Creutzfeldt-Jakob disease and homocysteine levels in plasma and cerebrospinal fluid

Background: There is evidence that homocysteine contributes to various neurodegenerative disorders. Objective: To assess the values of homocysteine in patients with Creutzfeldt-Jakob disease (CJD) in both cerebrospinal fluid (CSF) and plasma. Methods: Study design: Case control study. Total homocysteine was quantified in CSF and plasma samples of CJD patients (n = 13) and healthy controls (n = 13). Results: Mean values in healthy controls: 0.15 mumol/l +/- 0.07 (CSF) and 9.10 mumol/l +/- 2.99 (plasma); mean values in CJD patients: 0.13 mumol/l +/- 0.03 (CSF) and 9.22 mumol/l +/- 1.81 (plasma). No significant differences between CJD patients and controls were observed (Mann-Whitney U, p > 0.05). Conclusions: The results indicate that the CSF and plasma of CJD patients showed no higher endogenous levels of homocysteine as compared to normal healthy controls. These findings provide no evidence for an additional role of homocysteine in the pathogenetic mechanisms underlying CJD neurodegeneration. Copyright (C) 2005 S. Karger AG, Basel

Significant association of a M129V independent polymorphism in the 5\prime UTR of the PRNP gene with sporadic Creutzfeldt-Jakob disease in a large German case-control study

Background: A single nucleotide polymorphism (SNP) in the coding region of the prion protein gene (PRNP) at codon 129 has been repeatedly shown to be an associated factor to sporadic Creutzfeldt-Jakob disease (sCJD), but additional major predisposing DNA variants for sCJD are still unknown. Several previous studies focused on the characterisation of polymorphisms in PRNP and the prion-like doppel gene (PRND), generating contradictory results on relatively small sample sets. Thus, extensive studies are required for validation of the polymorphisms in PRNP and PRND.Methods: We evaluated a set of nine SNPs of PRNP and one SNP of PRND in 593 German sCJD patients and 748 German healthy controls. Genotyping was performed using MALDI-TOF mass spectrometry.Results: In addition to PRNP 129, we detected a significant association between sCJD and allele frequencies of six further PRNP SNPs. No significant association of PRND T174M with sCJD was shown. We observed strong linkage disequilibrium within eight adjacent PRNP SNPs, including PRNP 129. However, the association of sCJD with PRNP 1368 and PRNP 34296 appeared to be independent on the genotype of PRNP 129. We additionally identified the most common haplotypes of PRNP to be over-represented or under-represented in our cohort of patients with sCJD.Conclusion: Our study evaluated previous findings of the association of SNPs in the PRNP and PRND genes in the largest cohorts for association study in sCJD to date, and extends previous findings by defining for the first time the haplotypes associated with sCJD in a large population of the German CJD surveillance study

High-throughput discovery of rare human nucleotide polymorphisms by Ecotilling

Human individuals differ from one another at only ∼0.1% of nucleotide positions, but these single nucleotide differences account for most heritable phenotypic variation. Large-scale efforts to discover and genotype human variation have been limited to common polymorphisms. However, these efforts overlook rare nucleotide changes that may contribute to phenotypic diversity and genetic disorders, including cancer. Thus, there is an increasing need for high-throughput methods to robustly detect rare nucleotide differences. Toward this end, we have adapted the mismatch discovery method known as Ecotilling for the discovery of human single nucleotide polymorphisms. To increase throughput and reduce costs, we developed a universal primer strategy and implemented algorithms for automated band detection. Ecotilling was validated by screening 90 human DNA samples for nucleotide changes in 5 gene targets and by comparing results to public resequencing data. To increase throughput for discovery of rare alleles, we pooled samples 8-fold and found Ecotilling to be efficient relative to resequencing, with a false negative rate of 5% and a false discovery rate of 4%. We identified 28 new rare alleles, including some that are predicted to damage protein function. The detection of rare damaging mutations has implications for models of human disease

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. Method: In the framework of a multinational European study, we studied the results of 14-3-3, S100b, neurone specific enolase (NSE) and tau protein in 833 CSF samples from sCJD patients at different stages of disease and in 66 sequentially repeated lumbar punctures (LP). Results: 14-3-3 and tau protein tended to increase in sensitivity from onset (88%, 81%) to the advanced stage (91%, 90%). This was significant only in the methionine-valine (MV) heterozygous group of patients at codon 129. The absolute levels of S100b (p < 0.05), NSE and tau protein increased in the last stage of disease. High levels of tau protein, NSE and S100b were associated with shorter survival times (p < 0.01). Sixty-six sCJD patients underwent repeated LP. These sCJD patients were younger, had longer disease durations and were more frequently MV at codon 129 (p < 0.001) than the whole group. 14-3-3 sensitivity increased from 64% to 82% in the second LP (p = 0.025) and 88% sCJD patients had at least one positive result. Conclusions: Sensitivity and absolute levels of CJD markers increased with disease progression and were modulated by the codon 129 genotype. Early negative results should be inter-preted with caution, especially in young patients or those who are MV at codon 129

