Abstract
In vivo imaging and quantification of amyloid-β plaque (Aβ) burden in small-animal models of Alzheimer's disease (AD) is a valuable tool for translational research such as developing specific imaging markers and monitoring new therapy approaches. Methodological constraints such as image resolution of positron emission tomography (PET) and lack of suitable AD models have limited the feasibility of PET in mice. In this study, we evaluated a feasible protocol for PET imaging of Aβ in mouse brain with [11C]PiB and specific activities commonly used in human studies. In vivo mouse brain MRI for anatomical reference was acquired with a clinical 1.5 T system. A recently characterized APP/PS1 mouse was employed to measure Aβ at different disease stages in homozygous and hemizygous animals. We performed multi-modal cross-validations for the PET results with ex vivo and in vitro methodologies, including regional brain biodistribution, multi-label digital autoradiography, protein quantification with ELISA, fluorescence microscopy, semi-automated histological quantification and radioligand binding assays. Specific [11C]PiB uptake in individual brain regions with Aβ deposition was demonstrated and validated in all animals of the study cohort including homozygous AD animals as young as nine months. Corresponding to the extent of Aβ pathology, old homozygous AD animals (21 months) showed the highest uptake followed by old hemizygous (23 months) and young homozygous mice (9 months). In all AD age groups the cerebellum was shown to be suitable as an intracerebral reference region. PET results were cross-validated and consistent with all applied ex vivo and in vitro methodologies. The results confirm that the experimental setup for non-invasive [11C]PiB imaging of Aβ in the APP/PS1 mice provides a feasible, reproducible and robust protocol for small-animal Aβ imaging. It allows longitudinal imaging studies with follow-up periods of approximately one and a half years and provides a foundation for translational Alzheimer neuroimaging in transgenic mice.
Highlights
Neuritic plaques containing amyloid-b plaque (Ab) and neurofibrillary tangles continue to define the neuropathological entity of Alzheimer’s disease (AD) and a definite diagnosis can still only be established post-mortem [1,2,3,4]
Visual inspection of co-registered positron emission tomography (PET)/MR images revealed distinct activity retention in the cortex of all transgenic mice corresponding to their study group, whereas for all control animals the cortex appeared to be free of specific activity uptake (Figure 1)
In transgenic mouse brain the activity uptake expanded throughout the entire cortex, with slightly stronger signal in frontal neocortical compared to hippocampal regions and a stronger signal in the thalamus
Summary
Neuritic plaques containing Ab and neurofibrillary tangles continue to define the neuropathological entity of AD and a definite diagnosis can still only be established post-mortem [1,2,3,4]. Ab plaque imaging with PET has entered the realm of the revised criteria for diagnosis of Alzheimer’s disease [6] and helps to further improve early and specific diagnosis and treatment monitoring [7]. Several radiolabeled compounds with high affinity and specificity for Ab aggregates have been developed [8,9,10,11,12,13,14,15,16,17,18,19]. Among these compounds, [11C]6-OH-BTA-1 ([11C]PiB) is presently the one most extensively evaluated worldwide. The correspondence between preclinical and clinical data on Ab imaging remains a challenge in transgenic models of AD [32]
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