Cerebral Artery Occlusion Research Articles

Pleiotropic Roles of P2X7 in the Central Nervous System.

The purinergic receptor P2X7 is expressed in neural and immune cells known to be involved in neurological diseases. Its ligand, ATP, is a signaling molecule that can act as a neurotransmitter in physiological conditions or as a danger signal when released in high amount by damaged/dying cells or activated glial cells. Thus, ATP is a danger-associated molecular pattern. Binding of ATP by P2X7 leads to the activation of different biochemical pathways, depending on the physiological or pathological environment. The aim of this review is to discuss various functions of P2X7 in the immune and central nervous systems. We present evidence that P2X7 may have a detrimental or beneficial role in the nervous system, in the context of neurological pathologies: epilepsy, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, age-related macular degeneration and cerebral artery occlusion.

Symptomatic Carotid Stenosis: Stroke and Transient Ischemic Attack

Nearly 800,000 strokes are reported in the United States annually, with an economic impact upward of $33 billion. Carotid artery disease, familiar to all vascular surgeons, accounts for just over one fifth of these strokes. However, these cases reflect an opportunity for the surgeon to intervene and mitigate the substantial burden of stroke. This review includes the epidemiology of stroke in the United States and the carotid artery and noncarotid etiologies of stroke, including atherosclerotic disease, fibromuscular dysplasia, carotid artery dissection, and cardioembolism. The clinical presentations of ischemic and hemorrhagic stroke and transient ischemia attacks are examined, as are the major findings expected in the patient history and physical examination. Strategies for further evaluation of the patient are discussed, including the use of sonographic imaging of the carotid artery and the relative advantages and disadvantages among the dominant modes of brain imaging. New updates to the review include interventional approaches toward the treatment of acute ischemic stroke, as well as the latest strategies regarding the timing of carotid endarterectomy after stroke and the utility of carotid artery stenting in these patients, with active areas of current research highlighted. Figures show a computed tomographic (CT) angiogram of fibromuscular dysplasia of an internal carotid artery, a CT angiogram of an internal carotid artery dissection showing a defect in the dissection, a CT scan demonstrating hemorrhagic conversion of cardioembolic stroke, a CT scan of acute thalamic hemorrhage, a CT scan of evolving ischemic stroke, a T2-weighted image demonstrating acute left frontal stroke and remote right frontal stroke, T1- and T2-weighted images of right parietal ischemic stroke, and M1 occlusion of a middle cerebral artery treated successfully with transcatheter thrombectomy. Tables list Society of Radiologists in Ultrasound and University of Washington criteria for duplex ultrasound diagnosis of carotid artery stenosis. This review contains 8 figures, 8 tables, and 68 references. Keywords: Carotid stenosis, ischemic stroke, transient ischemic attack, endovascular therapy, thrombolysis, infarct, hemorrhagic stroke, atherosclerosis, embolism

Multiplex Profiling of Secreted Factors in the Cerebrospinal Fluid of Moyamoya Disease Patients

Abstract INTRODUCTION Moyamoya disease (MMD) is characterized by progressive occlusion of the internal cerebral arteries. We profiled 62 secreted factors in the cerebrospinal fluid (CSF) of MMD patients, and correlated the levels with the extent of neovascularization and functional outcomes following a revascularization procedure. METHODS CSF from angiographically confirmed MMD was collected. All MMD patients had undergone the revascularization procedure usually in the form of direct superficial temporal artery to middle cerebral artery bypass. Three groups were classified: 32 controls (Chiari or microvascular decompression), 37 patients with MMD (ischemic), and 34 patients with MMD (hemorrhagic). CSF proteins were measured using the multiplex luminex assay. Differential differences were conducted with least mean square (LMS) with CHEX4 as a covariate. All P-values are corrected by the Tukey test. An ELISA was also used to quantitate the level of cellular retinoic acid binding proteins (CRBP1) in CSF samples. Functional outcomes were assessed using the modified Rankin scale score (mRS), and Matsushima criteria was used for grading the neovascularization. RESULTS A total of 40 of 62 secreted factors were significantly elevated in both MMD groups in relation to controls. The most highly secreted CSF proteins include platelet-derived growth factor bb, chemokine ligand 5, and plasminogen activator inhibitor 1 (P < .001). CRBP1 and other growth factors such as brain-derived nerve growth factor, basic fibroblast growth factor, and vascular endothelial growth factor were elevated in both MMD groups (P < .01). These factors are involved in the inflammatory responses, including activation and migration of immune cells and angiogenesis. We also observed several unique genes that differ between the 2 MMD groups (ischemic vs hemorrhagic). CONCLUSION CSF analysis revealed that a number of cytokines, chemokines, and growth factors are elevated in the MMD. Increased CRBP1 in MMD is consistent with the literature and potentially causes an increase of growth factors and cytokines contributing to the pathogenesis.

