RESUMO
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.
RESUMO
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 18F-Fluorodeoxyglucose (18F-FDG) or amyloid-tracers is a well-established, non-invasive tool in the clinical diagnostics of AD assessing two major pathological hallmarks. 18F-FDG-PET is able to detect early changes in cerebral glucose metabolism and amyloid-PET shows cerebral amyloid load. However, the suitability of 18F-FDG- and 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 18F-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 18F-FDG-PET and amyloid-PET with 18F-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 18F-FDG and 18F-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.
RESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia. Hallmarks of AD are memory impairments and cognitive deficits, but non-cognitive impairments, especially motor dysfunctions are also associated with the disease and may even precede classic clinical symptoms. With an aging society and increasing hospitalization of the elderly, motor deficits are of major interest to improve independent activities in daily living. Consistent with clinical findings, a variety of AD mouse models develop motor deficits as well. We investigated the motor function of 3- and 7-month-old Tg4-42 mice in comparison to wild-type controls and 5XFAD mice and discuss the results in context with several other AD mouse model. Our study shows impaired balance and motor coordination in aged Tg4-42 mice in the balance beam and rotarod test, while general locomotor activity and muscle strength is not impaired at 7 months. The cerebellum is a major player in the regulation and coordination of balance and locomotion through practice. Particularly, the rotarod test is able to detect cerebellar deficits. Furthermore, supposed cerebellar impairment was verified by 18F-FDG PET/MRI. Aged Tg4-42 mice showed reduced cerebellar glucose metabolism in the 18F-FDG PET. Suggesting that, deficits in coordination and balance are most likely due to cerebellar impairment. In conclusion, Tg4-42 mice develop motor deficits before memory deficits, without confounding memory test. Thus, making the Tg4-42 mouse model a good model to study the effects on cognitive decline of therapies targeting motor impairments.
RESUMO
The evaluation of new therapeutic strategies in Alzheimer's disease (AD) relies heavily on in vivo imaging and suitable animal models that mimic the pathological changes seen in patients. 18F-Fluorodeoxyglucose (18F-FDG)-positron-emission tomography (PET) is a well-established non-invasive imaging tool for monitoring changes in cerebral brain glucose metabolism in vivo. 18F-FDG-PET is used as a functional biomarker for AD as patients show an early and progressive reduction of cerebral glucose metabolism. However, earlier studies in preclinical models of AD showed conflicting results. The aim of this study was the evaluation of cerebral glucose metabolism in the Tg4-42 mouse model of AD using 18F-FDG-PET/magnetic resonance imaging (MRI). Tg4-42 mice show an age-dependent reduction in glucose metabolism together with severe neuron loss and memory deficits. Similar to AD patients early decrease in 18F-FDG uptake was already detected in young (3 months) Tg4-42 mice. The altered glucose metabolism coupled with age- and disease related cognitive decline of Tg4-42 mice make it a well-suited model for preclinical testing of AD-relevant therapeutics.
