A Mouse Model of Embolic Focal Cerebral Ischemia

Zhang, Zhenggang; Chopp, Michael; Zhang, Rui Lan; Goussev, Anton

doi:10.1097/00004647-199710000-00010

Cited by 89 publications

(61 citation statements)

References 17 publications

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“…Moreover, because steady concentration of contrast agent is a prerequisite for measuring the WEI consistently, the effect of rapid clearance from the vascular space should be investigated. 38 In addition, we recently explored the use of clinically approved iron-oxide nanoparticles (Faraheme, AMAG Pharmaceuticals, Lexington, MA, USA) for quantifying the WEI in combination with ultrashort echo time imaging sequences. 39 The ultrashort echo time technique is particularly enticing since no correction for T2* relaxation, caused by almost any MRI contrast agents, is required.…”

Section: Discussionmentioning

confidence: 99%

Cerebral Blood Volume Affects Blood–Brain Barrier Integrity in an Acute Transient Stroke Model

Huang

Kim

Atochin

et al. 2013

J Cereb Blood Flow Metab

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Insufficient vascular reserve after an ischemic stroke may induce biochemical cascades that subsequently deteriorate the blood-brain barrier (BBB) function. However, the direct relationship between poor cerebral blood volume (CBV) restoration and BBB disruption has not been examined in acute stroke. To quantify BBB integrity at acute stages of transient stroke, in particular for cases in which extravasation of the standard contrast agent (Gd-DTPA) is not observed, we adopted the water exchange index (WEI), a novel magnetic resonance image-derived parameter to estimate the water permeability across the BBB. The apparent diffusion coefficient (ADC) and R 2 relaxation rate constant were also measured for outlining the tissue abnormality, while fractional CBV and WEI were quantified for assessing vascular alterations. The significantly decreased ADC and R 2 in the ischemic cortices did not correlate with the changes in CBV or WEI. In contrast, a strong negative correlation between the ipsilesional WEI and CBV was found, in which stroke mice were clustered into two groups: (1) high WEI and low CBV and (2) normal WEI and CBV. The low CBV observed for mice with a disrupted BBB, characterized by a high WEI, indicates the importance of CBV restoration for maintaining BBB stability in acute stroke.

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Section: Discussionmentioning

confidence: 99%

Cerebral Blood Volume Affects Blood–Brain Barrier Integrity in an Acute Transient Stroke Model

Huang

Kim

Atochin

et al. 2013

J Cereb Blood Flow Metab

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“…During the past years, thrombolytic models of stroke have been established in various animal species, including rat (13,16,17) and mice (18,19). However, the variability of reperfusion quality makes it difficult to derive viability markers from such experiments.…”

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confidence: 99%

Dynamic changes of ADC, perfusion, and NMR relaxation parameters in transient focal ischemia of rat brain

Dorsten

Oláh

Schwindt

et al. 2001

Magnetic Resonance in Med

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The potential of multiparametric MRI parameters for differentiating between reversibly and irreversibly damaged brain tissue was investigated in an experimental model of focal brain ischemia in the rat. The middle cerebral artery (MCA) was occluded by intraluminal suture insertion for 60 or 90 min, followed by 4.5 h of reperfusion. The apparent diffusion coefficient (ADC) of brain water, T 1 and T 2 relaxation times, and CBF i , an MRderived index of cerebral perfusion, were repeatedly measured and correlated with the outcome from the ischemic impact. A novel user-independent approach for segmentation of ADC maps into classes of increasing injury was introduced to define regions of interest (ROIs) in which these parameters were evaluated. MCA occlusion led to a graded decline of ADC, which corresponded with both the severity of flow reduction and an increase in T 1 and T 2 relaxation times. Removal of the suture led to a triphasic restitution of blood flow consisting of a fast initial rise, a secondary decline, and final normalization. Postischemic reperfusion led to a rise of ADC irrespective of the duration of ischemia. However, the quality of recovery declined with increasing severity of the ischemic impact. Throughout the observation time, T 1 and T 2 showed a continuous increase, the intensity of which correlated with the severity of ADC decline during ischemia. Particularly with longer ischemia time, elevated T 2 in combination with reduced ADC yielded a lower probability of recovery during recirculation, while intraischemic perfusion information contributed less to the prediction of outcome. In conclusion, the combination of MR parameters at the end of ischemia correlated with the probability of tissue recovery but did not permit reliable differentiation between reversibly and irreversibly damaged tissue. Magn Reson Med 47:97-104, 2002.