Small Vessels Are a Big Problem in Neurodegeneration and Neuroprotection.

The cerebral microcirculation holds a critical position to match the high metabolic demand by neuronal activity. Functionally, microcirculation is virtually inseparable from other nervous system cells under both physiological and pathological conditions. For successful bench-to-bedside translation of neuroprotection research, the role of microcirculation in acute and chronic neurodegenerative disorders appears to be under-recognized, which may have contributed to clinical trial failures with some neuroprotectants. Increasing data over the last decade suggest that microcirculatory impairments such as endothelial or pericyte dysfunction, morphological irregularities in capillaries or frequent dynamic stalls in blood cell flux resulting in excessive heterogeneity in capillary transit may significantly compromise tissue oxygen availability. We now know that ischemia-induced persistent abnormalities in capillary flow negatively impact restoration of reperfusion after recanalization of occluded cerebral arteries. Similarly, microcirculatory impairments can accompany or even precede neural loss in animal models of several neurodegenerative disorders including Alzheimer's disease. Macrovessels are relatively easy to evaluate with radiological or experimental imaging methods but they cannot faithfully reflect the downstream microcirculatory disturbances, which may be quite heterogeneous across the tissue at microscopic scale and/or happen fast and transiently. The complexity and size of the elements of microcirculation, therefore, require utilization of cutting-edge imaging techniques with high spatiotemporal resolution as well as multidisciplinary team effort to disclose microvascular-neurodegenerative connection and to test treatment approaches to advance the field. Developments in two photon microscopy, ultrafast ultrasound, and optical coherence tomography provide valuable experimental tools to reveal those microscopic events with high resolution. Here, we review the up-to-date advances in understanding of the primary microcirculatory abnormalities that can result in neurodegenerative processes and the combined neurovascular protection approaches that can prevent acute as well as chronic neurodegeneration.

Computational simulations of thrombolysis in acute stroke: Effect of clot size and location on recanalisation

Acute ischaemic stroke can be treated by intravenous thrombolysis whereby tissue plasminogen activator (tPA) is infused to dissolve clots that block blood supply to the brain. In this study, we aim to examine the influence of clot location and size on lysis pattern and recanalisation by using a recently developed computational modelling framework for thrombolysis under physiological flow conditions. An image-based patient-specific model is reconstructed which consists of the internal carotid bifurcation with the A1 segment of anterior cerebral arteries and M1 segment of middle cerebral arteries, and the M1 bifurcation containing the M2 segments. By varying the clot size and location, 7 scenarios are simulated mimicking thrombolysis of M1 and M2 occlusions. Our results show that initial breakthrough always occurs along the inner curvature of the occluded cerebral artery, due to prolonged tPA residence time in the recirculation zone. For a given occlusion site, lysis completion time appears to increase almost quadratically with the initial clot volume; whereas for a given clot volume, the simulated M2 occlusions take up to 30% longer for complete lysis compared to the corresponding M1 occlusions.

Frequency, predictors, and outcomes of readmission to index versus non-index hospitals after mechanical thrombectomy in patients with ischemic stroke

BackgroundStroke systems of care employ a hub-and-spoke model, with fewer centers performing mechanical thrombectomy (MT) compared with stroke-receiving centers, where a higher number offer high-level, centralized treatment to a large...

Quantitative evaluation using single-photon emission computed tomography with acetazolamide is reliable for preoperative evaluation before cardiac surgery in severe carotid intracranial artery stenotic and/or occlusive disease: a case report

