RT Journal Article
SR Electronic
T1 A Longitudinal PET/MRI Study of Colony-Stimulating Factor 1 Receptor–Mediated Microglia Depletion in Experimental Stroke
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 446
OP 452
DO 10.2967/jnumed.121.262279
VO 63
IS 3
A1 Cristina Barca
A1 Amanda J. Kiliaan
A1 Claudia Foray
A1 Lydia Wachsmuth
A1 Sven Hermann
A1 Cornelius Faber
A1 Michael Schäfers
A1 Maximilian Wiesmann
A1 Andreas H. Jacobs
A1 Bastian Zinnhardt
YR 2022
UL http://jnm.snmjournals.org/content/63/3/446.abstract
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.