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. 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 6-7 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.

• Authors: Steven Deleye, Ann-Marie Waldron, Jeroen Verhaeghe, Astrid Bottelbergs, Leonie Wyffels, Bianca Van Broeck, Xavier Langlois, Mark Schmidt, Sigrid Stroobants, Steven Staelens
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 58 Issue 12 Pg. 1977-1983 (12 2017) ISSN: 1535-5667 [Electronic] United States
• PMID: 28611242 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Chemical References

• Amyloid beta-Peptides
• Aniline Compounds
• Enzyme Inhibitors
• Ethylene Glycols
• Radiopharmaceuticals
• Fluorodeoxyglucose F18
• florbetapir
• Amyloid Precursor Protein Secretases
• Aspartic Acid Endopeptidases
• BACE1 protein, human

Topics

• Aging
• Alzheimer Disease (diagnostic imaging, drug therapy, pathology)
• Amyloid Neuropathies (pathology)
• Amyloid Precursor Protein Secretases (antagonists & inhibitors)
• Amyloid beta-Peptides (metabolism)
• Aniline Compounds
• Animals
• Aspartic Acid Endopeptidases (antagonists & inhibitors)
• Brain (diagnostic imaging, pathology)
• Brain Chemistry
• Enzyme Inhibitors (therapeutic use)
• Ethylene Glycols
• Fluorodeoxyglucose F18
• Humans
• Inflammation (pathology)
• Mice
• Mice, Transgenic
• Positron-Emission Tomography
• Radiopharmaceuticals
• Treatment Outcome