Early Reperfusion in the Anesthetized Baboon Reduces Brain Damage Following Middle Cerebral Artery Occlusion

Background and Purpose-We sought to characterize the spatial and temporal evolution of human cerebral infarction.Using a novel method of quantitatively mapping the distribution of hypoxic viable tissue identified by 18 Ffluoromisonidazole ( 18 F-FMISO) PET relative to the final infarct, we determined its evolution and spatial topography in human stroke. Methods-Patients with acute middle cerebral artery territory stroke were imaged with 18 F-FMISO PET (nϭ19; Ͻ6 hours, 4; 6 to 16 hours, 4; 16 to 24 hours, 5; 24 to 48 hours, 6). The hypoxic volume (HV) comprised voxels with significant (PϽ0.05; Ͼ1 mL) uptake on statistical parametric mapping compared with 15 age-matched controls. Central, peripheral, and external zones of the corresponding infarct on the anatomically coregistered delayed CT were defined according to voxel distance from the infarct center and subdivided into 24 regions by coronal, sagittal, and axial planes. Maps ("penumbragrams") displaying the percentage of HV in each region were generated for each time epoch. Results-Higher HV was observed in the central region of the infarct in patients studied within 6 hours of onset (analysis of covariance [ANCOVA]; PϽ0.05) compared with those studied later, in whom the HV was mainly in the periphery or external to the infarct. HV was maximal in the superior, mesial, and posterior regions of the infarct (ANCOVA; PϽ0.05). Conclusions-These observations suggest that infarct expansion occurs at the expense of hypoxic tissue from the center to the periphery of the ischemic region in humans, similar to that seen in experimental animal models. These findings have important pathophysiological and therapeutic implications.

Section: Discussionmentioning

confidence: 99%

Topography and Temporal Evolution of Hypoxic Viable Tissue Identified by ¹⁸ F-Fluoromisonidazole Positron Emission Tomography in Humans After Ischemic Stroke

Markus

Reutens

Kazui

et al. 2003

“…18,[22][23][24][25][26][27][28][29][30][31][32][33][34] Most of these are based on occlusion of the MCA in either macaques or baboons and use several techniques, including the following: intraluminal M1 embolization, 26,31,35 extraluminal M1 ligation, 25 lenticulostriate interruption, 28 -30 and either permanent or temporary M1 clipping. 22,23,27,[32][33][34] Unfortunately, the vast majority of the reports before 1980 involved qualitative assessments of neurological dysfunction and infarct volume, making assessment of their utility difficult. It was, however, evident from these early efforts that embolization/ligation techniques and lenticulostriate interruption had major limitations when it came to elucidating not only the pathophysiology of stroke but also the effect of therapeutic manipulations.…”

Section: Discussionmentioning

confidence: 99%

A Modified Transorbital Baboon Model of Reperfused Stroke

Huang

Mocco

Choudhri

et al. 2000

Background and Purpose-Although pathophysiological studies of focal cerebral ischemia in nonhuman primates can provide important information not obtainable in rodent models, primate experimentation is limited by considerations of cost, availability, effort, and ethics. A reproducible and quantitative model that minimizes the number of animals necessary to detect differences between treatment groups is therefore crucial. Methods-Eight male baboons (weight, 22Ϯ2 kg) underwent left transorbital craniectomy followed by 1 hour of temporary ipsilateral internal carotid artery occlusion at the level of the anterior choroidal artery together with bilateral temporary occlusion of both anterior cerebral arteries (A1) proximal to the anterior communicating artery. A tightly controlled nitrous oxide-narcotic anesthetic allowed for intraoperative motor evoked potential confirmation of middle cerebral artery (MCA) territory ischemia. Animals survived to 72 hours or 10 days if successfully self-caring. Outcomes were assessed with a 100-point neurological grading system, and infarct volume was quantified by planimetric analysis of both MRI and triphenyltetrazolium chloride-stained sections. Results-Infarction volumes (on T2-weighted images) were 32Ϯ7% (meanϮSEM) of the ipsilateral hemisphere, and neurological scores averaged 29Ϯ9. All animals demonstrated evidence of hemispheric infarction, with damage evident in both cortical and subcortical regions in the MCA vascular territory. Histologically determined infarction volumes differed by Ͻ3% and correlated with absolute neurological scores (rϭ0.9, Pϭ0.003). Conclusions-Transorbital temporary occlusion of the entire anterior cerebral circulation with strict control of physiological parameters can reliably produce reperfused MCA territory infarction. The magnitude of the resultant infarct with little interanimal variability diminishes the potential number of animals required to distinguish between 2 treatment regimens. The anatomic distribution of the infarct and associated functional deficits offer comparability to human hemispheric strokes. (Stroke. 2000;31:3054-3063.)

“…Anesthesia may depress cerebral blood flow and function, and affect the hyperacute evolution of the infarct, but it may also suppress a stress-induced exacerbation of cerebral ischemia in the acute phase. 30 The use of anesthesia was unavoidable for our MRI scans; however, anesthetic doses were kept as low as possible, and the animals awoke rapidly at the end of the experiments.…”

Section: Limitations and Future Workmentioning

confidence: 99%

Serial Diffusion Tensor MRI After Transient and Permanent Cerebral Ischemia in Nonhuman Primates

Liu

D’Arceuil

Westmoreland

et al. 2007

Background and Purpose-We measured the temporal evolution of the T2 and diffusion tensor imaging parameters after transient and permanent cerebral middle cerebral artery occlusion (MCAo) in macaques, and compared it to standard histological analysis at the study end point. Methods-Stroke was created in adult male macaques by occluding a middle cerebral artery branch for 3 hours (transient MCAo, nϭ4 or permanent occlusion, nϭ3). Conventional MRI and diffusion tensor imaging scans were performed 0 (acute day), 1, 3, 7, 10, 17, and 30 days after MCAo. Animals were euthanized after the final scan and the brains removed for histological analysis. Results-Apparent diffusion coefficient in the lesion was decreased acutely, fractional anisotropy was elevated, and T2 remained normal. Thereafter, apparent diffusion coefficient increased above normal, fractional anisotropy decreased to below normal, T2 increased to a maximum and then declined. Reperfusion at 3 hours accelerated these MRI changes.Only the fractional anisotropy value was significantly different between transient and permanent groups at 30 days. Final MRI-defined fractional lesion volumes were well correlated with corresponding histological lesion volumes. Permanent MCAO animals showed more severe histological damage than their transient MCAO counterparts, especially myelin damage and axonal swelling. Conclusions-Overall, the MRI evolution of stroke in macaques was closer to what has been observed in humans than in rodent models. This work supports the use of serial MRI in stroke studies in nonhuman primates.