title: Longitudinal amyloid imaging in mouse brain with 11C-PIB: comparison of APP23, Tg2576, and APPswe-PS1dE9 mouse models of Alzheimer disease.
abstract: Follow-up of β-amyloid (Aβ) deposition in transgenic mouse models of Alzheimer disease (AD) would be a valuable translational tool in the preclinical evaluation of potential antiamyloid therapies. This study aimed to evaluate the ability of the clinically used PET tracer (11)C-Pittsburgh compound B ((11)C-PIB) to detect changes over time in Aβ deposition in the brains of living mice representing the APP23, Tg2576, and APP(swe)-PS1(dE9) transgenic mouse models of AD.
  
  
  METHODS
  Mice from each transgenic strain were imaged with 60-min dynamic PET scans at 7-9, 12, 15, and 18-22 mo of age. Regional (11)C-PIB retention was quantitated as distribution volume ratios using Logan graphical analysis with cerebellar reference input, as radioactivity uptake ratios between the frontal cortex (FC) and the cerebellum (CB) during the 60-min scan, and as bound-to-free ratios in the late washout phase (40-60 min). Ex vivo autoradiography experiments were performed after the final imaging session to validate (11)C-PIB binding to Aβ deposits. Additionally, the presence of Aβ deposits was evaluated in vitro using staining with thioflavin-S and Aβ1-40, Aβ1-16, and AβN3(pE) immunohistochemistry.
  
  
  RESULTS
  Neocortical (11)C-PIB retention was markedly increased in old APP23 mice with large thioflavin-S-positive Aβ deposits. At 12 mo, the Logan distribution volume ratio for the FC was 1.03 and 0.93 (n = 2), increasing to 1.38 ± 0.03 (n = 3) and 1.34 (n = 1) at 18 and 21 mo of age, respectively. An increase was also observed in bound-to-free ratios for the FC between young (7- to 12-mo-old) and old (15- to 22-mo-old) APP23 mice. Binding of (11)C-PIB to Aβ-rich cortical regions was also evident in ex vivo autoradiograms of APP23 brain sections. In contrast, no increases in (11)C-PIB retention were observed in aging Tg2576 or APP(swe)-PS1(dE9) mice in vivo, although in the latter, extensive Aβ deposition was already observed at 9 mo of age with immunohistochemistry.
  
  
  CONCLUSIONS
  The results suggest that (11)C-PIB binding to Aβ deposits in transgenic mouse brain is highly dependent on the AD model and the structure of its Aβ plaques. Longitudinal in vivo (11)C-PIB uptake studies are possible in APP23 mice.
authors.affiliation: MediCity/PET Preclinical Laboratory, University of Turku, Turku PET Centre, Turku, Finland.
authors.forename: Anniina
authors.initials: A
authors.lastname: Snellman
authors.forename: Francisco R
authors.initials: FR
authors.lastname: López-Picón
authors.forename: Johanna
authors.initials: J
authors.lastname: Rokka
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.forename: Mika
authors.initials: M
authors.lastname: Scheinin
authors.forename: Olof
authors.initials: O
authors.lastname: Solin
authors.forename: Juha O
authors.initials: JO
authors.lastname: Rinne
authors.forename: Merja
authors.initials: M
authors.lastname: Haaparanta-Solin
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000814:Aniline Compounds; D000818:Animals; D001345:Autoradiography; D052160:Benzothiazoles; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D049268:Positron-Emission Tomography; D013844:Thiazoles
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D052160:Benzothiazoles; D013844:Thiazoles
keywords: 11C-PIB, Pittsburgh compound B; Alzheimer disease; amyloid imaging; positron emission tomography