PT  - JOURNAL ARTICLE
AU  - Christian Sacher
AU  - Tanja Blume
AU  - Leonie Beyer
AU  - Finn Peters
AU  - Florian Eckenweber
AU  - Carmelo Sgobio
AU  - Maximilian Deussing
AU  - Nathalie L. Albert
AU  - Marcus Unterrainer
AU  - Simon Lindner
AU  - Franz-Josef Gildehaus
AU  - Barbara von Ungern-Sternberg
AU  - Irena Brzak
AU  - Ulf Neumann
AU  - Takashi Saito
AU  - Takaomi C. Saido
AU  - Peter Bartenstein
AU  - Axel Rominger
AU  - Jochen Herms
AU  - Matthias Brendel
TI  - Longitudinal PET Monitoring of Amyloidosis and Microglial Activation in a Second-Generation Amyloid-β Mouse Model
AID  - 10.2967/jnumed.119.227322
DP  - 2019 Dec 01
TA  - Journal of Nuclear Medicine
PG  - 1787--1793
VI  - 60
IP  - 12
4099  - http://jnm.snmjournals.org/content/60/12/1787.short
4100  - http://jnm.snmjournals.org/content/60/12/1787.full
SO  - J Nucl Med2019 Dec 01; 60
AB  - Nonphysiologic overexpression of amyloid-β (Aβ) precursor protein in common transgenic Aβ mouse models of Alzheimer disease likely hampers their translational potential. The novel AppNL-G-F mouse incorporates a mutated knock-in, potentially presenting an improved model of Alzheimer disease for Aβ-targeting treatment trials. We aimed to establish serial small-animal PET of amyloidosis and neuroinflammation in AppNL-G-F mice as a tool for therapy monitoring. Methods: AppNL-G-F mice (20 homozygous and 21 heterogeneous) and 12 age-matched wild-type mice were investigated longitudinally from 2.5 to 10 mo of age with 18F-florbetaben Aβ PET and 18F-GE-180 18-kDa translocator protein (TSPO) PET. Voxelwise analysis of SUV ratio images was performed using statistical parametric mapping. All mice underwent a Morris water maze test of spatial learning after their final scan. Quantification of fibrillar Aβ and activated microglia by immunohistochemistry and biochemistry served for validation of the PET results. Results: The periaqueductal gray emerged as a suitable pseudo reference tissue for both tracers. Homozygous AppNL-G-F mice had a rising SUV ratio in cortex and hippocampus for Aβ (+9.1%, +3.8%) and TSPO (+19.8%, +14.2%) PET from 2.5 to 10 mo of age (all P < 0.05), whereas heterozygous AppNL-G-F mice did not show significant changes with age. Significant voxelwise clusters of Aβ deposition and microglial activation in homozygous mice appeared at 5 mo of age. Immunohistochemical and biochemical findings correlated strongly with the PET data. Water maze escape latency was significantly elevated in homozygous AppNL-G-F mice compared with wild-type at 10 mo of age and was associated with high TSPO binding. Conclusion: Longitudinal PET in AppNL-G-F knock-in mice enables monitoring of amyloidogenesis and neuroinflammation in homozygous mice but is insensitive to minor changes in heterozygous animals. The combination of PET with behavioral tasks in AppNL-G-F treatment trials is poised to provide important insights in preclinical drug development.