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Voxel-Based Analysis of Amyloid-Burden Measured with [11C]PiB PET in a Double Transgenic Mouse Model of Alzheimer’s Disease

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Abstract

Purpose

The purpose of this study is to validate the feasibility of a voxel-based analysis of in vivo amyloid-β positron emission tomography (PET) imaging studies in transgenic mouse models of Alzheimer’s disease.

Procedures

We performed [11C]PiB PET imaging in 20 APP/PS1 mice and 16 age-matched controls, and histologically determined the individual amyloid-β plaque load. Using SPM software, we performed a voxel-based group comparison plus a regression analysis between PiB retention and actual plaque load, both thresholded at p FWE < 0.05. In addition, we carried out an individual ROI analysis in every animal.

Results

The automated voxel-based group comparison allowed us to identify voxels with significantly increased PiB retention in the cortical and hippocampal regions in transgenic animals compared to controls. The voxel-based regression analysis revealed a significant association between this signal increase and the actual cerebral plaque load. The validity of these results was corroborated by the individual ROI-based analysis.

Conclusions

Voxel-based analysis of in vivo amyloid-β PET imaging studies in mouse models of Alzheimer’s disease is feasible and allows studying the PiB retention patterns in whole brain maps. Furthermore, the selected approach in our study also allowed us to establish a quantitative relation between tracer retention and actual plaque pathology in the brain in a voxel-wise manner.

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Abbreviations

PET:

Positron emission tomography

AD:

Alzheimer’s disease

PiB:

Pittsburgh compound B, [11C]-6-OH-BTA-1

Aβ:

Amyloid-β

ROI:

Region of interest

SPM:

Statistical parametric mapping

tg:

Transgenic

wt:

Wild type

MRI:

Magnetic resonance imaging

APP:

Amyloid precursor protein

PS1:

Presenilin 1

References

  1. Klunk WE, Engler H, Nordberg A et al (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 55:306–19

    Article  PubMed  CAS  Google Scholar 

  2. Shoghi-Jadid K, Small GW, Agdeppa ED et al (2002) Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry 10:24–35

    PubMed  Google Scholar 

  3. Verhoeff NP, Wilson AA, Takeshita S et al (2004) In-vivo imaging of Alzheimer disease beta-amyloid with [11C]SB-13 PET. Am J Geriatr Psychiatry 12:584–95

    PubMed  Google Scholar 

  4. Ikonomovic MD, Klunk WE, Abrahamson EE et al (2008) Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease. Brain 131:1630–45

    Article  PubMed  Google Scholar 

  5. Leinonen V, Alafuzoff I, Aalto S et al (2008) Assessment of beta-amyloid in a frontal cortical brain biopsy specimen and by positron emission tomography with carbon 11-labeled Pittsburgh Compound B. Arch Neurol 65:1304–9

    Article  PubMed  Google Scholar 

  6. Sojkova J, Driscoll I, Iacono D et al (2011) In vivo fibrillar beta-amyloid detected using [11C]PiB positron emission tomography and neuropathologic assessment in older adults. Arch Neurol 68:232–40

    Article  PubMed  Google Scholar 

  7. Maeda J, Ji B, Irie T et al (2007) Longitudinal, quantitative assessment of amyloid, neuroinflammation, and anti-amyloid treatment in a living mouse model of Alzheimer’s disease enabled by positron emission tomography. J Neurosci 27:10957–68

    Article  PubMed  CAS  Google Scholar 

  8. Manook A, Yousefi BH, Willuweit A et al (2012) 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. PLoS One 7:e31310

    Article  PubMed  CAS  Google Scholar 

  9. Klunk WE, Lopresti BJ, Ikonomovic MD et al (2005) Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-beta in Alzheimer’s disease brain but not in transgenic mouse brain. J Neurosci 25:10598–606

    Article  PubMed  CAS  Google Scholar 

  10. Toyama H, Ye D, Ichise M et al (2005) PET imaging of brain with the beta-amyloid probe, [11C]6-OH-BTA-1, in a transgenic mouse model of Alzheimer’s disease. Eur J Nucl Med Mol Imaging 32:593–600

    Article  PubMed  CAS  Google Scholar 

  11. Yousefi BH, Manook A, Drzezga A et al (2011) Synthesis and evaluation of 11C-labeled imidazo[2,1-b]benzothiazoles (IBTs) as PET tracers for imaging beta-amyloid plaques in Alzheimer’s disease. J Med Chem 54:949–56

