Evaluation of Small-Animal PET Outcome Measures to Detect Disease Modification Induced by BACE Inhibition in a Transgenic Mouse Model of Alzheimer Disease.

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. <b>Methods:</b> 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 6-7 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. <b>Results:</b> TG mice demonstrated significant age-associated increases in ¹⁸F-AV45 uptake. An effect of treatment was observed in the cortex (<i>P</i> = 0.0014), hippocampus (<i>P</i> = 0.0005), and thalamus (<i>P</i> < 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 (<i>P</i> = 0.0004) and hippocampus (<i>P</i> = 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 (<i>P</i> < 0.0001) but did not detect the treatment-induced reduction in activated microglia as demonstrated by histology. <b>Conclusion:</b> 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.