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Consensus classification of human prion disease histotypes allows reliable identification of molecular subtypes: an inter-rater study among surveillance centres in Europe and USA

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Abstract

The current classification of human sporadic prion diseases recognizes six major phenotypic subtypes with distinctive clinicopathological features, which largely correlate at the molecular level with the genotype at the polymorphic codon 129 (methionine, M, or valine, V) in the prion protein gene and with the size of the protease-resistant core of the abnormal prion protein, PrPSc (i.e. type 1 migrating at 21 kDa and type 2 at 19 kDa). We previously demonstrated that PrPSc typing by Western blotting is a reliable means of strain typing and disease classification. Limitations of this approach, however, particularly in the interlaboratory setting, are the association of PrPSc types 1 or 2 with more than one clinicopathological phenotype, which precludes definitive case classification if not supported by further analysis, and the difficulty of fully recognizing cases with mixed phenotypic features. In this study, we tested the inter-rater reliability of disease classification based only on histopathological criteria. Slides from 21 cases covering the whole phenotypic spectrum of human sporadic prion diseases, and also including two cases of variant Creutzfeldt–Jakob disease (CJD), were distributed blindly to 13 assessors for classification according to given instructions. The results showed good-to-excellent agreement between assessors in the classification of cases. In particular, there was full agreement (100 %) for the two most common sporadic CJD subtypes and variant CJD, and very high concordance in general for all pure phenotypes and the most common subtype with mixed phenotypic features. The present data fully support the basis for the current classification of sporadic human prion diseases and indicate that, besides molecular PrPSc typing, histopathological analysis permits reliable disease classification with high interlaboratory accuracy.

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References

  1. Aguzzi A, Heikenwalder M, Polymenidou M (2007) Insights into prion strains and neurotoxicity. Nat Rev Mol Cell Biol 8:552–561

    Article  PubMed  CAS  Google Scholar 

  2. Bishop MT, Will RG, Manson JC (2010) Defining sporadic Creutzfeldt–Jakob disease strains and their transmission properties. Proc Natl Acad Sci USA 107:12005–12010

    Article  PubMed  CAS  Google Scholar 

  3. Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, McCardle L, Chree A, Hope J, Birkett C, Cousens S, Fraser H, Bostock CJ (1997) Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature 389:498–501

    Article  PubMed  CAS  Google Scholar 

  4. Bruce ME, Boyle A, Cousens S, McConnell I, Foster J, Goldmann W, Fraser H (2002) Strain characterization of natural sheep scrapie and comparison with BSE. J Gen Virol 83:695–704

    PubMed  Google Scholar 

  5. Cali I, Castellani R, Alshekhlee A, Cohen Y, Blevins J, Yuan J, Langeveld JP, Parchi P, Safar JG, Zou WQ, Gambetti P (2009) Co-existence of scrapie prion protein types 1 and 2 in sporadic Creutzfeldt–Jakob disease: its effect on the phenotype and prion-type characteristics. Brain 132:2643–2658

    Article  PubMed  Google Scholar 

  6. Capellari S, Strammiello R, Saverioni D, Kretzschmar H, Parchi P (2011) Genetic Creutzfeldt–Jakob disease and fatal familial insomnia: insights into phenotypic variability and disease pathogenesis. Acta Neuropathol 121:21–37

    Article  PubMed  CAS  Google Scholar 

  7. Collinge J, Sidle KCL, Meads J, Ironside J, Hill AF (1996) Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature 383:685–690

    Article  PubMed  CAS  Google Scholar 

  8. Gambetti P, Kong Q, Zou W, Parchi P, Chen SG (2003) Sporadic and familial CJD: classification and characterisation. Br Med Bull 66:213–239

    Article  PubMed  CAS  Google Scholar 

  9. Ghetti B, Tagliavini F, Takao M, Bugiani O, Piccardo P (2003) Hereditary prion protein amyloidoses. Clin Lab Med 23:65–85

    Article  PubMed  Google Scholar 

  10. Head MW, Bunn TJR, Bishop MT, McLoughlin V, Lowrie S, McKimmie CS, Williams MC, McCardle L, MacKenzie J, Knight R, Will RG, Ironside JW (2004) Prion protein heterogeneity in sporadic but not variant Creutzfeldt–Jakob Disease: UK cases 1991–2002. Ann Neurol 55:851–859

