title: Small-animal PET imaging of amyloid-beta plaques with [11C]PiB and its multi-modal validation in an APP/PS1 mouse model of Alzheimer's disease.
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.
authors.affiliation: Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. andre.manook@tum.de
authors.forename: André
authors.initials: A
authors.lastname: Manook
authors.forename: Behrooz H
authors.initials: BH
authors.lastname: Yousefi
authors.forename: Antje
authors.initials: A
authors.lastname: Willuweit
authors.forename: Stefan
authors.initials: S
authors.lastname: Platzer
authors.forename: Sybille
authors.initials: S
authors.lastname: Reder
authors.forename: Andreas
authors.initials: A
authors.lastname: Voss
authors.forename: Marc
authors.initials: M
authors.lastname: Huisman
authors.forename: Markus
authors.initials: M
authors.lastname: Settles
authors.forename: Frauke
authors.initials: F
authors.lastname: Neff
authors.forename: Joachim
authors.initials: J
authors.lastname: Velden
authors.forename: Michael
authors.initials: M
authors.lastname: Schoor
authors.forename: Heinz
authors.initials: H
authors.lastname: von der Kammer
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaiger
authors.forename: Gjermund
authors.initials: G
authors.lastname: Henriksen
authors.forename: Alexander
authors.initials: A
authors.lastname: Drzezga
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000473:pathology*; D000814:Aniline Compounds; D000818:Animals; D052160:Benzothiazoles / Q000493:pharmacokinetics; D004797:Enzyme-Linked Immunosorbent Assay; D051379:Mice; D008817:Mice, Mutant Strains; D008856:Microscopy, Fluorescence; D058225:Plaque, Amyloid / Q000648:ultrastructure*; D049268:Positron-Emission Tomography / Q000379:methods*; D011869:Radioligand Assay; D013844:Thiazoles; D057170:Translational Research, Biomedical / Q000379:methods
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D000814:Aniline Compounds; D052160:Benzothiazoles; D013844:Thiazoles