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Research ArticleBasic Science Investigations

Glial Activation and Glucose Metabolism in a Transgenic Amyloid Mouse Model: A Triple-Tracer PET Study

Matthias Brendel, Federico Probst, Anna Jaworska, Felix Overhoff, Viktoria Korzhova, Nathalie L. Albert, Roswitha Beck, Simon Lindner, Franz-Josef Gildehaus, Karlheinz Baumann, Peter Bartenstein, Gernot Kleinberger, Christian Haass, Jochen Herms and Axel Rominger
Journal of Nuclear Medicine June 2016, 57 (6) 954-960; DOI: https://doi.org/10.2967/jnumed.115.167858
Matthias Brendel
1Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
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Federico Probst
1Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
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Anna Jaworska
2DZNE–German Center for Neurodegenerative Diseases, Munich, Germany
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Felix Overhoff
1Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
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Viktoria Korzhova
2DZNE–German Center for Neurodegenerative Diseases, Munich, Germany
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Nathalie L. Albert
1Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
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Roswitha Beck
1Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
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Simon Lindner
1Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
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Franz-Josef Gildehaus
1Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
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Karlheinz Baumann
3Roche Pharma Research and Early Development, Neuroscience Discovery, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland
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Peter Bartenstein
1Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
4SyNergy, Ludwig-Maximilians-University of Munich, Munich, Germany; and
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Gernot Kleinberger
2DZNE–German Center for Neurodegenerative Diseases, Munich, Germany
4SyNergy, Ludwig-Maximilians-University of Munich, Munich, Germany; and
5Biomedical Center (BMC), Ludwig-Maximilians-University of Munich, Munich, Germany
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Christian Haass
2DZNE–German Center for Neurodegenerative Diseases, Munich, Germany
4SyNergy, Ludwig-Maximilians-University of Munich, Munich, Germany; and
5Biomedical Center (BMC), Ludwig-Maximilians-University of Munich, Munich, Germany
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Jochen Herms
2DZNE–German Center for Neurodegenerative Diseases, Munich, Germany
4SyNergy, Ludwig-Maximilians-University of Munich, Munich, Germany; and
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Axel Rominger
1Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
4SyNergy, Ludwig-Maximilians-University of Munich, Munich, Germany; and
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  • FIGURE 1.
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    FIGURE 1.

    Definitions of forebrain (yellow), whole brain (orange), cerebellar (red), and white matter (purple) volumes of interest projected on mouse brain MRI atlas in coronal and sagittal slices.

  • FIGURE 2.
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    FIGURE 2.

    (A) Mean 18F-GE180 uptake reported as SUV for each of 3 reference regions as function of time after tracer administration in groups of PS2APP mice. Least evidence of pathology (i.e., stability between TG and WT) was detected for a white matter pseudo reference region. Error bars indicate SD for estimates in groups of 5–8 animals. (B) Target-to-reference ratios as functions of time after 18F-GE180 administration in groups of PS2APP mice. (C) Correlation of 18F-GE180 distribution volume ratio (DVR) calculated from 90-min dynamic small-animal PET recordings with corresponding SUVR (forebrain/white-matter) results from 60- to 90-min static frame. Dotted line represents a perfect line of identity (DVR = SUVR). (D) Stability of forebrain 18F-GE180 values after SUV calculation (blue) and pseudo reference tissue (orange) scaling as expressed by mean %-SD (± SD) in all 8 groups of TG and WT mice.

  • FIGURE 3.
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    FIGURE 3.

    (A) Coronal planes of 18F-GE180 mean SUVR maps at different ages of PS2APP animals projected on an MRI mouse atlas (gray scale). (B) Mean (±SD) SUVR estimates for PS2APP animals at different ages. Significant differences between subgroups are marked by ***P < 0.001; 1-way ANOVA. p.i. = after injection.

  • FIGURE 4.
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    FIGURE 4.

    (A) Coronal planes of mean SUVR maps for all 3 different radiotracers at different ages of PS2APP animals, projected on an MRI mouse atlas (gray scale). (B) Correlations between the different forebrain radiotracer SUVR for all PS2APP mice.

