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Concept: Anterior cerebral artery

442

Background The effect of endovascular thrombectomy that is performed more than 6 hours after the onset of ischemic stroke is uncertain. Patients with a clinical deficit that is disproportionately severe relative to the infarct volume may benefit from late thrombectomy. Methods We enrolled patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume, with mismatch criteria defined according to age (<80 years or ≥80 years). Patients were randomly assigned to thrombectomy plus standard care (the thrombectomy group) or to standard care alone (the control group). The coprimary end points were the mean score for disability on the utility-weighted modified Rankin scale (which ranges from 0 [death] to 10 [no symptoms or disability]) and the rate of functional independence (a score of 0, 1, or 2 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating more severe disability) at 90 days. Results A total of 206 patients were enrolled; 107 were assigned to the thrombectomy group and 99 to the control group. At 31 months, enrollment in the trial was stopped because of the results of a prespecified interim analysis. The mean score on the utility-weighted modified Rankin scale at 90 days was 5.5 in the thrombectomy group as compared with 3.4 in the control group (adjusted difference [Bayesian analysis], 2.0 points; 95% credible interval, 1.1 to 3.0; posterior probability of superiority, >0.999), and the rate of functional independence at 90 days was 49% in the thrombectomy group as compared with 13% in the control group (adjusted difference, 33 percentage points; 95% credible interval, 24 to 44; posterior probability of superiority, >0.999). The rate of symptomatic intracranial hemorrhage did not differ significantly between the two groups (6% in the thrombectomy group and 3% in the control group, P=0.50), nor did 90-day mortality (19% and 18%, respectively; P=1.00). Conclusions Among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone. (Funded by Stryker Neurovascular; DAWN ClinicalTrials.gov number, NCT02142283 .).

Concepts: Stroke, Modified Rankin Scale, Middle cerebral artery, Internal carotid artery, Common carotid artery, Anterior cerebral artery, Posterior communicating artery, Disability

161

We report on oxygenation changes noninvasively recorded by multichannel continuous-wave near infrared spectroscopy (CW-NIRS) during endovascular neuroradiologic interventions requiring temporary balloon occlusion of arteries supplying the cerebral circulation. Digital subtraction angiography (DSA) provides reference data on the site, timing, and effectiveness of the flow stagnation as well as on the amount and direction of collateral circulation. This setting allows us to relate CW-NIRS findings to brain specific perfusion changes. We focused our analysis on the transition from normal perfusion to vessel occlusion, i.e., before hypoxia becomes clinically apparent. The localization of the maximal response correlated either with the core (occlusion of the middle cerebral artery) or with the watershed areas (occlusion of the internal carotid artery) of the respective vascular territories. In one patient with clinically and angiographically confirmed insufficient collateral flow during carotid artery occlusion, the total hemoglobin concentration became significantly asymmetric, with decreased values in the ipsilateral watershed area and contralaterally increased values. Multichannel CW-NIRS monitoring might serve as an objective and early predictive marker of critical perfusion changes during interventions-to prevent hypoxic damage of the brain. It also might provide valuable human reference data on oxygenation changes as they typically occur during acute stroke.Journal of Cerebral Blood Flow & Metabolism advance online publication, 4 December 2013; doi:10.1038/jcbfm.2013.207.

Concepts: Spectroscopy, Blood, Middle cerebral artery, Internal carotid artery, Common carotid artery, Anterior cerebral artery, Infrared, Digital subtraction angiography

