% CI=0.22–27.87; allele ɛ2 vs. allele ɛ3: OR=1.39, 95% CI=0.80–2.44; allele ɛ4 vs. allele ɛ3: OR=1.16, 95% CI=0.68–1.98). In our meta-analysis, a significant association of ApoE gene polymorphism with IS was found in the genetic model of ɛ2/ɛ4 vs. ɛ3/ɛ3 (OR=2.04, 95% CI=1.45–2.85), ɛ3/ɛ4 vs. ɛ3/ɛ3 (OR=1.93, 95% CI=1.42–2.62), ɛ4/ɛ4 vs. ɛ3/ɛ3 (OR=3.41, 95% CI=2.17–5.34) and allele ɛ4 vs. allele ɛ3 (OR=2.34, 95% CI=1.91–2.86). However, no clear associations were found in the model of ɛ2/ɛ2 vs. ɛ3/ɛ3 (OR=1.56, 95% CI=0.90–2.71), ɛ2/ɛ3 vs. ɛ3/ɛ3 (OR=0.93, 95% CI=0.79–1.09) and allele ɛ2 vs. allele ɛ3 (OR=1.10, 95% CI=0.97–1.25). In conclusion, no association was found between ApoE gene polymorphism and IS in the Guangxi Han populations, while the results of the meta-analysis indicate that the ApoE mutation allele ɛ4 increases the risk of IS in Chinese populations.
PMCID: PMC3570227  PMID: 23407699
apolipoprotein E gene; polymorphism; ischemic stroke; association study; meta-analysis
18.  Non-High-Density Lipoprotein Cholesterol on the Risks of Stroke: A Result from the Kailuan Study 
PLoS ONE  2013;8(9):e74634.
To prospectively explore the association between non-high-density lipoprotein cholesterol (non-HDLC) and the risks of stroke and its subtypes.
A total of 95,916 participants (18-98 years old; 76,354 men and 19,562 women) from a Chinese urban community who were free of myocardial infarction and stroke at baseline time point (2006-2007) were eligible and enrolled in the study. The serum non-HDLC levels of participants were determined by subtracting the high-density lipoprotein cholesterol (HDLC) from total serum cholesterol. The primary outcome was the first occurrence of stroke, which was diagnosed according to the World Health Organization criteria and classified into three subtypes: ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. The Cox proportional hazards models were used to estimate risk of stroke and its subtypes.
During the four-year follow-up, we identified 1614 stroke events (1,156 ischemic, 416 intracerebral hemorrhagic and 42 subarachnoid hemorrhagic). Statistical analyses showed that hazard ratios (HR) (95% Confidence Interval: CI) of serum Non-HDLC level for total and subtypes of stroke were: 1.08 (1.03-1.12) (total), 1.10 (1.05-1.16) (ischemic), 1.03 (0.96-1.10) (intracerebral hemorrhage) and 0.83 (0.66-1.05) (subarachnoid hemorrhage). HR for non-HDLC refers to the increase per each 20 mg/dl. For total and ischemic stroke, the risks were significantly higher in the fourth and fifth quintiles of non-HDLC concentrations compared to the first quintile after adjusting the confounding factors (total stroke: 4th quintile HR=1.33 (1.12-1.59); 5th quintile HR = 1.36 (1.15-1.62); ischemic stroke: 4th quintile HR =1.34 (1.09-1.66); 5th quintile HR = 1.53 (1.24-1.88)).
Our data suggest that serum non-HDLC level is an independent risk factor for total and ischemic stroke, and that higher serum non-HDLC concentrations are associated with increased risks for total stroke and ischemic stroke, but not for intracerebral and subarachnoid hemorrhage.
PMCID: PMC3769236  PMID: 24058611
19.  Aging and cerebrovascular dysfunction: contribution of hypertension, cerebral amyloid angiopathy, and immunotherapy 
Age-related cerebrovascular dysfunction contributes to ischemic stroke, intracerebral hemorrhages, microbleeds, cerebral amyloid angiopathy (CAA), and cognitive decline. Importantly, there is increasing recognition that this dysfunction plays a critical aging secondary role in many neurodegenerative diseases, including Alzheimer’s disease (AD). Atherosclerosis, hypertension, and CAA are the most common causes of blood brain barrier (BBB) lesions. The accumulation of amyloid beta (Aβ) in the cerebrovascular system is a significant risk factor for intracerebral hemorrhage (ICH), and has been linked to endothelial transport failure and blockage of perivascular drainage. Moreover, recent anti-Aβ immunotherapy clinical trials demonstrated efficient clearance of parenchymal amyloid deposits, but have been plagued by CAA-associated adverse events. While management of hypertension and atherosclerosis can reduce the incidence of ICH, there are currently no approved therapies for attenuating CAA. Thus, there is a critical need for new strategies that improve BBB function and limit the development of beta-amyloidosis in the cerebral vasculature.
