RT Journal Article SR Electronic T1 Short-term colony stimulating factor-1 receptor inhibition-induced repopulation after stroke assessed by longitudinal 18F-DPA-714 PET imaging JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP jnumed.121.263004 DO 10.2967/jnumed.121.263004 A1 Cristina Barca A1 Amanda J Kiliaan A1 Lydia Wachsmuth A1 Claudia Foray A1 Sven Hermann A1 Cornelius Faber A1 Michael Schaefers A1 Maximilian Wiesmann A1 Bastian Zinnhardt A1 Andreas H Jacobs YR 2022 UL http://jnm.snmjournals.org/content/early/2022/02/03/jnumed.121.263004.abstract AB Studies on colony stimulating factor-1 receptor (CSF-1R) inhibition-induced microglia depletion indicated that inhibitor withdrawal allowed the renewal of the microglial compartment via repopulation and resolved the inflammatory imbalance. Therefore, we investigated for the first time the effects of microglia repopulation on inflammation and functional outcomes in an ischemic mouse model using translocator protein (TSPO) positron emission tomography (PET)- computed tomography (CT)/ magnetic resonance (MR) imaging, ex vivo characterization and behavioral tests. Methods: N = 8/group C57BL/6 mice underwent a 30 minutes transient middle cerebral artery occlusion. The treatment group received CSF-1R inhibitor 1200 ppm PLX5622 chow (Plexxikon Inc.) from days 3 to 7 to induce microglia/macrophages depletion, and went back to control diet to allow microglia repopulation. Mice underwent T2w-MR imaging on day 1 and 18F-DPA-714 (TSPO) PET-CT on days 7, 14, 21 and 30 post ischemia. Percentage of injected tracer dose (%ID/mL) within the infarct, contralateral striatum and spleen were assessed. Behavioral tests were performed to assess motor function recovery. Brains were harvested at days 14 and 35 post ischemia for ex vivo analyses (immunoreactivity, rt-qPCR) of microglia/macrophages-related markers. Results: Repopulation significantly increased 18F-DPA-714 tracer uptake within the infarct on days 14 (P < 0.001) and 21 (P = 0.002) post ischemia. On day 14, the Iba-1+ cell population showed significantly higher expression of TSPO, CSF-1R and CD68, in line with microglia repopulation. Gene expression analyses on day 14 indicated a significant increase in microglia-related markers (csf-1r, aif1, p2ry12) with repopulation while peripheral cell recruitment-related gene expression decreased (cx3cr1, ccr2), indicative of peripheral recruitment during CSF-1R inhibition. Similarly, uncorrected spleen tracer uptake was significantly higher on day 7 post ischemia with treatment (P = 0.001) and decreased after drug withdrawal. PLX5622-treated mice walked longer distance (P < 0.001) and faster (P = 0.009), and showed stronger forelimbs strength (P < 0.001) than control mice on day 14. Conclusion: This study highlights the potential of 18F-DPA-714 PET-CT imaging to track microglia/macrophages repopulation after short-term CSF-1R inhibition in stroke.