Stable Ischemic Stroke Research Articles

Efficacy and safety of clopidogrel and aspirin do not differ in patients with stable ischemic stroke.

The current study compared the efficacy and safety of clopidogrel vs aspirin in the secondary prevention of ischemic stroke (IS). We included patients from the Taiwan National Health Insurance Research Database who were aged between 20 and 80 years, had their first ever IS, had no diagnosis of atrial fibrillation, and had not used an oral anticoagulant before the index IS between 2002 and 2010. We excluded patients who died or were admitted to a hospital due to acute myocardial infarction, recurrent IS, or major bleeding within 3 months of IS. Patients were then classified into clopidogrel as aspirin users. Propensity score matching was adopted to select clopidogrel and aspirin groups with similar baseline characteristics (n = 8457 vs 16,914, mean follow-up period of 2.1 years and 1.9 years, respectively). Conditional Cox proportional hazard regression was used to compare risks of all-cause death, cardiovascular death, recurrent stroke, acute myocardial infarction, and major bleeding in clopidogrel users and aspirin users. The risks of all-cause death, cardiovascular death, recurrent stroke, and acute myocardial infarction did not differ between clopidogrel and aspirin users. Subgroup analyses revealed that the results were consistent regardless of age, disease severity, or comorbidity. According to real-world data, the efficacy and safety of clopidogrel and aspirin for secondary prevention of stable IS did not differ.

Intraluminal spindle-shaped-head suture induced occlusion of middle cerebral artery in the rats

Objective: This study aimed to introduce a modified animal model of middle cerebral arterial occlusion (MCAO) through placement of intraluminal spindle-shaped head suture by comparing the traditional MCAO model. Methods: A total of 60 male Spraque-Dawley (SD) rats were divided into two groups and MCAO was induced using spindle-shaped head suture or round head suture. The mortality, infarct volume, neurological function, success rate of the surgery, and stability of modeling were examined to evaluate the effectiveness of this model. Results: Our results showed the success rate was 90.0% in spindle-shaped head group and 83.3% in round head group showing no significant difference; spindle-shaped head achieved a better establishment of MCAO model as shown in neurological examination. The infarct volume was 31.99 ± 5.44% in spindle-shaped head group and was significantly higher than in round head group (24.59 ± 7.17%; p < 0.05), and the coefficient of variation of infarct volume in spindle-shaped head group was lower than in round head group. Conclusion: Our findings indicate that the modified suture induces a more reproducible and stable ischemic stroke following MCAO in SD rats.

Preliminary Reports of Stereotaxic Stem Cell Transplants in Chronic Stroke Patients.

Preclinical studies have suggested that stem cell–based therapies possess the potential to improve stroke outcomes. Recently, the results of two early-stage clinical trials of stem cell therapy for chronic stroke have been published: the United Kingdom–based ReNeuron phase I clinical trial, called “Pilot Investigation of Stem Cells in Stroke” (PISCES, NCT01151124),1 and the United States–based SanBio phase I/IIa clinical trial, called “A Study of Modified Stem Cells in Stable Ischemic Stroke” (NCT01287936).

Abstract W MP93: Changes in FDG-PET Activity Following Intraparenchymal Injection of SB623 Cells in Patients with Stable Ischemic Strokes