  • FIGURE 5.
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    FIGURE 5.

    Life-course kinetics for PS2APP mice as expressed by %-difference (±SD) versus C57BL/6 controls for the 3 different radiotracers.

  • FIGURE 6.
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    FIGURE 6.

    (A) Immunohistochemical costaining shows IBA-1– (red) and TSPO- (green) positive cells adjacent (white circle) to fibrillar amyloid plaques (blue) in the frontal cortex of a PS2APP mouse aged 22 mo. Yellow circle indicates low IBA-1 and TSPO staining between amyloid plaques. Scale bar represents 20 μm. (B) Sagittal plane for 18F-GE180 autoradiography ex vivo (60 min after injection) in a 22-mo-old PS2APP mouse indicates extensive radiotracer uptake in neocortex (red arrows), hippocampus, and thalamus, which is colocalized with fibrillar amyloid as detected in corresponding methoxy-X04 staining in these brain regions (C). No specific binding is observed in cerebellum.

Tables

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    TABLE 1

    Overview for Main Study

    Mouse modelAge (mo)18F-GE180 small-animal PET (n)18F-GE180 small-animal PET (SUVRFBR/WM)18F-florbetaben small-animal PET (n)18F-florbetaben small-animal PET (SUVRFBR/WM)18F-FDG small-animal PET (n)18F-FDG small-animal PET (SUVRFBR/CBL)
    PS2APP560.69 ± 0.03†60.80 ± 0.0260.85 ± 0.05‡
    850.72 ± 0.02‡40.82 ± 0.0340.90 ± 0.05‡
    1380.81 ± 0.03‡80.90 ± 0.02‡80.94 ± 0.02‡
    1680.83 ± 0.04‡70.96 ± 0.03‡70.91 ± 0.03*
    C57BL/6580.63 ± 0.0180.79 ± 0.0180.77 ± 0.03
    880.65 ± 0.0380.79 ± 0.0180.80 ± 0.03
    1380.66 ± 0.0280.78 ± 0.0280.86 ± 0.04‡
    1680.67 ± 0.02*80.78 ± 0.0280.86 ± 0.04‡
    • Groups of PS2APP and C57BL/6 mice are provided together with forebrain small-animal PET SUVRs for the 3 radiotracers. Significant differences in PS2APP mice versus age-matched C57BL/6 control or significant differences in C57BL/6 controls against their 5-mo-old littermates are marked by *P < 0.05; †P < 0.01; ‡P < 0.001; 1-way ANOVA.

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Journal of Nuclear Medicine: 57 (6)
Journal of Nuclear Medicine
Vol. 57, Issue 6
June 1, 2016
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Glial Activation and Glucose Metabolism in a Transgenic Amyloid Mouse Model: A Triple-Tracer PET Study
Matthias Brendel, Federico Probst, Anna Jaworska, Felix Overhoff, Viktoria Korzhova, Nathalie L. Albert, Roswitha Beck, Simon Lindner, Franz-Josef Gildehaus, Karlheinz Baumann, Peter Bartenstein, Gernot Kleinberger, Christian Haass, Jochen Herms, Axel Rominger
Journal of Nuclear Medicine Jun 2016, 57 (6) 954-960; DOI: 10.2967/jnumed.115.167858

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Glial Activation and Glucose Metabolism in a Transgenic Amyloid Mouse Model: A Triple-Tracer PET Study
Matthias Brendel, Federico Probst, Anna Jaworska, Felix Overhoff, Viktoria Korzhova, Nathalie L. Albert, Roswitha Beck, Simon Lindner, Franz-Josef Gildehaus, Karlheinz Baumann, Peter Bartenstein, Gernot Kleinberger, Christian Haass, Jochen Herms, Axel Rominger
Journal of Nuclear Medicine Jun 2016, 57 (6) 954-960; DOI: 10.2967/jnumed.115.167858
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