Diagnostic accuracy of cerebrospinal fluid biomarkers in genetic prion diseases.

Genetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders caused by pathogenic sequence variations in the prion protein gene, PRNP. Data on CSF biomarkers in patients with genetic prion diseases are limited and conflicting results have been reported for unclear reasons. Here, we aimed to analyse the diagnostic accuracy of CSF biomarkers currently used in prion clinical diagnosis in 302 symptomatic genetic prion disease cases from 11 prion diagnostic centres, encompassing a total of 36 different pathogenic sequence variations within the open reading frame of PRNP.

Genetic Risk Factors of Creutzfeldt-Jakob Disease in the Population of Newborns in Slovakia.

The most frequent human prion disease is Creutzfeldt-Jakob disease (CJD). It occurs as sporadic (sCJD), genetic (gCJD), iatrogenic (iCJD) form and as variant CJD. The genetic form represents about 10-15% of confirmed cases worldwide, in Slovakia as much as 65-75%.

Genetic Creutzfeldt-Jakob disease affected monozygotic twins: Analysis of survival time, age at death and possible exogenous risk factors.

Three monozygotic twin pairs with the Creutzfeldt-Jakob diseases-specific mutation E200K are described. All three have been concordant for genetic CJD and discordant for the age at death and the duration of the disease. Twin pairs have been compared with genetically non - identical sibling pairs also concordant for genetic CJD and discordant for the age at death.

Cerebrospinal Fluid Total Prion Protein in the Spectrum of Prion Diseases.

Cerebrospinal fluid (CSF) total prion protein (t-PrP) is decreased in sporadic Creutzfeldt-Jakob disease (sCJD). However, data on the comparative signatures of t-PrP across the spectrum of prion diseases, longitudinal changes during disease progression, and levels in pre-clinical cases are scarce. T-PrP was quantified in neurological diseases (ND, n = 147) and in prion diseases from different aetiologies including sporadic (sCJD, n = 193), iatrogenic (iCJD, n = 12) and genetic (n = 209) forms.

Evaluation of α-synuclein as a novel cerebrospinal fluid biomarker in different forms of prion diseases.

Introduction: Accurate diagnosis of prion diseases and discrimination from alternative dementias gain importance in the clinical routine, but partial overlap in cerebrospinal fluid (CSF) biomarkers impedes absolute discrimination in the differential diagnostic context.

Methods: We established the clinical parameters for prion disease diagnosis for the quantification of CSF α-synuclein in patients with sporadic (n = 234) and genetic (n = 56) prion diseases, in cases with cognitive impairment/dementia or neurodegenerative disease (n = 278), and in the neurologic control group (n = 111).

Results: An optimal cutoff value of 680 pg/mL α-synuclein results in 94% sensitivity and 96% specificity when diagnosing sporadic Creutzfeldt-Jakob disease (CJD).

Cerebrospinal Fluid Biomarkers in the Diagnosis of Creutzfeldt-Jakob Disease in Slovak Patients: over 10-Year Period Review.

Creutzfeldt-Jakob disease is a rare, but rapidly progressive, up to now untreatable and fatal neurodegenerative disorder. Clinical diagnosis of Creutzfeldt-Jakob disease (CJD) is difficult; however, it can be facilitated by suitable biomarkers. Aim of the present study is to compare levels of cerebrospinal fluid biomarkers (total tau protein, phosphorylated-tau protein, protein 14-3-3 and amyloid beta) in Slovak population of CJD suspect cases, retrospectively in over a 10-year period.

Validation of 14-3-3 Protein as a Marker in Sporadic Creutzfeldt-Jakob Disease Diagnostic.

At present, the testing of 14-3-3 protein in cerebrospinal fluid (CSF) is a standard biomarker test in suspected sporadic Creutzfeldt-Jakob disease (sCJD) diagnosis. Increasing 14-3-3 test referrals in CJD reference laboratories in the last years have led to an urgent need to improve established 14-3-3 test methods. The main result of our study was the validation of a commercially available 14-3-3 ELISA next to the commonly used Western blot method as a high-throughput screening test.

Stability and Reproducibility Underscore Utility of RT-QuIC for Diagnosis of Creutzfeldt-Jakob Disease.