BackgroundSevere carotid and intracranial artery stenosis disease (CIAD) is major risk for perioperative stroke in coronary artery bypass grafting. Then, preoperative risk assessment is quite important.Case presentationA 58-years old Japanese woman with bilateral carotid stenosis and bilateral middle cerebral artery occlusion was suffered from worsening effort angina due to severe three coronary vessel disease. Magnetic resonance imaging angiography demonstrated severe carotid and intracranial vessel stenosis. Selective carotid/cerebral angiography also showed severe stenosis and delayed filling of the right internal carotid artery and moderate stenosis of the left internal carotid artery, with occlusion of the bilateral middle cerebral arteries. However, quantitative evaluation with brain perfusion, single-photon emission computed tomography (SPECT) with acetazolamide showed depleted cerebral perfusion volume and vascular responses, particularly in the left middle cerebral artery area. However, both sides of MCA reserve cerebral blood flow was maintained at > 34 ml/100 g/min. So, we finally considered that her cerebral perfusion reserve was maintained a certain level and could tolerate open heart surgery. Then, she underwent off-pump coronary artery grafting. Before sternotomy, prophylactic intra-aortic balloon pump support was used to minimize possible perioperative stroke. As a result, hemodynamic status and brain regional oxygen saturation were stable throughout the operation, and recovered uneventfully.ConclusionsPreoperative quantitative evaluation using brain perfusion SPECT with acetazolamide is useful in assessing hemodynamic cerebrovascular risk in patients with severe obstructive CIAD. Off pump coronary artery bypass grafting with intra aortic balloon pump assist is a good option for prevention of cerebrovascular morbidity in ischemic heart disease with severe CIAD.

Protective effects on hippocampal neurons and the influence on hippocampal monoamine neurotransmitters with acupuncture for promoting the circulation of the governor vessel and regulating the mental state in rats with post-stroke depression

To observe the effects on hippocampal neuronal structure and hippocampal monoamine neurotransmitters such as norepinephrine (NE), 5-hydroxytryptamine (5-HT) and dopamine (DA) with acupuncture for promoting the circulation of the governor vessel and regulating the mental state (Tongdu Tiaoshen acupuncture) in rats with post-stroke depression and explore the underlying effect mechanism of Tongdu Tiaoshen acupuncture on post-stroke depression. A total of 48 clean-grade SD rats were randomized into a sham-operation group, a model group, a Tongdu Tiaoshen acupuncture group and a non-meridian-non-acupoint group, 12 rats in each one. In the model group, the Tongdu Tiaoshen acupuncture group and the non-meridian-non-acupoint group, the compound method of cerebral medial arterial occlusion and the chronic unpredictable mild stress was adopted to prepare the model of post-stroke depression. In the sham-operation group, skin was opened and the fascia muscle was separated, after artery exposed, no ligation was operated and the incision was sutured directly. In the sham-operation group and the model group, no any intervention was performed. In the Tongdu Tiaoshen acupuncture group, acupuncture was applied to "Baihui" (GV 20), "Shuigou" (GV 26), "Shenting" (CV 24) and "Dazhui" (GV 14) for 40 min in each treatment and the needles were manipulated at the acupoints once in 20 min. The treatment was given once a day, 6 times a week for 4 weeks consecutively. In the non-meridian-non-acupoint group, the depression between the 3rd and 4th metatarsal bones on the dorsum of the forelimb was selected in intervention and the needling technique was same as the Tongdu Tiaoshen acupuncture group. The behavioral changes were observed after intervention in each group. Using transmission electron microscopy, the ultrastructure of hippocampal CA 1 neurons was observed in the rats of each group. Using high performance liquid chromatography, the contents of NE, 5-HT and DA were determined. Compared with the sham-operation group, the Zea-longa neurobehavioral score was increased (P<0.01), the sucrose water consumption was reduced (P<0.01), the number of times of horizontal movement and vertical movement in open-field test were reduced (both P<0.01), the damage of the ultrastructure of hippocampal CA 1 neurons was aggravated and the contents of NE, 5-HT and DA were reduced in the model group (P<0.01). Compared with the model group, the Zea-Longa neurobehavioral score was reduced (P<0.01), the sucrose water consumption was increased (P<0.01), the number of times of horizontal movement and vertical movement in open-field test were increased (both P<0.01), the damage of the ultrastructure of hippocampal CA 1 neurons was alleviated and the contents of NE, 5-HT and DA were increased in the Tongdu Tiaoshen acupuncture group (P<0.01, P<0.05). Compared with the non-meridian-non-acupoint group, the Zea-Longa neurobehavioral score was reduced (P<0.01), the sucrose water consumption was increased (P<0.01), the number of times of horizontal movement and vertical movement in open-field test were increased (both P<0.01), the damage of the ultrastructure of hippocampal CA 1 neurons was alleviated and the contents of NE, 5-HT and DA were increased in the Tongdu Tiaoshen acupuncture group (P<0.01, P<0.05). The Tongdu Tiaoshen acupuncture improves the behavior of the model rats with post-stroke depression, repairs hippocampal neuronal damage, which is probably related to the contents of hippocampal monoamine neurotransmitters (NE, 5-HT and DA).

