J Neurol DOI 10.1007/s00415-009-5163-x
Cerebrospinal fluid biomarkers in human genetic transmissible spongiform encephalopathies
Anna Ladogana Æ Pascual Sanchez-Juan Æ Eva Mitrova´ Æ Alison Green Æ Natividad Cuadrado-Corrales Æ Raquel Sa´nchez-Valle Æ Silvia Koscova Æ Adriano Aguzzi Æ Theodoros Sklaviadis Æ Jerzy Kulczycki Æ Joanna Gawinecka Æ Albert Saiz Æ Miguel Calero Æ Cornelia M. van Duijn Æ Maurizio Pocchiari Æ Richard Knight Æ Inga Zerr
Received: 16 December 2008 / Revised: 8 April 2009 / Accepted: 27 April 2009 Springer-Verlag 2009
Abstract 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). Levels of brain-derived proteins in CSF varied in different forms of gTSE. Biomarkers were found positive in the majority of gCJD (81%) and insert gTSE (69%), while they were negative in most cases of fatal familial insomnia (13%) and Gerstmann-Stra¨ussler- Scheinker syndrome (10%). Disease duration and codon 129 genotype influence the findings in a different way than in sporadic CJD.
Data on brain-derived proteins in the CSF of patients with genetic TSE are limited and conflicting results have been reported, mostly because they are frequently based on single case observations (see Table 4). In these reports, sensitivity of biochemical markers in CSF is reported to be lower than in sporadic CJD and this was explained in terms of prolonged disease duration and relatively slow disease progression. Because of the limited numbers of patients, no detailed analysis on this topic is available.
In this study we provide data on four brain-derived proteins in a cohort of patients with various forms of genetic TSE. We found firm evidence for elevated concentrations of 14-3-3, tau, S100b and NSE in the CSF of patients with genetic CJD, but not in FFI or GSS patients. Of interest, the median concentrations for tau, S100b and NSE were similar to those detected in sporadic CJD in other studies [1, 16, 20]. In our previous study on sporadic CJD, we reported median tau levels in the range of
6,000 pg/ml, which is not significantly different from what we found in gCJD patients . These results are concordant with the observation that some gCJD might present clinical similarities with sporadic CJD [11, 15]. Indeed, these cases are often misclassified as sporadic CJD if family history and genetic testing are not done.
The rate of elevated levels of 14-3-3, tau, NSE and S100b in genetic CJD was comparable to that observed in sporadic CJD [3, 20, 26, 27]. In other forms of gTSE, such as FFI and GSS, these tests were consistently negative. Although levels of tau in FFI and GSS patients were lower than the cut-off levels given for CJD, they were still elevated if compared to non-demented controls .
The crude analyses of disease modifying factors of the 14-3-3 test in gCJD revealed that age at onset and PRNP codon 129 genotype influenced sensitivity. 14-3-3 test sensitivity was lower in patients with disease onset before 40 years. These data parallel the results performed on sporadic CJD . However, while in the multivariate analysis age remained as an independent variable in sporadic CJD, in gCJD it did not. Interestingly, in gCJD the PRNP codon 129 genotype influences 14-3-3 sensitivity in a different way with respect to what has been observed in sporadic CJD. Valine homozygous gCJD patients had a lower sensitivity in the 14-3-3 test than heterozygous patients. Though there are too few patients to draw any definite conclusions, a possible explanation might be that the PRNP mutations coupled with the valine alleles (R208H, D178N, E196K) confer low sensitivity to 14-3-3.
The biological significance of brain-derived proteins in the CSF of patients with TSEs remains to be determined. It is generally assumed that the release of 14-3-3, tau and
NSE proteins in the CSF is a consequence of leakage into the CSF following rapid neuronal damage. Recently, a systematic analysis of brain-derived proteins in CSF and neuropathological lesions has shown that the levels of these proteins are the consequence of both the degree of neuronal damage and the localization of the most affected areas . For example NSE levels correlated with damage of subcortical areas (such as the thalamus) and tau protein levels correlated with the degree of spongiform changes in the frontal cortex. Our findings on inverse correlation of tau levels and the number of octapeptide repeats are of interest, since the number of repeats has been correlated to the type of cerebellar PrPSc deposits .
In conclusion, the validity of the biomarkers varied among the different forms of gTSEs. Sensitivity of biomarkers was high in those forms, which are clinically more similar to sporadic CJD, such as genetic CJD and insert gTSEs.
Keywords Creutzfeldt-Jakob disease CSF proteins 14-3-3 protein Tau
A. Ladogana M. Pocchiari Department of Cellular Biology and Neurosciences, Instituto Superiore di Sanita, Viale Regina Elena 299, 00161 Rome, Italy e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000094/!x-usc:mailto:Ladogana@iss.it
M. Pocchiari e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000094/!x-usc:mailto:Maurizio.firstname.lastname@example.org
P. Sanchez-Juan Centro de Investigacion Biomedica en Red sobre Enferemedades neurodegenerativas (CIBERNED) and Institute for Formation and Research of the Fundacion ‘‘Marques de Valdecilla’’ (IFIMAV), Santander, Spain e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000094/!x-usc:mailto:email@example.com
E. Mitrova´ S. Koscova National Reference Centre for Prion Diseases, Research Base of Slovak Medical University, Limbova´ 14, 833-03 Bratislava, Slovakia e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000094/!x-usc:mailto:firstname.lastname@example.org
S. Koscova e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000094/!x-usc:mailto:email@example.com
A. Green R. Knight National CJD Surveillance Unit, The University of Edinburgh, EH4-2XU Edinburgh, UK e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000094/!x-usc:mailto:Alison.Green@ed.ac.uk
N. Cuadrado-Corrales M. Calero Instituto de Salud Carlos III, Centro Nacional de Microbiologia, Ctra. Majadahonda, 28220 Madrid, Spain e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000094/!x-usc:mailto:firstname.lastname@example.org
M. Calero e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000094/!x-usc:mailto:email@example.com
R. Sa´nchez-Valle A. Saiz Department of Neurology, Hospital Clinic Provincial de Barcelona, Villarroel 170, 08036 Barcelona, Spain e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000094/!x-usc:mailto:firstname.lastname@example.org
A. Saiz e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000094/!x-usc:mailto:email@example.com
A. Aguzzi National Reference Center for Human Prion Diseases (NRPE), Institute of Neuropathology, Schmelzbergstr.12, 8091 Zurich, Switzerland e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000094/!x-usc:mailto:firstname.lastname@example.org
T. Sklaviadis Laboratory of Pharmacology, Department of Pharmaceutical Sciences, School of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloni´ki, Greece e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000094/!x-usc:mailto:email@example.com
J. Kulczycki I-st Neurological Department, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000094/!x-usc:mailto:firstname.lastname@example.org
Sunday, May 10, 2009
Meeting of the Transmissible Spongiform Encephalopathies Committee On June 12, 2009 (Singeltary submission)