PMCID: PMC2958685  PMID: 20955427
Alzheimer disease; cerebral amyloid angiopathy; blood brain barrier; immunotherapy; hypertension
20.  Association of the APOE, MTHFR and ACE Genes Polymorphisms and Stroke in Zambian Patients 
Neurology International  2013;5(4):e20.
The aim of the present study was to investigate the association of APOE, MTHFR and ACE polymorphisms with stroke in the Zambian population. We analyzed 41 stroke patients and 116 control subjects all of Zambian origin for associations between the genotype of the APOE, MTHFR and ACE polymorphisms and stroke. The APOE ε2ε4 genotype showed increased risk for hemorrhagic stroke (P<0.05) and also a high risk for ischemic stroke (P=0.05). There was complete absence of the APOE ε2ε2 and the MTHFR TT genotypes in the Zambian population. The difference between cases and controls was not significant for the other genetic variants when analyzed for relationship between stroke, stroke subtype and genotype. We show that genetic variation at the APOE locus affects susceptibility to stroke. No detectable association were observed for the MTHFR and ACE genotypes and stroke in the Zambian population.
PMCID: PMC3883065  PMID: 24416484
Sub-Saharan Africa; Zambia; ischemic stroke; intra-cerebral hemorrhage; outcome; risks factors
21.  Prevalence of transthoracic echocardiographic abnormalities in patients with ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage 
This study investigated the prevalence of transthoracic echocardiographic abnormalities in patients with ischemic stroke (IS), subarachnoid hemorrhage (SAH), and intracerebral hemorrhage (ICH) in sinus rhythm.
Material and methods
The patients included 120 with IS, 30 with SAH, and 41 with ICH. All diagnoses were confirmed by magnetic resonance imaging or brain computed tomography. Two-dimensional echocardiograms were taken at the time stroke was diagnosed. All echocardiograms were interpreted by an experienced echocardiographer.
Of 120 IS patients, 1 (1%) had a left ventricular (LV) thrombus, 1 (1%) had mitral valve vegetations, 30 (25%) had LV hypertrophy, 26 (22%) had abnormal LV ejection fraction, 4 (3%) had mitral valve prolapse, 33 (28%) had mitral annular calcium (MAC), 40 (33%) had aortic valve calcium (AVC), 3 (3%) had a bioprosthetic aortic valve, 10 (8%) had aortic stenosis (AS), 6 (5%) had atrial septal aneurysm, 2 (2%) had patent foramen ovale, and 40 (33%) had no abnormalities. Of 30 SAH patients, 5 (17%) had LV hypertrophy, 1 (3%) had abnormal LV ejection fraction, 1 (3%) had AS, 4 (13%) had MAC, 5 (17%) had AVC, and 20 (67%) had no abnormalities. Of 41 ICH patients, 9 (22%) had LVH, 1 (2%) had abnormal LV ejection fraction, 1 (3%) had AS, 6 (15%) had MAC, 8 (20%) had AVC, and 22 (54%) had no abnormalities.
Transthoracic echocardiographic abnormalities are more prevalent in patients with IS than in patients with SAH or ICH.
PMCID: PMC3278941  PMID: 22371718
echocardiography; ischemic stroke; subarachnoid hemorrhage; intracerebral hemorrhage
22.  Apolipoprotein E gene polymorphism and the risk of intracerebral hemorrhage: a meta-analysis of epidemiologic studies 
Studies investigating the association between the apolipoprotein E (APOE) gene polymorphism and the risk of intracerebral hemorrhage (ICH) have reported conflicting results. We here performed a meta-analysis based on the evidence currently available from the literature to make a more precise estimation of this relationship.
Published literature from the National Library of Medline and Embase databases were retrieved. Odds ratio (OR) and 95% confidence interval (CI) were calculated in fixed- or random-effects models when appropriate. Subgroup analyses were performed by race.
This meta-analysis included 11 case–control studies, which included 1,238 ICH cases and 3,575 controls. The combined results based on all studies showed that ICH cases had a significantly higher frequency of APOE ϵ4 allele (OR= 1.42, 95% CI= 1.21,1.67, P<0.001). In the subgroup analysis by race, we also found that ICH cases had a significantly higher frequency of APOE ϵ4 allele in Asians (OR= 1.52, 95% CI= 1.20,1.93, P<0.001) and in Caucasians (OR= 1.34, 95% CI= 1.07,1.66, P=0.009). There was no significant relationship between APOE ϵ2 allele and the risk of ICH.
Our meta-analysis suggested that APOE ϵ4 allele was associated with a higher risk of ICH.
PMCID: PMC3984699  PMID: 24621278
Apolipoprotein E; Intracerebral hemorrhage; Gene polymorphism; Meta-analysis
23.  Interaction Between Sex and Apolipoprotein E Genetic Background in a Murine Model of Intracerebral Hemorrhage 
Translational stroke research  2012;3(1):94-101.