Combined endovascular and surgical treatment of symptomatic tandem occlusion of common carotid artery and middle cerebral artery – case report

Introduction: Cerebrovascular events are among the most common causes of invalidity or death. The aim of treatment in acute cerebral ischemia is to restore the blood flow before irreversible necrosis of brain tissue and persistent neurologic deficit occur. Pharmacological, endovascular and surgical methods are employed in the treatment of these patients. Case report: The authors present a case report of a 56-year-old woman with acute cerebral ischemia caused by tandem occlusion of the left com- mon carotid artery and the M1 segment of middle cerebral artery. In the initial phase the patient was treated by intravenous thrombolysis with minimal success. Common carotid artery was occluded and mechanical extraction of embolus was successfully performed through direct carotid bifurcation puncture. Almost complete regression of neurologic deficit occurred after the endovascular recanalization. Occluded common carotid stump and bifurcation was considered as a source of embolization and therefore, to prevent further cerebrovascular event, a subclavian-carotid bypass was performed on the 15th day after the stroke. Conclusion: In the reported patient with symptomatic tandem occlusion of common carotid artery and the M1 part of middle cerebral artery, recanalization of cerebral artery was attained by the combination of pharmacological and endovascular method. Consequent subclavian-to-carotid bypass was performed in tertiary prevention of further cerebrovascular event.

Type 2 diabetes in midlife and risk of cerebrovascular disease in late life: a prospective nested case\u2212control study in a nationwide Swedish twin cohort

Aims/hypothesisWe aimed to examine the association between midlife type 2 diabetes mellitus and cerebrovascular disease (CBD) in late life, and further to explore whether genetic and early-life familial environmental factors (such as shared childhood socioeconomic status and adolescent environment) play a role in this association.MethodsIn this prospective nested case−control study based on the Swedish Twin Registry, 33,086 twin individuals who were born in 1958 or earlier and were CBD-free before the age of 60 were included. Midlife (40–59 years) type 2 diabetes was ascertained from self-report, the National Patient Registry (NPR) and glucose-lowering medication use. CBD diagnosis (cerebral infarction, occlusion of cerebral arteries, subarachnoid haemorrhage, intracerebral haemorrhage and unspecified CBD) and onset age were identified from the NPR. Late-life CBD was defined as CBD onset age ≥60 years. Generalised estimating equation (GEE) models were used to analyse unmatched case−control data (adjusted for the clustering of twins within a pair). Conditional logistic regression was used in co-twin matched case−control analyses in CBD-discordant twin pairs.ResultsOf all the participants, 1248 (3.8%) had midlife type 2 diabetes and 3121 (9.4%) had CBD in late life. In GEE models adjusted for age, sex, education, BMI, smoking, alcohol consumption, marital status, hypertension and heart disease, the ORs (95% CIs) of type 2 diabetes were 1.29 (1.03, 1.61) for cerebral infarction, 2.03 (1.20, 3.44) for occlusion of cerebral arteries, 0.52 (0.12, 2.21) for subarachnoid haemorrhage and 0.78 (0.45, 1.36) for intracerebral haemorrhage. In multi-adjusted conditional logistic regression, the OR of the type 2 diabetes–cerebral infarction association was 0.96 (0.51, 1.80). The differences in ORs from the GEE and co-twin control analyses were not statistically significant (p = 0.780).Conclusions/interpretationMidlife type 2 diabetes is significantly associated with increased risk of cerebral infarction and occlusion of cerebral arteries, but not intracerebral haemorrhage or subarachnoid haemorrhage in late life. Genetic and early-life familial environmental factors do not appear to account for the type 2 diabetes–cerebral infarction association, but further clarification is needed.

Influence of endothelial dysfunction caused by estrogen deficiency on the severity of cerebral ischemia in rats

The aim of this study was to assess the effect of endothelial dysfunction caused by a decrease in the estrogen level on the severity of cerebral ischemia.&#x0D; Methods. Endothelial dysfunction was caused by extirpation of the uterus with appendages and was confirmed by counting circulating endothelial cells and evaluating stimulated and basal secretion of nitric oxide. Focal cerebral ischemia was modeled by intravasal occlusion of the middle cerebral artery. The severity of ischemia was assessed according to the scales of neurological deficit (Combs &amp; D’Alecy and McGraw), in the Rotarod test and in terms of the volume of necrosis.&#x0D; Results. Estrogen deficiency resulted in an increase in the circulating endothelial cells by 88%, as well as a decrease in stimulated and basal nitric oxide secretion by 17.1% and 14.7% respectively. Focal cerebral ischemia in animals with endothelial dysfunction caused by estrogen deficiency resulted in greater cerebral damage, resulting in an increase in the level of neurological deficit on the Combs &amp; D’Alecy and McGraw scales for 7 days, a decrease in the retention time on the rotating rod by 32%, as well as an increase in the infarct volume by 89% relative to the group of animals without sexual hormones failure.&#x0D; Conclusion. It has been shown that endothelial dysfunction caused by estrogen deficiency complicates the severity of cerebral ischemia, causing a more pronounced neurological and motor deficit, and contributes to an increase in the size of infarct volume.

