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

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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Funding

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).

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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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Keywords

  • Alzheimer disease
  • Amyloid-β plaques
  • PiB PET
  • Stereology