Background: Ischemic stroke remains a major cause of disability with 90% of patients achieving no improvement after 90 days. The primary objective of this study was to evaluate the safety and feasibility of intraparenchymal administration of SB623 cells in chronic stroke. SB623 cells are adult bone-marrow-derived cells transfected with a plasmid encoding the intracellular domain of Notch-1 that have demonstrated improvement in functional testing in animal models of stroke. Methods: Patients with hemiparesis from stable subcortical ischemic stroke and NIHSS &gt; 7 received intracranial injection of 2.5, 5 or 10 million SB623 cells. Clinical outcome measures included NIHSS, MRS, ESS and FMA measured at baseline and repeated at 6 and 12 months. FDG-PET was analyzed at each time point using cluster analysis within 5 regions of interest (contralateral frontal cortex, medial ventral to infarct, contralateral putamen, contralateral sensori-motor cortex, and contralateral thalamus). Results: Five patients enrolled at one academic center were included in this initial FDG-PET analysis. In these 5 patients, there was improvement in NIHSS (p = 0.008) and ESS (p = 0.006), which was most apparent from 0 to 6 months (p = 0.005; p = 0.005). There was also an increase in FDG-PET activity in the contralateral sensori-motor cortex from 0-6 months (p = 0.005), which was related to NIHSS, ESS and FMA (p = 0.043). Analyses of individual patients showed increased FDG uptake contralateral to the injection site in 3/5 patients. There was an increase near the area of infarct in 2/5 patients that was seen at 6 months but not at 12 months. Conclusions: Intraparenchymal injection of SB623 cells in chronic ischemic strokes resulted in increased FDG uptake predominantly in areas contralateral to stem cell injection in some patients. These increases were associated with improved clinical outcome measures suggesting that the PET changes might reflect activation of neural pathways due to stem cell therapy. Further PET studies with appropriate controls are warranted.

Abstract 34: Cognitive Outcomes Following Intracranial Injection of SB623 Cells in Patients with Stable Ischemic Strokes

Background: Ischemic stroke remains a major cause of disability with 90% of patients achieving no improvement after 90 days. The primary objective of this study was to evaluate the safety and feasibility of intraparenchymal administration of SB623 cells in chronic stroke. SB623 cells are adult bone-marrow-derived cells transfected with a plasmid encoding the intracellular domain of Notch-1 and have been shown to secrete factors that protect neurons in animal models. Methods: Patients with hemiparesis from stable subcortical ischemic stroke and NIHSS &gt; 7 received intracranial injection of 2.5, 5 or 10 million SB623 cells. Clinical outcome measures including NIHSS, MRS, ESS, FMA and cognitive testing including Rey verbal learning and figure copy, digit vigilance, digit-symbol coding, trails, logical memory, word association, Stroop interference and letter-number sequencing were recorded at baseline and then repeated at 6 and 12 months. Results: 18 patients were enrolled, 11 had complete data available for analysis. There was improvement from 0-12 months in Rey verbal learning (p = 0.033); and from 0-6 months in categorical word association (p = 0.014), which was affected by cell dose (p = 0.043). Patients with cortical versus deep infarcts showed more improvement on Rey figure immediate (p = 0.01) and delayed recall (p = 0.014), and digit-symbol coding (p = 0.042). Patients with left-sided infarcts showed more improvement on logical memory (T1 p = 0.038, T2 p = 0.008), but worsened performance on letter number sequencing (p = 0.046). Conclusions: Intraparenchymal injection of SB623 cells in chronic ischemic strokes resulted in improvement of some measures of cognitive function. Further investigation of cognitive function in stem cell therapy for stroke is warranted.

Association of inflammation and oxidative stress with obstructive sleep apnea in ischemic stroke patients

ObjectiveThe role of obstructive sleep apnea (OSA) in the mortality and further cardiovascular risk in subjects with ischemic stroke remains a contentious issue. Oxidative stress and inflammatory reaction due to OSA have seldom been studied in stable ischemic stroke patients. Patients/MethodsThis cross-sectional, prospective study involved 92 consecutive ischemic stroke patients who were admitted to the Rehabilitation ward. All subjects received polysomnography and laboratory tests for oxidative stress and inflammatory biomarkers, including: C-reactive protein (CRP), interleukin 6 (IL-6), total antioxidant capacity (TAC), and urinary 8-hydroxy-2-deoxyguanosine. Differences in study variables between patients with or without severe OSA were compared, and multivariate linear regression analyses were used to assess the relationship between OSA severity and target biomarkers. ResultsParticipants in the severe OSA group were significantly older (p = 0.002), had a significantly higher risk of hypertension (p = 0.021) and a lower level of CRP (p = 0.006). Among the subjects with ischemic stroke and severe OSA, the levels of CRP, IL-6, and TAC were positively correlated with the desaturation index (DI) and the TAC levels were negatively correlated with mean arterial oxygen saturation (SaO2). Regression analysis results indicated that the TAC levels remained significantly and negatively correlated with mean SaO2 levels. Moreover, the CRP levels remained significantly correlated with the apnea–hypopnea index and DI after controlling for covariates. ConclusionsThe present study demonstrated that a preferentially adaptive antioxidative response to hypoxia emerges, and the role of OSA with respect to inflammatory reaction is attenuated, in ischemic stroke patients with OSA.

