PT  - JOURNAL ARTICLE
AU  - Cristina Barca
AU  - Amanda J. Kiliaan
AU  - Claudia Foray
AU  - Lydia Wachsmuth
AU  - Sven Hermann
AU  - Cornelius Faber
AU  - Michael Schäfers
AU  - Maximilian Wiesmann
AU  - Andreas H. Jacobs
AU  - Bastian Zinnhardt
TI  - A Longitudinal PET/MRI Study of Colony-Stimulating Factor 1 Receptor–Mediated Microglia Depletion in Experimental Stroke
AID  - 10.2967/jnumed.121.262279
DP  - 2022 Mar 01
TA  - Journal of Nuclear Medicine
PG  - 446--452
VI  - 63
IP  - 3
4099  - http://jnm.snmjournals.org/content/63/3/446.short
4100  - http://jnm.snmjournals.org/content/63/3/446.full
SO  - J Nucl Med2022 Mar 01; 63
AB  - Microglia-induced neuroinflammation after stroke contributes to the exacerbation of postischemic damage but also supports neurorestorative events. Longitudinal molecular imaging of microglia-targeted therapies will support the assessment of target engagement, therapy efficacy, and deciphering of 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 PET/MRI. Methods: Forty C57BL/6 mice underwent a 30-min transient occlusion of the middle cerebral artery and were randomly assigned to either a control group or a group treated with CSF-1R inhibitor (PLX5622). Eight mice per group were used for N,N-diethyl-2-(2-(4-(2-18F-fluoroethoxy) phenyl)5,7dimethylpyrazolo[1, 5a]pyrimidin-3-yl)acetamide (18F-DPA-714) (TSPO) PET imaging on days 7, 14, 21, and 30 after ischemia and behavioral tests before and after surgery. An extra group of 8 mice underwent MRI, including T2-weighted (infarct), perfusion-weighted (cerebral blood flow), and diffusion-weighted (water diffusion, cellular density) sequences, on days 1, 3, 7, 14, 21, and 30. Ex vivo analysis (immunoreactivity, gene expression) was performed to characterize the inflammatory environment. Results: We demonstrated that long-term CSF-1R inhibition transiently decreased the TSPO PET signal within the infarct. Residual TSPO activity was partly due to a potentially resistant Iba-1–positive cell populations with low CSF-1R and transmembrane 119 expression. The decrease in selected pro- and antiinflammatory marker expression suggested an apparent global dampening of the neuroinflammatory response. Furthermore, the temporal changes in the MRI parameters highlighted treatment-induced effects on reperfusion and tissue homeostasis, associated with impaired motor function at late stages. Conclusion: Longitudinal TSPO PET/MRI 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.