Multi-site laser Doppler flowmetry for assessing collateral flow in experimental ischemic stroke: Validation of outcome prediction with acute MRI

High variability in infarct size is common in experimental stroke models and affects statistical power and validity of neuroprotection trials. The aim of this study was to explore cerebral collateral flow as a stratification factor for the prediction of ischemic outcome. Transient intraluminal occlusion of the middle cerebral artery was induced for 90 min in 18 Wistar rats. Cerebral collateral flow was assessed intra-procedurally using multi-site laser Doppler flowmetry monitoring in both the lateral middle cerebral artery territory and the borderzone territory between middle cerebral artery and anterior cerebral artery. Multi-modal magnetic resonance imaging was used to assess acute ischemic lesion (diffusion-weighted imaging, DWI), acute perfusion deficit (time-to-peak, TTP), and final ischemic lesion at 24 h. Infarct volumes and typology at 24 h (large hemispheric versus basal ganglia infarcts) were predicted by both intra-ischemic collateral perfusion and acute DWI lesion volume. Collateral flow assessed by multi-site laser Doppler flowmetry correlated with the corresponding acute perfusion deficit using TTP maps. Multi-site laser Doppler flowmetry monitoring was able to predict ischemic outcome and perfusion deficit in good agreement with acute MRI. Our results support the additional value of cerebral collateral flow monitoring for outcome prediction in experimental ischemic stroke, especially when acute MRI facilities are not available

Assessing the effects of Ang-(1-7) therapy following transient middle cerebral artery occlusion

The counter-regulatory axis, Angiotensin Converting Enzyme 2, Angiotensin-(1-7), Mas receptor (ACE2/Ang-1-7/MasR), of the renin angiotensin system (RAS) is a potential therapeutic target in stroke, with Ang-(1-7) reported to have neuroprotective effects in pre-clinical stroke models. Here, an extensive investigation of the functional and mechanistic effects of Ang-(1-7) was performed in a rodent model of stroke. Using longitudinal magnetic resonance imaging (MRI) it was observed that central administration of Ang-(1-7) following transient middle cerebral artery occlusion (MCAO) increased the amount of tissue salvage compared to reperfusion alone. This protective effect was not due to early changes in blood brain barrier (BBB) permeability, microglia activation or inflammatory gene expression. However, increases in NADPH oxidase 1 (Nox1) mRNA expression were observed in the treatment group compared to control. In order to determine whether Ang-(1-7) has direct cerebrovascular effects, laser speckle contrast imaging (LSCI) was performed to measure dynamic changes in cortical perfusion following reperfusion. Delivery of Ang-(1-7) did not have any effect on cortical perfusion following reperfusion however; it showed an indication to prevent the ‘steal phenomenon’ within the contralateral hemisphere. The comprehensive series of studies have demonstrated a moderate protective effect of Ang-(1-7) when given alongside reperfusion to increase tissue salvage

Hemodynamic monitoring of intracranial collateral flow predicts tissue and functional outcome in experimental ischemic stroke.

Intracranial collaterals provide residual blood flow to penumbral tissue in acute ischemic stroke and contribute to infarct size variability in humans. In the present study, hemodynamic monitoring of the borderzone territory between the leptomeningeal branches of middle cerebral artery and anterior cerebral artery was compared to lateral middle cerebral artery territory, during common carotid artery occlusion and middle cerebral artery occlusion in rats. The functional performance of intracranial collaterals, shown by perfusion deficit in the territory of leptomeningeal branches either during common carotid artery occlusion or middle cerebral artery occlusion, showed significant variability among animals and consistently predicted infarct size and functional deficit. Our findings indicate that leptomeningeal collateral flow is a strong predictor of stroke severity in rats, similarly to humans. Monitoring of collateral blood flow in experimental stroke is essential for reducing variability in neuroprotection studies and accelerating the development of collateral therapeutics

Hemodynamic monitoring of intracranial collateral flow predicts tissue and functional outcome in experimental ischemic stroke

Intracranial collaterals provide residual blood flow to penumbral tissue in acute ischemic stroke and contribute to infarct size variability in humans. In the present study, hemodynamic monitoring of the borderzone territory between the leptomeningeal branches of middle cerebral artery and anterior cerebral artery was compared to lateral middle cerebral artery territory, during common carotid artery occlusion and middle cerebral artery occlusion in rats. The functional performance of intracranial collaterals, shown by perfusion deficit in the territory of leptomeningeal branches either during common carotid artery occlusion or middle cerebral artery occlusion, showed significant variability among animals and consistently predicted infarct size and functional deficit. Our findings indicate that leptomeningeal collateral flow is a strong predictor of stroke severity in rats, similarly to humans. Monitoring of collateral blood flow in experimental stroke is essential for reducing variability in neuroprotection studies and accelerating the development of collateral therapeutics. © 2011 Elsevier Inc

Head down tilt 15° to preserve salvageable brain tissue in acute ischemic stroke: A pre-clinical pooled analysis, with focus on cerebral hemodynamics

International audienceNeurological outcome after ischemic stroke depends on residual salvageable brain tissue at the time of recanalization. Head down tilt 15° (HDT15) was proven effective in reducing infarct size and improving functional outcome in rats with transient middle cerebral artery occlusion (t-MCAO) by increasing cerebral perfusion within the ischemic penumbra. In this pooled analysis, individual animal-level data from three experimental series were combined in a study population of 104 t-MCAO rats (45 in HDT15 group and 59 in flat position group). Co-primary outcomes were infarct size and functional outcome at 24 h in both groups. The secondary outcome was hemodynamic change induced by HDT15 in ischemic and non-ischemic hemispheres in a subgroup of animals. Infarct size at 24 h was smaller in HDT15 group than in flat position group (absolute mean difference 31.69 mm(3) , 95% CI 9.1-54.2, Cohen's d 0.56, p = 0.006). Functional outcome at 24 h was better in HDT15 group than in flat position group (median [IQR]: 13[10-16] vs. 11), with a shift in the distribution of the neurobehavioural scores in favour of HDT15. Mean cerebral perfusion in the ischemic hemisphere was higher during HDT15 than before its application (Perfusion Unit [P.U.], mean ± SD: 52.5 ± 19.52 P.U. vs. 41.25 ± 14.54 P.U., mean of differences 13.36, 95% CI 7.5-19.18, p = 0.0002). Mean cerebral perfusion in the non-ischemic hemisphere before and during HDT15 was unchanged (P.U., mean ± SD: 94.1 ± 33.8 P.U. vs. 100.25 ± 25.34 P.U., mean of differences 3.95, 95%, CI -1.9 to 9.6, p = 0.1576). This study confirmed that HDT15 improves the outcome in t-MCAO rats by promoting cerebral perfusion in the ischemic territory, without disrupting hemodynamics in non-ischemic areas