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Journal of Neural Transmission

, Volume 122, Issue 7, pp 957–972 | Cite as

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

  • Irina Alafuzoff
  • Maria Pikkarainen
  • Manuela Neumann
  • Thomas Arzberger
  • Safa Al-Sarraj
  • Istvan Bodi
  • Nenad Bogdanovic
  • Orso Bugiani
  • Isidro Ferrer
  • Ellen Gelpi
  • Stephen Gentleman
  • Giorgio Giaccone
  • Manuel B. Graeber
  • Tibor Hortobagyi
  • Paul G. Ince
  • James W. Ironside
  • Nikolaos Kavantzas
  • Andrew King
  • Penelope Korkolopoulou
  • Gábor G. Kovács
  • David Meyronet
  • Camelia Monoranu
  • Tatjana Nilsson
  • Piero Parchi
  • Efstratios Patsouris
  • Tamas Revesz
  • Wolfgang Roggendorf
  • Annemieke Rozemuller
  • Danielle Seilhean
  • Nathalie Streichenberger
  • Dietmar R. Thal
  • Stephen B. Wharton
  • Hans Kretzschmar
Neurology and Preclinical Neurological Studies - Original Article

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.

Keywords

Ubiquitin p62 TDP43 Phosphorylated TDP43 FTLD-TDP BrainNet Europe Immunohistochemistry Inter-laboratory study Tissue microarray 

Notes

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.

Supplementary material

702_2014_1304_MOESM1_ESM.ppt (540 kb)
Supplement Fig. 1 Summary of the published subtyping recommendations in tabulated form and the instructions of assessment of immunoreactive lesions (PPT 540 kb)
702_2014_1304_MOESM2_ESM.ppt (156 kb)
Supplement Fig. 2 Assessments sheet used in part II (PPT 155 kb)
702_2014_1304_MOESM3_ESM.doc (372 kb)
Supplementary material 3 (DOC 372 kb)

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Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  • Irina Alafuzoff
    • 1
  • Maria Pikkarainen
    • 20
  • Manuela Neumann
    • 17
  • Thomas Arzberger
    • 2
  • Safa Al-Sarraj
    • 3
  • Istvan Bodi
    • 3
  • Nenad Bogdanovic
    • 4
  • Orso Bugiani
    • 5
  • Isidro Ferrer
    • 6
  • Ellen Gelpi
    • 7
  • Stephen Gentleman
    • 8
  • Giorgio Giaccone
    • 5
  • Manuel B. Graeber
    • 9
  • Tibor Hortobagyi
    • 10
  • Paul G. Ince
    • 13
  • James W. Ironside
    • 14
  • Nikolaos Kavantzas
    • 11
  • Andrew King
    • 3
  • Penelope Korkolopoulou
    • 11
  • Gábor G. Kovács
    • 12
  • David Meyronet
    • 15
  • Camelia Monoranu
    • 16
  • Tatjana Nilsson
    • 18
  • Piero Parchi
    • 19
  • Efstratios Patsouris
    • 11
  • Tamas Revesz
    • 21
  • Wolfgang Roggendorf
    • 16
  • Annemieke Rozemuller
    • 22
  • Danielle Seilhean
    • 23
  • Nathalie Streichenberger
    • 15
  • Dietmar R. Thal
    • 24
  • Stephen B. Wharton
    • 13
  • Hans Kretzschmar
    • 2
  1. 1.Section of Clinical Pathology Uppsala University Hospital, Rudbeck’s Laboratory, Department of Immunology, Genetics and PathologyUppsala UniversityUppsalaSweden
  2. 2.Centre for Neuropathology and Prion ResearchMünchen Ludwig-Maximilians-UniversityMunichGermany
  3. 3.Department of Clinical Neuropathology, Institute of PsychiatryKing’s College Hospital and MRC London Neurodegenerative Diseases Brain BankLondonUK
  4. 4.Geriatric Department, Institute for Clinical MedicineOslo UniversityOsloNorway
  5. 5.Division of Neuropathology and Neurology 5IRCSS Foundation Istituto Neurologico Carlo BestaMilanItaly
  6. 6.Institute of NeuropathologyBellvitge University Hospital, University of Barcelona, CEBERNEDBarcelonaSpain
  7. 7.Neurological Tissue Bank of the Biobanc-Hospital Clínic-IDIBAPSBarcelonaSpain
  8. 8.Neuropathology Unit, Department of MedicineImperial College LondonLondonUK
  9. 9.Faculty of Medicine and Faculty of Health Science, Brain and Mind Research InstituteThe University of SydneySydneyAustralia
  10. 10.Department of Neuropathology, Instutute of PathologyUniversity of DebrecenDebrecenHungary
  11. 11.Department of PathologyNational and Capodistrian University of AthensAthensGreece
  12. 12.Institute of NeurologyMedical University of ViennaViennaAustria
  13. 13.Sheffield Institute for Translational NeuroscienceUniversity of SheffieldSheffieldUK
  14. 14.National CJD Research & Surveillance Unit, Western General HospitalUniversity of EdinburghEdinburghUK
  15. 15.Hospices Civils de Lyon, Centre de Pathologie et de Neuropathologie Est, Lyon Neuroscience Research CenterUniversite LyonLyonFrance
  16. 16.Abteilung NeuropathologiePathologisches Institut der Univeristät WurzburgWurzburgGermany
  17. 17.Department of Neuropatology, German Center of Neurodegenerative DiseasesUniversity of Tubingen and DZNETubingenGermany
  18. 18.Department of GeriatricsKarolinska Institutet, HuddingeStockholmSweden
  19. 19.Department of Biomedical and Neuromotor Sciences, Istituto delle Scienze NeurologicheUniversity of Bologna, IRCCSBolognaItaly
  20. 20.Department of Clinical MedicineUniversity of Eastern FinlandKuopioFinland
  21. 21.Department of Molecular Neuroscience, Queen Square Brain BankUCL Institute of NeurologyLondonUK
  22. 22.VU University Medical CenterAmsterdamThe Netherlands
  23. 23.Laboratoire de Neuropathologie Raymond Escourolle, Assistance Publique-hopitaux de ParisUniversité Pierre et Marie Curie and INSERMParisFrance
  24. 24.Institute of Pathology, Laboratory of NeuropathologyUniversity of UlmUlmGermany

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