Dynamic Penumbra Demonstrated by Sequential Multitracer PET after Middle Cerebral Artery Occlusion in Cats

Experimental models of focal cerebral ischemia have provided important data on early circulatory and biochemical changes, but typically their correspondence with metabolic and hemodynamic findings in stroke patients has been poor. To fill the gap between experimental studies at early time points and rather late clinical studies, we repeatedly measured CBF, CMRO2, oxygen extraction fraction (OEF), cerebral blood volume (CBV), and CMRglc in six cats before and up to 24 h after permanent middle cerebral artery (MCA) occlusion (MCAO), using the 15O steady state and [18F]fluorodeoxyglucose methods and a high-resolution positron emission tomography (PET) scanner. Likewise, three sham-operated control cats were studied during the same period. Final infarct size was determined on serial histologic sections. In the areas of final glucose metabolic depression that were slightly larger than the histologic infarcts, mean CBF dropped to ∼40% of control values immediately on arterial occlusion. It further decreased to <20% during the course of the experiment. This progressive ischemia was most conspicuous in border zones. CMRO2 fell to a lesser degree (55%), eventually reaching ∼25% of its control level. At early stages, OEF increased mainly in the center of ischemia. With time, areas of increased OEF moved from the center to the periphery of the MCA territory. Concurrently, progressive secondary decreases in OEF in conjunction with further reductions of CBF and CMRO2 indicated the development of central necrosis. The findings are highly suggestive of a dynamic penumbra. In five cats with complete MCA infarcts, CBF decreased and OEF increased in the contralateral hemisphere after 24 h, suggesting whole-brain damage. This effect may be explained by the widespread brain edema found histologically in addition to the nonspecific CBF reductions and OEF elevations observed also in the sham-operated controls after 1 day in the experimental condition. In one cat, cortical OEF increased only transiently. Normal CMRO2 and CMRglc were eventually restored, and the final infarct was small. This study demonstrates that acute regional pathophysiologic changes can be repeatedly assessed by multivariate PET in cats. Viable tissue can be detected up to several hours after MCA occlusion, and the transition of misery-perfused regions into necrosis or preserved tissue can be followed over time. The present results support the concept of a dynamic penumbra, in which for up to 24 h tissue damage spreads progressively from the center to the periphery of ischemia. Sequential high-resolution PET provides insight into the dynamics of regional pathophysiology and may thus further the development of rational therapeutic strategies.

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Thresholds of focal cerebral ischemia in awake monkeys

Journal of Neurosurgery ◽

10.3171/jns.1981.54.6.0773 ◽

1981 ◽

Vol 54 (6) ◽

pp. 773-782 ◽

Cited By ~ 841

Author(s):

Thomas H. Jones ◽

Richard B. Morawetz ◽

Robert M. Crowell ◽

Frank W. Marcoux ◽

Stuart J. FitzGibbon ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Ischemia ◽

Middle Cerebral Artery ◽

Cerebral Artery ◽

Focal Cerebral Ischemia ◽

Neurological Function ◽

Local Flow ◽

Content Type ◽

Mca Occlusion ◽

Fine Print

✓ An awake-primate model has been developed which permits reversible middle cerebral artery (MCA) occlusion during physiological monitoring. This method eliminates the ischemia-modifying effects of anesthesia, and permits correlation of neurological function with cerebral blood flow (CBF) and neuropathology. The model was used to assess the brain's tolerance to focal cerebral ischemia. The MCA was occluded for 15 or 30 minutes, 2 to 3 hours, or permanently. Serial monitoring evaluated neurological function, local CBF (hydrogen clearance), and other physiological parameters (blood pressure, blood gases, and intracranial pressure). After 2 weeks, neuropathological evaluation identified infarcts and their relation to blood flow recording sites. Middle cerebral artery occlusion usually caused substantial decreases in local CBF. Variable reduction in flow correlated directly with the variable severity of deficit. Release of occlusion at up to 3 hours led to clinical improvement. Pathological examination showed microscopic foci of infarction after 15 to 30 minutes of ischemia, moderate to large infarcts after 2 to 3 hours of ischemia, and in most cases large infarcts after permanent MCA occlusion. Local CBF appeared to define thresholds for paralysis and infarction. When local flow dropped below about 23 cc/100 gm/min, reversible paralysis occurred. When local flow fell below 10 to 12 cc/100 gm/min for 2 to 3 hours or below 17 to 18 cc/100 gm/min during permanent occlusion, irreversible local damage was observed. These studies imply that some cases of acute hemiplegia, with blood flow in the paralysis range, might be improved by surgical revascularization. Studies of local CBF might help identify suitable cases for emergency revascularization.