Order parameter model for unstable multilane traffic flow

We discuss a phenomenological approach to the description of unstable vehicle motion on multilane highways that explains in a simple way the observed sequence of the phase transitions "free flow -> synchronized motion -> jam" as well as the hysteresis in the transition "free flow synchronized motion". We introduce a new variable called order parameter that accounts for possible correlations in the vehicle motion at different lanes. So, it is principally due to the "many-body" effects in the car interaction, which enables us to regard it as an additional independent state variable of traffic flow. Basing on the latest experimental data (cond-mat/9905216) we assume that these correlations are due to a small group of "fast" drivers. Taking into account the general properties of the driver behavior we write the governing equation for the order parameter. In this context we analyze the instability of homogeneous traffic flow manifesting itself in both of the mentioned above phase transitions where, in addition, the transition "synchronized motion -> jam" also exhibits a similar hysteresis. Besides, the jam is characterized by the vehicle flows at different lanes being independent of one another. We specify a certain simplified model in order to study the general features of the car cluster self-formation under the phase transition "free flow synchronized motion". In particular, we show that the main local parameters of the developed cluster are determined by the state characteristics of vehicle motion only.Comment: REVTeX 3.1, 10 pages with 10 PostScript figure

Rapidly Progressive Dementia Due to Mycobacterium neoaurum Meningoencephalitis

Dementia developed in a patient with widespread neurologic manifestations; she died within 5 months. Pathologic findings showed granulomatous inflammation with caseation necrosis, foreign body–type giant cells, and proliferative endarteritis with vascular occlusions. Broad-range polymerase chain reaction identified Mycobacterium neoaurum as the possible pathogen. Central nervous system infection by M. neoaurum may result in rapidly progressive dementia

Follow-up investigations of tau protein and S-100B levels in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease

Background: S-100B and tau protein have a high differential diagnostic potential for the diagnosis of Creutzfeldt-Jakob disease (CJD). So far there has been only limited information available about the dynamics of these parameters in the cerebrospinal fluid (CSF). However, there is a special interest in finding biochemical markers to monitor disease progression for differential diagnosis and treatment. Patients and Methods: We analyzed CSF of 45 patients with CJD and of 45 patients with other neurological diseases for tau protein and S-100B in a follow-up setting. All diagnoses of CJD were later neuropathologically verified. A ratio between tau protein differences and the time between lumbar puncture was calculated. The same was done for S-100B. Results: Tau protein levels of 34 cases were above the cut-off level for CJD (>1,300 pg/ml) in the first CSF sample. In 7 of 11 patients with lower tau levels in the first CSF sample, tau levels rose. The above-mentioned ratio was significantly higher in the CJD group than in the group with other neurological diseases. Similar results were obtained for S-100B. Conclusion: We conclude that follow-up investigations and calculation of ratios is a useful tool in the differential diagnosis of CJD. Variations in this pattern were observed in single cases. Copyright (C) 2005 S. Karger AG, Basel

Proteomic analysis of the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease

So far, only the detection of 14-3-3 proteins in cerebrospinal fluid (CSF) has been accepted as diagnostic criterion for Creutzfeldt-Jakob disease (CJD). However, this assay cannot be used for screening because of the high rate of false-positive results, whereas patients with variant CJD are often negative for 14-3-3 proteins. The aim of this study was to compare the spot patterns of CSF by 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) to search for a CJD-specific spot pattern. We analyzed the CSF of 28 patients {[}11 CJD, 9 Alzheimer's disease ( AD), 8 nondemented controls (NDC)] employing 2D-PAGE which was optimized for minimal volumes of CSF (0.1 ml; 7-cm strips). All samples were run at least three times, gels were silver stained and analyzed by an analysis software and manually revised. We could consistently match 268 spots which were then compared between all groups. By the use of 5 spots, we were able to differentiate CJD from AD or NDC with a sensitivity of 100%. CJD could also be distinguished from both groups by using a heuristic clustering algorithm of 2 spots. We conclude that this proteomic approach can differentiate CJD from other diseases and may serve as a model for other neurodegenerative diseases. Copyright (C) 2007 S. Karger AG, Basel