In Vivo Detection of Age- and Disease-Related Increases in Neuroinflammation by F-18-GE180 TSPO MicroPET Imaging in Wild-Type and Alzheimer's Transgenic Mice

摘要

Alzheimer's disease (AD) is the most common cause of dementia. Neuroinflammation appears to play an important role in AD pathogenesis. Ligands of the 18 kDa translocator protein (TSPO), a marker for activated microglia, have been used as positron emission tomography (PET) tracers to reflect neuroinflammation in humans and mouse models. Here, we used the novel TSPO-targeted PET tracer F-18-GE180 (flutriciclamide) to investigate differences in neuroinflammation between young and old WT and APP/PS1dE9 transgenic (Tg) mice. In vivo PET scans revealed an overt age-dependent elevation in whole-brain uptake of F-18-GE180 in bothWTand Tg mice, and a significant increase in whole-brain uptake of F-18-GE180 (peak-uptake and retention) in old Tg mice compared with young Tg mice and all WT mice. Similarly, the F-18-GE180 binding potential in hippocampus was highest to lowest in old Tg > old WT > young Tg > young WT mice using MRI coregistration. Ex vivo PET and autoradiography analysis further confirmed our in vivo PET results: enhanced uptake and specific binding (SUV75%) of F-18-GE180 in hippocampus and cortex was highest in old Tg mice followed by old WT, young Tg, and finally youngWTmice. F-18-GE180 specificity was confirmed by an in vivo cold tracer competition study. Wealso examined F-18-GE180 metabolites in 4-month-oldWTmice and found that, although total radioactivity declined over 2 h, of the remaining radioactivity, similar to 90% was due to parent F-18-GE180. In conclusion, F-18-GE180 PET scans may be useful for longitudinal monitoring of neuroinflammation during AD progression and treatment.