Quantitative Brain Positron Emission Tomography in Female 5XFAD Alzheimer Mice: Pathological Features and Sex-Specific Alterations.

Caroline Bouter,Timon N Franke,Yvonne Bouter,Caroline Irwin,Nicola Beindorff

doi:10.3389/fmed.2021.745064

Caroline Bouter, Timon N Franke + Show 3 more

Open Access

https://doi.org/10.3389/fmed.2021.745064

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Abstract

Successful back-translating clinical biomarkers and molecular imaging methods of Alzheimer's disease (AD), including positron emission tomography (PET), are very valuable for the evaluation of new therapeutic strategies and increase the quality of preclinical studies. 18F-Fluorodeoxyglucose (FDG)–PET and 18F-Florbetaben–PET are clinically established biomarkers capturing two key pathological features of AD. However, the suitability of 18F-FDG– and amyloid–PET in the widely used 5XFAD mouse model of AD is still unclear. Furthermore, only data on male 5XFAD mice have been published so far, whereas studies in female mice and possible sex differences in 18F-FDG and 18F-Florbetaben uptake are missing. The aim of this study was to evaluate the suitability of 18F-FDG– and 18F-Florbetaben–PET in 7-month-old female 5XFAD and to assess possible sex differences between male and female 5XFAD mice. We could demonstrate that female 5XFAD mice showed a significant reduction in brain glucose metabolism and increased cerebral amyloid deposition compared with wild type animals, in accordance with the pathology seen in AD patients. Furthermore, we showed for the first time that the hypometabolism in 5XFAD mice is gender-dependent and more pronounced in female mice. Therefore, these results support the feasibility of small animal PET imaging with 18F-FDG- and 18F-Florbetaben in 5XFAD mice in both, male and female animals. Moreover, our findings highlight the need to account for sex differences in studies working with 5XFAD mice.

Highlights

Alzheimer’s disease (AD), the most common form of dementia, affects more than 40 million people worldwide and is characterized by the decline of cognitive abilities and progressive memory loss [1]
Seven-month-old female 5XFAD and age- and sex-matched wild type (WT) mice were scanned with 18F-FDG-positron emission tomography (PET) to determine cerebral glucose metabolism in vivo. 18F-FDG uptake was measured in the whole brain volumes of interest (VOI), and several brain region VOIs and glucose correction were performed (Figures 1A–L). 18F-FDG uptake was detected in the brain of all mice and regular extracranial uptake within Harderian glands, myocardium, brown adipose tissue, intestines, kidneys, and the urinary bladder
Seven-month-old female 5XFAD mice showed significantly lower 18F-FDG uptake in the whole brain compared with WT mice (Figure 1M, unpaired t-test: p = 0.0015)

Summary

Introduction

Alzheimer’s disease (AD), the most common form of dementia, affects more than 40 million people worldwide and is characterized by the decline of cognitive abilities and progressive memory loss [1]. To establish new treatments for AD, both preclinical models of the disease as well as reliable in vivo biomarkers are essential. Clinical biomarkers include measurement of Abeta and (phosphorylated) tau in cerebrospinal fluid, and MRI and molecular imaging with positron emission tomography (PET). 18F-Fluorodeoxyglucose (FDG)–PET and 18F-Florbetaben– PET are clinically established biomarkers for the diagnosis of AD capturing two key pathological features of the disease [5, 6]. Successful back-translating clinical biomarkers and molecular imaging methods of AD, including PET, is very valuable for the evaluation of new therapeutic strategies and to increase the quality of preclinical studies. While PET is an established tool in the assessment of AD patients, its role in preclinical studies using AD mouse models remains unclear

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