Skip to main content

Advertisement

SpringerLink
Log in

Diagnostic value of surrogate CSF biomarkers for Creutzfeldt–Jakob disease in the era of RT-QuIC

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Prion real-time quaking-induced conversion (RT-QuIC) is emerging as the most potent assay for the in vivo diagnosis of Creutzfeldt–Jakob disease (CJD), but its full application, especially as a screening test, is limited by suboptimal substrate availability, reagent costs, and incomplete assay standardization. Therefore, the search for the most informative cerebrospinal fluid (CSF) surrogate biomarker is still of primary importance. We compared the diagnostic accuracy of CSF protein 14-3-3, measured with both western blot (WB) and enzyme-linked immunosorbent assay (ELISA), total (t)-tau and neurofilament light chain protein (NfL) alone or in combination with RT-QuIC in 212 subjects with rapidly progressive dementia in which we reached a highly probable clinical diagnosis at follow-up or a definite neuropathological diagnosis. T-tau performed best as surrogate CSF biomarker for the diagnosis of CJD (91.3% sensitivity and 78.9% specificity). The 14-3-3 ELISA assay demonstrated a slightly higher diagnostic value compared to the WB analysis (76.9% vs. 72.2%), but both methods performed worse than the t-tau assay. NfL was the most sensitive biomarker for all sCJD subtypes (> 95%), including those with low values of t-tau or 14-3-3, but showed the lowest specificity (43.1%). When ELISA-based biomarkers were adopted as screening tests followed by RT-QuIC, t-tau correctly excluded a higher number of non-CJD cases compared to NfL and 14-3-3 ELISA. Our study showed that among the CSF surrogate biomarkers of potential application for the clinical diagnosis of CJD, t-tau performs best either alone or as screening test followed by RT-QuIC as a second-level confirmatory test.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Baiardi S, Rossi M, Capellari S, Parchi P (2019) Recent advances in the histo-molecular pathology of human prion disease. Brain Pathol 29:278–300

    Article  Google Scholar 

  2. Parchi P, Giese A, Capellari S et al (1999) Classification of sporadic Creutzfeldt–Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 46:224–233

    Article  CAS  Google Scholar 

  3. Parchi P, Strammiello R, Notari S et al (2009) Incidence and spectrum of sporadic Creutzfeldt–Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification. Acta Neuropathol 118:659–671

    Article  CAS  Google Scholar 

  4. Parchi P, de Boni L, Saverioni D et al (2012) Consensus classification of human prion disease histotypes allows reliable identification of molecular subtypes: an inter-rater study among surveillance centres in Europe and USA. Acta Neuropathol 124:517–529

    Article  Google Scholar 

  5. Baiardi S, Capellari S, Bartoletti Stella A, Parchi P (2018) Unusual clinical presentations challenging the early clinical diagnosis of Creutzfeldt–Jakob disease. J Alzheimers Dis 64:1051–1065

    Article  CAS  Google Scholar 

  6. Zerr I, Kallenberg K, Summers DM et al (2009) Updated clinical diagnostic criteria for sporadic Creutzfeldt–Jakob disease. Brain 132:2659–2668

    Article  CAS  Google Scholar 

  7. Chohan G, Pennington C, Mackenzie JM et al (2010) The role of cerebrospinal fluid 14-3-3 and other proteins in the diagnosis of sporadic Creutzfeldt–Jakob disease in the UK: a 10-year review. J Neurol Neurosurg Psychiatry 81:1243–1248

    Article  CAS  Google Scholar 

  8. Hamlin C, Puoti G, Berri S et al (2012) A comparison of tau and 14-3-3 protein in the diagnosis of Creutzfeldt–Jakob disease. Neurology 79:547–552

    Article  CAS  Google Scholar 

  9. Lattanzio F, Abu-Rumeileh S, Franceschini A et al (2017) Prion-specific and surrogate CSF biomarkers in Creutzfeldt–Jakob disease: diagnostic accuracy in relation to molecular subtypes and analysis of neuropathological correlates of p-tau and Aβ42 levels. Acta Neuropathol 133:559–578

    Article  CAS  Google Scholar 

  10. Rudge P, Hyare H, Green A, Collinge J, Mead S (2018) Imaging and CSF analyses effectively distinguish CJD from its mimics. J Neurol Neurosurg Psychiatry 89:461–466

    Article  Google Scholar 

  11. McGuire LI, Peden AH, Orrú CD et al (2012) Real time quaking-induced conversion analysis of cerebrospinal fluid in sporadic Creutzfeldt–Jakob disease. Ann Neurol 72:278–285

    Article  Google Scholar 

  12. Groveman BR, Orrú CD, Hughson AG et al (2016) Extended and direct evaluation of RT-QuIC assays for Creutzfeldt–Jakob disease diagnosis. Ann Clin Transl Neurol 4:139–144

    Article  Google Scholar 

  13. Foutz A, Appleby BS, Hamlin C et al (2017) Diagnostic and prognostic value of human prion detection in cerebrospinal fluid. Ann Neurol 81:79–92

    Article  CAS  Google Scholar 

  14. Franceschini A, Baiardi S, Hughson AG et al (2017) High diagnostic value of second generation CSF RT-QuIC across the wide spectrum of CJD prions. Sci Rep 7:10655

    Article  Google Scholar 

  15. Schmitz M, Ebert E, Stoeck K et al (2016) Validation of 14-3-3 protein as a marker in sporadic Creutzfeldt–Jakob disease diagnostic. Mol Neurobiol 53:2189–2199