Real-time quaking-induced conversion (RT-QuIC) allows the amplification of miniscule amounts of scrapie prion protein (PrP(Sc)). Recent studies applied the RT-QuIC methodology to cerebrospinal fluid (CSF) for diagnosing human prion diseases. However, to date, there has not been a formal multi-centre assessment of the reproducibility, validity and stability of RT-QuIC in this context, an indispensable step for establishment as a diagnostic test in clinical practice.

Characteristic CSF prion seeding efficiency in humans with prion diseases.

The development of in vitro amplification systems allows detecting femtomolar amounts of prion protein scrapie (PrP(Sc)) in human cerebrospinal fluid (CSF). We performed a CSF study to determine the effects of prion disease type, codon 129 genotype, PrP(Sc) type, and other disease-related factors on the real-time quaking-induced conversion (RT-QuIC) response. We analyzed times to 10,000 relative fluorescence units, areas under the curve and the signal maximum of RT-QuIC response as seeding parameters of interest.

Association of prion protein genotype and scrapie prion protein type with cellular prion protein charge isoform profiles in cerebrospinal fluid of humans with sporadic or familial prion diseases.

The present study investigates whether posttranslational modifications of cellular prion protein (PrP(C)) in the cerebrospinal fluid (CSF) of humans with prion diseases are associated with methionine (M) and/or valine (V) polymorphism at codon 129 of the prion protein gene (PRNP), scrapie prion protein (PrP(Sc)) type in sporadic Creutzfeldt-Jakob disease (sCJD), or PRNP mutations in familial Creutzfeldt-Jakob disease (fCJD/E200K), and fatal familial insomnia (FFI). We performed comparative 2-dimensional immunoblotting of PrP(C) charge isoforms in CSF samples from cohorts of diseased and control donors. Mean levels of total PrP(C) were significantly lower in the CSF from fCJD patients than from those with sCJD or FFI.

Cerebrospinal fluid biomarker supported diagnosis of Creutzfeldt-Jakob disease and rapid dementias: a longitudinal multicentre study over 10 years.

To date, cerebrospinal fluid analysis, particularly protein 14-3-3 testing, presents an important approach in the identification of Creutzfeldt-Jakob disease cases. However, one special point of criticism of 14-3-3 testing is the specificity in the differential diagnosis of rapid dementia. The constant observation of increased cerebrospinal fluid referrals in the national surveillance centres over the last years raises the concern of declining specificity due to higher number of cerebrospinal fluid tests performed in various neurological conditions.

Health professions and risk of sporadic Creutzfeldt-Jakob disease, 1965 to 2010.

In 2009, a pathologist with sporadic Creutzfeldt-Jakob Disease (sCJD) was reported to the Spanish registry. This case prompted a request for information on health-related occupation in sCJD cases from countries participating in the European Creutzfeldt Jakob Disease Surveillance network (EuroCJD). Responses from registries in 21 countries revealed that of 8,321 registered cases, 65 physicians or dentists, two of whom were pathologists, and another 137 healthcare workers had been identified with sCJD.

Geographic accumulation of Creutzfeldt-Jakob disease in Slovakia--environmental metal imbalance as a possible cofactor.

Slovakia is characterised by an unusually high number of patients affected by genetic Creutzfeldt-Jakob disease (CJD) with E200K mutation at the PRNP gene. Penetrance of the mutation is incomplete (59%). Therefore, for the onset of the clinical manifestation, an influence of other endo- or exogenous factors could not be excluded.

Experience with preventive genetic testing of corneal donors in slovakia.

Purpose: The purpose of this study was (1) to detect asymptomatic carriers of the prion protein gene mutation E200K, which is associated with Creutzfeldt-Jakob disease (CJD), in corneal donors and in the general population of Slovakia and (2) to assess the genetic testing of corneal donors as an effective preventive measure against iatrogenic infection in a country with an unusually high incidence of genetic CJD.

Methods: The prion protein gene (PRNP) was analyzed in 1133 corneal donors and 970 control subjects to search for E200K mutation and to determine the genotype at codon 129.

Results: Mutation E200K was found in 2 of the 1133 donors and in 4 of the 970 control subjects.

[Dynamics of the incidence of Creutzfeldt-Jakob disease in Slovakia in 1975-2008].