Abstract 149: A Novel Phase 1/2A Study of Intraparenchymal Transplantation of Human Modified Bone Marrow Derived Cells in Patients with Stable Ischemic Stroke

Introduction: No treatment exists to restore lost brain function after stroke. Animal studies demonstrate that brain transplantation of SB623, a human bone marrow derived stromal cell with transient transfection of Notch-1 gene, after experimental stroke can improve neurologic outcome. This clinical study is the first North American trial of intraparenchymal transplantation of bone marrow derived cell therapy for chronic stroke patients. METHODS: This is a two center (Stanford University and the University of Pittsburgh) open label safety and dose escalation feasibility study. Stereotactic transplantation is targeted to the subcortical peri-infarct area. Inclusion criteria include 18-75 yo, 6-60 mos post subcortical MCA ischemic stroke, mRS 3-4 and NIHSS &gt; 7. Safety endpoints include WHO toxicity scale, MRIs and clinical follow-up to 2 years. The primary efficacy endpoint is European Stroke Scale (ESS) at 6 mos; secondary efficacy measures are ESS, NIHSS, Fugl-Meyer, mRS, cognitive scores up to 2 years, and FDG-PET at 6 months. RESULTS: Seventeen patients have been treated (6 with 2.5M cells, 6 with 5M and 5 with 10M). Follow-up is currently 6 mos in 12 pts, 9 mos in 9 pts and 12 mos in 6 pts. There were 3 serious adverse events related to the surgery, but not to the cells (seizure, subdural hematoma, pneumonia). Cytokine levels, HLA antibody levels, and PBMC function did not change from baseline. Three measures of efficacy (NIHSS, ESS, Fugl-Meyer) all show a trend toward improvement. Since the sample size is small, no statistical analysis has been done. Two patients showed remarkable improvement in their motor (2) and language function (1) within 24 h of surgery, effects which have been sustained during follow-up (12 and 3 mos). These were the only 2 patients with new FLAIR lesions (DWI neg) in the motor cortex that resolved at 2 mos. CONCLUSIONS: Intraparenchymal transplantation of human modified bone marrow derived stromal cells in chronic stroke patients is safe, feasible, and shows a trend toward neurologic improvement. Larger studies will be initiated to further assess clinical efficacy.

Abstract W P209: Development of a Useful Brain Ischemic Stroke Model via a Transient Occlusion of Middle Cerebral Artery in the Nonhuman Primate

Objectives: Most experimental stroke research is carried out in rodents, but given differences between rodents and human, the nonhuman primate (NHP) models may provide a valuable tool to study the clinical therapy. We developed a surgical method for transient occlusion of the middle cerebral artery (MCA-M1) in the Cynomolgus monkeys to evaluate the MCA territory blood flow, the model stability, animal clinical neurological behavior, morphology changes under magnetic resonance imaging (MRI) and histopathology. Methods: The left brain sylvian fissure was exposed by a small fronto-temporal craniotomy. The MCA-M1 was exposed by microsurgical dissection and clipped for 4 hours. The brain blood flow was measured in the MCA territory during the ischemia period and early phase of reperfusion period. The clinical neurological examinations and MRI were carried out at regular post-operative course till 4 weeks of stroke. Results: During MCA occlusion, the MCA territory blood flow was decreased significantly in 80%. This territory was reflowed right after reperfusion and showed an overload in about 20% over pre ischemia flow within 1hr after reperfusion and gradually returned to previous flow (Fig 1). Animal neurological behavior changed significantly within 1 week and became a steady status of neurological impairment. MRI demonstrated extensive MCA territory infarction. Histologically, at the end of 4 week stroke the brain showed a clear board of glia proliferation between infarct and normal brain tissue. Conclusion: These results indicate a stable ischemic stroke model in cynomolgus monkeys after complete MCA-M1 occlusion, which will be a useful NHP stroke model for stroke research and the clinical therapeutic studies. Fig 1 Changes in MCA territory blood flow during ischemia-reperfusion period

Acupuncture modulates the functional connectivity of the default mode network in stroke patients.