Correlation between the distribution of intracranial and extracranial aterial lesions and risk factors in Chinese patients with ischemic stroke: a multicenter registry study

Objective To investigate the distribution characteristics and risk factors of intracranial and extracranial aterial lesions in Chinese patients with ischemic stroke. Methods In this multi-center study, 2 310 continuously inpatients with ischemic stroke diagnosed in 20 stroke screening and prevention project base hospitals from June 2015 to May 2016 were enrolled. Carotid ultrasonography and transcranial color-coded sonography or transcranial Doppler were performed in all patients to confirm the presence of cerebral artery stenosis or occlusion. According to the distribution of lesions, the subjects were divided into 2 groups: the simple intracranial artery stenosis group and the simple extracranial artery stenosis group. The difference of risk factors between the two groups was compared. Results Of the 2 310 patients with ischemic stroke, 1 516 (65.6%) had simple intracranial artery stenosis and 794 (34.4%) had simple extracranial artery stenosis. The incidence of anterior circulation artery stenosis was higher in the group of intracranial artery stenosis than that in the extracranial artery stenosis group (68.1% vs 48.7%, P<0.001). Posterior circulation artery stenosis and combined anterior with posterior circulation artery stenosis were more common in patients with extracranial artery stenosis group than those in intracranial artery stenosis group (36.4% vs 22.1%, 14.9% vs 9.8%; all P<0.001). Univariate analysis of risk factors for stroke showed that patients with intracranial arterial stenosis had a higher prevelence of hypertension, diabetes, obesity, and family history of stroke, and their systolic blood pressure, diastolic blood pressure, body mass index (BMI), fasting blood-glucose, glycosylated hemoglobin, triacylglycerol, total cholesterol, and low-density lipoprotein cholesterol were significantly higher than those in the extracranial arterial stenosis group (all P<0.05). The proportion of elderly (≥65 years old), male and smokers in the extracranial arterial stenosis group was significantly higher than that in the intracranial arterial stenosis group (all P<0.05). Multivariate logistic regression analysis showed that elderly (≥65 years old), male, and smoking history were independent risk factors for extracranial arterial stenosis (OR=2.012, 1.637, 1.325, respectively; all P<0.05). While hypertension, diabetes, less physical activity, and high BMI levels were independent risk factors for simple intracranial arterial disease (OR=1.301, 1.252, 1.248, 1.030, respectively; all P<0.05). Conclusions There are significant differences in the distribution characteristics and risk factors of intracranial and extracranial aterial lesions in patients with ischemic stroke in China. Key words: Ultrasonography; Ischemic stroke; Atherosclerosis; Distribution; Risk factor

Ischemic stroke: clinical pathway impact

PurposeA clinical pathway for patients with acute ischemic stroke was implemented in 2014 by one Italian teaching hospital multidisciplinary team. The purpose of this paper is to determine whether this clinical pathway had a positive effect on patient management by comparing performance data.Design/methodology/approachVolume, process and outcome indicators were analyzed in a pre-post retrospective observational study. Patients’ (admitted in 2013 and 2015) medical records with International Classification of Diseases, ICD-9 code 433.x (precerebral artery occlusion and stenosis), 434.x (cerebral artery occlusion) and 435.x (transient cerebral ischemia) and registered correctly according to hospital guidelines were included.FindingsAn increase context-sensitive in-patient numbers with more severe cerebrovascular events and an increase in patient transfers from the Stroke to Neurology Unit within three days (70 percent, p=0.25) were noted. Clinical pathway implementation led to an increase in patient flow from the Emergency Department to dedicated specialized wards such as the Stroke and Neurology Unit (23.7 percent, p<0.001). Results revealed no statistically significant decrease in readmission rates within 30 days (5.7 percent, p=0.85) and no statistically significant differences in 30-day mortality.Research limitations/implicationsThe pre-post retrospective observational study design was considered suitable to evaluate likely changes in patient flow after clinical pathway implementation, even though this design comes with limitations, describing only associations between exposure and outcome.Originality/valueClinical pathway implementation showed an overall positive effect on patient management and service efficiency owing to the standardized application in time-dependent protocols and multidisciplinary/integrated care implementation, which improved all phases in acute ischemic stroke care.

