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CSF Tau proteins reduce misdiagnosis of sporadic Creutzfeldt–Jakob disease suspected cases with inconclusive 14-3-3 result

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Abstract

Cerebrospinal fluid (CSF) 14-3-3 protein supports sporadic Creutzfeldt–Jakob (sCJD) diagnosis, but often leads to weak-positive results and lacks standardization. In this study, we explored the added diagnostic value of Total Tau (t-Tau) and phosphorylated Tau (p-Tau) in sCJD diagnosis, particularly in the cases with inconclusive 14-3-3 result. 95 definite sCJD and 287 patients without prion disease (non-CJD) were included in this study. CSF samples were collected in routine clinical diagnosis and analysed for 14-3-3 detection by Western blot (WB). CSF t-Tau and p-Tau were quantified by commercial ELISA kits and PRNP and APOE genotyping assessed by PCR–RFLP. In a regression analysis of the whole cohort, 14-3-3 protein revealed an overall accuracy of 82 % (sensitivity = 96.7 %; specificity = 75.6 %) for sCJD. Regarding 14-3-3 clear positive results, we observed no added value either of t-Tau alone or p-Tau/t-Tau ratio in the model. On the other hand, considering 14-3-3 weak-positive cases, t-Tau protein increased the overall accuracy of 14-3-3 alone from 91 to 94 % and specificity from 74 to 93 % (p < 0.05), with no sensitivity improvement. However, inclusion of p-Tau/t-Tau ratio did not significantly improve the first model (p = 0.0595). Globally, t-Tau protein allowed a further discrimination of 65 % within 14-3-3 inconclusive results. Furthermore, PRNP MV genotype showed a trend to decrease 14-3-3 sensitivity (p = 0.051), but such effect was not seen on t-Tau protein. In light of these results, we suggest that t-Tau protein assay is of significant importance as a second marker in identifying 14-3-3 false-positive results among sCJD probable cases.

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Abbreviations

sCJD:

Sporadic Creutzfeldt–Jakob

Non-CJD:

Non-prion disease

CSF:

Cerebrospinal fluid

LP:

Lumbar puncture

CNS:

Central nervous system

t-Tau:

Total Tau protein

p-Tau:

Phosphorylated Tau protein

ELISA:

Enzyme-linked immunosorbent assay

WB:

Western blot

AD:

Alzheimer’s disease

APOE :

Apolipoprotein E gene

PRNP :

Prionic protein gene

PrPSc:

Scrapie prion protein

EEG:

Electroencephalogram

MRI:

Magnetic resonance imaging

WHO:

World health organization

RPD:

Rapidly progressive dementia

RT-QuIC:

Real-time quaking-induced conversion

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Acknowledgments

The authors thank the Portuguese Surveillance Group for Human Prion Diseases, for support and implementation of the study. We also wish to thank all the physicians who sent us the CSF and blood samples and clinical and neuropathological information on suspected CJD cases: Centro Hospitalar e Universitário de Coimbra (Coimbra)—José Tomás, Isabel Santana, Hospital de Braga (Braga)—Sofia Rocha, Hospital de São João (Porto)—Carolina Garrett, Hospital de Santo António (Porto)—Bastos Lima, Centro Hospitalar entre Douro e Vouga (Santa Maria da Feira)—José Leal Loureiro, Hospital Pedro Hispano (Matosinhos)—Maria Manuela Costa, Hospital Fernando Fonseca (Amadora)- Simão Cruz, Hospital Egas Moniz (Lisboa)—Luísa Alves, and Hospital de Santa Maria (Lisboa)—José Pimentel. All authors have contributed to the work and agree with the presented findings. This study has not been published before and is not under review with any another journal. The work was supported in part by the Portuguese Foundation for Science and Technology (FCT) through JPND/0001/2011, under the aegis of an EU Joint Program—Neurodegenerative Disease Research (JPND) project and funded by FEDER through Competitive Factors Operational Program—COMPETE 2020—as well as by the National Funds through FCT on the scope of strataegic CNC.IBILI UID/NEU/04539/2013 project.

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The study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. This study was approved by the Ethics Board of Coimbra University Hospital and all subjects or responsible caregivers, whichever appropriate, gave their informed consent.

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Leitão, M.J., Baldeiras, I., Almeida, M.R. et al. CSF Tau proteins reduce misdiagnosis of sporadic Creutzfeldt–Jakob disease suspected cases with inconclusive 14-3-3 result. J Neurol 263, 1847–1861 (2016). https://doi.org/10.1007/s00415-016-8209-x

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