Cross-sectional Comparison of Small Animal [18F]-Florbetaben Amyloid-PET Between Transgenic AD Mouse Models

Abstract

PET imaging of cerebral β-amyloid in small animal models of Alzheimer’s disease (AD) now offers the possibility of experimental treatment monitoring in vivo. However, there is no consensus concerning the optimal transgenic mouse model or choice of β-amyloid radiotracers. Therefore, we aimed to compare cross-sectional PET findings in four established AD models using the previously evaluated β-amyloid ligand [18F]-florbetaben (FBB). In addition, we carried out further validation of our partial volume effect correction (PVEC) for FBB in mouse brain. We investigated a total of 20 mice using a standardized FBB PET protocol: APPswe/PS2 (N = 5; 8, 12 and 19 mo), APPswe/PS1dE9 (N = 4; 12 and 24 mo), APPswe/PS1G384A (N = 3; 5 and 16 mo), and C57Bl/6 controls (WT) at a range of ages (N = 8; 6 - 22 mo), and used historical data from APPswe (N = 10; 13 - 20 mo). For each mouse, we calculated volume-of-interest (VOI)-based cortical standard-uptake-value-ratios (SUVR) and applied PVEC. We carried out hemispheric autoradiography ex vivo for comparison with PET results in representative mice, and carried out histological analysis of β-amyloid using methoxy-X04 staining in all 20 mice. Compared to WT (SUVR: 0.95), APPswe/PS2 animals had elevated SUVR (1.03) at eight mo, with further increases to 1.17 at 12 mo and 1.31 at 19 mo. APPswe/PS1G384A mice had normal SUVR (0.95) at 5 mo which increased to 1.11 at 16 mo, a result comparable to our earlier SUVR finding (1.12) in APPswe mice at 20 mo. The SUVR for APPswe/PS1dE9 mice declined from 0.96 to 0.91 at 24 mo due to increasing cerebellar plaque load. PVEC reduced discrepancies between SUVR-PET and autoradiography, such that corrected SUVR was as high as 1.89 in 19 mo APPswe/PS2 mice. There was for all transgenic strains a high correlation between SUVR and histology (R = 0.94, p < 0.001). APPswe/PS2 and APPswe/PS1G384A mice seemed superior to APPswe mice for longitudinal imaging due to earlier onset of amyloidosis. The cerebellar labelling in APPswe/PS1dE9 mice interferes with quantitation by SUVR. PVEC improved accuracy of PET results relative to autoradiographic gold standard