Abstract
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Objectives Microglial activation is a key molecular process observed in Alzheimer’s disease (AD), however its exact role in AD is unknown. Positron emission tomography (PET) imaging of translocator protein 18 kDa (TSPO), a biomarker of microglial activation, could enhance our understanding of the in vivo role of microglia in AD, and might serve as a marker of AD progression and treatment response. We aim to evaluate a TSPO-specific radioligand [18F]PBR06 for visualizing alterations in TSPO and microglial activation in a transgenic mouse model of AD, Thy1-hAPPLond/Swe (APPL/S).
Methods Two cohorts of mice containing APPL/S (n=6-12) and wild-type (wt) littermates (n=6-12) underwent [18F]PBR06-PET/CT imaging at either 5-6 and 9-10 months or 14-15 and 15-16 months of age. 7T-MR images were fused with PET/CT data (attenuation corrected) to quantify [18F]PBR06 uptake in hippocampus (H) and cortex (Ctx). Brain sections from mice (15-16 mo) were analyzed via digital autoradiography (ARG) and immunostaining (CD68, ThioS, TSPO).
Results [18F]PBR06 was synthesized (RCY=2.2±1.0% at EOB) with SA ~3 Ci/μmol (n=7). Brain [18F]PBR06 signal was significantly higher in APPL/S mice compared to wts ≥14-15 months (1.36 ±0.06 vs 1.06 ±0.10 %ID/g, p<0.05). No significant difference was found between mice ≤9-10 months (p = 0.49). Analysis of brain regions known to contain increasing levels of microglial activation in AD revealed an even greater difference in [18F]PBR06 signal between APPL/S and wts ≥14-15 months (Ctx: 1.37±0.04 vs 0.88±0.10 %ID/g, p<0.005; H: 1.43±0.07 vs 0.93±0.10 %ID/g, p<0.005). ARG and PET results correlated well with immunostaining - i.e., increased [18F]PBR06 uptake in brain regions containing elevated CD68, ThioS, and TSPO staining in APPL/S compared to wt mice.
Conclusions [18F]PBR06-multimodality imaging shows great potential as a tool for investigating the in vivo role of microglia in the progression and treatment of AD.