Acta Neuropathol (2009) 118:659–671 DOI 10.1007/s00401-009-0585-1 O R I G I N A L P A P E R Incidence and spectrum of sporadic Creutzfeldt–Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classiﬁcation Piero Parchi Æ Rosaria Strammiello Æ Silvio Notari Æ Armin Giese Æ Jan P. M. Langeveld Æ Anna Ladogana Æ Inga Zerr Æ Federico Roncaroli Æ Patrich Cras Æ Bernardino Ghetti Æ Maurizio Pocchiari Æ Hans Kretzschmar Æ Sabina Capellari Received: 30 June 2009 / Revised: 16 August 2009 / Accepted: 17 August 2009 / Published online: 29 August 2009 The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Six subtypes of sporadic Creutzfeldt–Jakob disease with distinctive clinico-pathological features have been identiﬁed largely based on two types of the abnormal prion protein, PrPSc, and the methionine (M)/valine (V) polymorphic codon 129 of the prion protein. The existence of affected subjects showing mixed phenotypic features and concurrent PrPSc types has been reported but with incon- sistencies among studies in both results and their interpretation. The issue currently complicates diagnosis and classiﬁcation of cases and also has implications for disease pathogenesis. To explore the issue in depth, we carried out a systematic regional study in a large series of 225 cases. PrPSc types 1 and 2 concurrence was detected in 35% of cases and was higher in MM than in MV or VV subjects. The deposition of either type 1 or 2, when con- current, was not random and always characterized by the coexistence of phenotypic features previously described in the pure subtypes. PrPSc type 1 accumulation and related pathology predominated in MM and MV cases, while the type 2 phenotype prevailed in VVs. Neuropathological examination best identiﬁed the mixed types 1 and 2 features in MMs and most MVs, and also uniquely revealed the co- occurrence of pathological variants sharing PrPSc type 2. In contrast, molecular typing best detected the concurrent PrPSc types in VV subjects and MV cases with kuru plaques. The present data provide an updated disease classiﬁcation and are of importance for future epidemiologic and trans- mission studies aimed to identify etiology and extent of strain variation in sporadic Creutzfeldt–Jakob disease. Keywords Prion protein Brain mapping Molecular typing Neurodegeneration Classiﬁcation P. Parchi R. Strammiello S. Notari S. Capellari Dipartimento di Scienze Neurologiche, Universita` di Bologna, Bologna, Italy A. Giese H. Kretzschmar Institut fu¨r Neuropathologie, Ludwig-Maximilians-Universita¨t Mu¨nchen, Munich, Germany J. P. M. Langeveld Central Veterinary Institute of Wageningen UR, Lelystad, The Netherlands A. Ladogana M. Pocchiari Department of Cell Biology and Neurosciences, Istituto Superiore di Sanita`, Rome, Italy I. Zerr Department of Neurology, National Reference Center for TSE Surveillance, Georg-August University, Go¨ttingen, Germany F. Roncaroli Division of Neuroscience and Mental Health, Department of Clinical Neuroscience, Imperial College, London, UK P. Cras Born-Bunge Institute (BBI), University of Antwerp (UA), Antwerp, Belgium B. Ghetti Department of Pathology, Indiana University, Indianapolis, IN, USA P. Parchi (&) Department of Neurological Sciences, Universtity of Bologna, Via Foscolo 7, 40123 Bologna, Italy e-mail: piero.parchi@unibo.it 123