Decreased Chronic-Stage Cortical 11 C-Flumazenil Binding After Focal Ischemia-Reperfusion in Baboons

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Abstract
Background and Purpose— Although the penumbra can be saved by early reperfusion, in the rat it is consistently affected by selective neuronal loss. Mapping selective neuronal loss in the living primate would be desirable. Methods— Five young adult baboons underwent 15 O positron emission tomography for cerebral blood flow, cerebral oxygen consumption, and oxygen extraction fraction mapping at baseline and serially during and after 20-hour temporary middle cerebral artery occlusion. At approximately day 30, 11 C-flumazenil (FMZ), a potential positron emission tomography marker of selective neuronal loss, and structural magnetic resonance-based infarct mapping were obtained, and the brain was perfused-fixed. Reduced FMZ binding in noninfarcted cortical middle cerebral artery areas was searched voxel-wise, and specific binding was assessed using compartmental modeling of FMZ time-activity curves. Results— Visual inspection revealed reduced late FMZ uptake in the affected cortical territory, extending well beyond the infarct. Accordingly, the incidence of selected voxels was greater than chance, documenting mildly but significantly reduced FMZ uptake and specific binding. Serial 15 O positron emission tomography revealed moderately severe acute ischemia followed by reperfusion. Histopathology documented only mild neuronal changes in or near the affected areas. Conclusions— We document moderate but definite late FMZ binding decrements in noninfarcted cortical areas in the baboon, consistent with previous rat and human studies. These were acutely characterized by moderate ischemia followed by reperfusion, consistent with neuronal damage from ischemic or reperfusion injury in the salvaged at-risk tissue. Only mild histopathological changes subtended these FMZ alterations suggesting subtle processes such as isolated dendrite or synapse loss. Whether these changes impact on clinical outcome deserves studying because they may be targeted by specific neuroprotection.

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