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The A/T/N model applied through imaging biomarkers in a memory clinic

European Journal of Nuclear Medicine and Molecular Imaging volume 47, pages 247–255 (2020)Cite this article

Abstract

Purpose

The A/T/N model is a research framework proposed to investigate Alzheimer’s disease (AD) pathological bases (i.e., amyloidosis A, neurofibrillary tangles T, and neurodegeneration N). The application of this system on clinical populations is still limited. The aim of the study is to evaluate the topography of T distribution by 18F-flortaucipir PET in relation to A and N and to describe the A/T/N status through imaging biomarkers in memory clinic patients.

Methods

Eighty-one patients with subjective and objective cognitive impairment were classified as A+/A− and N+/N− through amyloid PET and structural MRI. Tau deposition was compared across A/N subgroups at voxel level. T status was defined through a global cut point based on A/N subgroups and subjects were categorized following the A/T/N model.

Results

A+N+ and A+N− subgroups showed higher tau burden compared to A−N− group, with A+N− showing significant deposition limited to the medial and lateral temporal regions. Global cut point discriminated A+N+ and A+N− from A−N− subjects. On A/T/N classification, 23% of patients showed a negative biomarker profile, 58% fell within the Alzheimer’s continuum, and 19% of the sample was characterized by non-AD pathologic change.

Conclusion

Medial and lateral temporal regions represent a site of significant tau accumulation in A+ subjects and possibly a useful marker of early clinical changes. This is the first study in which the A/T/N model is applied using 18F-flortaucipir PET in a memory clinic population. The majority of patients showed a profile consistent with the Alzheimer’s continuum, while a minor percentage showed a profile suggestive of possible other neurodegenerative diseases. These results support the applicability of the A/T/N model in clinical practice.

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Acknowledgments

We thank all patients and volunteers for participating in this study. We thank Avid Radiopharmaceuticals (Lilly) for supplying the precursor for the manufacturing of 18F-flortaucipir.

Funding

The study has been supported by the Swiss National Science Foundation (“The Biological Basis of Cognitive Impairment due to SNAP: Studying the interplay between amyloidosis and tau-related neurodegeneration”—SNF 320030_169876) and partially supported by the Personalized Health and Related Technology Initiative (“Advanced Translational Imaging”—PHRT 2017-512).

This study is part of CoSTREAM (www.costream.eu) and received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 667375.

The Centre de la mémoire at Geneva University Hospital is funded by private donors: A.P.R.A.—Association Suisse pour la Recherche sur la Maladie d’Alzheimer, Genève; Fondation Segré, Genève; Ivan Pictet, Genève; Fondazione Agusta, Lugano; Fondation Chmielewski, Genève.

Author information

Affiliations

  1. NIMTlab, Neuroimaging and Innovative Molecular Tracers Laboratory, University of Geneva, 4 rue Gabrielle-Perret-Gentil, CH-1211, Geneva 14, Switzerland

    Alessandra Dodich & Valentina Garibotto

  2. Department of Rehabilitation and Geriatrics, Geneva University Hospitals, Geneva, Switzerland

    Aline Mendes, Dina Zekry & Gabriel Gold

  3. Cognitive Neurology Unit, Department of Neurology, Geneva University Hospitals, Geneva, Switzerland

    Frédéric Assal

  4. Memory Center - Department of Rehabilitation and Geriatrics, Geneva University Hospitals, Geneva, Switzerland

    Christian Chicherio, Paulina Andryszak & Giovanni B. Frisoni

  5. Center for the Interdisciplinary Study of Gerontology and Vulnerability (CIGEV), University of Geneva, Geneva, Switzerland

    Christian Chicherio

  6. LANVIE - Laboratory of Neuroimaging of Aging, University of Geneva, Geneva, Switzerland

    Barinjaka Rakotomiaramanana, Paulina Andryszak, Federica Ribaldi, Marina Boccardi & Giovanni B. Frisoni

  7. LANE – Laboratory of Alzheimer’s Neuroimaging and Epidemiology, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy

    Cristina Festari, Federica Ribaldi, Marina Boccardi & Giovanni B. Frisoni

  8. Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy

    Cristina Festari & Federica Ribaldi

  9. Radiology Division, Diagnostic Department, Geneva University Hospitals, Geneva, Switzerland

    Max Scheffler

  10. Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland

    Roger Schibli

  11. Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, Villigen-PSI, Switzerland

    Roger Schibli

  12. Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA

    Adam J. Schwarz

  13. Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA

    Adam J. Schwarz

  14. Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA

    Adam J. Schwarz

  15. Neurodiagnostic and Neurointerventional Division, Diagnostic Department, Geneva University Hospitals, Geneva, Switzerland

    Karl-Olof Lövblad

  16. Hospital for Psychogeriatric Medicine, Psychiatric University Hospital Zurich (PUK), Zurich, Switzerland

    Paul G. Unschuld

  17. Nuclear Medicine and Molecular Imaging Division, Diagnostic Department, Geneva University Hospitals, Geneva, Switzerland

    Valentina Garibotto

Authors
  1. Alessandra Dodich
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  2. Aline Mendes
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  3. Frédéric Assal
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  4. Christian Chicherio
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  5. Barinjaka Rakotomiaramanana
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  6. Paulina Andryszak
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  7. Cristina Festari
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  8. Federica Ribaldi
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  9. Max Scheffler
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  10. Roger Schibli
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  11. Adam J. Schwarz
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  13. Karl-Olof Lövblad
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  14. Marina Boccardi
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  15. Paul G. Unschuld
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  16. Gabriel Gold
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  17. Giovanni B. Frisoni
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  18. Valentina Garibotto
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Contributions

Study concept and design: Dodich, Frisoni, Garibotto. Clinical consultant and data acquisition: Mendes, Assal, Chicherio, Rakotomiaramanana, Andryszak, Sheffler, Zekry, Lovblad. Statistical analysis and data interpretation: Dodich, Festari, Ribaldi, Frisoni, Garibotto. Drafting of the manuscript: Dodich, Garibotto. All the authors contributed to the critical revision of the manuscript for important intellectual content.

Corresponding author

Correspondence to Alessandra Dodich.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval and consent to participate

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research committee (Commission cantonale d’éthique de la recherche—CCER)) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All subjects participating in this study have signed an informed consent form.

Data policy

The datasets generated during and/or analyzed during the current study are part of the Geneva Memory Clinic dataset and available from the corresponding author on founded request.

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The manuscript has been seen and approved by all authors for submission to EJNMMI.

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Dodich, A., Mendes, A., Assal, F. et al. The A/T/N model applied through imaging biomarkers in a memory clinic. Eur J Nucl Med Mol Imaging 47, 247–255 (2020). https://doi.org/10.1007/s00259-019-04536-9

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Keywords

  • Alzheimer’s disease
  • PET
  • 18F-flortaucipir
  • A/T/N model