Cerebrospinal fluid non-phosphorylated tau in the differential diagnosis of Creutzfeldt–Jakob disease: a comparative prospective study with 14-3-3
Cerebrospinal fluid (CSF) non-phosphorylated tau (non-p-tau) is increased in sporadic Creutzfeldt–Jakob disease (CJD), but its accuracy in the differential diagnosis has not been previously established. Here, we first used a retrospective cohort of non-CJD (n = 135) and CJD (n = 137) cases to determine the optimal cutoff point for the discrimination of CJD cases. Next, we prospectively quantified non-p-tau and 14-3-3 protein in a cohort of 1427 cases received for CSF testing at the German National Reference Center for transmissible spongiform encephalopathies. Among them, 36 were subsequently diagnosed as CJD. The diagnostic accuracy of both proteins discriminating CJD cases was evaluated. Using a cutoff of 650 pg/mL, non-p-tau displayed 94.39% accuracy in discriminating CJD cases, while 92.92% accuracy was achieved by 14-3-3 using a cutoff of 20,000 AU/mL. Diagnostic test evaluation for both proteins showed a slightly better performance of non-p-tau compared to 14-3-3. The two biomarkers’ concentrations showed a significant positive correlation, both in the total population and in CJD cases (p < 0.001). Finally, the analysis of CSF non-p-tau concentrations when undergoing pre-analytical factors showed high stability in front of temperature storage and freeze/thaw cycles. Therefore, we conclude that when used in the appropriate clinical context of a prion disease surveillance center, non-p-tau is a highly sensitive and specific diagnostic marker for CJD.
KeywordsCerebrospinal fluid Creutzfeldt–Jakob disease Tau Non-phosphorylated tau 14-3-3 RT-QuIC Biomarker
FL, AV-P, and IZ designed the study. AV-P and FL performed experiments. FL, AV-P, PH and MS analysed data and interpreted the results. PH, SG and IZ contributed to sample collection and characterization. KW and IL contributed to technical expertise. FL, AV-P and PH wrote the manuscript draft. All authors critically revised the manuscript and approved its content before submission.
This study was funded by Robert Koch Institute through funds from the Federal Ministry of Health of Germany (Grant no. 1369–341) to IZ, by the Instituto Carlos III/ Fondo Social Europeo (CP16/00041) and by Fundació la Marató de TV3 (grant 201821-30-31-32) to FL. This project has been funded at 65% by the Fondo Europeo de Desarrollo Regional (FEDER) through the Interreg V-A España-Francia-Andorra (POCTEFA 2014-2020) programme.
Compliance with ethical standards
Conflicts of interest
Dr. Lachmann and Dr. Waniek report they are employers of AJ Roboscreen GmbH, Leipzig, Germany. No other conflict of interest is reported.
This study was conducted according to the revised Declaration of Helsinki and Good Clinical Practice guidelines and was approved by local Ethics commitee (Reference number 11/11/93), Universitätzmedizin Göttingen, Germany).
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