Small-Animal PET Imaging of Amyloid-Beta Plaques with [C]PiB and Its Multi-Modal Validation in an APP/PS1 Mouse Model of Alzheimer's Disease

Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
PLoS ONE (Impact Factor: 3.23). 03/2012; 7(3):e31310. DOI: 10.1371/journal.pone.0031310
Source: PubMed

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 [(11)C]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 [(11)C]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 [(11)C]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.

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Available from: Frauke Neff, Sep 27, 2015
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    • "No plaques or tangles were found in the cerebellum of any of the mice, consistent with the lack of plaques in this region previously observed in mouse models (Manook et al., 2012) and the very mild plaque load observed even at end stage in live imaging or postmortem tissue from AD patients (Driscoll et al., 2012; Thal et al., 2004). "
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    • "Studies of [11C]PiB imaging in PS1/APP mice and post mortem histological analysis have shown diverging results of different attempts to find a correlation between the [11C]PiB images and Aβ deposits in vitro (Klunk et al., 2005a; Manook et al., 2012). The negative results may be explained in part by the presence of lower affinity PiB binding sites on Aβ deposits in the transgenic mouse brains than in AD brains (Klunk et al., 2005a; Toyama et al., 2005). "
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    • "List of biomarkers examined in AD animal systems Biomarker Reference(s) Aβ42 [12, 13, 16, 17, 23- 26, 29, 33-35] Aβ oligomers [16] Protofibrillar Aβ42 [133] [134] Soluble APPβ [23] Fragmented Aβ [37] Cytokines [38] [39] [40] [41] Isoprostanes [43] Tau [47] Ptau [48] FDG-PET [50] [51] [52] [53] [54] [55] [56] [57] Pittsburgh Compound B [58] [59] [60] [61] [62] [63] [64] FDDNP [64] [65] 18 F-THK523 [66] Florbetapir [67] [68] Microglial probes [70] [71] MRI-based atrophy [72] [73] [74] [75] [76] [77] [78] [79] ASL-MRI [83] [84] MRI amyloid contrast agents [85] [86] [87] [88] [89] [90] [91] [92] [93] [94] MRI amyloid without contrast [95] [96] [97] [98] [99] Axonal transport via MEMRI [101] [102] DTI [103] 1 H-MRS metabolites [106] [107] [108] [109] [110] [111] [112] [114] Proteome [129] MicroRNAs [132] Alzheimer's disease biomarkers in animal models 113 Am J Neurodegener Dis 2013;2(2):108-120 approach may also greatly accelerate translational efforts to impact clinical research. Equally pressing is the need for more data from animal systems investigating biomarkers that can be directly translated to human biomarkers . "
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