    Article  PubMed  CAS  Google Scholar 

  11. Ironside JW, McCardle L, Horsburgh A, Lim Z, Head MW (2002) Pathological diagnosis of variant Creutzfeldt–Jakob disease. APMIS 110:79–87

    Article  PubMed  CAS  Google Scholar 

  12. Jansen C, Parchi P, Capellari S, Ibrahim-Verbaas CA, Schuur M, Strammiello R, Corrado P, Bishop MT, van Gool VA, Verbeek MM, Baas F, van Saane V, Spliet WGM, Jansen GH, van Duijn CM, Rozemuller AJM (2012) Human prion diseases in The Netherlands (1998–2009): clinical, genetic and molecular aspects. PLoS ONE 7:e36333

    Article  PubMed  CAS  Google Scholar 

  13. Kobayashi A, Arima K, Ogawa M, Murata M, Fukuda T, Kitamoto T (2008) Plaque-type deposition of prion protein in the damaged white matter of sporadic Creutzfeldt–Jakob disease MM1 patients. Acta Neuropathol 116:561–566

    Article  PubMed  CAS  Google Scholar 

  14. Kobayashi A, Sakuma N, Matsuura Y, Mohri S, Aguzzi A, Kitamoto T (2010) Experimental verification of a traceback phenomenon in prion infection. J Virol 84:3230–3238

    Article  PubMed  CAS  Google Scholar 

  15. Korth C, Kaneko K, Groth D, Heye N, Telling G, Mastrianni J, Parchi P, Gambetti P, Will R, Ironside J, Heinrich C, Tremblay P, De-Armond SJ, Prusiner SB (2003) Abbreviated incubation times for human prions in mice expressing a chimeric mouse-human prion protein transgene. Proc Natl Acad Sci USA 100:4784–4789

    Article  PubMed  CAS  Google Scholar 

  16. Mastrianni JA, Nixon R, Layzer R, Telling GC, Han D, DeArmond SJ, Prusiner SB (1999) Prion protein conformation in a patient with sporadic fatal insomnia. N Engl J Med 340:1630–1638

    Article  PubMed  CAS  Google Scholar 

  17. Moda F, Suardi S, Di Fede G, Indaco A, Limido L, Vimercati C, Ruggerone M, Campagnani I, Langeveld J, Terruzzi A, Brambilla A, Zerbi P, Fociani P, Bishop MT, Will RG, Manson JC, Giaccone G, Tagliavini F (2012) MM2-thalamic Creutzfeldt–Jakob disease: neuropathological, biochemical and transmission studies identify a distinctive prion strain. Brain Pathol (in press). doi: 10.1111/j.1750-3639.2012.00572

  18. Monari L, Chen SG, Brown P, Parchi P, Petersen RB, Mikol J, Cortelli P, Montagna P, Ghetti B, Goldfarb LG, Gajdusek DC, Lugaresi E, Gambetti P, Autilio-Gambetti L (1994) Fatal familial insomnia and familial Creutzfeldt–Jakob disease: different prion proteins determined by a DNA polymorphism. Proc Natl Acad Sci USA 91:2839–2842

    Article  PubMed  CAS  Google Scholar 

  19. Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Trojanowski JQ, Vinters HV, Hyman BT (2012) National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 123:1–11

    Google Scholar 

  20. Nonno R, Di Bari M, Cardone F, Vaccari G, Fazzi P, Dell’Omo G, Cartoni C, Ingrosso L, Boyle A, Galeno R, Sbriccoli M, Lipp HP, Bruce M, Pocchiari M, Agrimi U (2006) Efficient transmission and characterization of Creutzfeldt–Jakob disease strains in bank voles. PLoS Pathog 2:e12

    Article  PubMed  Google Scholar 

  21. Notari S, Capellari S, Giese A, Westner I, Baruzzi A, Ghetti B, Gambetti P, Kretzschmar HA, Parchi P (2004) Effects of different experimental conditions on the PrPSc core generated by protease digestion. J Biol Chem 279:16797–16804

    Article  PubMed  CAS  Google Scholar 

  22. Notari S, Strammiello R, Capellari S, Giese A, Cescatti M, Grassi J, Ghetti B, Langeveld JP, Zou WQ, Gambetti P, Kretzschmar HA, Parchi P (2008) Characterization of truncated forms of abnormal prion protein in Creutzfeldt–Jakob disease. J Biol Chem 283:30557–30565