Emerging evidence suggests sex and apolipoprotein E (APOE) genotype separately modify outcomes after intracerebral hemorrhage (ICH). We test the hypothesis that an interaction exists between sex and APOE polymorphism in modifying outcomes after ICH and is altered by administration of exogenous apoE-mimetic peptide. To define the effects of sex and APOE polymorphism in ICH, we created collagenase-induced ICH in male and female APOETR mice (targeted replacement mice homozygous for APOE3 or APOE4 alleles; n=12/group) and assessed performance on Rotarod (RR) and Morris water maze (MWM). To evaluate hematoma formation, we used hematoxylin and eosin staining at 24 h after injury (n=8/group). Using separate cohorts (n=12/group), apoE-mimetic peptide (COG1410 at 2 mg/kg) was administered after ICH, and mice were assessed by RR and MWM. Female mice outperformed male mice via RR and MWM by over 190% improvement through 7 days (RR) and 32 days (MWM) of testing after ICH (p<0.01). Female APOE3TR mice demonstrated improved function compared with all other groups (p<0.05) without any difference in hematoma volume at 24 h after injury in any group. Administration of a therapeutic apoE-mimetic peptide improved RR latencies through 7 days after ICH in male and female APOE4TR mice and MWM latencies over days 28–32 after ICH in male APOE4TR mice (p<0.05). Sex and APOE polymorphism influence functional outcomes in our murine model of ICH. Moreover, administration of exogenous apoE-mimetic peptide after injury differentially modifies the interaction between sex and APOE polymorphism.
PMCID: PMC3736996  PMID: 23935764
Apolipoprotein E; Sex differences; Murine; Intracerebral hemorrhage; Female
24.  Cerebral Microbleeds on Magnetic Resonance Imaging and Anticoagulant-Associated Intracerebral Hemorrhage Risk 
The increasing use of antithrombotic drugs in an aging population [including anticoagulants to prevent future ischemic stroke in individuals with atrial fibrillation (AF)] has been associated with a dramatic increase in the incidence of intracerebral hemorrhage (ICH) in users of antithrombotic drugs. Several lines of evidence suggest that cerebral small vessel disease (particularly sporadic cerebral amyloid angiopathy) is a risk factor for this rare but devastating complication of these commonly used treatments. Cerebral microbleeds (CMBs) have emerged as a key MRI marker of small vessel disease and a potentially powerful marker of future ICH risk, but adequately powered, high quality prospective studies of CMBs and ICH risk on anticoagulation are not available. Further data are urgently needed to determine how neuroimaging and other biomarkers may contribute to individualized risk prediction to make anticoagulation as safe and effective as possible. In this review we discuss the available evidence on cerebral small vessel disease and CMBs in the context of antithrombotic treatments, especially regarding their role as a predictor of future ICH risk after ischemic stroke, where risk-benefit judgments can be a major challenge for physicians. We will focus on patients with AF because these are frequently treated with anticoagulation. We briefly describe the rationale and design of a new prospective observational inception cohort study (Clinical Relevance of Microbleeds in Stroke; CROMIS-2) which investigates the value of MRI markers of small vessel disease (including CMBs) and genetic factors in assessing the risk of oral anticoagulation-associated ICH.
PMCID: PMC3446731  PMID: 23015806
cerebral microbleeds; cerebral small vessel disease; cerebral amyloid angiopathy; intracerebral hemorrhage; atrial fibrillation; anticoagulation; antithrombotics
25.  Mixed Cerebrovascular Disease and the Future of Stroke Prevention 
Translational Stroke Research  2012;3(Suppl 1):39-51.
Stroke prevention efforts typically focus on either ischemic or hemorrhagic stroke. This approach is overly simplistic due to the frequent coexistence of ischemic and hemorrhagic cerebrovascular disease. This coexistence, termed “mixed cerebrovascular disease”, offers a conceptual framework that appears useful for stroke prevention strategies. Mixed cerebrovascular disease incorporates clinical and subclinical syndromes, including ischemic stroke, subclinical infarct, white matter disease of aging (leukoaraiosis), intracerebral hemorrhage, and cerebral microbleeds. Reliance on mixed cerebrovascular disease as a diagnostic entity may assist in stratifying risk of hemorrhagic stroke associated with platelet therapy and anticoagulants. Animal models of hemorrhagic cerebrovascular disease, particularly models of cerebral amyloid angiopathy and hypertension, offer novel means for identifying underlying mechanisms and developing focused therapy. Phosphodiesterase (PDE) inhibitors represent a class of agents that, by targeting both platelets and vessel wall, provide the kind of dual actions necessary for stroke prevention, given the spectrum of disorders that characterizes mixed cerebrovascular disease.
PMCID: PMC3372772  PMID: 22707990
Stroke; Cerebrovascular; Hemorrhage; Hemorrhagic transformation; Microbleeds; Leukoaraiosis; Amyloid; Hypertension; Phosphodiesterase inhibitor

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