Longitudinal amyloid imaging in mouse brain with 11C-PIB: Comparison of APP23, Tg2576, and APPswe-PS1dE9 mouse models of Alzheimer disease

Anniina Snellman, Francisco R. López-Picón, Johanna Rokka, Mario Salmona, Gianluigi Forloni, Mika Scheinin, Olof Solin, Juha O. Rinne, Merja Haaparanta-Solin

Research output: Contribution to journalArticle

Abstract

Follow-up of b-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 11C-Pittsburgh compound B (11C-PIB) to detect changes over time in Ab deposition in the brains of living mice representing the APP23, Tg2576, and APPswe-PS1 dE9 transgenic mouse models of AD. Methods: Mice from each transgenic strain were imaged with 60-min dynamic PET scans at 729, 12, 15, and 18222 mo of age. Regional 11C-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-tofree ratios in the late washout phase (40260 min). Ex vivo autoradiography experiments were performed after the final imaging session to validate 11C-PIB binding to Ab deposits. Additionally, the presence of Ab deposits was evaluated in vitro using staining with thioflavin-S and Aβ1-40, Aβ1-16, and AβN3(pE) immunohistochemistry. Results: Neocortical 11C-PIB retention was markedly increased in old APP23 mice with large thioflavin-S-positive Ab deposits. At 12 mo, the Logan distribution volume ratio for the FC was 1.03 and 0.93 (n = 2), increasing to 1.38 6 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 11C-PIB to Ab-rich cortical regions was also evident in ex vivo autoradiograms of APP23 brain sections. In contrast, no increases in 11C-PIB retention were observed in aging Tg2576 or APPswe-PS1dE9 mice in vivo, although in the latter, extensive Ab deposition was already observed at 9 mo of age with immunohistochemistry. Conclusion: The results suggest that 11C-PIB binding to Ab deposits in transgenic mouse brain is highly dependent on the AD model and the structure of its Ab plaques. Longitudinal in vivo 11C-PIB uptake studies are possible in APP23 mice. COPYRIGHT

Original languageEnglish
Pages (from-to)1434-1441
Number of pages8
JournalJournal of Nuclear Medicine
Volume54
Issue number8
DOIs
Publication statusPublished - Aug 1 2013

Fingerprint

Amyloid
Alzheimer Disease
Brain
Transgenic Mice
Frontal Lobe
Immunohistochemistry
Aptitude
2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole
Autoradiography
Positron-Emission Tomography
Cerebellum
Radioactivity
Staining and Labeling

Keywords

  • C-PIB
  • Alzheimer disease
  • Amyloid imaging
  • Pittsburgh compound B
  • Positron emission tomography

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

Longitudinal amyloid imaging in mouse brain with 11C-PIB : Comparison of APP23, Tg2576, and APPswe-PS1dE9 mouse models of Alzheimer disease. / Snellman, Anniina; López-Picón, Francisco R.; Rokka, Johanna; Salmona, Mario; Forloni, Gianluigi; Scheinin, Mika; Solin, Olof; Rinne, Juha O.; Haaparanta-Solin, Merja.

In: Journal of Nuclear Medicine, Vol. 54, No. 8, 01.08.2013, p. 1434-1441.

Research output: Contribution to journalArticle

Snellman, Anniina ; López-Picón, Francisco R. ; Rokka, Johanna ; Salmona, Mario ; Forloni, Gianluigi ; Scheinin, Mika ; Solin, Olof ; Rinne, Juha O. ; Haaparanta-Solin, Merja. / Longitudinal amyloid imaging in mouse brain with 11C-PIB : Comparison of APP23, Tg2576, and APPswe-PS1dE9 mouse models of Alzheimer disease. In: Journal of Nuclear Medicine. 2013 ; Vol. 54, No. 8. pp. 1434-1441.
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abstract = "Follow-up of b-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 11C-Pittsburgh compound B (11C-PIB) to detect changes over time in Ab deposition in the brains of living mice representing the APP23, Tg2576, and APPswe-PS1 dE9 transgenic mouse models of AD. Methods: Mice from each transgenic strain were imaged with 60-min dynamic PET scans at 729, 12, 15, and 18222 mo of age. Regional 11C-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-tofree ratios in the late washout phase (40260 min). Ex vivo autoradiography experiments were performed after the final imaging session to validate 11C-PIB binding to Ab deposits. Additionally, the presence of Ab deposits was evaluated in vitro using staining with thioflavin-S and Aβ1-40, Aβ1-16, and AβN3(pE) immunohistochemistry. Results: Neocortical 11C-PIB retention was markedly increased in old APP23 mice with large thioflavin-S-positive Ab deposits. At 12 mo, the Logan distribution volume ratio for the FC was 1.03 and 0.93 (n = 2), increasing to 1.38 6 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 11C-PIB to Ab-rich cortical regions was also evident in ex vivo autoradiograms of APP23 brain sections. In contrast, no increases in 11C-PIB retention were observed in aging Tg2576 or APPswe-PS1dE9 mice in vivo, although in the latter, extensive Ab deposition was already observed at 9 mo of age with immunohistochemistry. Conclusion: The results suggest that 11C-PIB binding to Ab deposits in transgenic mouse brain is highly dependent on the AD model and the structure of its Ab plaques. Longitudinal in vivo 11C-PIB uptake studies are possible in APP23 mice. COPYRIGHT",
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T1 - Longitudinal amyloid imaging in mouse brain with 11C-PIB

