Molecular classification of sporadic Creutzfeldt–Jakob disease

Hill, Andrew F.; Joiner, Susan; Wadsworth, Jonathan D. F.; Sidle, Katie; Bell, Jeanne E.; Budka, Herbert; Ironside, James W.; Collinge, John

doi:10.1093/brain/awg125

Cited by 306 publications

(296 citation statements)

References 50 publications

Supporting

Mentioning

272

Contrasting

Unclassified

Order By: Relevance

“…This difference in the protein markers sensitivity between sCJD subtypes might be accounted by the modulation of clinical phenotype by molecular characteristics. A host genotype effect has been reported, with codon 129 heterozygosity increasing the duration of illness, [15] and prion strain influencing disease onset [9]. In fact, in our study, there was a trend for MV and PrP-type 2A patients to be younger and with a longer disease course (data not shown).…”

Section: Discussioncontrasting

confidence: 42%

Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients

et al. 2009

View full text Add to dashboard Cite

The clinical diagnosis of sporadic CreutzfeldtJakob disease (sCJD) is difficult, and reliable markers are highly desired. In this work we assess the value of several cerebrospinal fluid (CSF) markers for sCJD diagnosis. Within the framework of the Portuguese Epidemiological Surveillance Program for Human Prion Diseases, CSF samples from 71 patients with clinically suspected sCJD, 30 definite sCJD and 41 non-CJD patients, were analysed for the presence of 14-3-3 protein. CSF levels of tau (t-tau), and phosphorylated tau (p-tau181), S-100b and b amyloid (Ab42) proteins were determined. The influence of clinical and genetic characteristics on CSF markers sensitivity was also evaluated. Protein 14-3-3 was detected in 29/30 sCJD patients and 9/41 non-CJD patients. Extremely elevated t-tau and S-100b protein levels were found in sCJD patients, while p-tau181 levels were only slightly elevated and Ab42 showed no differences compared to controls. 14-3-3 was the most sensitive parameter (97%), but its specificity was low (78%); sensitivity/specificity for other proteins were: S-100b-93/93%, t-tau-93/95%, with maximum accuracy being obtained by a combination of tests (14-3-3 combined with either t-tau or S-100b, or combining S-100b with t-tau/Ab42 or p-tau/t-tau ratios). The sensitivity of 14-3-3, as well as of p-tau181/t-tau ratio, was decreased in younger patients with long disease duration, with the PrP-2 isotype and MV genotype. Both 14-3-3, t-tau and S-100b are sensitive markers for sCJD, but 14-3-3 specificity seems to be lower in this special clinical setting of rapidly progressing dementias. We propose that in cases with a 14-3-3 weak positive result, or in young patients with long disease duration, a second CSF marker would be valuable for the diagnosis of sCJD.

show abstract

Section: Discussioncontrasting

confidence: 42%

Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Their specificity for PrP res in Western blotting is dependent on the presence of the 3F4 and 6H4 epitopes in the protease-resistant core fragment of PrP res [11,12,26]. The 3F4 antibody (CE marked) has been consistently used for over 10 years in diagnostic testing for human prion disease by the majority of human prion disease surveillance and research centres worldwide [11,12,27,28]. KG9 has been used extensively for many years in the detection of abnormal PrP in all human prion diseases and is particularly suitable for assessment of PrP accumulation in extraneural tissues [11].…”

Section: Primary Antibodiesmentioning

confidence: 99%

Disease‐associated prion protein is not detectable in human systemic amyloid deposits

Tennent

Head

Bishop

et al. 2007

The Journal of Pathology

View full text Add to dashboard Cite

Cerebral and cardiac amyloid deposits have been reported after scrapie infection in transgenic mice expressing variant prion protein (PrP C ) lacking the glycophosphatidylinositol anchor. The amyloid fibril protein in the systemic amyloid deposits was not characterized, and there is no clinical or pathological association between prion diseases and systemic amyloidosis in humans. Nevertheless, in view of the potential clinical significance of these murine observations, we tested both human amyloidotic tissues and isolated amyloid fibrils for the presence of PrP Sc , the prion protein conformation associated with transmissible spongiform encephalopathy (TSE). We also sequenced the complete prion protein gene, PRNP, in amyloidosis patients. No specific immunohistochemical staining for PrP Sc was obtained in the amyloidotic cardiac and other visceral tissues of patients with different types of systemic amyloidosis. No protease-resistant prion protein, PrP res , was detectable by Western blotting of amyloid fibrils isolated from cardiac and other systemic amyloid deposits. Only the complete normal wild-type PRNP gene sequence was identified, including the usual distribution of codon 129 polymorphisms. These reassuringly negative results do not support the idea that there is any relationship of prions or TSE with human systemic amyloidosis, including cardiac amyloid deposition.

show abstract

“…Polymorphism at residue 129 of human PrP [encoding either methionine (M) or valine (V)] powerfully affects susceptibility to human prion diseases, with residue 129 acting to restrict the propagation of particular prion strains through conformational selection [6,51,52] and heterozygosity conferring resistance by inhibiting homologous protein-protein interactions [52][53][54]. To date, all patients with neuropathologically confirmed vCJD have been PRNP codon 129 methionine homozygotes [7,26] and have a remarkably uniform and distinct neuropathological phenotype defined by the presence of abundant florid PrP plaques [1] and the propagation of type 4 PrP Sc [2,55] in the brain.…”

Section: Introductionmentioning

confidence: 99%

Effect of fixation on brain and lymphoreticular vCJD prions and bioassay of key positive specimens from a retrospective vCJD prevalence study

Wadsworth

Dalmau-Mena

Joiner

et al. 2010

The Journal of Pathology

Self Cite

View full text Add to dashboard Cite

Anonymous screening of lymphoreticular tissues removed during routine surgery has been applied to estimate the UK population prevalence of asymptomatic vCJD prion infection. The retrospective study of Hilton et al (J Pathol 2004; 203: 733-739) found accumulation of abnormal prion protein in three formalin-fixed appendix specimens. This led to an estimated UK prevalence of vCJD infection of ∼1 in 4000, which remains the key evidence supporting current risk reduction measures to reduce iatrogenic transmission of vCJD prions in the UK. Confirmatory testing of these positives has been hampered by the inability to perform immunoblotting of formalin-fixed tissue. Animal transmission studies offer the potential for 'gold standard' confirmatory testing but are limited by both transmission barrier effects and known effects of fixation on scrapie prion titre in experimental models. Here we report the effects of fixation on brain and lymphoreticular human vCJD prions and comparative bioassay of two of the three prevalence study formalin-fixed, paraffin-embedded (FFPE) appendix specimens using transgenic mice expressing human prion protein (PrP). While transgenic mice expressing human PrP 129M readily reported vCJD prion infection after inoculation with frozen vCJD brain or appendix, and also FFPE vCJD brain, no infectivity was detected in FFPE vCJD spleen. No prion transmission was observed from either of the FFPE appendix specimens. The absence of detectable infectivity in fixed, known positive vCJD lymphoreticular tissue precludes interpreting negative transmissions from vCJD prevalence study appendix specimens. In this context, the Hilton et al study should continue to inform risk assessment pending the outcome of larger-scale studies on discarded surgical tissues and autopsy samples.

show abstract

Molecular classification of sporadic Creutzfeldt–Jakob disease

Cited by 306 publications

References 50 publications

Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients

Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients

Disease‐associated prion protein is not detectable in human systemic amyloid deposits

Effect of fixation on brain and lymphoreticular vCJD prions and bioassay of key positive specimens from a retrospective vCJD prevalence study

Contact Info

Product

Resources

About