146

We recently reported isolation of viable rat amniotic fluid-derived stem (AFS) cells [1]. Here, we tested the therapeutic benefits of AFS cells in a rodent model of ischemic stroke. Adult male Sprague-Dawley rats received a 60-minute middle cerebral artery occlusion (MCAo). Thirty-five days later, animals exhibiting significant motor deficits received intravenous transplants of rat AFS cells or vehicle. At days 60-63 post-MCAo, significant recovery of motor and cognitive function was seen in stroke animals transplanted with AFS cells compared to vehicle-infused stroke animals. Infarct volume, as revealed by hematoxylin and eosin (H&E) staining, was significantly reduced, coupled with significant increments in the cell proliferation marker, Ki67, and the neuronal marker, MAP2, in the dentate gyrus (DG) [2] and the subventricular zone (SVZ) of AFS cell-transplanted stroke animals compared to vehicle-infused stroke animals. A significantly higher number of double-labeled Ki67/MAP2-positive cells and a similar trend towards increased Ki67/MAP2 double-labeling were observed in the DG and SVZ of AFS cell-transplanted stroke animals, respectively, compared to vehicle-infused stroke animals. This study reports the therapeutic potential of AFS cell transplantation in stroke animals, possibly via enhancement of endogenous repair mechanisms.

Concepts: Cell division, Stroke, Cerebrum, Middle cerebral artery, Anterior cerebral artery, Dentate gyrus, Neurogenesis, Organ transplant

85

Background Trials of endovascular therapy for ischemic stroke have produced variable results. We conducted this study to test whether more advanced imaging selection, recently developed devices, and earlier intervention improve outcomes. Methods We randomly assigned patients with ischemic stroke who were receiving 0.9 mg of alteplase per kilogram of body weight less than 4.5 hours after the onset of ischemic stroke either to undergo endovascular thrombectomy with the Solitaire FR (Flow Restoration) stent retriever or to continue receiving alteplase alone. All the patients had occlusion of the internal carotid or middle cerebral artery and evidence of salvageable brain tissue and ischemic core of less than 70 ml on computed tomographic (CT) perfusion imaging. The coprimary outcomes were reperfusion at 24 hours and early neurologic improvement (≥8-point reduction on the National Institutes of Health Stroke Scale or a score of 0 or 1 at day 3). Secondary outcomes included the functional score on the modified Rankin scale at 90 days. Results The trial was stopped early because of efficacy after 70 patients had undergone randomization (35 patients in each group). The percentage of ischemic territory that had undergone reperfusion at 24 hours was greater in the endovascular-therapy group than in the alteplase-only group (median, 100% vs. 37%; P<0.001). Endovascular therapy, initiated at a median of 210 minutes after the onset of stroke, increased early neurologic improvement at 3 days (80% vs. 37%, P=0.002) and improved the functional outcome at 90 days, with more patients achieving functional independence (score of 0 to 2 on the modified Rankin scale, 71% vs. 40%; P=0.01). There were no significant differences in rates of death or symptomatic intracerebral hemorrhage. Conclusions In patients with ischemic stroke with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging, early thrombectomy with the Solitaire FR stent retriever, as compared with alteplase alone, improved reperfusion, early neurologic recovery, and functional outcome. (Funded by the Australian National Health and Medical Research Council and others; EXTEND-IA ClinicalTrials.gov number, NCT01492725 , and Australian New Zealand Clinical Trials Registry number, ACTRN12611000969965 .).

Concepts: Better, Blood, Stroke, Modified Rankin Scale, Middle cerebral artery, Internal carotid artery, Common carotid artery, Anterior cerebral artery

28

The assessment of both geometry and hemodynamics of the intracranial arteries has important diagnostic value in internal carotid occlusion, sickle cell disease, and aneurysm development. Provided that signal to noise ratio (SNR) and resolution are high, these factors can be measured with time-resolved three-dimensional phase contrast MRI. However, within a given scan time duration, an increase in resolution causes a decrease in SNR and vice versa, hampering flow quantification and visualization. To study the benefits of higher SNR at 7 T, three-dimensional phase contrast MRI in the Circle of Willis was performed at 3 T and 7 T in five volunteers. Results showed that the SNR at 7 T was roughly 2.6 times higher than at 3 T. Therefore, segmentation of small vessels such as the anterior and posterior communicating arteries succeeded more frequently at 7 T. Direction of flow and smoothness of streamlines in the anterior and posterior communicating arteries were more pronounced at 7 T. Mean velocity magnitude values in the vessels of the Circle of Willis were higher at 3 T due to noise compared to 7 T. Likewise, areas of the vessels were lower at 3 T. In conclusion, the gain in SNR at 7 T compared to 3 T allows for improved flow visualization and quantification in intracranial arteries. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.

