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Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease

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      Abstract

      Several molecular subtypes of sporadic Creutzfeldt–Jakob disease have been identified and electroencephalogram and cerebrospinal fluid biomarkers have been reported to support clinical diagnosis but with variable utility according to subtype. In recent years, a series of publications have demonstrated a potentially important role for magnetic resonance imaging in the pre-mortem diagnosis of sporadic Creutzfeldt–Jakob disease. Magnetic resonance imaging signal alterations correlate with distinct sporadic Creutzfeldt–Jakob disease molecular subtypes and thus might contribute to the earlier identification of the whole spectrum of sporadic Creutzfeldt–Jakob disease cases. This multi-centre international study aimed to provide a rationale for the amendment of the clinical diagnostic criteria for sporadic Creutzfeldt–Jakob disease. Patients with sporadic Creutzfeldt–Jakob disease and fluid attenuated inversion recovery or diffusion-weight imaging were recruited from 12 countries. Patients referred as ‘suspected sporadic Creutzfeldt–Jakob disease’ but with an alternative diagnosis after thorough follow up, were analysed as controls. All magnetic resonance imaging scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus and cerebellum. Magnetic resonance imaging scans were evaluated in 436 sporadic Creutzfeldt–Jakob disease patients and 141 controls. The pattern of high signal intensity with the best sensitivity and specificity in the differential diagnosis of sporadic Creutzfeldt–Jakob disease was identified. The optimum diagnostic accuracy in the differential diagnosis of rapid progressive dementia was obtained when either at least two cortical regions (temporal, parietal or occipital) or both caudate nucleus and putamen displayed a high signal in fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging. Based on our analyses, magnetic resonance imaging was positive in 83% of cases. In all definite cases, the amended criteria would cover the vast majority of suspected cases, being positive in 98%. Cerebral cortical signal increase and high signal in caudate nucleus and putamen on fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging are useful in the diagnosis of sporadic Creutzfeldt–Jakob disease. We propose an amendment to the clinical diagnostic criteria for sporadic Creutzfeldt–Jakob disease to include findings from magnetic resonance imaging scans.

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      Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects.

      Phenotypic heterogeneity in sporadic Creutzfeldt-Jakob disease (sCJD) is well documented, but there is not yet a systematic classification of the disease variants. In a previous study, we showed that the polymorphic codon 129 of the prion protein gene (PRNP), and two types of protease-resistant prion protein (PrP(Sc)) with distinct physicochemical properties, are major determinants of these variants. To define the full spectrum of variants, we have examined a series of 300 sCJD patients. Clinical features, PRNP genotype, and PrP(Sc) properties were determined in all subjects. In 187, we also studied neuropathological features and immunohistochemical pattern of PrP(Sc) deposition. Seventy percent of subjects showed the classic CJD phenotype, PrP(Sc) type 1, and at least one methionine allele at codon 129; 25% of cases displayed the ataxic and kuru-plaque variants, associated to PrP(Sc) type 2, and valine homozygosity or heterozygosity at codon 129, respectively. Two additional variants, which included a thalamic form of CJD and a phenotype characterized by prominent dementia and cortical pathology, were linked to PrP(Sc) type 2 and methionine homozygosity. Finally, a rare phenotype characterized by progressive dementia was linked to PrP(Sc) type 1 and valine homozygosity. The present data demonstrate the existence of six phenotypic variants of sCJD. The physicochemical properties of PrP(Sc) in conjunction with the PRNP codon 129 genotype largely determine this phenotypic variability, and allow a molecular classification of the disease variants.
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        Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease.

        We sequenced the prion protein gene and studied the biochemical characteristics and the intracerebral distribution of protease-resistant prion protein with Western blot and immunohistochemistry in 19 cases of sporadic Creutzfeldt-Jakob disease. We identified four groups of subjects defined by the genotype at codon 129 of the prion protein gene, the site of a common methionine/valine polymorphism, and two types of protease-resistant prion proteins that differed in size and glycosylation. The four Creutzfeldt-Jakob disease groups showed distinct clinicopathological features that corresponded to previously described variants. The typical Creutzfeldt-Jakob disease phenotype or myoclonic variant and the Heidenhain variant were linked to methionine homozygosity at codon 129 and to "type 1" protease-resistant prion protein. The atypical and rarer variants such as that with dementia of long duration, the ataxic variant, and the variant with kuru plaques were linked to different genotypes at codon 129 and shared the "type 2" protease-resistant prion protein. Our data indicate that the sporadic form of Creutzfeldt-Jakob disease comprises a limited number of variants. The methionine/valine polymorphism at codon 129 of the prion protein gene and two types of protease-resistant prion proteins are the major determinants of these variants. These findings suggest the existence of prion strains in humans and provide the molecular basis for a novel classification of sporadic Creutzfeldt-Jakob disease.
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          Sporadic and familial CJD: classification and characterisation.

