Longitudinal Assessment of Cerebral β-Amyloid Deposition in Mice Overexpressing Swedish Mutant β-Amyloid Precursor Protein Using ¹⁸F-Florbetaben PET

Abstract

The progression of b-amyloid deposition in the brains of mice overexpressing Swedish mutant b-amyloid precursor protein (APPSwe), a model of Alzheimer disease (AD), was investigated in a longitudinal PET study using the novel b-amyloid tracer 18 Fflorbetaben. Methods: Groups of APP-Swe and age-matched wild-type (WT) mice (age range, 10-20 mo) were investigated. Dynamic emission recordings were acquired with a small-animal PET scanner during 90 min after the administration of 18 F-florbetaben (9 MBq, intravenously). After spatial normalization of individual PET recordings to common coordinates for mouse brain, binding potentials (BP ND ) and standardized uptake value ratios (SUVRs) were calculated relative to the cerebellum. Voxelwise analyses were performed using statistical parametric mapping (SPM). Histochemical analyses and ex vivo autoradiography were ultimately performed in a subset of animals as a gold standard assessment of b-amyloid plaque load. Results: SUVRs calculated from static recordings during the interval of 30-60 min after tracer injection correlated highly with estimates of BP ND based on the entire dynamic emission recordings. 18 F-florbetaben binding did not significantly differ in APP-Swe mice and WT animals at 10 and 13 mo of age. At 16 mo of age, the APP-Swe mice had a significant 7.9% increase (P , 0.01) in cortical 18 F-florbetaben uptake above baseline and at 20 mo there was a 16.6% increase (P , 0.001), whereas WT mice did not show any temporal changes in tracer uptake during the interval of follow-up. Voxelwise SPM analyses revealed the first signs of increased cortical binding at 13 mo and confirmed progressive binding increases in both the frontal and the temporal cortices (P , 0.001 uncorrected) to 20 mo. The SUVR strongly correlated with percentage plaque load (R 5 0.95, P , 0.001). Conclusion: In the first longitudinal PET study in an AD mouse model using the novel b-amyloid tracer 18 F-florbetaben, the temporal and spatial progression of amyloidogenesis in the brain of APP-Swe mice were sensitively monitored. This method should afford the means for preclinical testing of novel therapeutic approaches to the treatment of AD.

Glial Activation and Glucose Metabolism in a Transgenic Amyloid Mouse Model: A Triple-Tracer PET Study

“…18 F-florbetaben uptake and percentage plaque load (%) as assessed by methoxy-X04 histology had a high correlation finding (R 5 0.80; P , 0.001), as in our previous b-amyloid-PET studies (10,17). Both immunohistochemical staining methods indicated a progression of pathophysiology with age in a manner congruent with the PET data (Supplemental Fig.…”

“…Radiosynthesis of 18 F-florbetaben was performed as previously described (10). This procedure yielded a radiochemical purity exceeding 98% and a specific activity of 80 6 20 GBq/mmol at the end of synthesis.…”

“…Many aspects of the classic b-amyloid pathology are emulated in various transgenic rodent models for AD (6,7), and translational studies of these processes are facilitated by small-animal PET using radioligands for imaging of AD biomarkers in these rodent models (8). In particular, small-animal PET imaging of b-amyloid has been successfully established in the past few years (9,10). However, information regarding neuroinflammation in these models remains sparse and rather inconsistent (11)(12)(13).…”

Small-Animal PET Imaging of Tau Pathology with 18F-THK5117 in 2 Transgenic Mouse Models

“…For whole-brain voxelwise comparisons between groups of TG versus pooled WT mice, SPM was performed using SPM5 routines (Wellcome Department of Cognitive Neurology) implemented in MATLAB (version 7.1; MathWorks Inc.) (10). Individual SUV maps from TG mice were also compared with pooled WT mice to calculate for each mouse a voxelwise z score map expressing the divergence in SDs from the WT group.…”

“…Although b-amyloid small-animal PET in TG mice has been successfully established for preclinical in vivo imaging (9)(10)(11), there have been few reports on tau small-animal PET data in wild-type (WT) and TG mice (12,13). Successful molecular imaging with 18 F-fluorinated radiotracers of neurofibrillary tangle accumulation is a recent development (14); the 2-arylquinoline derivative 18 F-THK5117 has shown high affinity for neurofibrillary tangles in vitro and in brain sections from AD patients (13).…”