Longitudinal amyloid imaging in mouse brain with 11C-PIB: Comparison of APP23, Tg2576, and APPswe-PS1dE9 mouse models of Alzheimer disease

Follow-up of b-amyloid (Aβ) deposition in transgenic mouse models of Alzheimer disease (AD) would be a valuable translational tool in the preclinical evaluation of potential antiamyloid therapies. This study aimed to evaluate the ability of the clinically used PET tracer ¹¹C-Pittsburgh compound B (¹¹C-PIB) to detect changes over time in Ab deposition in the brains of living mice representing the APP23, Tg2576, and APP_swe-PS1 _dE9 transgenic mouse models of AD. Methods: Mice from each transgenic strain were imaged with 60-min dynamic PET scans at 729, 12, 15, and 18222 mo of age. Regional ¹¹C-PIB retention was quantitated as distribution volume ratios using Logan graphical analysis with cerebellar reference input, as radioactivity uptake ratios between the frontal cortex (FC) and the cerebellum (CB) during the 60-min scan, and as bound-tofree ratios in the late washout phase (40260 min). Ex vivo autoradiography experiments were performed after the final imaging session to validate ¹¹C-PIB binding to Ab deposits. Additionally, the presence of Ab deposits was evaluated in vitro using staining with thioflavin-S and Aβ_1-40, Aβ_1-16, and Aβ_N3(pE) immunohistochemistry. Results: Neocortical ¹¹C-PIB retention was markedly increased in old APP23 mice with large thioflavin-S-positive Ab deposits. At 12 mo, the Logan distribution volume ratio for the FC was 1.03 and 0.93 (n = 2), increasing to 1.38 6 0.03 (n = 3) and 1.34 (n = 1) at 18 and 21 mo of age, respectively. An increase was also observed in bound-to-free ratios for the FC between young (7- to 12-mo-old) and old (15- to 22-mo-old) APP23 mice. Binding of ¹¹C-PIB to Ab-rich cortical regions was also evident in ex vivo autoradiograms of APP23 brain sections. In contrast, no increases in ¹¹C-PIB retention were observed in aging Tg2576 or APP_swe-PS1_dE9 mice in vivo, although in the latter, extensive Ab deposition was already observed at 9 mo of age with immunohistochemistry. Conclusion: The results suggest that ¹¹C-PIB binding to Ab deposits in transgenic mouse brain is highly dependent on the AD model and the structure of its Ab plaques. Longitudinal in vivo ¹¹C-PIB uptake studies are possible in APP23 mice. COPYRIGHT