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Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions: an inter-laboratory study by the BrainNet Europe consortium

  • Neurology and Preclinical Neurological Studies - Original Article
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An Erratum to this article was published on 25 November 2014

Abstract

The BrainNet Europe consortium assessed the reproducibility in the assignment of the type of frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) 43 following current recommendations. The agreement rates were influenced by the immunohistochemical (IHC) method and by the classification strategy followed. p62-IHC staining yielded good uniform quality of stains, but the most reliable results were obtained implementing specific Abs directed against the hallmark protein TDP43. Both assessment of the type and the extent of lesions were influenced by the Abs and by the quality of stain. Assessment of the extent of the lesions yielded poor results repeatedly; thus, the extent of pathology should not be used in diagnostic consensus criteria. Whilst 31 neuropathologists typed 30 FTLD-TDP cases, inter-rater agreement ranged from 19 to 100 per cent, being highest when applying phosphorylated TDP43/IHC. The agreement was highest when designating Type C or Type A/B. In contrast, there was a poor agreement when attempting to separate Type A or Type B FTLD-TDP. In conclusion, we can expect that neuropathologist, independent of his/her familiarity with FTLD-TDP pathology, can identify a TDP43-positive FTLD case. The goal should be to state a Type (A, B, C, D) or a mixture of Types (A/B, A/C or B/C). Neuropathologists, other clinicians and researchers should be aware of the pitfalls whilst doing so. Agreement can be reached in an inter-laboratory setting regarding Type C cases with thick and long neurites, whereas the differentiation between Types A and B may be more troublesome.

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Acknowledgments

We thank Tarja Kauppinen and all other laboratory technicians of the BNE members for their skilful technical assistance and Meena Strömqvist for her critical reading of the manuscript. We acknowledge the following BNE centres (in alphabetical order of the cities) for contributing the material with generic data used in this study: Netherlands Brain Bank (Amsterdam), Hospital de Bellvitge/Universitat de Barcelona (Barcelona), National Institute of Psychiatry and Neurology (Budapest, OPNI) closed in 2007, Georg-August-University (Göttingen), Karolinska Institutet (Huddinge), Kuopio University Hospital (Kuopio), MRC London Neurodegenerative Disease Brain Bank Institute of Psychiatry (London), Hospices Civils de Lyon (Lyon), Istituto Nazionale Neurologico Carlo Besta (Milan), Ludwig-Maximilians-University of Munich (Munich), Medical University Vienna (Vienna) and University of Wuerzburg (Wuerzburg). This study was supported by the European Union Grant FP6: BNEII No LSHM-CT-2004-503039. TA, HK and DRT were also supported by the German ministry for education and research (BMBF; FTLDc). IA was also supported by the local Grants (ALF) from Uppsala University Hospital, Sweden. This article reflects only the authors’ views, and the community is not liable for any use that may be made of the information contained herein. The study has been authorised by the Ethics Committee of Kuopio University Hospital. DRT received consultant honorary from Simon Kucher and partners, GE-Healthcare, and Covance Laboratories, speaker honorary from GE-Healthcare and collaboration with Novartis Pharma AG.

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Authors and Affiliations

  1. Section of Clinical Pathology Uppsala University Hospital, Rudbeck’s Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 85, Uppsala, Sweden

    Irina Alafuzoff

  2. Centre for Neuropathology and Prion Research, München Ludwig-Maximilians-University, Munich, Germany

    Thomas Arzberger & Hans Kretzschmar

  3. Department of Clinical Neuropathology, Institute of Psychiatry, King’s College Hospital and MRC London Neurodegenerative Diseases Brain Bank, London, UK

    Safa Al-Sarraj, Istvan Bodi & Andrew King

  4. Geriatric Department, Institute for Clinical Medicine, Oslo University, Oslo, Norway

    Nenad Bogdanovic

  5. Division of Neuropathology and Neurology 5, IRCSS Foundation Istituto Neurologico Carlo Besta, Milan, Italy

    Orso Bugiani & Giorgio Giaccone

  6. Institute of Neuropathology, Bellvitge University Hospital, University of Barcelona, CEBERNED, Barcelona, Spain

    Isidro Ferrer

  7. Neurological Tissue Bank of the Biobanc-Hospital Clínic-IDIBAPS, Barcelona, Spain

    Ellen Gelpi

  8. Neuropathology Unit, Department of Medicine, Imperial College London, London, UK

    Stephen Gentleman

  9. Faculty of Medicine and Faculty of Health Science, Brain and Mind Research Institute, The University of Sydney, Sydney, Australia

    Manuel B. Graeber

  10. Department of Neuropathology, Instutute of Pathology, University of Debrecen, Debrecen, Hungary

    Tibor Hortobagyi

  11. Department of Pathology, National and Capodistrian University of Athens, Athens, Greece

    Nikolaos Kavantzas, Penelope Korkolopoulou & Efstratios Patsouris

  12. Institute of Neurology, Medical University of Vienna, Vienna, Austria

    Gábor G. Kovács

  13. Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK

    Paul G. Ince & Stephen B. Wharton

  14. National CJD Research & Surveillance Unit, Western General Hospital, University of Edinburgh, Edinburgh, UK

    James W. Ironside

  15. Hospices Civils de Lyon, Centre de Pathologie et de Neuropathologie Est, Lyon Neuroscience Research Center, Universite Lyon, Lyon, France

    David Meyronet & Nathalie Streichenberger

  16. Abteilung Neuropathologie, Pathologisches Institut der Univeristät Wurzburg, Wurzburg, Germany

    Camelia Monoranu & Wolfgang Roggendorf

  17. Department of Neuropatology, German Center of Neurodegenerative Diseases, University of Tubingen and DZNE, Tubingen, Germany

    Manuela Neumann

  18. Department of Geriatrics, Karolinska Institutet, Huddinge, Stockholm, Sweden

    Tatjana Nilsson

  19. Department of Biomedical and Neuromotor Sciences, Istituto delle Scienze Neurologiche, University of Bologna, IRCCS, Bologna, Italy

    Piero Parchi

  20. Department of Clinical Medicine, University of Eastern Finland, Kuopio, Finland

    Maria Pikkarainen

  21. Department of Molecular Neuroscience, Queen Square Brain Bank, UCL Institute of Neurology, London, UK

    Tamas Revesz

  22. VU University Medical Center, Amsterdam, The Netherlands

    Annemieke Rozemuller

  23. Laboratoire de Neuropathologie Raymond Escourolle, Assistance Publique-hopitaux de Paris, Université Pierre et Marie Curie and INSERM, Paris, France

    Danielle Seilhean

  24. Institute of Pathology, Laboratory of Neuropathology, University of Ulm, Ulm, Germany

    Dietmar R. Thal

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  1. Irina Alafuzoff
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  2. Maria Pikkarainen
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Corresponding author

Correspondence to Irina Alafuzoff.

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BrainNet Europe: http://www.brainnet-europe.org/.

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702_2014_1304_MOESM1_ESM.ppt

Supplement Fig. 1 Summary of the published subtyping recommendations in tabulated form and the instructions of assessment of immunoreactive lesions (PPT 540 kb)

Supplement Fig. 2 Assessments sheet used in part II (PPT 155 kb)

Supplementary material 3 (DOC 372 kb)

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Alafuzoff, I., Pikkarainen, M., Neumann, M. et al. Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions: an inter-laboratory study by the BrainNet Europe consortium. J Neural Transm 122, 957–972 (2015). https://doi.org/10.1007/s00702-014-1304-1

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