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Reduction of Infarct Volume by Magnesium after Middle Cerebral Artery Occlusion in Rats

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1991.170 ◽

1991 ◽

Vol 11 (6) ◽

pp. 1025-1030 ◽

Cited By ~ 122

Author(s):

Yoshio Izumi ◽

Simon Roussel ◽

Elisabeth Pinard ◽

Jacques Seylaz

Keyword(s):

Middle Cerebral Artery ◽

Cerebral Artery ◽

Focal Cerebral Ischemia ◽

Infarct Volume ◽

Artery Occlusion ◽

Triphenyltetrazolium Chloride ◽

Ischemic Brain ◽

Mca Occlusion ◽

Cerebral Artery Occlusion ◽

Hyperglycemic Effect

The effects of magnesium, an endogenous inhibitor of calcium entry into neurons, upon ischemic brain damage were investigated using a well-characterized model of focal cerebral ischemia in rats. Infarct volumes were determined by 2,3,5-triphenyltetrazolium chloride transcardiac perfusion 48 h after middle cerebral artery (MCA) occlusion. The area of ischemic damage was quantified by image analysis in coronal sections taken every 0.5 mm. MgCl2 (1 mmol/kg) was injected intraperitoneally just after MCA occlusion and again 1 h later. Posttreatment with MgCl2 (16 control and 16 treated rats) significantly reduced the cortical infarct volume. Compensation for the hyperglycemic effect of MgCl2 with insulin (17 rats) further reduced the infarct volume in the neocortex. No systemic effects of either treatment could account for the observed neuroprotection.

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High-dose ibuprofen for reduction of striatal infarcts during middle cerebral artery occlusion in rats

Journal of Neurosurgery ◽

10.3171/jns.2003.98.4.0860 ◽

2003 ◽

Vol 98 (4) ◽

pp. 860-866 ◽

Cited By ~ 34

Author(s):

David F. Antezana ◽

Richard E. Clatterbuck ◽

Nabil J. Alkayed ◽

Stephanie J. Murphy ◽

Lauren G. Anderson ◽

...

Keyword(s):

Middle Cerebral Artery ◽

Cerebral Artery ◽

Focal Cerebral Ischemia ◽

Intercellular Adhesion Molecule ◽

High Dose ◽

Neurosurgical Procedures ◽

Intercellular Adhesion Molecule 1 ◽

Content Type ◽

Mca Occlusion ◽

Fine Print

Object. Ibuprofen is an antiinflammatory drug that disrupts leukocyte—endothelial cell interactions by limiting expression of endothelial adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), also known as CD54. The authors hypothesized that ibuprofen could reduce the size of the infarct associated with transient focal ischemia by inhibition of ICAM-1 expression, and they evaluated its effects in rats treated with middle cerebral artery (MCA) occlusion. Ibuprofen treatment was compared with mild systemic hypothermia, which is known to be neuroprotective and is commonly used during neurosurgical procedures. Methods. The maximum ibuprofen dose (240 mg/kg/day) that could be tolerated with no systemic toxicity was established in the initial experiments. In the efficacy experiment, rats were pretreated with vehicle, ibuprofen, or hypothermia (33°C) prior to 2 hours of MCA occlusion; then their brains were harvested at 24 hours of reperfusion for histological studies. End-ischemic cerebral blood flow (CBF) was evaluated using [14C]iodoantipyrine autoradiography in additional cohorts. Expression of ICAM-1 within ischemic compared with nonischemic caudate nucleus and putamen (striatum) or cortex was evaluated using immunohistochemical studies. Compared with vehicle treatment, ibuprofen produced a 46.2% reduction (p = 0.01) in striatal infarcts, which was comparable to hypothermia (48.7% reduction, p = 0.02). Ibuprofen did not alter end-ischemic CBF in any region studied, and the ibuprofen treatment group had the lowest proportion of animals with marked ICAM-1 staining. Conclusions. Ibuprofen given in maximum tolerated doses reduces the striatal infarct size after focal cerebral ischemia. The neuroprotective mechanism does not work through preservation of intraischemic CBF and is consistent with inhibition of ICAM-1 expression; however, at the doses used in this study, other effects of ibuprofen on platelet and endothelial function are possible.

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The Significance of Brain Temperature in Focal Cerebral Ischemia: Histopathological Consequences of Middle Cerebral Artery Occlusion in the Rat

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1992.55 ◽

1992 ◽

Vol 12 (3) ◽

pp. 380-389 ◽

Cited By ~ 292

Author(s):

Eiharu Morikawa ◽

Myron D. Ginsberg ◽

W. Dalton Dietrich ◽

Robert C. Duncan ◽

Susan Kraydieh ◽

...

