@article {Deleye1977, author = {Steven Deleye and Ann-Marie Waldron and Jeroen Verhaeghe and Astrid Bottelbergs and Leonie Wyffels and Bianca Van Broeck and Xavier Langlois and Mark Schmidt and Sigrid Stroobants and Steven Staelens}, title = {Evaluation of Small-Animal PET Outcome Measures to Detect Disease Modification Induced by BACE Inhibition in a Transgenic Mouse Model of Alzheimer Disease}, volume = {58}, number = {12}, pages = {1977--1983}, year = {2017}, doi = {10.2967/jnumed.116.187625}, publisher = {Society of Nuclear Medicine}, abstract = {In this study, we investigated the effects of chronic administration of an inhibitor of the β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) on Alzheimer-related pathology by multitracer PET imaging in transgenic APPPS1-21 (TG) mice. Methods: Wild-type (WT) and TG mice received vehicle or BACE inhibitor (60 mg/kg) starting at 7 wk of age. Outcome measures of brain metabolism, neuroinflammation, and amyloid-β pathology were obtained through small-animal PET imaging with 18F-FDG, 18F-peripheral benzodiazepine receptor (18F-PBR), and 18F-florbetapir (18F-AV45), respectively. Baseline scans were acquired at 6{\textendash}7 wk of age and follow-up scans at 4, 7, and 12 mo. 18F-AV45 uptake was measured at 8 and 13 mo of age. After the final scans, histologic measures of amyloid-β (4G8), microglia (ionized calcium binding adaptor molecule 1), astrocytes (glial fibrillary acidic protein), and neuronal nuclei were performed. Results: TG mice demonstrated significant age-associated increases in 18F-AV45 uptake. An effect of treatment was observed in the cortex (P = 0.0014), hippocampus (P = 0.0005), and thalamus (P \< 0.0001). Histology confirmed reduction of amyloid-β pathology in TG-BACE mice. Regardless of treatment, TG mice demonstrated significantly lower 18F-FDG uptake than WT mice in the thalamus (P = 0.0004) and hippocampus (P = 0.0332). Neuronal nucleus staining was lower in both TG groups in the thalamus and cortex. 18F-PBR111 detected a significant age-related increase in TG mice (P \< 0.0001) but did not detect the treatment-induced reduction in activated microglia as demonstrated by histology. Conclusion: Although 18F-FDG, 18F-PBR111, and 18F-AV45 all detected pathologic alterations between TG and WT mice, only 18F-AV45 could detect an effect of BACE inhibitor treatment. However, changes in WT binding of 18F-AV45 undermine the specificity of this effect.}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/58/12/1977}, eprint = {https://jnm.snmjournals.org/content/58/12/1977.full.pdf}, journal = {Journal of Nuclear Medicine} }