    Article  PubMed  CAS  Google Scholar 

  12. Price JC, Klunk WE, Lopresti BJ et al (2005) Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B. J Cereb Blood Flow Metab 25:1528–47

    Article  PubMed  CAS  Google Scholar 

  13. Kemppainen NM, Aalto S, Wilson IA et al (2006) Voxel-based analysis of PET amyloid ligand [11C]PIB uptake in Alzheimer disease. Neurology 67:1575–80

    Article  PubMed  CAS  Google Scholar 

  14. Ziolko SK, Weissfeld LA, Klunk WE et al (2006) Evaluation of voxel-based methods for the statistical analysis of PIB PET amyloid imaging studies in Alzheimer’s disease. NeuroImage 33:94–102

    Article  PubMed  Google Scholar 

  15. Mikhno A, Devanand D, Pelton G et al (2008) Voxel-based analysis of 11C-PIB scans for diagnosing Alzheimer’s disease. J Nucl Med 49:1262–9

    Article  PubMed  Google Scholar 

  16. Kemppainen NM, Aalto S, Wilson IA et al (2007) PET amyloid ligand [11C]PIB uptake is increased in mild cognitive impairment. Neurology 68:1603–6

    Article  PubMed  CAS  Google Scholar 

  17. Grimmer T, Henriksen G, Wester HJ et al (2009) Clinical severity of Alzheimer’s disease is associated with PIB uptake in PET. Neurobiol Aging 30:1902–9

    Article  PubMed  CAS  Google Scholar 

  18. Shin J, Lee SY, Kim SJ et al (2010) Voxel-based analysis of Alzheimer’s disease PET imaging using a triplet of radiotracers: PIB, FDDNP, and FDG. NeuroImage 52:488–96

    Article  PubMed  Google Scholar 

  19. Scheinin NM, Aalto S, Koikkalainen J et al (2009) Follow-up of [11C]PIB uptake and brain volume in patients with Alzheimer disease and controls. Neurology 73:1186–92

    Article  PubMed  CAS  Google Scholar 

  20. Edison P, Archer HA, Gerhard A et al (2008) Microglia, amyloid, and cognition in Alzheimer’s disease: An [11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiol Dis 32:412–9

    Article  PubMed  CAS  Google Scholar 

  21. Jack CR Jr, Lowe VJ, Senjem ML et al (2008) 11C PiB and structural MRI provide complementary information in imaging of Alzheimer’s disease and amnestic mild cognitive impairment. Brain 131:665–80

    Article  PubMed  Google Scholar 

  22. Dubois A, Herard AS, Delatour B et al (2010) Detection by voxel-wise statistical analysis of significant changes in regional cerebral glucose uptake in an APP/PS1 transgenic mouse model of Alzheimer’s disease. NeuroImage 51:586–98

    Article  PubMed  Google Scholar 

  23. Hooker JM, Patel V, Kothari S, Schiffer WK (2009) Metabolic changes in the rodent brain after acute administration of salvinorin A. Mol Imaging Biol 11:137–43

    Article  PubMed  Google Scholar 

  24. Prieto E, Collantes M, Delgado M et al (2011) Statistical parametric maps of (1)(8)F-FDG PET and 3-D autoradiography in the rat brain: A cross-validation study. Eur J Nucl Med Mol Imaging 38:2228–37

    Article  PubMed  Google Scholar 

  25. Casteels C, Bormans G, Van Laere K (2010) The effect of anaesthesia on [(18)F]MK-9470 binding to the type 1 cannabinoid receptor in the rat brain. Eur J Nucl Med Mol Imaging 37:1164–73

    Article  PubMed  CAS  Google Scholar 

  26. Casteels C, Lauwers E, Baitar A et al (2010) In vivo type 1 cannabinoid receptor mapping in the 6-hydroxydopamine lesion rat model of Parkinson’s disease. Brain Res 1316:153–62

    Article  PubMed  CAS  Google Scholar 

  27. Willuweit A, Velden J, Godemann R et al (2009) Early-onset and robust amyloid pathology in a new homozygous mouse model of Alzheimer’s disease. PLoS One 4:e7931