Keyword(s):

Middle Cerebral Artery ◽

Cerebral Artery ◽

Repeated Measures ◽

Focal Cerebral Ischemia ◽

Brain Temperature ◽

Infarct Volume ◽

Histopathological Analysis ◽

Sprague Dawley ◽

Mca Occlusion ◽

Significant Difference

The purpose of this study was to determine the effect of selective modulation of brain temperature in the experimental settings of permanent and reversible middle cerebral artery (MCA) occlusion in Sprague–Dawley rats. Three models of proximal MCA occlusion were used, in which the effect of brain-temperature modulations could be studied. These included (a) permanent MCA occlusion with an initial 30-min period of hypotension (30 or 36°C × 4 h), (b) permanent MCA occlusion alone (30, 36, or 39°C × 2 h), and (c) 2 h of reversible MCA occlusion (30, 36, or 39°C × 2 h). In the transient MCA occlusion series, intra- and postischemic cortical blood flow was assessed using a laser–Doppler flowmeter placed over the dorsolateral cortex. After a 3-day survival, all rats were perfusion fixed for histopathological analysis and the determination of infarct volume. In animals with permanent MCA occlusion plus hypotension, no significant difference in infarct volume was demonstrated between the 30 and 36°C groups. In rats with permanent MCA occlusion without hypotension, significant differences in infarct volume were again not demonstrable, but an interaction between infarct area and temperature class was shown by repeated-measures analysis, indicating that hypothermia altered the topographic pattern of the cortical infarct. With 2 h of reversible MCA occlusion, there was a statistically significant reduction in infarct volume in the 30°C group compared to 39°C rats. Although intra- and postischemic CBF were not significantly different among the three temperature groups, the cortical infarct volume was positively correlated with postischemic CBF. The postischemic CBF, in turn, was positively correlated to the intraischemic brain temperature and was negatively correlated to CBF during the ischemic period. These findings demonstrate that moderate manipulations of brain temperature have a greater influence on the resulting cortical infarction in the setting of transient focal ischemia than in the context of permanent vascular occlusion.

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Outcome of Acutely Ischemic Brain Tissue in Prolonged Middle Cerebral Artery Occlusion: A Serial Positron Emission Tomography Investigation in the Baboon

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200405000-00003 ◽

2004 ◽

Vol 24 (5) ◽

pp. 495-508 ◽

Cited By ~ 32

Author(s):

Cyrille Giffard ◽

Alan R. Young ◽

Nacer Kerrouche ◽

Jean-Michel Derlon ◽

Jean-Claude Baron

Keyword(s):

Positron Emission Tomography ◽

At Risk ◽

Middle Cerebral Artery ◽

Cerebral Artery ◽

Oxygen Metabolism ◽

Emission Tomography ◽

Oxygen Extraction Fraction ◽

Mca Occlusion ◽

Positron Emission ◽

Time Point

Thrombolysis within 3 to 6 hours of symptom onset is recommended therapy for acute middle cerebral artery (MCA) stroke, but recent imaging studies in humans suggest that the penumbra may last much longer in some patients. It is therefore important to study the events that take place with occlusions that last longer than 6 hours. Based upon positron emission tomography (PET), the tissue with high oxygen extraction fraction (OEF) is at risk of infarction. In a previous sequential PET study in anesthetized baboons, we documented that when reperfusion was initiated at 6 hours after MCA occlusion, the region with the acutely highest OEF was not incorporated within the final magnetic resonance imaging (MRI)-defined infarct, suggesting reperfusion prevented such demise. In agreement with this hypothesis, we report here using the same sequential PET paradigm with final chronic-stage volume MRI that a 20-hour MCA occlusion resulted in, on average, 36% of the highest OEF area being recruited into the final infarct. We also found that the portion of the highest OEF area that went on to infarct had at the earliest time-point significantly lower cerebral blood flow and cerebral oxygen metabolism (mean reductions relative to unoccluded side, 56% and 32%, respectively) than the portion that did not (41% and 11%, respectively) and that some reperfusion occurred in the latter at second time-point, that is, before recanalization. Thus, apart from duration of occlusion, the fate of the at-risk tissue is predicated by the initial severity of the ischemia as well as by early secondary events such as partial spontaneous reperfusion.

