Cerebrospinal Fluid Prion Disease Biomarkers in Pre-clinical and Clinical Naturally Occurring Scrapie
The analysis of the cerebrospinal fluid (CSF) biomarkers in patients with suspected prion diseases became a useful tool in diagnostic routine. Prion diseases can only be identified at clinical stages when the disease already spread throughout the brain and massive neuronal damage occurs. Consequently, the accuracy of CSF tests detecting non-symptomatic patients is unknown. Here, we aimed to investigate the usefulness of CSF-based diagnostic tests in pre-clinical and clinical naturally occurring scrapie. While decreased total prion protein (PrP) levels and positive PrP seeding activity were already detectable at pre-symptomatic stages, the surrogate markers of neuronal damage total tau (tau) and 14-3-3 proteins were exclusively increased at clinical stages. The present findings confirm that alterations in PrP levels and conformation are primary events in the pathology of prion diseases preceding neuronal damage. Our work also supports the potential use of these tests in the screening of pre-symptomatic scrapie and human prion disease cases.
KeywordsScrapie Cerebrospinal fluid Prion disease Biomarkers Prion protein 14-3-3 protein Tau protein
We thank Nadine Gotzmann, Silja Koechy, and Sonia Gómez for technical assistance.
Study conception and design: FL, RB, IZ. Project supervision: FL. Data collection: FL, TB, AC, AV-P, KT, PL, J-JB, MS, RB. Assay development and technical expertise: IL. Data analysis and interpretation: FL, TB, RB, IZ. Drafting the article: FL, TB, RB. Final approval of the version to be published: all authors.
This study was funded by Robert Koch Institute through funds from the Federal Ministry of Health of Germany (grant no. 1369-341) and DZNE to IZ; by the Spanish Ministry of Health, Instituto Carlos III/Fondo Social Europeo (CP16/00041) to FL; by the Red Nacional de priones (AGL2015-71764-REDT-MINECO) to FL, IZ, RB, and JJB; and by the Spanish Ministry of Economy (grant no. AGL2015-65560-R) to RB. TB was supported by a research grant from the Spanish Ministry of Education and Science (FPU14/04348). 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. AV-P is funded by a Dorothea Schlözer Scholarship (Georg August University – Göttingen).
Compliance with Ethical Standards
Conflict of Interest
Dr. Lachmann reports he is the employer of AJ Roboscreen GmbH, Leipzig, Germany. No other conflict of interest is reported.
- 7.Sanchez-Juan P, Green A, Ladogana A, Cuadrado-Corrales N, Saanchez-Valle R, Mitrovaa E, Stoeck K, Sklaviadis T et al (2006) CSF tests in the differential diagnosis of Creutzfeldt-Jakob disease. Neurology 67:637–643. https://doi.org/10.1212/01.wnl.0000230159.67128.00 CrossRefPubMedGoogle Scholar
- 10.Dorey A, Tholance Y, Vighetto A, Perret-Liaudet A, Lachman I, Krolak-Salmon P, Wagner U, Struyfs H et al (2015) Association of cerebrospinal fluid prion protein levels and the distinction between Alzheimer disease and Creutzfeldt-Jakob disease. JAMA Neurol 72:267–275. https://doi.org/10.1001/jamaneurol.2014.4068 CrossRefPubMedGoogle Scholar
- 11.Meyne F, Gloeckner SF, Ciesielczyk B, Heinemann U, Krasnianski A, Meissner B, Zerr I (2009) Total prion protein levels in the cerebrospinal fluid are reduced in patients with various neurological disorders. J Alzheimers Dis 17:863–873. https://doi.org/10.3233/JAD-2009-1110 CrossRefPubMedGoogle Scholar
- 12.Rumeileh SA, Lattanzio F, Maserati MS et al (2016) Diagnostic accuracy of a combined analysis of cerebrospinal fluid t-PrP, t-tau, p-tau, and Aβ42 in the differential diagnosis of Creutzfeldt-Jakob disease from Alzheimer’s disease with emphasis on atypical disease variants. J Alzheimers Dis 55:1–10. https://doi.org/10.3233/JAD-160740 CrossRefGoogle Scholar
- 16.van Keulen LJ, Schreuder BE, Vromans ME et al (2000) Pathogenesis of natural scrapie in sheep. Arch Virol Suppl 16:57–71Google Scholar
- 18.Monleón E, Garza MC, Sarasa R, Álvarez-Rodriguez J, Bolea R, Monzón M, Vargas MA, Badiola JJ et al (2011) An assessment of the efficiency of PrPsc detection in rectal mucosa and third-eyelid biopsies from animals infected with scrapie. Vet Microbiol 147:237–243. https://doi.org/10.1016/j.vetmic.2010.06.028 CrossRefPubMedGoogle Scholar
- 21.Llorens F, Schmitz M, Karch A et al (2015) Comparative analysis of cerebrospinal fluid biomarkers in the differential diagnosis of neurodegenerative dementia. Alzheimers Dement 1–13. https://doi.org/10.1016/j.jalz.2015.10.009
- 22.Schmitz M, Cramm M, Llorens F, Müller-Cramm D, Collins S, Atarashi R, Satoh K, Orrù CD et al (2016) The real-time quaking-induced conversion assay for detection of human prion disease and study of other protein misfolding diseases. Nat Protoc 11:2233–2242. https://doi.org/10.1038/nprot.2016.120 CrossRefPubMedGoogle Scholar
- 24.Forloni G, Tettamanti M, Lucca U, Albanese Y, Quaglio E, Chiesa R, Erbetta A, Villani F et al (2015) Preventive study in subjects at risk of fatal familial insomnia: Innovative approach to rare diseases. Prion 9:75–79. https://doi.org/10.1080/19336896.2015.1027857 CrossRefPubMedPubMedCentralGoogle Scholar