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Longitudinal PET-MRI reveals β-amyloid deposition and rCBF dynamics and connects vascular amyloidosis to quantitative loss of perfusion

Nature Medicine volume 20, pages 1485–1492 (2014)Cite this article

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Abstract

The dynamics of β-amyloid deposition and related second-order physiological effects, such as regional cerebral blood flow (rCBF), are key factors for a deeper understanding of Alzheimer's disease (AD). We present longitudinal in vivo data on the dynamics of β-amyloid deposition and the decline of rCBF in two different amyloid precursor protein (APP) transgenic mouse models of AD. Using a multiparametric positron emission tomography and magnetic resonance imaging approach, we demonstrate that in the presence of cerebral β-amyloid angiopathy (CAA), β-amyloid deposition is accompanied by a decline of rCBF. Loss of perfusion correlates with the growth of β-amyloid plaque burden but is not related to the number of CAA-induced microhemorrhages. However, in a mouse model of parenchymal β-amyloidosis and negligible CAA, rCBF is unchanged. Because synaptically driven spontaneous network activity is similar in both transgenic mouse strains, we conclude that the disease-related decline of rCBF is caused by CAA.

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Figure 1: β-amyloid deposition in APPPS1 mice quantified with [11C]PIB-PET.
Figure 2: β-amyloid deposition in APP23 mice quantified with [11C]PIB-PET.
Figure 3: Quantitative rCBF measurements in APPPS1 and APP23 mice.
Figure 4: Quantification of synaptically driven network activity in APP23 and APPPS1 mice.
Figure 5: Quantification of microhemorrhages in APP23 mice.

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Acknowledgements

This work was funded by the German Federal Ministry of Education and Research (BMBF) grant 01 Gi 0705, the German Research Foundation (DFG) (PI 771/1-1), the Interdisciplinary Center for Clinical Research (IZKF) junior research group program (Functional and Metabolic Brain Imaging, fortüne number 2209-0-0) and the Werner Siemens Foundation. We acknowledge support from P. Martirosian, J. van den Hoff and M. Kneilling. We thank D. Bukala, F. Cay, M. Harant and M. Lehnhoff for their excellent technical assistance during all experiments. We thank J. Odenthal (Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen) for providing APPPS1 mice. We thank S.C. Vega for confirmative data evaluation. We thank M. Eichner for statistical expert advice.

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Authors and Affiliations

  1. Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University Tübingen, Tübingen, Germany

    Florian C Maier, Hans F Wehrl, Andreas M Schmid, Julia G Mannheim, Stefan Wiehr, Carsten Calaminus, Anke Stahlschmidt, Gerald Reischl & Bernd J Pichler

  2. Institute of Physiology II, Eberhard Karls University Tübingen, Tübingen, Germany

    Chommanad Lerdkrai & Olga Garaschuk

  3. Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, and DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany

    Lan Ye & Mathias Jucker

  4. Synovo GmbH, Tübingen, Germany

    Michael Burnet

  5. Target Discovery Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

    Detlef Stiller

  6. Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany

    Osama Sabri

  7. Novartis Institutes for BioMedical Research, Basel, Switzerland

    Mathias Staufenbiel

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Contributions

F.C.M. and B.J.P. designed the research. F.C.M., H.F.W., A.M.S., J.G.M., S.W., C.L., L.Y. and O.G. performed the research. M.B., D.S., M.S. and M.J. provided the AD mouse models. A.S. and G.R. provided the PET tracers. F.C.M. and S.W. designed the figures. O.S. provided input of clinical relevance and edited the manuscript. C.C. obtained ethical approval of the study, aided study planning and edited the manuscript. F.C.M. analyzed the data, conducted the statistics and wrote the manuscript. All authors edited the manuscript.

Corresponding author

Correspondence to Bernd J Pichler.

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Competing interests

B.J.P. receives grant and research support from AstraZeneca, Bayer Healthcare, Boehringer-Ingelheim, Bruker, Oncodesign, Merck and Siemens; however, none of the grants is directly related to this work. D.S. is an employee of Boehringer-Ingelheim. O.S. receives grant and research support from G.E., Bayer Healthcare, Siemens, Piramal and Navidea; however, none of the grant issuers is directly related to this work. M.S. was an employee of Novartis while the studies were conducted. M.B. is the CEO of Synovo.

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Maier, F., Wehrl, H., Schmid, A. et al. Longitudinal PET-MRI reveals β-amyloid deposition and rCBF dynamics and connects vascular amyloidosis to quantitative loss of perfusion. Nat Med 20, 1485–1492 (2014). https://doi.org/10.1038/nm.3734

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