    Article  CAS  Google Scholar 

  16. Leitão MJ, Baldeiras I, Almeida MR et al (2016) Sporadic Creutzfeldt–Jakob disease diagnostic accuracy is improved by a new CSF ELISA 14-3-3γ assay. Neuroscience 322:398–407

    Article  Google Scholar 

  17. Steinacker P, Blennow K, Halbgebauer S et al (2016) Neurofilaments in blood and CSF for diagnosis and prediction of onset in Creutzfeldt–Jakob disease. Sci Rep 6:38737

    Article  CAS  Google Scholar 

  18. Abu-Rumeileh S, Capellari S, Stanzani-Maserati M et al (2018) The CSF neurofilament light signature in rapidly progressive neurodegenerative dementias. Alzheimers Res Ther 10:3

    Article  Google Scholar 

  19. Zerr I, Schmitz M, Karch A et al (2018) Cerebrospinal fluid neurofilament light levels in neurodegenerative dementia: evaluation of diagnostic accuracy in the differential diagnosis of prion diseases. Alzheimers Dement 14:751–763

    Article  Google Scholar 

  20. Kanata E, Golanska E, Villar-Piqué A et al (2019) Cerebrospinal fluid neurofilament light in suspected sporadic Creutzfeldt–Jakob disease. J Clin Neurosci 60:124–127

    Article  Google Scholar 

  21. Grau-Rivera O, Gelpi E, Nos C et al (2015) Clinicopathological correlations and concomitant pathologies in rapidly progressive dementia: a brain bank series. Neurodegener Dis 15:350–360

    Article  CAS  Google Scholar 

  22. Geschwind MD, Murray K (2018) Differential diagnosis with other rapid progressive dementias in human prion diseases. Handb Clin Neurol 153:371–397

    Article  Google Scholar 

  23. Zerr I, Hermann P (2018) Diagnostic challenges in rapidly progressive dementia. Expert Rev Neurother 18:761–772

    Article  CAS  Google Scholar 

  24. Jansen C, Parchi P, Capellari S et al (2012) Human prion diseases in the Netherlands (1998–2009): clinical, genetic and molecular aspects. PLoS ONE 7:e36333

    Article  CAS  Google Scholar 

  25. ECDC (2017) https://www.cjd.ed.ac.uk/sites/default/files/criteria_0.pdf. Accessed 10 July 2019

  26. McGuire LI, Poleggi A, Poggiolini I et al (2016) Cerebrospinal fluid real-time quaking-induced conversion is a robust and reliable test for sporadic Creutzfeldt–Jakob disease: an international study. Ann Neurol 80:160–165

    Article  CAS  Google Scholar 

  27. Otto M, Wiltfang J, Cepek L et al (2002) Tau protein and 14-3-3 protein in the differential diagnosis of Creutzfeldt–Jakob disease. Neurology 58:192–197

    Article  CAS  Google Scholar 

  28. Skillbäck T, Rosén C, Asztely F et al (2014) Diagnostic performance of cerebrospinal fluid total tau and phosphorylated tau in Creutzfeldt–Jakob disease: results from the Swedish Mortality Registry. JAMA Neurol 71:476–483

    Article  Google Scholar 

  29. Gaetani L, Blennow K, Calabresi P et al (2019) Neurofilament light chain as a biomarker in neurological disorders. J Neurol Neurosurg Psychiatry 90:870–881

    Article  Google Scholar 

  30. Kovacs GG, Andreasson U, Liman V et al (2017) Plasma and cerebrospinal fluid tau and neurofilament concentrations in rapidly progressive neurological syndromes: a neuropathology-based cohort. Eur J Neurol 24:1326–e77

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We sincerely thank Dr. Byron Caughey for providing the substrate for IQ-CSF RT-QuIC. This work was supported by the Italian Ministry of Health (“Ricerca Corrente”).

Author information

Authors and Affiliations

  1. Department of Biomedical and Neuromotor Sciences, University of Bologna, 40139, Bologna, Italy

    Samir Abu-Rumeileh, Simone Baiardi & Sabina Capellari

  2. IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139, Bologna, Italy

    Barbara Polischi, Angela Mammana, Alessia Franceschini, Sabina Capellari & Piero Parchi

  3. The National CJD Research and Surveillance Unit, University of Edinburgh, Edinburgh, EH4 2XU, UK

    Alison Green

  4. Department of Experimental Diagnostic and Specialty Medicine, University of Bologna, 40139, Bologna, Italy

    Piero Parchi

Authors
  1. Samir Abu-Rumeileh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Simone Baiardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Barbara Polischi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Angela Mammana
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alessia Franceschini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alison Green
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sabina Capellari
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Piero Parchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: SA-R and PP; methodology, formal analysis and investigation: all authors; writing—original draft preparation: SA-R and PP; writing—review and editing: PP based on the critical revision of all authors—supervision: PP.

Corresponding author

Correspondence to Piero Parchi.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical standards

The study was conducted according to the revised Declaration of Helsinki and Good Clinical Practice guidelines and approved by the “Area Vasta Emilia Centro” ethics committee (CE-AVEC: 18025, 113/2018/OSS/AUSLBO). Informed consent was given by study participants or the next of kin.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 3317 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abu-Rumeileh, S., Baiardi, S., Polischi, B. et al. Diagnostic value of surrogate CSF biomarkers for Creutzfeldt–Jakob disease in the era of RT-QuIC. J Neurol 266, 3136–3143 (2019). https://doi.org/10.1007/s00415-019-09537-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-019-09537-0

Keywords

Search

Navigation