A microPET study of the regional distribution of [11C]-PK11195 binding following temporary focal cerebral ischemia in the rat. Correlation with post mortem mapping of microglia activation

• Published in: NeuroImage (Orlando, Fla.) Vol. 59; no. 3; pp. 2007 - 2016
• Main Authors: Hughes, J.L., Jones, P.S., Beech, J.S., Wang, D., Menon, D.K., Aigbirhio, F.I., Fryer, T.D., Baron, J.C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2012; Elsevier Limited
• Subjects: Animals; Antibodies; Biomedical research; Brain Mapping - methods; CD11b Antigen; Cerebrovascular Circulation - physiology; Image Processing, Computer-Assisted; Immunohistochemistry; Infarction, Middle Cerebral Artery - pathology; Ischemia; Ischemic Attack, Transient - diagnostic imaging; Ischemic Attack, Transient - pathology; Isoquinolines; Ligands; Macrophage Activation - physiology; Male; Microglia - physiology; PBR; Peripheral benzodiazepine receptor; PET; Positron-Emission Tomography - methods; Radiopharmaceuticals; Rats; Rats, Inbred SHR; Receptors, GABA-A - metabolism; Reproducibility of Results; Rodents; Stroke; Studies; Tissue Fixation; TSPO: neuroinflammation; Peripheral benzodiazepine receptor; PBR; Stroke; TSPO: neuroinflammation; PET
• ISSN: 1053-8119; 1095-9572
• DOI: 10.1016/j.neuroimage.2011.10.060

Post-stroke microglial activation (MA) may have both neurotoxic and pro-repair effects, particularly in the salvaged penumbra. Mapping MA in vivo is therefore an important goal. 11C-PK11195, a ligand for the 18kDa translocator protein, is the reference radioligand for MA imaging, but a correlation between the regional distributions of in vivo tracer binding and post mortem MA after stroke, as assessed with PET and immunohistochemistry, respectively, has not been demonstrated so far. Here we performed 11C-PK11195 microPET in a rat model previously shown to induce extensive cortical MA, and determined the correlation between 11C-PK11195 and immunostaining with the CD11 antibody OX42, so as to verify the presence of activated microglia, in a template of PET-resolution size regions-of-interest (ROIs) spanning the whole affected hemisphere. Adult spontaneously hypertensive rats underwent 45min distal middle cerebral artery occlusion and 11C-PK11195 PET at Days 2 and 14 after stroke according to a longitudinal design. Following perfusion-fixation at Day 14, brains were removed and coronally cut for OX42 staining. 11C-PK11195 binding potential (BPND) parametric maps were generated, and in each rat both BPND and OX42 (intensity×extent score) were obtained in the same set of 44 ROIs extracted from a cytoarchitectonic atlas to cover the whole hemisphere. Correlations were computed across the 44 ROIs both within and across subjects. Significant BPND increases were observed in both the infarct and surrounding areas in all rats at day 14; less strong but still significant increases were present at day 2. There were highly significant (all p<0.001) positive correlations, both within- and across-subjects, between day 14 BPND values and OX42 scores. The correlation between Day 14 11C-PK11195 and OX42 across the affected hemisphere from the same brain regions and animals further supports the validity of 11C-PK11195 as an in vivo imaging marker of MA following stroke. The finding of statistically significant increases in 11C-PK11195 as early as 48h after stroke is novel. These results have implications for mapping MA after stroke, with potential therapeutic applications. ► Microglia activation (MA) has both neurotoxic and prorepair effects after stroke. ► Does the regional distribution of 11C-PK11195 correlate with in vitro MA post stroke? ► In rats we found significant correlation between Day 14 11C-PK11195 and OX42 staining. ► Statistically significant 11C-PK11195 binding increases were also present at Day 2. ► These results further validate the use of 11C-PK11195 PET for MA imaging after stroke.