    Article  PubMed  Google Scholar 

  28. Bacskai BJ, Hickey GA, Skoch J et al (2003) Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-beta ligand in transgenic mice. Proc Natl Acad Sci U S A 100:12462–7

    Article  PubMed  CAS  Google Scholar 

  29. Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates. Academic Press, San Diego

    Google Scholar 

  30. Sawiak SJ, Wood NI, Williams GB et al (2009) Voxel-based morphometry in the R6/2 transgenic mouse reveals differences between genotypes not seen with manual 2D morphometry. Neurobiol Dis 33:20–7

    Article  PubMed  CAS  Google Scholar 

  31. Brammer DW, Riley JM, Kreuser SC et al (2007) Harderian gland adenectomy: a method to eliminate confounding radio-opacity in the assessment of rat brain metabolism by 18F-fluoro-2-deoxy-D-glucose positron emission tomography. J Am Assoc Lab Anim Sci 46:42–5

    PubMed  CAS  Google Scholar 

  32. Fukuyama H, Hayashi T, Katsumi Y et al (1998) Issues in measuring glucose metabolism of rat brain using PET: the effect of harderian glands on the frontal lobe. Neurosci Lett 255:99–102

    Article  PubMed  CAS  Google Scholar 

  33. Kuge Y, Kawashima H, Yamazaki S et al (1996) [1-11C]octanoate as a potential PET tracer for studying glial functions: PET evaluation in rats and cats. Nucl Med Biol 23:1009–12

    Article  PubMed  CAS  Google Scholar 

  34. Kuge Y, Minematsu K, Hasegawa Y et al (1997) Positron emission tomography for quantitative determination of glucose metabolism in normal and ischemic brains in rats: An insoluble problem by the Harderian glands. J Cereb Blood Flow Metab 17:116–20

    Article  PubMed  CAS  Google Scholar 

  35. Mevel K, Desgranges B, Baron JC et al (2007) Detecting hippocampal hypometabolism in mild cognitive impairment using automatic voxel-based approaches. NeuroImage 37:18–25

    Article  PubMed  Google Scholar 

  36. Nestor PJ, Fryer TD, Smielewski P, Hodges JR (2003) Limbic hypometabolism in Alzheimer’s disease and mild cognitive impairment. Ann Neurol 54:343–51

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants of the German Research Foundation (DFG) [DR 445/3-1, 4–1 to A.D.] and by the University of Technology Munich Graduate School [to B.v.R.]. Elisabeth Aiwanger, Galina Bursow, Isabell Cardaun, Annette Frank, Dr. Heinz von der Kammer, Christina Lesti, Dr. Markus Mandler, Sybille Reder, Dr. Philipp Sämann, Dr. Radmila Santic, Dr. Marcus Settles, Rainer Winter and Prof. Dr. Sibylle Ziegler are hereby acknowledged.

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Institute of Neuroscience and Medicine (INM-3), Research Centre Jülich, 52425, Jülich, Germany

    Boris von Reutern

  2. Department of Nuclear Medicine, Klinikum rechts der Isar, University of Technology Munich, Ismaninger Str. 22, 81675, Munich, Germany

    Boris von Reutern, Behrooz H. Yousefi, Gjermund Henriksen & Alexander Drzezga

  3. Neuroimaging, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804, Munich, Germany

    Barbara Grünecker & Michael Czisch

  4. Department of Pharmaceutical Radiochemistry, Faculties of Chemistry and Medicine, University of Technology Munich, Walther-Meißner Str. 3, 85748, Garching, Germany

    Behrooz H. Yousefi

  5. Department of Nuclear Medicine, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany

    Alexander Drzezga

Authors
  1. Boris von Reutern
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  2. Barbara Grünecker
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  3. Behrooz H. Yousefi
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  4. Gjermund Henriksen
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  5. Michael Czisch
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  6. Alexander Drzezga
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Corresponding author

Correspondence to Boris von Reutern.

Additional information

Authors Boris von Reutern and Barbara Grünecker contributed equally to this work.

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von Reutern, B., Grünecker, B., Yousefi, B.H. et al. Voxel-Based Analysis of Amyloid-Burden Measured with [11C]PiB PET in a Double Transgenic Mouse Model of Alzheimer’s Disease. Mol Imaging Biol 15, 576–584 (2013). https://doi.org/10.1007/s11307-013-0625-z

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  • DOI: https://doi.org/10.1007/s11307-013-0625-z

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