Time Courses of Cortical Glucose Metabolism and Microglial Activity Across the Life Span of Wild-Type Mice: A PET Study

Abstract

Contrary to findings in the human brain, ¹⁸F-FDG PET shows cerebral hypermetabolism of aged wild-type (WT) mice relative to younger animals, supposedly due to microglial activation. Therefore, we used dual-tracer small-animal PET to examine directly the link between neuroinflammation and hypermetabolism in aged mice. <b>Methods:</b> WT mice (5-20 mo) were investigated in a cross-sectional design using ¹⁸F-FDG (<i>n</i> = 43) and translocator protein (TSPO) (¹⁸F-GE180; <i>n</i> = 58) small-animal PET, with volume-of-interest and voxelwise analyses. Biochemical analysis of plasma cytokine levels and immunohistochemical confirmation of microglial activity were also performed. <b>Results:</b> Age-dependent cortical hypermetabolism in WT mice relative to young animals aged 5 mo peaked at 14.5 mo (+16%, <i>P</i> < 0.001) and declined to baseline at 20 mo. Similarly, cortical TSPO binding increased to a maximum at 14.5 mo (+15%, <i>P</i> < 0.001) and remained high to 20 mo, resulting in an overall correlation between ¹⁸F-FDG uptake and TSPO binding (R = 0.69, <i>P</i> < 0.005). Biochemical and immunohistochemical analyses confirmed the TSPO small-animal PET findings. <b>Conclusion:</b> Age-dependent neuroinflammation is associated with the controversial observation of cerebral hypermetabolism in aging WT mice.