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Comparing amyloid-β plaque burden with antemortem PiB PET in autosomal dominant and late-onset Alzheimer disease

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Abstract

Pittsburgh compound B (PiB) radiotracer for positron emission tomography (PET) imaging can bind to different types of amyloid-β plaques and blood vessels (cerebral amyloid angiopathy). However, the relative contributions of different plaque subtypes (diffuse versus cored/compact) to in vivo PiB PET signal on a region-by-region basis are incompletely understood. Of particular interest is whether the same staging schemes for summarizing amyloid-β burden are appropriate for both late-onset and autosomal dominant forms of Alzheimer disease (LOAD and ADAD). Here, we compared antemortem PiB PET with follow-up postmortem estimation of amyloid-β burden using stereologic methods to estimate the relative area fraction of diffuse and cored/compact amyloid-β plaques across 16 brain regions in 15 individuals with ADAD and 14 individuals with LOAD. In ADAD, we found that PiB PET correlated with diffuse plaques in the frontal, parietal, temporal, and striatal regions commonly used to summarize amyloid-β burden in PiB PET, and correlated with both diffuse and cored/compact plaques in the occipital lobe and parahippocampal gyrus. In LOAD, we found that PiB PET correlated with both diffuse and cored/compact plaques in the anterior cingulate, frontal lobe (middle frontal gyrus), and parietal lobe, and showed additional correlations with diffuse plaque in the amygdala and occipital lobe, and with cored/compact plaque in the temporal lobe. Thus, commonly used PiB PET summary regions predominantly reflect diffuse plaque burden in ADAD and a mixture of diffuse and cored/compact plaque burden in LOAD. In direct comparisons of ADAD and LOAD, postmortem stereology identified much greater mean amyloid-β plaque burdens in ADAD versus LOAD across almost all brain regions studied. However, standard PiB PET did not recapitulate these stereologic findings, likely due to non-trivial amyloid-β plaque burdens in ADAD within the cerebellum and brainstem—commonly used reference regions in PiB PET. Our findings suggest that PiB PET summary regions correlate with amyloid-β plaque burden in both ADAD and LOAD; however, they might not be reliable in direct comparisons of regional amyloid-β plaque burden between the two forms of AD.

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Data collection and sharing for this project was supported by the Knight Alzheimer Disease Research Center (Knight ADRC, P30AG066444, P01AG026276, and P01AG03991) and the Dominantly Inherited Alzheimer Network (DIAN, U19AG032438). This manuscript has been reviewed by DIAN Study investigators for scientific content and consistency of data interpretation with previous DIAN Study publications. We acknowledge the altruism of the participants and their families and contributions of the Knight ADRC and DIAN research and support staff at each of the participating sites for their contributions to this study. For the provision of brain tissue and staining, we acknowledge the Knight ADRC Neuropathology Core and the DIAN Neuropathology Core (P01AG003991). We thank the staff of the Betty Martz Laboratory for Neurodegenerative Disease for their excellent technical support. The authors also acknowledge support from the Neuroimaging Informatics and Analysis Center (P30NS098577). C.D.C. acknowledges support from the NSF GRFP (DGE-1745038). N.J-M. acknowledges support from the Alzheimer’s Association International Research Grant Program (AARFD-20-681815). B.A.G. acknowledges support from the NIH (K01AG053474). J.C.M. acknowledges support from the NIH (UF1AG032438).

