The first Third-generation Alzheimer mouse, PLB1: An 18F-FDG-PET study

Background: Recent advances in small animal PET scanners have enabled the use of this technique to study the functional changes in a range of disorders, including neurodegenerative disease. Here, we used a newly generated triple knock-in Alzheimer mouse, PLB1triple (containing mutated human APPswe&lon, tau, and PSEN, see accompanying contributions). PLB1 mice do not show sensory-motor deficits at 14 months, but present with behavioural and electrophysiological alterations from 5-6 months of age. The aim of the present study was to investigate correlations between in vivo imaging and their behavioural phenotype, and establish whether PET can be used as a sensitive, non-invasive and translational procedure to identify degenerative processes. Methods: After 18F-FDG uptake was optimised in wild type animals, PET scans were conducted in 5-6 (triple n = 9; wild type n = 7) and 15-17 (triple n = 4; wild type n = 9) months old animals (male and female). PET scans were obtained using a GE Healthcare eXplore VISTA dual ring PET/CT scanner with a ring diameter of 11.8 cm and a 4.8 cm axial field of view (FOV). Images were reconstructed using Fourier Rebinning and a 2D OSEM algorithm to produce 3D volumes of 175x175x61 voxels with dimensions of 0.39x0.39x0.78 mm. Reconstructed resolution was 1.4 mm at the centre of the field of view. Reconstructed PET images were registered to the Digimouse atlas using the CT images as an intermediate step and normalised using the total counts in the cerebellum. Finally, statistical parametric maps were produced showing regions with statistically significant differences in uptake between the groups. Results: Forebrain regions with statistically significant (uncorrected p < 0.05) differences in glucose metabolic demand (known to correlate with neuronal activation) were identified between the various groups. In particular, hippocampal regions with reduced metabolic demand were identified when comparing older to younger animals and when comparing transgenic animals with wild types. Conclusions: We here shown that 18F-FDG-PET can be used to identify changes in glucose metabolic demand in mouse models of neurodegenerative disease, likely to correspond to impaired neuronal function. Thus, 18F-FDG-PET imaging presents a sensitive non-invasive, and translational procedure that allows longitudinal preclinical studies.