    Article  PubMed  CAS  Google Scholar 

  23. Parchi P, Capellari S, Chen SG, Petersen RB, Gambetti P, Kopp N, Brown P, Kitamoto T, Tateishi J, Giese A, Kretzschmar H (1997) Typing prion isoforms. Nature 386:232–233

    Article  PubMed  CAS  Google Scholar 

  24. Parchi P, Capellari S, Chin S, Schwartz HB, Schecter NP, Butts JD, Hudkins P, Burns DK, Powers JM, Gambetti P (1999) A subtype of sporadic prion disease mimicking fatal familial insomnia. Neurology 52:1757–1763

    Article  PubMed  CAS  Google Scholar 

  25. Parchi P, Castellani R, Capellari S, Ghetti B, Young K, Chen SG, Farlow M, Dickson DW, Sima AAF, Trojanowski JQ, Petersen RB, Gambetti P (1996) Molecular basis of phenotypic variability in sporadic Creutzfeldt–Jakob disease. Ann Neurol 39:767–778

    Article  PubMed  CAS  Google Scholar 

  26. Parchi P, Cescatti M, Notari S, Schulz-Schaeffer WJ, Capellari S, Giese A, Zou WQ, Kretzschmar H, Ghetti B, Brown P (2010) Agent strain variation in human prion disease: insights from a molecular and pathological review of the National Institutes of Health series of experimentally transmitted disease. Brain 133:3030–3042

    Article  PubMed  Google Scholar 

  27. Parchi P, Chen SG, Brown P, Zou W, Capellari S, Budka H, Hainfellner J, Reyes PF, Golden GT, Hauw JJ, Gajdusek DC, Gambetti P (1998) Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann–Sträussler–Scheinker disease. Proc Natl Acad Sci USA 95:8322–8327

    Google Scholar 

  28. Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, Zerr I, Budka H, Kopp N, Piccardo P, Poser S, Rojiani A, Streichemberger N, Julien J, Vital C, Ghetti B, Gambetti P, Kretzschmar H (1999) Classification of sporadic Creutzfeldt–Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 46:224–233

    Article  PubMed  CAS  Google Scholar 

  29. Parchi P, Notari S, Weber P, Schimmel H, Budka H, Ferrer I, Haik S, Hauw JJ, Head MW, Ironside JW, Limido L, Rodriguez A, Ströbel T, Tagliavini F, Kretzschmar HA (2009) Inter-laboratory assessment of PrPSc typing in Creutzfeldt–Jakob disease: a Western blot study within the NeuroPrion Consortium. Brain Pathol 19:384–391

    Article  PubMed  CAS  Google Scholar 

  30. Parchi P, Strammiello R, Giese A, Kretzschmar H (2011) Phenotypic variability of sporadic human prion disease and its molecular basis: past, present, and future. Acta Neuropathol 121:91–112

    Article  PubMed  CAS  Google Scholar 

  31. Parchi P, Strammiello R, Notari S, Giese A, Langeveld JP, Ladogana A, Zerr I, Roncaroli F, Cras P, Ghetti B, Pocchiari M, Kretzschmar H, Capellari S (2009) Incidence and spectrum of sporadic Creutzfeldt–Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification. Acta Neuropathol 118:659–671

    Article  PubMed  CAS  Google Scholar 

  32. Parchi P, Zou W, Wang W, Brown P, Capellari S, Ghetti B, Kopp N, Schulz-Schaeffer WJ, Kretzschmar HA, Head MW, Ironside JW, Gambetti P, Chen SG (2000) Genetic influence on the structural variations of the abnormal prion protein. Proc Natl Acad Sci USA 97:10168–10172

    Article  PubMed  CAS  Google Scholar 

  33. Piccardo P, Dlouhy SR, Lievens PM, Young K, Bird TD, Nochlin D, Dickson DW, Vinters HV, Zimmerman TR, Mackenzie IR, Kish SJ, Ang LC, De Carli C, Pocchiari M, Brown P, Gibbs CJ Jr, Gajdusek DC, Bugiani O, Ironside J, Tagliavini F, Ghetti B (1998) Phenotypic variability of Gerstmann-Sträussler-Scheinker disease is associated with prion protein heterogeneity. J Neuropathol Exp Neurol 57:979–988

    Article  PubMed  CAS  Google Scholar 

  34. Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95:13363–13383

    Article  PubMed  CAS  Google Scholar 

  35. Puoti G, Giaccone G, Rossi G, Canciani B, Bugiani O, Tagliavini F (1999) Sporadic Creutzfeldt–Jakob disease: co-occurrence of different types of PrPSc in the same brain. Neurology 53:2173–2176