The paper reports on Creutzfeldt-Jakob disease (CJD) occurrence in Slovakia in years 1975-2008. Changes in the incidence of this most important human prion disease, occurrence of individual forms of the classical CJD variant and the unique, unusually high proportion of genetic CJD are documented. Endo- and exogenous risk factors are analyzed, gaps in the prevention of iatrogenic infection are pointed out and the prophylaxis of genetic CJD is discussed.

Codon 129 polymorphism and the E200K mutation do not affect the cellular prion protein isoform composition in the cerebrospinal fluid from patients with Creutzfeldt-Jakob disease.

The cellular prion protein (PrP(c)) is a multifunctional, highly conserved and ubiquitously expressed protein. It undergoes a number of modifications during its post-translational processing, resulting in different PrP(c) glycoforms and truncated PrP(c) fragments. Limited data are available in humans on the expression and cleavage of PrP(c).

Ubiquitin as potential cerebrospinal fluid marker of Creutzfeldt-Jakob disease.

Until today, a definite diagnosis of Creutzfeldt-Jakob disease (CJD) can only be made neuropathologically. At lifetime the early and differential diagnosis is often a problem. With SELDI we analyzed cerebrospinal fluid (CSF) from 32 CJD patients, 32 patients having other dementive diseases and 31 non-demented control subjects for diagnosis-dependent protein pattern differences.

Cathepsin D (C224T) polymorphism in sporadic and genetic Creutzfeldt-Jakob disease.

Accumulation of cathepsin D immunoreactive lysosomes correlates with tissue pathology in sporadic Creutzfeldt-Jakob disease (CJD) brains. The C-to-T transition within exon 2 of the cathepsin D (CTSD) gene is associated with altered enzymatic activity. Possession of the TT genotype is a risk factor for variant CJD.

Cerebrospinal fluid biomarkers in human genetic transmissible spongiform encephalopathies.

The 14-3-3 protein test has been shown to support the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) when associated with an adequate clinical context, and a high differential potential for the diagnosis of sporadic CJD has been attributed to other cerebrospinal fluid (CSF) proteins such as tau protein, S100b and neuron specific enolase (NSE). So far there has been only limited information available about biochemical markers in genetic transmissible spongiform encephalopathies (gTSE), although they represent 10-15% of human TSEs. In this study, we analyzed CSF of 174 patients with gTSEs for 14-3-3 (n = 166), tau protein (n = 78), S100b (n = 46) and NSE (n = 50).

[Human prion diseases: the Hungarian experience].

Background: Sporadic Creutzfeldt-Jakob disease is the most frequent human prion disease. Genetic forms are associated with mutations in the human prion protein gene (PRNP) and thought to comprise 5-15% of cases. Acquired forms include iatrogenic and variant Creutzfeldt-Jakob disease.

Manganese and copper imbalance in the food chain constituents in relation to Creutzfeldt-Jakob disease.

The objective of the study was to investigate the possible role of manganese and copper (Mn/Cu) imbalance of the food chain in the focally increased occurrence of Creutzfeldt-Jakob disease (CJD). Mn and Cu concentrations in soil, drinking water and foodstuffs collected from households in the region of focal accumulation of CJD patients and the control region were measured by FAAS. Considerably higher Mn/Cu ratios in the studied region than those in the control region were found for soil (49.

Influence of timing on CSF tests value for Creutzfeldt-Jakob disease diagnosis.

Background: The analysis of markers in the cerebrospinal fluid (CSF) is useful in the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD). However, the time at which the study of these markers is most sensitive remains controversal.

Objective: To assess the influence of time of sampling on the value of CSF tests in the diagnosis of sCJD.

CSF analysis in patients with sporadic CJD and other transmissible spongiform encephalopathies.

Patients with suspected Creutzfeldt-Jakob disease (CJD) often have routine cerebrospinal fluid (CSF) analysis performed to exclude treatable inflammatory conditions; however, little information is available about the range of results obtained for CSF tests in patients with sporadic CJD and other transmissible spongiform encephalopathies (TSE). Data from 450 patients with sporadic CJD and 47 patients with other TSEs were collected as part of an EC-supported multinational study. Raised white cell counts of >5 cells/microl were found in three of 298 patients with sporadic CJD, with two cell counts of 7 cells/microl and one of 20 cells/microl.