TY - JOUR T1 - A longitudinal PET/MR imaging study of colony stimulating factor-1 receptor-mediated microglia depletion in experimental stroke JF - Journal of Nuclear Medicine JO - J Nucl Med DO - 10.2967/jnumed.121.262279 SP - jnumed.121.262279 AU - Cristina Barca AU - Amanda J Kiliaan AU - Claudia Foray AU - Lydia Wachsmuth AU - Sven Hermann AU - Cornelius Faber AU - Michael Schaefers AU - Maximilian Wiesmann AU - Andreas H Jacobs AU - Bastian Zinnhardt Y1 - 2021/06/01 UR - http://jnm.snmjournals.org/content/early/2021/06/24/jnumed.121.262279.abstract N2 - Microglia-induced neuroinflammation after stroke contributes to the exacerbation of post-ischemic damage but also supports neurorestorative events. Longitudinal molecular imaging of microglia-targeted therapies will support the assessment of target engagement, therapy efficacy, and deciphering the mode of action. We investigated the effects of chronic colony stimulating factor-1 receptor (CSF-1R) inhibitor-mediated microglia depletion on translocator protein (TSPO)-dependent neuroinflammation and cerebrovascular parameters using positron emission tomography (PET)/magnetic resonance (MR) imaging. Methods: N = 40 C57BL/6 mice underwent a 30 minutes transient middle cerebral artery occlusion (tMCAo) and were randomly assigned to either control group or treated with CSF-1R inhibitor (PLX5622; Plexxikon Inc.). N = 8 mice/group were used for 18F-DPA-714 (TSPO) PET imaging at days 7, 14, 21, and 30 post ischemia and behavioural tests prior to and after surgery. An extra group of n = 8 mice/group underwent MR imaging including T2-weighted (infarct), perfusion- (cerebral blood flow) and diffusion-weighted (water diffusion, cellular density) at days 1, 3, 7, 14, 21 and 30. Ex vivo analysis (immunoreactivity, gene expression) were performed to characterize the inflammatory environment. Results: We demonstrated that long-term CSF-1R inhibition transiently decreases the TSPO-PET signal within the infarct. Residual TSPO activity was partly due to potentially resistant Iba-1+ cell populations with low CSF-1R and transmembrane 119 (TMEM119) expression. The decrease in selected pro- and anti-inflammatory marker expression suggested an apparent global dampening of the neuroinflammatory response. Furthermore, the temporal changes of the MRI parameters highlighted treatment-induced effects on reperfusion and tissue homeostasis, associated with impaired motor functions at late stages. Conclusion: Longitudinal TSPO-PET/MR imaging allows the assessment of target engagement and optimization of drug efficiency. PLX5622 has promising immunomodulatory effects and the optimal therapeutic time window for its application needs to be defined. ER -