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

Abstract

Amyloid imaging by small-animal PET in models of Alzheimer disease (AD) offers the possibility to track amyloidogenesis and brain energy metabolism. Because microglial activation is thought to contribute to AD pathology, we undertook a triple-tracer smallanimal PET study to assess microglial activation and glucose metabolism in association with amyloid plaque load in a transgenic AD mouse model. Methods: Groups of PS2APP and C57BL/6 wildtype mice of various ages were examined by small-animal PET. We acquired 90-min dynamic emission data with 18 F-GE180 for imaging activated microglia (18-kD translocator protein ligand [TSPO]) and static 30-to 60-min recordings with 18 F-FDG for energy metabolism and 18 F-florbetaben for amyloidosis. Optimal fusion of PET data was obtained through automatic nonlinear spatial normalization, and SUVRs were calculated. For the novel TSPO tracer 18 F-GE180, we then calculated distribution volume ratios 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 after injection gave robust quantitation of 18 F-GE180, which correlated well with distribution volume ratios calculated from the entire recording and using a white matter reference region. Relative to age-matched wild-type, 18 F-GE180 SUVR was slightly elevated in PS2APP mice at 5 mo (19%; P , 0.01) and distinctly increased at 16 mo (125%; P , 0.001). Over this age range, there was a high positive correlation between small-animal PET findings of microglial activation with amyloid load (R 5 0.85; P , 0.001) and likewise with metabolism (R 5 0.61; P , 0.005). Immunohistochemical and autoradiographic findings confirmed the in vivo small-animal PET data. Conclusion: In this first triple-tracer small-animal PET in a well-established AD mouse model, we found evidence for age-dependent microglial activation. This activation, correlating positively with the amyloid load, implies a relationship between amyloidosis and inflammation in the PS2APP AD mouse model.

The FTD‐like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism

“…In line with previous results Brendel et al, 2016), we found an agedependent increase in TSPO lPET signal in wild-type mice (Fig 5A and B). To do so, we conducted a longitudinal study (3, 5, 8, and 12 months) using the PET tracer [ 18 ]F-GE180 (18-kD translocator protein ligand [TSPO]) for imaging activated microglia in vivo by lPET.…”

Brain and Brown Adipose Tissue Metabolism in Transgenic Tg2576 Mice Models of Alzheimer Disease Assessed Using 18F-FDG PET Imaging

“…28-31 These studies observed increases in 18 F-FDG at younger ages, while in older mice either there were no changes compared to WT or there were increases. The 5-time familial AD (5×FAD) mouse model exhibit increases at younger ages, but there were decreases of 18 F-FDG uptake at ages older than 13 months.…”

Evaluation of Small-Animal PET Outcome Measures to Detect Disease Modification Induced by BACE Inhibition in a Transgenic Mouse Model of Alzheimer Disease

“…Moreover, 18 F-FDG imaging detected age-dependent decreases in the tauopathy mouse model tauVLW (37) and thus may be more applicable in models with tau pathology. Because activated glial cells also take up 18 have demonstrated age-related increases in PS2APP, APPPS1-d9, 5xFAD, and TG mouse models (33,39). Additionally, chronic BACE inhibitor treatment (NB-360) has previously been shown to reduce glial cells in APP51/16 mice (12), and thus we herein evaluated the ability of 18 F-PBR111 to detect changes in neuroinflammation in response to disease and treatment.…”