Imaging the Ischemic Penumbra with ¹⁸ F-Fluoromisonidazole in a Rat Model of Ischemic Stroke

Abstract

Background and Purpose— The ischemic penumbra is a major focus of stroke research. 18 F-fluoromisonidazole ( 18 F-FMISO), a positron emission tomography (PET) marker of hypoxic cells, has shown promise as a technique to image the penumbra in humans. Our aim was to delineate the pattern of 18 F-FMISO binding in a rat middle cerebral artery transient thread-occlusion model, and correlate this with tissue outcome at 24 hours. We hypothesized that the pattern of 18 F-FMISO binding would mimic that seen in humans. Methods— Thirty-eight rats underwent 2 hours transient middle cerebral artery (MCA) occlusion, and then received 18 F-FMISO at time points from 0.5 to 22 hours post-MCA occlusion and were killed 2 hours later. Autoradiographic assessment of 18 F-FMISO binding and assessment (triphenyltetrazolium chloride) of the area of infarction were performed on tissue slices. Results— Until 1 hour after MCA occlusion, 18 F-FMISO binding was increased in the entire MCA territory, with little or no infarction visible. Over the next 5 hours, the pattern of binding evolved to a small rim of intensely binding tissue surrounding the infarct core, which itself showed reduced binding compared with the contralateral hemisphere. By 24 hours, there was minimal accumulation of 18 F-FMISO binding and a large area of infarction. Conclusions— The pattern of 18 F-FMISO binding rats reproduced the pattern seen in humans, consistent with this tracer being a marker of the ischemic penumbra in both species. This technique may have application in studying the ischemic penumbra in animal models, and correlating this with similar studies in humans.

Multivariate Dynamic Prediction of Ischemic Infarction and Tissue Salvage as a Function of Time and Degree of Recanalization

“…Dynamic progression of lesion volume over time is not well characterized in human stroke, logarithmic and sigmoidal growth patterns have been shown in various experimental animal stroke models depending on sampling resolution and range of time interval. 35,36 Both recanalization groups showed initially faster infarct volume increase at shorter treatment intervals up to 18 hours followed by a tail of asymptotic growth tapering off beyond 22 hours. This was above a reported estimated range for the average duration of nonlacunar lesion evolution for supratentorial strokes (10 hours, range 6 to 18 hours) 34 but corresponded to the range of dynamic time curves of penumbra in human and animal studies.…”

Time Is Brain—Quantified

“…The morphology of the growth function is not well-defined for human stroke and is model-specific in various experimental animal stroke models, 4 with a logarithmic pattern being most common 5,6 but sigmoidal 7 and other patterns also observed. Growth patterns in the geometrically more complex human cerebrum may differ from those in the rodent.…”

Applications of Nitroimidazole In Vivo Hypoxia Imaging in Ischemic Stroke

“…Nevertheless, both studies agree that nitroimidazoles will show substantial retention in the moderately to severely hypoperfused tissue, provided it is still viable. Recently, Saita et al 30 reported on 18 F-FMISO ex vivo autoradiography in rats subjected to 2-hour MCAO. Rats were injected at varying time points from occlusion (0.5 to 22 hour) and euthanized 2 hour later, and tracer retention was compared to triphenyltetrazolium chloride (TTC) postmortem staining.…”