PET Imaging of Peripheral Benzodiazepine Receptor Standard Uptake Value Increases After Controlled Cortical Impact, a Rodent Model of Traumatic Brain Injury.

Abstract

Background: Traumatic brain injury (TBI) disrupts the complex arrangement of neuronal and glial cells. As a result of TBI there is activation of microglia. Activated microglia after injury can be measured in vivo by using positron emission topography (PET) ligand peripheral benzodiazepine receptor (PBR28) and their phenotypes (activated vs resting) can be assessed (ex vivo) using morphology. This study aims to utilize in vivo (PET) and ex vivo (morphology) to assess the changes in microglia after a controlled cortical impact (CCI), a rodent model for TBI.Methods: Male Sprague Dawley rats underwent a sham injury or severe CCI. Microglia activation was assessed 120 hours after the injury by PET/CT imaging using the radioligand [11C] PBR-28. Standardized uptake values (PBR28suv) were calculated over the duration of the scan and mean values were compared. In order to verify in vivo results, ex vivo morphological analysis [ramified (resting) or amoeboid-shaped (activated)] was performed (dentate gyrus, corpus callosum and thalamus) with the antibody IBA-1. To further conclude that PBR is a marker for activated microglia after CCI, we examined co-staining of PBR with microglia and astrocytes.Results: In vivo and ex vivo results were complementary. Injured animals displayed greater PBR28suv when compared to sham animals. Immunohistochemistry demonstrated elevated numbers of activated microglia in the ipsilateral dentate gyrus, corpus callosum and thalami of injured animals compared to sham animals. Additionally, PBR co-stained with microglia and not astrocytes.Conclusion: CCI, a rodent model of TBI resulted in a significant increase in PBR28suv due to injury. Similarly, morphological analysis demonstrated a significant increase in amoeboid-shaped (activated) microglia. These results serve as a surrogate marker for increased neuroinflammation in the brains of severely injured animals. PBR28suv can serve as an in vivo tracking system for monitoring neuroinflammation following TBI and cellular therapies.