          Prion diseases are unique transmissible neurodegenerative diseases that have diverse phenotypes and can be familial, sporadic, or acquired by infection. Recent findings indicate that the PrP genotype and the PrP(Sc) type have a major influence on the disease phenotype in both sporadic and familial human prion diseases. This review attempts to classify and characterise sporadic and familial Creutzfeldt-Jakob disease (CJD) as a function of these two disease determinants. Based on the genotype at codon 129 on both PRNP alleles, the size of protease resistant PrP(Sc) fragments and disease phenotype, we divide sporadic CJD into six subtypes: sCJDMM1/sCJDMV1, sCJDVV2, sCJDMV2, sCJDMM2, sCJDVV1, and sporadic fatal insomnia (sFI). Familial CJD is classified into many haplotypes based on the PRNP mutation and codon 129 (and other polymorphic codons) on the mutant allele. The clinical and pathological features are summarised for each sporadic CJD subtype and familial CJD haplotype.
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            Author and article information

            Affiliations
            1 National TSE Reference Center, Department of Neurology, Georg-August University Goettingen, Goettingen, Germany
            2 Department of Neuroradiology, Georg-August University Goettingen, Goettingen, Germany
            3 CJD Surveillance Unit, Western General Hospital, Edinburgh, UK
            4 Departamento de Neuropatologia, Centro de Referencia de Encefalopatias Espongiformes Transmisibles, Instituto de Investigaciones Neurologicas/FLENI Montañeses 2325 C1428AQK, Buenos Aires, Argentina
            5 Istituto Superiore di Sanità, Department of Cell Biology and Neurosciences, Roma, Italy
            6 Genetic Epidemiology Unit, Department of Epidemiology, Biostatistics and Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
            7 INSERM UMRS 975, Hôpital de la Salpêtrière Cellule Nationale de référence des maladies de Creutzfeldt-Jakob Paris, F-75013, France
            8 Australian National Creutzfeldt-Jakob Disease Registry, Department of Pathology, the University of Melbourne, Parkville, Australia 3010
            9 Creutzfeldt-Jakob Disease Surveillance System, Prion Diseases Program, Public Health Agency of Canada, Ottawa, Canada
            10 Division of Neurology, University Medical Center and Gerontopsychiatric Unit, University Psychiatric Hospital, SI-1000 Ljubljana, Slovenia
            11 Department of Neurology, Laboratory of Neuropathology, Institute of Molecular Medicine, Hospital de Santa Maria, Lisbon Faculty of Medicine, Lisbon, Portugal
            12 Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland
            13 Clinic Director, Mercy Private Radiology, Grey st, East Melbourne, 3002, Australia
            14 Laboratory of Neurobiology, Department of Neurology, Born Bunge Institute, University of Antwerp, Belgium
            15 Fundación ‘Marqués de Valdecilla’ IFIMAV and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED). Santander, Spain
            Author notes
            Corresponding author: Inga Zerr, MD, National TSE Reference Center, Department of Neurology, Georg-August University Goettingen, Robert-Koch-Str. 40, 37075 Goettingen, Germany E-mail: epicjd@123456med.uni-goettingen.de
            Journal
            Brain
            brainj
            brain
            Brain
            Oxford University Press
            0006-8950
            1460-2156
            October 2009
            22 September 2009
            22 September 2009
            : 132
            : 10
            : 2659-2668
            2759336
            19773352
            10.1093/brain/awp191
            awp191
            © The Author(s) 2009. Published by Oxford University Press on behalf of Brain.

            This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

            Categories
            Original Articles

            Neurosciences

            cjd, molecular subtypes, dwi, flair, mri, dementia

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