Author information

Author notes

  1. Nelly Joseph-Mathurin, Namita Sinha and Aihong Zhou have contributed equally to this work.

  2. Nigel J. Cairns and Tammie L.S. Benzinger are co-senior authors.

Authors and Affiliations

  1. Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, USA

    Charles D. Chen, Nelly Joseph-Mathurin, Austin McCullough, Russ Hornbeck, Brian Gordon, Vijay Sharma & Tammie L. S. Benzinger

  2. Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA

    Namita Sinha, Erin E. Franklin, Richard J. Perrin & Nigel J. Cairns

  3. Department of Pathology, University of Manitoba, Shared Health, Winnipeg, MB, Canada

    Namita Sinha

  4. Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China

    Aihong Zhou

  5. Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA

    Yan Li, Eric McDade, Chengjie Xiong, Randall J. Bateman, John C. Morris, Richard J. Perrin & Nigel J. Cairns

  6. Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, MO, USA

    Karl Friedrichsen

  7. Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA

    Carlos Cruchaga & Celeste Karch

  8. Department of Genetics and Genomic Sciences, Ichan School of Medicine at Mount Sinai, New York, NY, USA

    Alison Goate

  9. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Bernardino Ghetti

  10. Department of Neurology, Keck School of Medicine of USC, Los Angeles, CA, USA

    John M. Ringman

  11. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Jasmeer Chhatwal

  12. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia

    Colin L. Masters

  13. Department of Anatomic Pathology, Alfred Hospital, Melbourne, VIC, Australia

    Catriona McLean

  14. UCL Queen Square Institute of Neurology, University College London, London, UK

    Tammaryn Lashley

  15. Queen Square Brain Bank for Neurological Disorders, University College London, London, UK

    Tammaryn Lashley

  16. Banner Alzheimer’s Institute, Banner Health, Phoenix, AZ, USA

    Yi Su

  17. Arizona Alzheimer’s Consortium, Banner Health, Phoenix, AZ, USA

    Yi Su

  18. Department of Radiology, University of Michigan, Ann Arbor, MI, USA

    Robert Koeppe

  19. Department of Radiology, Mayo Clinic, Rochester, MN, USA

    Clifford Jack

  20. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    William E. Klunk

  21. College of Medicine and Health, University of Exeter, Exeter, UK

    Nigel J. Cairns

Authors
  1. Charles D. Chen
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  2. Nelly Joseph-Mathurin
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  3. Namita Sinha
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  5. Yan Li
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  9. Russ Hornbeck
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  24. Yi Su
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  26. Clifford Jack
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  28. John C. Morris
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  29. Richard J. Perrin
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  30. Nigel J. Cairns
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  31. Tammie L. S. Benzinger
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Corresponding author

Correspondence to Tammie L. S. Benzinger.

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Conflict of interest

J.C. has served on a medical advisory board for Otsuka Pharmaceuticals. GE Healthcare holds a license agreement with the University of Pittsburgh based on the PiB-PET technology described in this manuscript. W.E.K. is a co-inventor of PiB and, as such, has a financial interest in this license agreement. GE Healthcare provided no grant support for this study and had no role in the design or interpretation of results or preparation of this manuscript. All other authors have no conflicts of interest with PiB-PET and had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. J.C.M. is funded by NIH grants # P30 AG066444; P01AG003991; P01AG026276; U19 AG032438; and U19 AG024904. Neither J.C.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. T.L.S.B. has investigator-initiated research funding from the NIH, the Alzheimer’s Association, the Barnes-Jewish Hospital Foundation, and Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly); participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly, Biogen, Eisai, Jaansen, and Roche; serves as an unpaid consultant to Eisai and Siemens; and is on the Speaker’s Bureau for Biogen.

Data and materials availability

Data are available by request to the Knight ADRC (knightadrc.wustl.edu/research/resourcerequest.htm) and the DIAN-Obs (dian.wustl.edu/our-research/observational-study/dian-observational-study-investigator-resources/data-request-terms-and-instructions/).

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Chen, C.D., Joseph-Mathurin, N., Sinha, N. et al. Comparing amyloid-β plaque burden with antemortem PiB PET in autosomal dominant and late-onset Alzheimer disease. Acta Neuropathol 142, 689–706 (2021). https://doi.org/10.1007/s00401-021-02342-y

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  • DOI: https://doi.org/10.1007/s00401-021-02342-y

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