T2 - Comparison of APP23, Tg2576, and APPswe-PS1dE9 mouse models of Alzheimer disease

AU - Snellman, Anniina

AU - López-Picón, Francisco R.

AU - Rokka, Johanna

AU - Salmona, Mario

AU - Forloni, Gianluigi

AU - Scheinin, Mika

AU - Solin, Olof

AU - Rinne, Juha O.

AU - Haaparanta-Solin, Merja

PY - 2013/8/1

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N2 - Follow-up of b-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 11C-Pittsburgh compound B (11C-PIB) to detect changes over time in Ab deposition in the brains of living mice representing the APP23, Tg2576, and APPswe-PS1 dE9 transgenic mouse models of AD. Methods: Mice from each transgenic strain were imaged with 60-min dynamic PET scans at 729, 12, 15, and 18222 mo of age. Regional 11C-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-tofree ratios in the late washout phase (40260 min). Ex vivo autoradiography experiments were performed after the final imaging session to validate 11C-PIB binding to Ab deposits. Additionally, the presence of Ab deposits was evaluated in vitro using staining with thioflavin-S and Aβ1-40, Aβ1-16, and AβN3(pE) immunohistochemistry. Results: Neocortical 11C-PIB retention was markedly increased in old APP23 mice with large thioflavin-S-positive Ab deposits. At 12 mo, the Logan distribution volume ratio for the FC was 1.03 and 0.93 (n = 2), increasing to 1.38 6 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 11C-PIB to Ab-rich cortical regions was also evident in ex vivo autoradiograms of APP23 brain sections. In contrast, no increases in 11C-PIB retention were observed in aging Tg2576 or APPswe-PS1dE9 mice in vivo, although in the latter, extensive Ab deposition was already observed at 9 mo of age with immunohistochemistry. Conclusion: The results suggest that 11C-PIB binding to Ab deposits in transgenic mouse brain is highly dependent on the AD model and the structure of its Ab plaques. Longitudinal in vivo 11C-PIB uptake studies are possible in APP23 mice. COPYRIGHT

AB - Follow-up of b-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 11C-Pittsburgh compound B (11C-PIB) to detect changes over time in Ab deposition in the brains of living mice representing the APP23, Tg2576, and APPswe-PS1 dE9 transgenic mouse models of AD. Methods: Mice from each transgenic strain were imaged with 60-min dynamic PET scans at 729, 12, 15, and 18222 mo of age. Regional 11C-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-tofree ratios in the late washout phase (40260 min). Ex vivo autoradiography experiments were performed after the final imaging session to validate 11C-PIB binding to Ab deposits. Additionally, the presence of Ab deposits was evaluated in vitro using staining with thioflavin-S and Aβ1-40, Aβ1-16, and AβN3(pE) immunohistochemistry. Results: Neocortical 11C-PIB retention was markedly increased in old APP23 mice with large thioflavin-S-positive Ab deposits. At 12 mo, the Logan distribution volume ratio for the FC was 1.03 and 0.93 (n = 2), increasing to 1.38 6 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 11C-PIB to Ab-rich cortical regions was also evident in ex vivo autoradiograms of APP23 brain sections. In contrast, no increases in 11C-PIB retention were observed in aging Tg2576 or APPswe-PS1dE9 mice in vivo, although in the latter, extensive Ab deposition was already observed at 9 mo of age with immunohistochemistry. Conclusion: The results suggest that 11C-PIB binding to Ab deposits in transgenic mouse brain is highly dependent on the AD model and the structure of its Ab plaques. Longitudinal in vivo 11C-PIB uptake studies are possible in APP23 mice. COPYRIGHT

KW - C-PIB

KW - Alzheimer disease

KW - Amyloid imaging

KW - Pittsburgh compound B

KW - Positron emission tomography

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