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Indication of retrograde tau spreading along Braak stages and functional connectivity pathways

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Tau pathology progression in Alzheimer’s disease (AD) is explained through the network degeneration hypothesis and the neuropathological Braak stages; however, the compatibility of these models remains unclear.

Methods

We utilized [18F]AV-1451 tau-PET scans of 39 subjects with AD and 39 sex-matched amyloid-negative healthy controls (HC) in the ADNI (Alzheimer’s Disease Neuroimaging Initiative) dataset. The peak cluster of tau-tracer uptake was identified in each Braak stage of neuropathological tau deposition and used to create a seed-based functional connectivity network (FCN) using 198 HC subjects, to identify healthy networks unaffected by neurodegeneration.

Results

Voxel-wise tau deposition was both significantly higher inside relative to outside FCNs and correlated significantly and positively with levels of healthy functional connectivity. Within many isolated Braak stages and regions, the correlation between tau and intrinsic functional connectivity was significantly stronger than it was across the whole brain. In this way, each peak cluster of tau was related to multiple Braak stages traditionally associated with both earlier and later stages of disease.

Conclusion

We show specificity of healthy FCN topography for AD-pathological tau as well as positive voxel-by-voxel correlations between pathological tau and healthy functional connectivity. We propose a model of “up- and downstream” functional tau progression, suggesting that tau pathology evolves along functional connectivity networks not only “downstream” (i.e., along the expected sequence of the established Braak stages) but also in part “upstream” or “retrograde” (i.e., against the expected sequence of the established Braak stages), with pathology in earlier Braak stages intensified by its functional relationship to later disease stages.

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Acknowledgments

We thank all the patients who participated in this study as well as their friends and family, and the staff at the University Hospital of Cologne Department of Nuclear Medicine. We thank Michael Greicius, M.D., Ph.D., and Mojtaba Zarei, M.D., Ph.D., for their helpful comments. Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Funding

This project was supported by funding from the DFG (German Research Foundation) DR 445/9-1 to A.D. and T.v.E., a Fulbright Program grant to J.S. sponsored by the Bureau of Educational and Cultural Affairs of the United States Department of State and administered by the Institute of International Education. Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

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Authors and Affiliations

  1. Department of Neurology, Geisinger Medical Center, 100 N. Academy Ave, Danville, PA, 17822, USA

    Joseph Seemiller

  2. Multimodal Neuroimaging Group, Department of Nuclear Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937, Cologne, Germany

    Gérard N. Bischof, Merle C. Hoenig, Thilo van Eimeren & Alexander Drzezga

  3. Molecular Organization of the Brain, Institute of Neuroscience and Medicine 2, Research Center Juelich, Jülich, 52428, Germany

    Merle C. Hoenig & Alexander Drzezga

  4. Institute of Medical Science and Technology, Shahid Beheshti University, Tehran, Iran

    Masoud Tahmasian

  5. Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937, Cologne, Germany

    Thilo van Eimeren

  6. German Center for Neurodegenerative Diseases (DZNE), Bonn/Cologne, Germany

    Thilo van Eimeren & Alexander Drzezga

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  1. Joseph Seemiller
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  2. Gérard N. Bischof
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  4. Masoud Tahmasian
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Contributions

A.D., G.B., and J.S. conceived the project. All authors designed and executed the experiments to analyze the data and interpret the results. J.S., G.B., and A.D. wrote the manuscript. All authors edited the manuscript.

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Correspondence to Joseph Seemiller.

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This article does not contain any studies with human participants or animals performed by any of the authors; all imaging data was obtained through independent repositories as described in methods.

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The authors declare that they have no conflict of interest.

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Seemiller, J., Bischof, G.N., Hoenig, M.C. et al. Indication of retrograde tau spreading along Braak stages and functional connectivity pathways. Eur J Nucl Med Mol Imaging 48, 2272–2282 (2021). https://doi.org/10.1007/s00259-020-05183-1

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