Effect of ulinastatin on expression of metabotropic glutamate receptor II during cerebral ischemia-reperfusion in rats

Objective To evaluate the effect of ulinastatin on the expression of metabotropic glutamate receptor Ⅱ (mGluRⅡ) during cerebral ischemia-reperfusion (I/R) in rats. Methods Forty-eight male Sprague-Dawley rats, aged 6-8 weeks, weighing 230-280 g, were divided into 3 groups (n=16 each) by a random number table method: sham operation group (S group), cerebral I/R group (I/R group) and ulinastatin group (U group). The model of cerebral I/R injury was established by occluding the right middle cerebral artery using a nylon thread with a rounded tip inserted into internal carotid artery and advanced cranially until resistance was met.Middle cerebral artery occlusion was maintained for 2 h followed by 24-h reperfusion.Ulinastatin 100 000 U/kg was injected via the tail vein immediately after onset of reperfusion in group U. The neurological deficit score (NDS) was assessed after 24 h of reperfusion.The rats were then sacrificed, and brain tissues were obtained for determination of brain infarction (by TTC staining), expression of IκB-α in cerebral ischemic penumbra (by Western blot) and expression of mGluR Ⅱ in cerebral ischemic penumbra (by immunofluorescent staining). The percentage of cerebral infarct volume was calculated. Results Compared with S group, the NDS and percentage of cerebral infarct volume were significantly increased, the expression of mGluRⅡ in cerebral ischemic penumbra was up-regulated, and the expression of IκB-α in cerebral ischemic penumbra was down-regulated in I/R and U groups (P<0.05). Compared with I/R group, the NDS and percentage of cerebral infarct volume were significantly decreased, the expression of mGluRⅡ in cerebral ischemic penumbra was down-regulated, and the expression of IκB-α in cerebral ischemic penumbra was up-regulated in U group (P<0.05). Conclusion The mechanism by which ulinastatin mitigates cerebral I/R injury may be related to inhibiting the expression of mGluR Ⅱ in cerebral ischemic penumbra of rats. Key words: Trypsin inhibitor; Reperfusion injury; Brain; Receptor, glutamate

Exposure to female estrous is beneficial for male mice against transient ischemic stroke

ABSTRACTObjective: Exposure to female estrous, a natural rewarding experience, alleviates anxiety and depression, and the contribution of this behavior to stroke outcome is unknown. The aim of this study was to evaluate whether exposure to female estrous is beneficial to recovery following transient ischemic stroke in male mice.Methods: Cerebral ischemia was induced in male ICR mice with thread occlusion of the middle cerebral artery (MCAO) for 30 min followed by reperfusion. MCAO mice were randomly divided into MCAO group and Estrous Female Exposure (EFE) group. The mice in the EFE group were subjected to estrous female mouse interaction from day 1 until the end of the experiment. Mortality was recorded during the investigation. Behavioral functions were assessed by a beam-walking test and corner test from day 1 to day 10 after MCAO. Serum testosterone levels were analyzed with ELISA, and the expression levels of growth-associated protein-43 (GAP-43) and synaptophysin in the cortex of the ischemic hemisphere were determined by western blot on day 7 after MCAO.Results: Exposure to female estrous reduced the mortality induced by cerebral ischemic lesions. The beam-walking test demonstrated that exposure to female estrous significantly improved motor function recovery. The serum testosterone levels and ischemic cortex GAP-43 expression were significantly higher in MCAO male mice exposed to female estrous.Conclusion: Exposure to female estrous reduces mortality and improves functional recovery in MCAO male mice. The study provides the first evidence to support the importance of female interaction to male stroke rehabilitation.Abbreviations: GAP-43: growth-associated protein-43; SYP: Synaptophysin; MCAO: middle cerebral artery occlusion; OVXs: ovariectomies; CCA: common carotid artery; ECA: external carotid artery; EFE: estrous female exposure; TTC: 2,3,5-triphenyltetrazolium chloride; PAGE: polyacrylamide gel electrophoresis; PVDF: polyvinylidene difluoride; ANOVA: analysis of variance; LSD: least significant difference

Abstract TP78: Density Analysis of Hyperdense Middle Cerebral Artery Sign for Detection of Embolic Stroke of Undetermined Source and Prediction of Successful Reperfusion Following Endovascular Therapy