Concepts: Internal carotid artery, Common carotid artery, Anterior cerebral artery, Posterior communicating artery, Sickle-cell disease, Arteries of the head and neck, Circle of Willis, Signal-to-noise ratio

28

Previous studies have demonstrated that the knockdown or knockout of the three Na(+)/Ca(2+) exchanger (NCX) isoforms, NCX1, NCX2, and NCX3, worsens ischemic brain damage. This suggests that the activation of these antiporters exerts a neuroprotective action against stroke damage. However, drugs able to increase the activity of NCXs are not yet available. We have here succeeded in synthesizing a new compound, named neurounina-1 (7-nitro-5-phenyl-1-(pyrrolidin-1-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one), provided with an high lipophilicity index and able to increase NCX activity. Ca(2+) radiotracer, Fura-2 microfluorimetry, and patch-clamp techniques revealed that neurounina-1 stimulated NCX1 and NCX2 activities with an EC(50) in the picomolar to low nanomolar range, whereas it did not affect NCX3 activity. Furthermore, by using chimera strategy and site-directed mutagenesis, three specific molecular determinants of NCX1 responsible for neurounina-1 activity were identified in the α-repeats. Interestingly, NCX3 became responsive to neurounina-1 when both α-repeats were replaced with the corresponding regions of NCX1. In vitro studies showed that 10 nM neurounina-1 reduced cell death of primary cortical neurons exposed to oxygen-glucose deprivation followed by reoxygenation. Moreover, in vitro, neurounina-1 also reduced γ-aminobutyric acid (GABA) release, enhanced GABA(A) currents, and inhibited both glutamate release and N-methyl-d-aspartate receptors. More important, neurounina-1 proved to have a wide therapeutic window in vivo. Indeed, when administered at doses of 0.003 to 30 μg/kg i.p., it was able to reduce the infarct volume of mice subjected to transient middle cerebral artery occlusion even up to 3 to 5 hours after stroke onset. Collectively, the present study shows that neurounina-1 exerts a remarkable neuroprotective effect during stroke and increases NCX1 and NCX2 activities.

Concepts: Stroke, Traumatic brain injury, In vivo, Cerebral cortex, Middle cerebral artery, Anterior cerebral artery, Ischemia, In vitro

28

Object Patients with ruptured anterior communicating artery (ACoA) aneurysms have historically been observed to have poor neuropsychological outcomes, and ACoA aneurysms have accounted for a higher proportion of ruptured than unruptured aneurysms. Authors of this study aimed to investigate the morphological and clinical characteristics predisposing to ACoA aneurysm rupture. Methods Data from 140 consecutive patients with ACoA aneurysms managed at the authors' facility between July 2003 and November 2011 were retrospectively reviewed. Patients with (78) and without (62) aneurysm rupture were divided into groups, and morphological and clinical characteristics were compared. Morphological characteristics were evaluated based on 3D CT angiography and included aneurysm location, dominance of the A(1) portion of the anterior cerebral artery, direction of the aneurysm dome around the ACoA, aneurysm bleb(s), size of the aneurysm and its neck, aneurysm-parent artery angle, and existence of other intracranial unruptured aneurysms. Results Patients with ruptured ACoA aneurysms were significantly younger (a higher proportion were younger than 60 years of age) than those with unruptured lesions, and a significantly smaller proportion had hypercholesterolemia. A significantly larger proportion of patients with ruptured aneurysms showed an anterior direction of the aneurysm dome around the ACoA, had a bleb(s), and/or had an aneurysm size ≥ 5 mm. Multivariate logistic regression analysis showed that an anterior direction of the aneurysm dome around the ACoA (OR 6.0, p = 0.0012), the presence of a bleb(s) (OR 22, p < 0.0001), and an aneurysm size ≥ 5 mm (OR 3.16, p = 0.035) were significantly associated with ACoA aneurysm rupture. Conclusions Findings in the present study demonstrated that the anterior projection of an ACoA aneurysm may be related to rupturing. The authors would perhaps recommend treatment to patients with unruptured ACoA aneurysms that have an anterior dome projection, a bleb(s), and a size ≥ 5 mm.

