In vivo Imaging With 18F-FDG- and 18F-Florbetaben-PET/MRI Detects Pathological Changes in the Brain of the Commonly Used 5XFAD Mouse Model of Alzheimer's Disease

Abstract

Imaging biomarkers of Alzheimer's disease (AD) that are able to detect molecular changes in vivo and transgenic animal models mimicking AD pathologies are essential for the evaluation of new therapeutic strategies. Positron-emission tomography (PET) using either 18 F-Fluorodeoxyglucose (18 F-FDG) or amyloid-tracers is a well-established, non-invasive tool in the clinical diagnostics of AD assessing two major pathological hallmarks. 18 F-FDG-PET is able to detect early changes in cerebral glucose metabolism and amyloid-PET shows cerebral amyloid load. However, the suitability of 18 F-FDGand amyloid-PET in the widely used 5XFAD mouse model of AD is unclear as only a few studies on the use of PET biomarkers are available showing some conflicting results. The aim of this study was the evaluation of 18 F-FDG-PET and amyloid-PET in 5XFAD mice in comparison to neurological deficits and neuropathological changes. Seven-and 12-month-old male 5XFAD mice showed a significant reduction in brain glucose metabolism in 18 F-FDG-PET and amyloid-PET with 18 F-Florbetaben demonstrated an increased cerebral amyloid deposition (n = 4-6 per group). Deficits in spatial reference memory were detected in 12-month-old 5XFAD mice in the Morris Water Maze (n = 10-12 per group). Furthermore, an increased plaque load and gliosis could be proven immunohistochemically in 5XFAD mice (n = 4-6 per group). PET biomarkers 18 F-FDG and 18 F-Florbetaben detected cerebral hypometabolism and increased plaque load even before the onset of severe memory deficits. Therefore, the 5XFAD mouse model of AD is well-suited for in vivo monitoring of AD pathologies and longitudinal testing of new therapeutic approaches.

Comprehensive Evaluation of the 5XFAD Mouse Model for Preclinical Testing Applications: A MODEL-AD Study

“…Our [18F]-AV45 data are consistent with previous in vivo imaging studies in 5XFAD mice that looked at amyloid using a different tracer (18F-Florbetaben) and observed agedependent increases in amyloid (Jankowsky and Zheng, 2017;Franke et al, 2020). This study also observed alterations in brain glucose metabolism and amyloid deposition prior to the onset of behavioral changes (Franke et al, 2020). Although previous studies detected cerebral hypometabolism (Franke et al, 2020), the methods for quantification, ROI and ages of animals were different in the present study.…”

“…Specifically, PET using [18F]-FDG and PET with [18F]-AV45 revealed significant uptake at all ages in both male and female mice (Figures 6, 7), demonstrating that [18F]-AV45 PET/MRI is feasible for quantifying Aβ in this model but should be confirmed with additional methods (Jankowsky and Zheng, 2017). Our [18F]-AV45 data are consistent with previous in vivo imaging studies in 5XFAD mice that looked at amyloid using a different tracer (18F-Florbetaben) and observed agedependent increases in amyloid (Jankowsky and Zheng, 2017;Franke et al, 2020). This study also observed alterations in brain glucose metabolism and amyloid deposition prior to the onset of behavioral changes (Franke et al, 2020).…”

“…This study also observed alterations in brain glucose metabolism and amyloid deposition prior to the onset of behavioral changes (Franke et al, 2020). Although previous studies detected cerebral hypometabolism (Franke et al, 2020), the methods for quantification, ROI and ages of animals were different in the present study. In addition, the animals in the present study did not undergo behavioral studies to monitor cognitive changes and PET imaging alterations.…”

“…In addition to sex-based differences and gene expression changes, 5XFAD mice were also confirmed to express several features of AD pathology, demonstrating the model as useful for studies relying on the use of brain imaging and Aββ quantification strategies (Girard et al, 2013;Spencer et al, 2013;Macdonald et al, 2014;Tang et al, 2016;Kesler et al, 2018;Nie et al, 2019;Franke et al, 2020;Chang et al, 2021). Specifically, PET using [18F]-FDG and PET with [18F]-AV45 revealed significant uptake at all ages in both male and female mice (Figures 6, 7), demonstrating that [18F]-AV45 PET/MRI is feasible for quantifying Aβ in this model but should be confirmed with additional methods (Jankowsky and Zheng, 2017).…”

“…To understand regional amyloid deposition (Figure 6) and glycolysis (Figure 7), we performed in vivo PET imaging using the [18F] tracers, AV45 and FDG, respectively, similar to what has been done previously in the field (Girard et al, 2013;Tang et al, 2016;Franke et al, 2020;Chang et al, 2021). Amyloid deposition can be observed as early as 4 months in regions involved in emotion and memory (orbital cortex, parietal association cortices), as well as the thalamus and motor cortex using PET (Figure 6A).…”