Introduction: Density of hyperdense middle cerebral artery sign (HMCAS) quantified via Hounsfield units (HU) on CT may predict clot composition and stroke TOAST subtype, with clots from cardioembolism displaying lower HMCAS densities due to fibrin predominance than erythrocyte-dominant clots originating from large artery atherosclerosis (LAA). Hypothesis: We hypothesized that embolic stroke of undetermined source (ESUS) is linked to higher density of HMCAS due to its high probability of a cardiac source and that HMCAS as a surrogate marker of clot composition predicts successful reperfusion following endovascular therapy (EVT). Methods: We analyzed data from an ongoing prospective observational study (since 01/2016) in consecutive patients with acute ischemic stroke (AIS) undergoing EVT for proximal occlusion of the middle cerebral artery (MCA) detected on CT-angiography and confirmed on digital subtraction angiography. Stroke subtypes were determined according to TOAST and ESUS criteria. On thin-slice (1.5mm) non-contrast CT, a blinded neuroradiologist assessed average and maximum HU values for HMCAS. Multiple regression analyses were undertaken to explore the association of HMCAS density normalized for contralateral MCA (HMCAS ratio) with stroke subtypes and major reperfusion (TICI 2b/3) following EVT. Results: In this interim analysis 110 out of 253 patients were included (55.1% females, ages 74 [64-80], median [IQR], baseline NIHSS 17 [13-20], 76 with IVT before EVT) of which 19 (17.8%) had ESUS, 65 (60.8%) had cardioembolism and 23 (21.5%) had LAA. Density analyses showed HMCAS ratios of 1.26 ± 0.22 (mean ± SD) in the entire cohort with no differences among subgroups (ESUS: 1.19 ± 0.26, LAA: 1.24 ± 0.25, cardioembolic stroke: 1.29 ± 0.19, p = ns), the latter being also true for HMCAS ratios of maximum HU values and absolute HU values (p = ns). On multivariate regression model adjusted for intravenous tPA and onset to groin puncture time, HMCAS average ratio did not predict major reperfusion (per 1-unit HU increase: 2.13; [0.25-18.29], OR [95% CI]) or stroke subtype. Discussion: Density analysis of HMCAS appears not to be helpful in detection of ESUS, diagnostic discrimination between stroke subtypes, or prediction of reperfusion following EVT.

Abstract WP59: Endovascular Therapy for Distal Middle Cerebral Artery Occlusion: Sub-analyses of the Recovery by Endovascular Salvage for Cerebral Ultra-acute Embolism Japan Registry 2 (RESCUE-Japan Registry 2)

Objective: The efficacy of endovascular therapy (EVT) for distal middle cerebral artery (MCA) occlusion remain debatable. We compared the EVT with conservative therapy (no EVT) in real-world patients with distal MCA occlusion. Methods: We analyzed the data from the Recovery by Endovascular Salvage for Cerebral Ultra-acute Embolism Japan Registry 2, which enrolled the consecutive patients with acute ischemic stroke due to large vessel occlusions. We selected patients with isolated M2 or M3 occlusion, and those with functional independence (modified Rankin Scale [mRS] score =&lt;1) before the onset. We divided patients into EVT and no EVT groups. The primary outcome was a favorable outcome (mRS 0-2 at 90 days). Multivariable logistic regression model was developed to compare both groups. We conducted the subgroup analyses for age, gender, ASPECTS score, NIH Stroke Scale (NIHSS) time from onset to arrival, use of t-PA, location of occlusions (M2 vs M3). Results: A total of 427 patients [372 (87%) were M2 occlusion] were analyzed from 2420 patients originally enrolled in the registry. There were 190 patients in EVT and 237 in no EVT groups. The EVT group showed a higher baseline NIHSS score (median interquartile range [IQR], 15 [9-19] versus 8 [4-15]). The primary outcome occurred in 55.7% and 54.4% of the EVT and no EVT groups, respectively. There were no significant differences for a favorable outcome as a whole and the adjusted odds ratio (aOR) was 1.52 [95%CI, 0.97-2.42; p=0.06]. Subgroup analyses showed a favorable outcome for EVT group in the subgroup of M2 occlusion with aOR of 1.84 (95%CI, 1.13-3.00) and of NIHSS≥6 with aOR of 2.14 (95%CI, 1.29-3.55). Conclusions: In patients with distal MCA occlusion, EVT seems effective for patients with M2 segment occlusion or NIHSS≥6.

