Abstract WMP84: Predicting Cortical Selective Neuronal Loss Using 11 C-flumazenil PET After Temporary Focal Ischemia in Spontaneously Hypertensive Rats

Abstract

Background: Predicting ischemic brain damage early after stroke is an important goal. T2-Weighted MRI >3hrs after stroke onset accurately predicts infarction but is insensitive to selective neuronal loss (SNL). Chronic-stage 11 C-flumazenil PET (FMZ-PET) is a positive marker of SNL in rats (Ejaz, Neurobiol. Dis. 2013), and previous studies in man, baboons and cats suggest early-stage FMZ-PET could predict infarction. Here we assessed whether early FMZ-PET quantitatively predicts SNL. Methods: Six adult male spontaneously hypertensive rats underwent 45min distal MCA occlusion, and dynamic FMZ-PET was obtained at 1hr and 48hrs post-reperfusion to map distribution volume (DV), which reflects specific binding. Following perfusion-fixation at Day 14, immunohistochemistry using NeuN as neuronal marker was performed. Comparison of normalized FMZ DV to %NeuN loss (determined visually) was done by means of Pearson correlations across 44 cytoarchitectonic ROIs from 8 coronal sections spanning the hemisphere and matching Paxinos atlas, according to previously published methods (Hughes, NeuroImage 2012; Emmrich, JCBFM 2015). Results: NeuN revealed cortical infarction and isolated SNL in 1 and 5 rats, respectively. 1-hr post-reperfusion FMZ-DV was unaffected and did not predict tissue outcome. In contrast, 48-hr FMZ-DV was significantly increased and across the 44 ROIs negatively predicted SNL intensity both individually in 3/5 rats (r range: 0.38-0.60; trend in 2/5 rats) and across the 5 rats (r=0.59, p <0.001), i.e. the higher the DV, the more severe the SNL; similar but stronger correlation (r=0.76) was found in the rat with infarction. Conclusion: The lack of FMZ changes 1hr after reperfusion suggests post-synaptic GABA- A receptors are still present onto dying neurons. Regardless of the underlying mechanism, e.g. receptor upregulation or increased binding via BBB damage, the FMZ binding increase present at 48hrs - which is consistent with earlier rat studies - was predictive of tissue outcome, including SNL - a new finding with potential clinical relevance.