Glial Activation and Glucose Metabolism in a Transgenic Amyloid Mouse Model: A Triple Tracer PET Study

Abstract

Amyloid imaging by small animal PET (µPET) in models of Alzheimer’s disease (AD) offers the possibility to track amyloidogenesis and brain energy metabolism. Since microglial activation is thought to contribute to AD pathology, we undertook a triple tracer µPET study to assess microglia activation and glucose metabolism in association with amyloid plaque load in a transgenic AD mouse model. Methods: Groups of PS2APP and C57Bl/6 wild-type (WT) mice of various ages were examined by µPET. We acquired 90 min dynamic emission data with ¹⁸F-GE180 for imaging activated microglia (18kD translocator protein ligand, TSPO), and static 30-60 min recordings with ¹⁸F-FDG for energy metabolism and ¹⁸F-florbetaben for amyloidosis. Optimal fusion of PET data was obtained through automatic non-linear spatial normalization, and standardized-uptake-value-ratios (SUVR) were calculated. For the novel TSPO tracer ¹⁸F-GE180, we then calculated distribution volume ratios (DVR) after establishing a suitable reference region. Immunohistochemical analyses with TSPO antisera, methoxy-X04 staining for fibrillary β-amyloid, and ex vivo autoradiography served as terminal gold standard assessments. Results: SUVR at 60-90 min p.i. gave robust quantitation of ¹⁸F-GE180, which correlated well with DVR calculated from the entire recording, and using a white matter reference region. Relative to age-matched WT, ¹⁸F-GE180 SUVR was slightly elevated in PS2APP mice at five months (+9%; p<0.01), and distinctly increased at 16 months (+25%; p<0.001). Over this age range, there was high positive correlation between µPET findings of microglial activation with amyloid load (R=0.85; p<0.001), and likewise with metabolism (R=0.61; p<0.005). Immunohistochemical and autoradiographic findings confirmed the in vivo µPET data. Conclusion: In this first triple tracer µPET in a well-established AD mouse model, we find evidence for age-dependent microglia activation. This activation, correlating positively with the amyloid-load, implies a relationship between amyloidosis and inflammation in the PS2APP AD mouse model.