Abundant evidence from previous fMRI studies on acupuncture has revealed significant modulatory effects at widespread brain regions. However, few reports on the modulation to the default mode network (DMN) of stroke patients have been investigated in the field of acupuncture. To study the modulatory effects of acupuncture on the DMN of stroke patients, eight right hemispheric infarction and stable ischemic stroke patients and ten healthy subjects were recruited to undergo resting state fMRI scanning before and after acupuncture stimulation. Functional connectivity analysis was applied with the bilateral posterior cingulate cortices chosen as the seed regions. The main finding demonstrated that the interregional interactions between the ACC and PCC especially enhanced after acupuncture at GB34 in stroke patients, compared with healthy controls. The results indicated that the possible mechanisms of the modulatory effects of acupuncture on the DMN of stroke patients could be interpreted in terms of cognitive ability and motor function recovery.

Allogeneic Gene-Modified Mesenchymal Stem Cells for Stable Stroke: Mechanism of Action and Translation to the Clinic (IN8-2.004)

Objective: MSCs transfected with Notch-1 have demonstrated regenerative properties in rodent models of stable stroke. While cell replacement mechanisms have been ruled out, the details of the cell9s regenerative mechanism of action are not clear. Here we test several hypotheses; the production of soluble trophic factors, the production of beneficial extracellular matrix, and anti-inflammatory/immunosuppressive effects. Background MSCs secrete soluble factors that could serve as positive signals for regeneration and have well-established anti-inflammatory properties. Less well-studied is the production of beneficial extracellular matrix. Here we demonstrate these mechanisms at play in vitro and in rat models of stroke. Design/Methods: Rescue of primary neurons from insults (oxygen-glucose deprivation, excitotoxicity) can be mediated by co-culture with MSCs or by conditioned medium, demonstrating the effects of soluble factors. Analysis of conditioned medium revealed several key factors and demonstrated phenotypic differences between MSCs and Notch-transfected MSCs. Similar co-culture experiments demonstrated the beneficial effects of extracellular matrix produced by these cells. Mixed lymphocyte reactions demonstrated the immunosuppressive effects and again showed the phenotypic effects of Notch transfection. Immunohistochemical observations in models of neural injury supported the in vitro findings. Results: Secreted factors from Notch-transfected MSCs provide neurotrophic support to primary neurons in vitro. Analysis of extracellular matrix produced by these cells identified proteins contributing to their efficacy. Inflammation acts as a barrier to neural regeneration. MSCs attenuate these effects. Conclusions: Failure of regeneration after stroke appears to be a lack of sufficent positive stimuli (trophic factors etc.) and the presence of inhibitory stimuli (inflammation). No single entity has been found that can overcome these barriers. Cell therapy, working by multiple mechanisms, may provide a way forward. While mechanistic studies continue, GMP manufacturing and GLP safety studies have led to an active IND. A Phase 1 clinical trial is underway for patients with stable ischemic stroke. Supported by: SanBio Inc. Disclosure: Dr. Case has received personal compensation for activities with SanBio. Dr. Case holds stock and/or stock options in SanBio, which sponsored research in which Dr. Case was involved as an investigator.

Lower blood flow velocity, higher resistance index, and larger diameter of extracranial carotid arteries are associated with ischemic stroke independently of carotid atherosclerosis and cardiovascular risk factors