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“…Embolic stroke was induced as previously reported, 6,7,9 with some modifications by injecting the C15-labeled clot (diameter, 0.15 mm; length, 15 mm) into the MCA-ACA bifurcation area of 10-week-old C57/BL6 mice (nϭ56; Supplemental Methods). Instead of 10 mm thrombus, 9 we injected 15 mm thrombus after considering that the thrombus was diluted 7:3 during the labeling process.…”

Section: Animal Experimentsmentioning

confidence: 99%

Direct Thrombus Imaging as a Means to Control the Variability of Mouse Embolic Infarct Models

Kim

Nahrendorf

et al. 2011

Stroke

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Background and Purpose-High experimental variability in mouse embolic stroke models could mask the effects of experimental treatments. We hypothesized that imaging thrombus directly would allow this variability to be controlled. Methods-We optically labeled thrombi with a near-infrared fluorescent (NIRF) probe C15 that is covalently linked to fibrin by factor-XIIIa. Labeled thrombus was injected into the left distal internal carotid artery (ICA) of C57/BL6 mice (nϭ47), near its bifurcation, and laser-Doppler cerebral-blood-flow (CBF) was assessed for 30 minutes. NIRF thrombus imaging was done ex vivo at 24 hours. Results-CBF variably decreased to 43.9Ϯ17.3% at 5 minutes (rCBF; 11.2ϳ80.4%). NIRF thrombus imaging at 24 hours showed variability in distribution (ICA bifurcation, adjacent and/or remote areas) and burden (2279Ϯ1270 pixels; 0ϳ5940 pixels). Final infarct size was also variable (21.0Ϯ10.3%; 4.7ϳ60.3% of the bihemispheric volume). Despite this heterogeneity, a strong thrombus-infarct correlation was maintained. The left hemispheric target infarct size (% of the hemisphere) correlated with thrombus burden, as a stronger predictor of infarct volume (PϽ0.001, rϭ0.50) than rCBF (Pϭ0.02, rϭϪ0.34). The infarct size was best predicted by a combination of thrombus imaging and CBF: left-hemispheric big-thrombi (Ͼ1865 pixels)/low-rCBF (Յ42%) had an infarct volume of 56.9Ϯ10.4% (nϭ12), big-thrombi/high-rCBF had 45.9Ϯ23.5% (nϭ11), small-thrombi/low-rCBF 35.7Ϯ17.3% (nϭ11) and small-thrombi/ high-rCBF 27.3Ϯ16.4% (nϭ12). Conclusions-This is the first study to demonstrate that the highly heterogeneous nature of the mouse embolic stroke model can be characterized and managed by using near-infrared fluorescent thrombus imaging combined with CBF monitoring to stratify animals into useful subgroups. Key Words: thrombus imaging Ⅲ embolic cerebral infarction Ⅲ molecular imaging Ⅲ optical imaging I schemic stroke caused by cerebral thromboembolism is a leading cause of death and disability. Much effort has been put into developing effective neuroprotective treatments, but with limited success. 1,2 A major difficulty in stroke research has been experimental variability in animal stroke models, [3][4][5] leading to failures in identifying neuroprotective drugs. Embolic stroke models, in which preformed clots are injected into the middle cerebral artery-anterior cerebral artery (MCA-ACA) bifurcation area, mimic human stroke more closely than do other models of cerebral ischemia. 6 -9 However, they provide less control over the location and extent of the resulting cerebral infarction. 3 Factors, such as spontaneous lysis 8 or distal embolization of thrombi after injection into the MCA, as well as anatomic variations in the circle of Willis, could have major and variable impacts on the resulting infarct. 10 This variability could mask and confound the potential therapeutic effects 3 of neuroprotective drugs, and by adding to experimental noise, might mask or heighten the effects of experimental treatments, leading to hard-to-interp...

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A Mouse Model of Embolic Focal Cerebral Ischemia

Cited by 89 publications

References 17 publications

Cerebral Blood Volume Affects Blood–Brain Barrier Integrity in an Acute Transient Stroke Model

Cerebral Blood Volume Affects Blood–Brain Barrier Integrity in an Acute Transient Stroke Model

Dynamic changes of ADC, perfusion, and NMR relaxation parameters in transient focal ischemia of rat brain

Direct Thrombus Imaging as a Means to Control the Variability of Mouse Embolic Infarct Models

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