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Temporal Profile of in situ DNA Fragmentation after Transient Middle Cerebral Artery Occlusion in the Rat

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1995.49 ◽

1995 ◽

Vol 15 (3) ◽

pp. 389-397 ◽

Cited By ~ 373

Author(s):

Yi Li ◽

Michael Chopp ◽

Ning Jiang ◽

Fayi Yao ◽

Cecylia Zaloga

Keyword(s):

Middle Cerebral Artery ◽

Dna Fragmentation ◽

Cerebral Artery ◽

Gel Electrophoresis ◽

Focal Cerebral Ischemia ◽

Artery Occlusion ◽

Anatomical Location ◽

Temporal Profile ◽

Mca Occlusion

We measured the temporal profile and anatomic distribution of cells exhibiting DNA fragmentation at various durations of reperfusion after middle cerebral artery (MCA) occlusion in the rat. Focal cerebral ischemia was induced in male Wistar rats (n = 62) using an intraluminal monofilament blockade of the MCA. After 2 h of MCA occlusion, the animals were killed at different durations of reperfusion (0.5, 3, 6, 9, and 12 h and 1, 2, 4, 7, 14, 21, and 28 days, n = 4 per time point). Sham-operated rats (n = 4) and normal rats not subjected to any surgical procedure (n = 4) were used as controls. Coronal brain sections (5 μm) were analyzed, using an in situ ApopTag kit, hematoxylin and eosin, and immunohistochemical double-staining methods. Six rats subjected to 2 h of MCA occlusion were killed at 24 h for measurement of DNA fragmentation by gel electrophoresis. Our data indicate that within a coronal section, DNA fragmentation was present in zero to three cells in each hemisphere of normal and sham-operated rats as well as in the contralateral hemisphere of ischemic rats. The number of cells exhibiting DNA fragmentation increased as early as 0.5 h (8 ± 6), peaked at 24–48 h (213 ± 59), and persisted for 4 weeks (10 ± 2) after onset of reperfusion (p < 0.01). Groups of cells exhibiting DNA fragmentation (>95% neurons) were located primarily in the inner boundary zone of the infarct. With use of gel electrophoresis, purified DNA obtained from the ischemic tissue exhibited the characteristic nucleosome ladder pattern associated with apoptosis. The presence and anatomical location of cells exhibiting DNA fragmentation after transient MCA occlusion suggest that apoptosis contributes to the development of ischemic infarct. In addition, the prolonged presence of DNA fragmentation after the onset of ischemia suggests that apoptotic ischemic brain damage is a dynamic ongoing process.

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Ideal Suture Diameter is Critical for Consistent Middle Cerebral Artery Occlusion in Mice

Operative Neurosurgery ◽

10.1227/01.neu.0000144490.92966.59 ◽

2005 ◽

Vol 56 (suppl_1) ◽

pp. ONS-196-ONS-200 ◽

Cited By ~ 8

Author(s):

Kudret Türeyen ◽

Raghu Vemuganti ◽

Kurt A. Sailor ◽

Robert J. Dempsey

Keyword(s):

Carotid Artery ◽

Middle Cerebral Artery ◽

Cerebral Artery ◽

Focal Cerebral Ischemia ◽

Infarct Volume ◽

Great Majority ◽

External Carotid ◽

Blue Dye ◽

Triphenyltetrazolium Chloride ◽

Mca Occlusion

Abstract OBJECTIVE: The use of transgenic and knockout mice has led to a need for a consistent model of mouse transient focal cerebral ischemia. In a great majority of the published mouse middle cerebral artery (MCA) occlusion studies, the methods indicated the type of intraluminal suture used without indicating the actual suture diameter after modification. We attempted to determine the ideal suture diameter to produce consistent occlusion in the MCA of adult male C57BL/6 mice. METHODS: Suture tips were coated to a depth 4 mm with glue, and 6-0 sutures of eight different, precisely measured diameters were produced. The coated 6-0 sutures in different diameters were introduced 10 mm into the internal carotid artery via the external carotid artery of the mice to produce MCA occlusion (n = 40; five animals for each diameter), and the mice (22–24 g) were transaortically perfused with saline. The base of the brain was exposed, and photographs of the vessels were obtained before and after transaortic injection of Evans blue dye to determine the consistency of MCA occlusion for each suture diameter. Cerebral blood flow was measured 10 minutes before occlusion and 20 minutes after reperfusion, and 2,3,5-triphenyltetrazolium chloride staining was performed to demonstrate the ischemic damage in additional animals with 110-μm (n = 5) and 180-μm (n = 8) diameter sutures. RESULTS: Sutures measuring 170 μm and 180 μm in diameter consistently occluded the MCA of C57BL/6 mice. In addition, 2,3,5-triphenyltetrazolium chloride staining demonstrated consistent infarction with180-μm diameter sutures. The infarct volume was 36.3 ± 4.2 mm3. CONCLUSION: Small changes in the diameter of the occlusion suture tip affect consistency in the mouse MCA occlusion model.

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