RT Journal Article
SR Electronic
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
FD Society of Nuclear Medicine
SP jnumed.121.262279
DO 10.2967/jnumed.121.262279
A1 Cristina Barca
A1 Amanda J Kiliaan
A1 Claudia Foray
A1 Lydia Wachsmuth
A1 Sven Hermann
A1 Cornelius Faber
A1 Michael Schaefers
A1 Maximilian Wiesmann
A1 Andreas H Jacobs
A1 Bastian Zinnhardt
YR 2021
UL http://jnm.snmjournals.org/content/early/2021/06/24/jnumed.121.262279.abstract
AB 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.