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. 2009 Nov;118(5):659-71.
doi: 10.1007/s00401-009-0585-1. Epub 2009 Aug 29.

Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification

Piero Parchi  1 , Rosaria Strammiello, Silvio Notari, Armin Giese, Jan P M Langeveld, Anna Ladogana, Inga Zerr, Federico Roncaroli, Patrich Cras, Bernardino Ghetti, Maurizio Pocchiari, Hans Kretzschmar, Sabina Capellari
Affiliations

Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification

Piero Parchi et al. Acta Neuropathol. 2009 Nov.

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, PrP(Sc), and the methionine (M)/valine (V) polymorphic codon 129 of the prion protein. The existence of affected subjects showing mixed phenotypic features and concurrent PrP(Sc) types has been reported but with inconsistencies 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. PrP(Sc) 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 concurrent, was not random and always characterized by the coexistence of phenotypic features previously described in the pure subtypes. PrP(Sc) 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 PrP(Sc) type 2. In contrast, molecular typing best detected the concurrent PrP(Sc) 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 transmission studies aimed to identify etiology and extent of strain variation in sporadic Creutzfeldt-Jakob disease.

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Figures

Fig. 1
Fig. 1
a mAb 1E4 shows a relative higher affinity for PrPSc type 2 than for PrPSc type 1. Western blot profiles of PrPSc from 3 sCJD MM subjects showing various relative proportions of PrPSc type 1 and type 2. Each sample has been loaded twice at the same concentration and probed either with 3F4 (left) and 1E4 (right). Lane 1 sample with dominant type 1 and only 3–5% of type 2; Lane 2 sample with 60/40% type1/type2 ratio; Lane 3 sample with pure type 2. b Western blot profiles of PrPSc (3F4 antibody) from sCJD subjects with concurrent PrPSc types 1 and 2 carrying different codon 129 PRNP genotypes (lanes 2–4). PrPSc type 1 from a MM1 case (lane 1), and PrPSc type 2 from a VV2 case (lane 6) are included as controls. The PrPSc profile associated with the sCJD MV2 phenotype with kuru plaques (sCJD MV2K) is shown in lane 5. The upper band of the PrPSc doublet in lane 5 migrates faster than the type 1 band. Frontal cortex homogenates were treated with PK and probed with 3F4. Approximate molecular masses are in kilodaltons
Fig. 2
Fig. 2
Western blot profiles of PrPSc (3F4 antibody) from different brain regions of a one sCJD MM 1+2C subject showing the type 2 protein only focally in the cerebral cortex (arrowheads) and b one sCJD MM 2C+1 subject showing a widespread PrPSc type 2 accumulation, a focal deposition of the type 1 protein (arrowheads) in the cerebral cortex, putamen, and thalamus, and a dominant type 1 in the cerebellum. Areas shown include the middle frontal gyrus (MFG), middle temporal gyrus (MTG), parietal cortex (PC), lateral occipital cortex (OCC2), insular cortex (INS), putamen nucleus (PUT), medial thalamic nuclei (TH1), and cerebellum (CE). Approximate molecular masses are in kilodaltons
Fig. 3
Fig. 3
Prevalence and regional distribution of PrPSc type 2 in a series of 57 MM 1+2C subjects. PrPSc type 1 was detected in all areas. Subjects are divided in 3 groups based on the number of areas with a detectable PrPSc type 2 signal on WB. For each group, the % of type 2 positive samples in each brain region is shown. The mean total type 2 “load” for each group, as defined in “Materials and methods”, is given in brackets. FC frontal cortex, TC temporal cortex, PC parietal cortex, OCC occipital cortex, Limbic CTX limbic cortices, Hipp + AMG hippocampus+amygdala, STR striatum, HYP hypothalamus, TH thalamus, BRST brainstem, CE cerebellum
Fig. 4
Fig. 4
a Western blot profiles of PrPSc (3F4 antibody) from different brain regions of the sCJD VV 2+1 subject with the more significant type 1 deposition. Areas shown include the middle frontal gyrus (MFG), middle temporal gyrus (MTG), parietal cortex (PC), lateral occipital cortex (OCC2), insular cortex (INS), putamen nucleus (PUT), medial thalamic nuclei (TH1), and cerebellum (CE). Approximate molecular masses are in kilodaltons. b Western blot profiles of PrPSc doublets in sCJD VV2, sCJD MM 1+2 and sCJD MV 2K. Lanes 1 and 2 show the association of a ~18.5 kDa fragment with the typical 19 kDa type 2 band in sCJD VV2 cerebellum (CE, V = vermis, H = hemisphere). Approximate molecular masses are in kilodaltons
Fig. 5
Fig. 5
Relative severity of lesions (i.e. spongiform degeneration and astrogliosis) in the cerebral cortex (mean of scores in neocortical and limbic cortical areas) and cerebellum: comparison between MM/MV 1 (n = 65), MM/MV 1+2C (n = 63), MM/MV 2C+1 (n = 9), and MM/MV 2C (n = 4) sCJD groups. The line slope expresses the ratio between the degree of cortical and cerebellar pathology. Group MM/MV 1+2C* includes only the cases within the MM/MV 1+2C group showing type 2 in at least 5 areas (n = 17)
Fig. 6
Fig. 6
a A “grape-like” focus of spongiform degeneration with large confluent vacuoles surrounded by typical spongiform degeneration with fine, relatively small vacuoles in sCJD MM 1+2C (hematoxylin and eosin ×200, frontal cortex); b focal perivacuolar staining surrounded by a synaptic pattern of PrP immunoreactivity (×200) in the cerebral cortex of a sCJD MM 1+2C; c spongiform degeneration with large vacuoles (hematoxylin and eosin ×200) and d perivacuolar PrP deposition (×200) in the cerebral cortex of a sCJD MV 2K
Fig. 7
Fig. 7
Regional distribution of the coarse/perivacuolar pattern of PrPSc deposition in 40 MM/MV 1+2C cases divided in 3 groups according to the number of regions showing the perivacuolar pattern in individual cases. For each group, the % of cases revealing the perivacuolar pattern in each brain region is shown. FC frontal cortex, TC temporal cortex, PC parietal cortex, OCC occipital cortex, Limbic CTX limbic cortices, Hipp + AMG hippocampus+amygdala, STR striatum, HYP hypothalamus, TH thalamus, BRST brainstem, CE cerebellum
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