To investigate the association between diameter and flow velocity of the carotid arteries and ischemic stroke. Peak systolic velocity, end diastolic velocity, Pourcelot resistance index, blood flow volume, luminal diameter, and carotid plaque burden were measured and compared in 240 ischemic stroke (IS) patients without history of stroke, 163 chronic stable IS patients, and 236 nonstroke controls (age, >or=40 years). Data were also compared between stroke subtypes (large artery atherosclerosis, lacunar, cardioembolic, or undetermined origin). Acute as well as chronic stable IS patients had significantly lower flow velocities and flow volume, higher resistance index than nonstroke controls in the common carotid artery (CCA), internal carotid artery and external carotid artery, and larger common carotid artery diameter. The differences were found across all IS subtypes and in stroke patients with as well as without carotid plaque. Comparisons between these subgroups showed significant differences in end diastolic velocity, resistance index, flow velocity, and diameter that were more prominent in the CCA. After adjusting for carotid plaque and cardiovascular risk factors, the associations between the above-mentioned parameter and stroke remained significant. Stroke patients in acute as well as chronic stable phase appeared to have larger CCA diameters, lower carotid flow velocities and volume, and higher resistance index than nonstroke patients independently of extracranial carotid atherosclerosis. These findings need to be confirmed by a prospective study.

Intravenous unfractionated heparin in patients with acute ischemic stroke: a treatment to be used in the context of randomized trials only.

There is no reliable evidence from randomized controlled trials to support the routine use of intravenous unfractionated heparin in acute ischemic stroke, yet this treatment is very widely used in the United States and elsewhere. The Collaborative Embolism Study Group trial included just 45 patients within 48 hours of stroke onset, and a study by Duke et al in 1986 included 225 patients with stable ischemic stroke.1 Neither of these trials showed clear evidence of benefit. It seems quite extraordinary that clinicians continue to use this treatment in the absence of reliable data from randomized trial evidence: a triumph of opinion over evidence. A …

Relations between coagulation profiles, lipid profiles, and other risk factors with risk of first-ever ischemic stroke: a novel case-control study

P156 Background and objectives: Several hemostatic factors and lipid parameters are associated with risk of coronary heart disease. Few studies have investigated the relations between these factors and risk of ischemic stroke. The major aim of this study was to estimate the risks of hypercoagulability, hyperlipidemia, hypertension, and hyperglycemia in acquiring first-ever ischemic stroke. An ancillary aim was to observe changes including biochemical and coagulation profiles in first-ever ischemic stroke inpatients from admission to 3 months later. Methods: One hundred and forty-four first-ever ischemic stroke inpatients and two types of controls (including 142 stable ischemic stroke outpatients and 181 non-stroke outpatients) were recruited from 1996 to 1999. Uric acid and glucose levels, status of hypertension, diabetes, left ventricular hypertrophy (LVH), and atrial fibrillation (AF), and coagulation (clotting times, fibrinogen, factor VIIc, and factor VIIIc) and lipid (cholesterol, triglyceride, HDL-C and LDL-C) profiles were obtained. Results: The proportions of cases with elevated fibrinogen and factor VIIIc from admission to 3 months later were significantly higher than those of non-stroke controls, either with or without anticoagulants. The proportions of cases with decreased HDL-C and hyperglycemia were also significantly higher than those of non-stroke controls. After adjusting for multiple cardiovascular risk factors, elevated fibrinogen (OR=3.21; p=0.0071), hyperglycemia (OR=2.65; p=0.0076), hypertension (OR=1.97; p=0.0424), history of LVH (OR=3.15; p=0.0010), and carotid plaque states (OR=2.27; p=0.0185) were significantly associated with risk of first-ever ischemic stroke. Elevated factor VIIIc was at borderline significance level (OR=2.12; p=0.0722). Conclusion: Hypertension, hyperglycemia, LVH and positive carotid plaque were associated with risk of first-ever ischemic stroke. Elevated fibrinogen and factor VIIIc were also associated with first-ever ischemic stroke, indicating a role of coagulation profiles in the pathogenesis of ischemic stroke.