Abstract 107: Rescue Tirofiban in Mechanical Thrombectomy for Acute Cerebral Large Artery Occlusion: A Multicenter Prospective Registry Study

Background and Purpose: Preferred rescue treatment has not yet been recommended for recanalization refractory stroke patients during mechanical thrombectomy (MT). We aim to evaluate the safety and efficacy of rescue tirofiban in acute ischemic stroke(AIS) patients undergoing MT. Methods: We derived data from the ANGEL study, a multi-centric, prospective registry study that included MT patients owing to proximal large-artery occlusionfrom June 2015 to December 2017. Patients in this study were dichotomized into tirofiban and non-tirofiban group according to whether rescue tirofiban was performed during and after MT. Safety (symptomatic intracerebral hemorrhage [sICH], ICH and thrombus distalization) and efficacy outcomes (artery recanalization and functional outcomes at 3-month follow-up) were compared between groups. Results: We included 662 patients from the entire 917 patients in the Registry. Among them, there were 230 in tirofiban group and 432 in non-tirofiban group, and 47 (7.1%) patients suffered sICH and 102 (15.4%) suffered ICH within post-MT 24 hours; 33 (5.0%) experienced thrombus distalization; 289 (43.7%) achieved functional independence and 135 (20.4%) died after three-month follow-up. No significant differences of safety outcomes on sICH, ICH thrombus distalization and efficacy outcomes on artery recanalization and long-term functional independence were found between tirofiban and non-tirofiban groupeither for the entire cohort, anterior circulation stroke(ACS) patients or posterior circulation stroke(PCS) patients (p&gt;0.05 for all groups). Yet, rescue tirofiban was significantly correlated with long-term mortality reduction for PCS patients (adjusted hazard ratio 0.35 [0.14-0.92], p=0.03). Conclusion: Rescue tirofiban during and after MT was not associated with increased risk of safety outcomes on sICH, ICH and thrombus distalization for AIS patients, and was correlated with long-term mortality reduction for PCS.

SU91THE VALUE OF POLYGENIC RISK SCORES IN PREDICTING THE TRANSITION FROM CHILDHOOD AND ADOLESCENT PSYCHIATRIC SYMPTOMS INTO CHRONIC ADULT PSYCHOPATHOLOGY

Nitric oxide (NO) plays a key role in ischemia and shows potential as a biomarker for ischemia. We measured mixed venous nitrite (NO2-) as a proxy for NO, during controlled cerebral ischemia in patients with moyamoya disease (MMD) during direct extracranial/intracranial (EC/IC) bypass surgery with temporary occlusion of the M4 branch of the middle cerebral artery (MCA) to permit anastomosis with the superficial temporal artery (STA). This small, focal ischemic event is not reliably detected using cerebral oximetry, somatosensory evoked potentials (SSEPs) or electroencephalography (EEG).We enrolled nine adult MMD patients (n=8 female, n=1 male) undergoing direct EC/IC bypass surgery. Nitrite was measured at least one hour prior to MCA occlusion, and before, during and after anastomosis. Cortical function was monitored using either multi-lead EEG and SSEPs, or frontal EEG activity.Mixed venous NO2- was significantly elevated (p<0.05) within 12 min following arterial occlusion vs. baseline. An M4 branch of the MCA was cross clamped for a median duration of 18 (IQR = 5) minutes during anastomosis. One patient with elevated NO2- showed a transient neurologic deficit that resolved 3 days post-operatively.Mixed venous NO2- was significantly elevated shortly following cerebral artery occlusion vs. baseline in a majority of the study subjects, suggesting that NO2- is a potential biomarker for ischemia. Since all patients received identical burst suppression anesthesia and vasopressors, the fact that NO2- was not elevated during cross-clamp in all patients supports the conclusion that the NO2- elevation is likely due to ischemia.

Enhancing Base Excision Repair of Mitochondrial DNA to Reduce Ischemic Injury Following Reperfusion

We hypothesize that enhancing mitochondrial base excision repair (BER) capability in brain will reduce reperfusion-associated ischemic brain injury. Post-stroke reperfusion was modeled in mice via transient filament occlusion of the middle cerebral artery (60 min) (transient MCAO). Administration of a TAT-modified form of a DNA glycosylase (EndoIII) following reperfusion of the brain reduced resultant brain infarct volume. Protection was dose-dependent, BER enzyme specific, and regionally specific (more effective via the jugular vein). EndoIII is compatible with tissue plasminogen activator (tPA). The time window of a single dose of EndoIII effect is 3 h following reperfusion onset. These data suggest a novel approach to enhance protection of reperfused brain in the setting of revascularization procedures (thrombectomy or thrombolytic therapy) following stroke.