Concepts: Regression analysis, Atherosclerosis, Anterior cerebral artery, Aneurysm, Cerebral aneurysm, Arteries of the head and neck, Circle of Willis, Anterior communicating artery

25

Acute tandem occlusions of the cervical and distal internal carotid artery (ICA) or middle cerebral artery (MCA) are associated with major stroke with intravenous (i.v.) thrombolysis alone in approximately 90 % of patients. The data on endovascular management of tandem occlusions is still limited. The purpose of this study was to review technical aspects and the current state of the literature on acute ICA stenting in combination with stent retriever-based intracranial thrombectomy.

Concepts: Stroke, Middle cerebral artery, Internal carotid artery, Common carotid artery, Anterior cerebral artery, Posterior communicating artery, External carotid artery, Arteries of the head and neck

8

Stroke survivors often experience social isolation. Social interaction improves quality of life and decreases mortality after stroke. Male mice (20-25 g; C57BL/6N), all initially pair housed, were subjected to middle cerebral artery occlusion (MCAO). Mice were subsequently assigned into one of three housing conditions: (1) Isolated (SI); (2) Paired with their original cage mate who was also subjected to stroke (stroke partner (PH-SP)); or (3) Paired with their original cage mate who underwent sham surgery (healthy partner (PH-HP)). Infarct analysis was performed 72 h after stroke and chronic survival was assessed at day 30. Immediate post-stroke isolation led to a significant increase in infarct size and mortality. Interestingly, mice paired with a healthy partner had significantly lower mortality than mice paired with a stroke partner, despite equivalent infarct damage. To control for changes in infarct size induced by immediate post-stroke isolation, additional cohorts were assessed that remained pair housed for three days after stroke prior to randomization. Levels of brain-derived neurotrophic factor (BDNF) were assessed at 90 days and cell proliferation (in cohorts injected with 5-bromo-2'-deoxyuridine, BrdU) was evaluated at 8 and 90 days after stroke. All mice in the delayed housing protocol had equivalent infarct volumes (SI, PH-HP and PH-SP). Mice paired with a healthy partner showed enhanced behavioral recovery compared with either isolated mice or mice paired with a stroke partner. Behavioral improvements paralleled changes in BDNF levels and neurogenesis. These findings suggest that the social environment has an important role in recovery after ischemic brain injury.

Concepts: Traumatic brain injury, Middle cerebral artery, Anterior cerebral artery, Ischemia, Neurotrophin, Brain-derived neurotrophic factor, Nerve growth factor, Neurotrophins

5

The gaseous neuromodulator H2S is associated with neuronal cell death pursuant to cerebral ischemia. As cystathionine β-synthase (CBS) is the primary mediator of H2S biogenesis in the brain, it has emerged as a potential target for the treatment of stroke. Herein, a “zipped” approach by alkene cross-metathesis into CBS inhibitor candidate synthesis is demonstrated. The inhibitors are modeled after the pseudo-C 2-symmetric CBS product (l,l)-cystathionine. The “zipped” concept means only half of the inhibitor needs be constructed; the two halves are then fused by olefin cross-metathesis. Inhibitor design is also mechanism-based, exploiting the favorable kinetics associated with hydrazine-imine interchange as opposed to the usual imine-imine interchange. It is demonstrated that the most potent “zipped” inhibitor 6S reduces H2S production in SH-SY5Y cells overexpressing CBS, thereby reducing cell death. Most importantly, CBS inhibitor 6S dramatically reduces infarct volume (1 h post-stroke treatment; ∼70% reduction) in a rat transient middle cerebral artery occlusion model for ischemia.

Concepts: Brain, Myocardial infarction, Atherosclerosis, Stroke, Traumatic brain injury, Middle cerebral artery, Anterior cerebral artery, Necrosis