Relations between coagulation profiles, lipid profiles, and other risk factors with risk of first-ever ischemic stroke: a novel case-control study

P156 Background and objectives: Several hemostatic factors and lipid parameters are associated with risk of coronary heart disease. Few studies have investigated the relations between these factors and risk of ischemic stroke. The major aim of this study was to estimate the risks of hypercoagulability, hyperlipidemia, hypertension, and hyperglycemia in acquiring first-ever ischemic stroke. An ancillary aim was to observe changes including biochemical and coagulation profiles in first-ever ischemic stroke inpatients from admission to 3 months later. Methods: One hundred and forty-four first-ever ischemic stroke inpatients and two types of controls (including 142 stable ischemic stroke outpatients and 181 non-stroke outpatients) were recruited from 1996 to 1999. Uric acid and glucose levels, status of hypertension, diabetes, left ventricular hypertrophy (LVH), and atrial fibrillation (AF), and coagulation (clotting times, fibrinogen, factor VIIc, and factor VIIIc) and lipid (cholesterol, triglyceride, HDL-C and LDL-C) profiles were obtained. Results: The proportions of cases with elevated fibrinogen and factor VIIIc from admission to 3 months later were significantly higher than those of non-stroke controls, either with or without anticoagulants. The proportions of cases with decreased HDL-C and hyperglycemia were also significantly higher than those of non-stroke controls. After adjusting for multiple cardiovascular risk factors, elevated fibrinogen (OR=3.21; p=0.0071), hyperglycemia (OR=2.65; p=0.0076), hypertension (OR=1.97; p=0.0424), history of LVH (OR=3.15; p=0.0010), and carotid plaque states (OR=2.27; p=0.0185) were significantly associated with risk of first-ever ischemic stroke. Elevated factor VIIIc was at borderline significance level (OR=2.12; p=0.0722). Conclusion: Hypertension, hyperglycemia, LVH and positive carotid plaque were associated with risk of first-ever ischemic stroke. Elevated fibrinogen and factor VIIIc were also associated with first-ever ischemic stroke, indicating a role of coagulation profiles in the pathogenesis of ischemic stroke.

Serum Amino Acid Levels after Permanent Middle Cerebral Artery Occlusion in the Rat

Background and Purpose: High levels of glutamate in plasma and cerebrospinal fluid (CSF) have been demonstrated in patients with acute ischemic stroke. Whereas this glutamate increase in CSF is only evidenced during the first 6 h in stable ischemic stroke, it is sustained for 24 h in progressing stroke. The aim of this investigation was to study the evolution of serum glutamate levels after stroke in a rat model of permanent cerebral artery occlusion. Methods: Glutamate, glycine, aspartate, taurine and tryptophan were measured by high-performance liquid chromatography from serum samples taken before and at different times after permanent middle cerebral artery occlusion (MCAO) and from sham-operated rats. Results: After MCAO, a 3-fold increase in glutamate and a 2-fold increase in glycine and aspartate were observed in rat serum. The onset of this amino acid increase began 4–6 h after ischemic induction, reached peak values at 8–24 h and returned to preischemic values by 48–72 h. Serum concentrations of taurine and tryptophan were not modified after MCAO. Sham-operated rats did not exhibit changes of basal amino acid concentrations in serum. Conclusions: The serum excitatory amino acid profile in this experimental model confirms that the early detection of increased concentrations of glutamate and glycine at systemic circulation observed in patients with acute stroke is a consequence of the cerebral ischemic process.

Duration of glutamate release after acute ischemic stroke.

High levels of glutamate in plasma and cerebrospinal fluid (CSF) have been demonstrated in patients with acute ischemic stroke. The duration of this excitatory amino acid release has not been studied, and therefore the window of opportunity of treatment with glutamate antagonists is unknown. The aim of this investigation was to study the duration of the glutamate increase in patients with stable and progressing ischemic stroke. Glutamate in CSF was measured by high-performance liquid chromatography in 184 patients with an acute cerebral infarction of less than 24 hours' duration and in 43 control subjects. Among the 120 patients with stable ischemic stroke, median glutamate levels were significantly lower- and within the reference range of control subjects-in those patients studied 6 to 24 hours from onset of symptoms than in patients studied in the first 6 hours (3 [range, 2 to 10] versus 5 mumol/L [range, 2 to 17]; P < .0001). In 64 patients with progressing ischemic stroke, glutamate concentrations measured at any time interval during the first 24 hours from onset were significantly higher than in the stable stroke and control groups. The presence of glutamate increase in the CSF cannot be documented for greater than 6 hours in stable ischemic stroke. The sustained elevation of glutamate observed in progressing stroke suggests that the window to prevent neurological deterioration may be wider.