    Article  PubMed  CAS  Google Scholar 

  36. Telling GC, Parchi P, DeArmond SJ, Cortelli P, Montagna P, Gabizon R, Mastrianni J, Lugaresi E, Gambetti P, Prusiner SB (1996) Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 274:2079–2082

    Article  PubMed  CAS  Google Scholar 

  37. Vorberg I, Buschmann A, Harmeyer S, Saalmüller A, Pfaff E, Groschup MH (1999) A novel epitope for the specific detection of exogenous prion proteins in transgenic mice and transfected murine cell lines. Virology 255:26–31

    Article  PubMed  CAS  Google Scholar 

  38. Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, Poser S, Pocchiari M, Hofman A, Smith PG (1996) A new variant of Creutzfeldt–Jakob disease in the UK. Lancet 347:921–925

    Article  PubMed  CAS  Google Scholar 

  39. Zou WQ, Puoti G, Xiao X, Yuan J, Qing L, Cali I, Shimoji M, Langeveld JP, Castellani R, Notari S, Crain B, Schmidt RE, Geschwind M, Dearmond SJ, Cairns NJ, Dickson D, Honig L, Torres JM, Mastrianni J, Capellari S, Giaccone G, Belay ED, Schonberger LB, Cohen M, Perry G, Kong Q, Parchi P, Tagliavini F, Gambetti P (2010) Variably protease-sensitive prionopathy: a new sporadic disease of the prion protein. Ann Neurol 68:162–172

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the European Commission (contract: FOOD-CT-2004-506579). We wish to thank Prof. Martin Groschup, Friedrich-Löffler-Institut, Greifswald-Insel Riems, for his generous gift of monoclonal antibody L42, as well as Angelika Henn, Ursula Jung, and Sabrina Boninsegna for technical assistance.

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Authors and Affiliations

  1. IRCCS Istituto delle Scienze Neurologiche and Dipartimento di Scienze Neurologiche, Università di Bologna, Bologna, Italy

    Piero Parchi & Daniela Saverioni

  2. Institut für Neuropathologie, Ludwig-Maximilians-Universität, Munich, Germany

    Laura de Boni, Armin Giese & Hans A. Kretzschmar

  3. National Prion Pathology Surveillance Centre, CWRU, Cleveland, OH, USA

    Mark L. Cohen & Pierluigi Gambetti

  4. Institut de Neuropatologia, Hospital Universitari de Bellvitage, Universitat de Barcelona, Barcelona, Spain

    Isidro Ferrer

  5. Neurological Tissue Bank of the Biobanc-Hospital Clinic-IDIBAPS, Barcelona, Spain

    Ellen Gelpi

  6. Laboratorio di Neuropatologia, Fondazione IRCCS Istituto Nazionale Neurologico Carlo Besta, Milan, Italy

    Giorgio Giaccone & Fabrizio Tagliavini

  7. APHP, Laboratoire de Neuropathologie Raymond Escourolle, GH Pitiè-Salpêtrière Université Pierre et Marie Curie (UPMC-Paris 6), Sorbonne-Universités, Paris, France

    Jean-Jacques Hauw & Danielle Seilhean

  8. Institute of Neurology, AKH 4J, Medical University of Vienna, Vienna, Austria

    Romana Höftberger & Gabor G. Kovacs

  9. National CJD Research and Surveillance Unit, Western General Hospital, Edinburgh, EH4 2XU, UK

    James W. Ironside

  10. Dutch Surveillance Centre for Prion Diseases, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands

    Casper Jansen & Annemieke Rozemuller

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  1. Piero Parchi
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  2. Laura de Boni
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  3. Daniela Saverioni
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  6. Pierluigi Gambetti
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  7. Ellen Gelpi
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  8. Giorgio Giaccone
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  10. Romana Höftberger
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  11. James W. Ironside
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  14. Annemieke Rozemuller
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  16. Fabrizio Tagliavini
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  17. Armin Giese
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  18. Hans A. Kretzschmar
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Correspondence to Piero Parchi or Hans A. Kretzschmar.

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Parchi, P., de Boni, L., Saverioni, D. et al. Consensus classification of human prion disease histotypes allows reliable identification of molecular subtypes: an inter-rater study among surveillance centres in Europe and USA. Acta Neuropathol 124, 517–529 (2012). https://doi.org/10.1007/s00401-012-1002-8

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