Molecular Neurobiology

, Volume 56, Issue 4, pp 2811–2821 | Cite as

Cerebrospinal Fluid Total Prion Protein in the Spectrum of Prion Diseases

  • Anna Villar-PiquéEmail author
  • Matthias SchmitzEmail author
  • Ingolf Lachmann
  • André Karch
  • Olga Calero
  • Christiane Stehmann
  • Shannon Sarros
  • Anna Ladogana
  • Anna Poleggi
  • Isabel Santana
  • Isidre Ferrer
  • Eva Mitrova
  • Dana Žáková
  • Maurizio Pocchiari
  • Inês Baldeiras
  • Miguel Calero
  • Steven J. Collins
  • Michael D. Geschwind
  • Raquel Sánchez-Valle
  • Inga Zerr
  • Franc LlorensEmail author


Cerebrospinal fluid (CSF) total prion protein (t-PrP) is decreased in sporadic Creutzfeldt-Jakob disease (sCJD). However, data on the comparative signatures of t-PrP across the spectrum of prion diseases, longitudinal changes during disease progression, and levels in pre-clinical cases are scarce. T-PrP was quantified in neurological diseases (ND, n = 147) and in prion diseases from different aetiologies including sporadic (sCJD, n = 193), iatrogenic (iCJD, n = 12) and genetic (n = 209) forms. T-PrP was also measured in serial lumbar punctures obtained from sCJD cases at different symptomatic disease stages, and in asymptomatic prion protein gene (PRNP) mutation carriers. Compared to ND, t-PrP concentrations were significantly decreased in sCJD, iCJD and in genetic prion diseases associated with the three most common mutations E200K, V210I (associated with genetic CJD) and D178N-129M (associated with fatal familial insomnia). In contrast, t-PrP concentrations in P102L mutants (associated with the Gerstmann-Sträussler-Scheinker syndrome) remained unaltered. In serial lumbar punctures obtained at different disease stages of sCJD patients, t-PrP concentrations inversely correlated with disease progression. Decreased mean t-PrP values were detected in asymptomatic D178-129M mutant carriers, but not in E200K and P102L carriers. The presence of low CSF t-PrP is common to all types of prion diseases regardless of their aetiology albeit with mutation-specific exceptions in a minority of genetic cases. In some genetic prion disease, decreased levels are already detected at pre-clinical stages and diminish in parallel with disease progression. Our data indicate that CSF t-PrP concentrations may have a role as a pre-clinical or early symptomatic diagnostic biomarker in prion diseases as well as in the evaluation of therapeutic interventions.


Cerebrospinal fluid Prion protein Sporadic Creutzfeldt-Jakob disease Genetic prion disease Iatrogenic prion disease 



Gerstmann–Sträussler–Scheinker syndrome


Receiver operating characteristic


Octapeptide repeat insertion


Prion protein gene


Genetic Creutzfeldt-Jakob disease


Iatrogenic Creutzfeldt-Jakob disease


Variant Creutzfeldt-Jakob disease


Fatal Familial Insomnia


Neurofilament light


PrPsc: Prion protein scrapie


Lumbar puncture


Area under the curve


Sporadic Creutzfeldt-Jakob disease


Cerebrospinal fluid


Enzyme-linked immunosorbent assays


Neurological diseases


Total prion protein



We thank Silja Köchy for indispensable technical assistance.

Authors’ Contributions

AV-P, MS, IZ and FL designed the study. AV-P, MS and FL performed experiments. AV-P, MS, AK, IZ and FL analysed data and interpreted the results. IL, OC, CS, SS, AL, AP, IS, IF, EM, D.Z, MP, IB, MC, SJC, MDG, RS-V and IZ contributed to samples and/or technical expertise. FL and AV-P 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 Spanish Ministry of Health - Instituto Carlos III/ Fondo Social Europeo (CP16/00041) 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

Ethics Approval and Consent to Participate

The study was conducted according to the revised Declaration of Helsinki and Good Clinical Practice guidelines, and was approved by all local Ethics committees. All study participants or their legal guardians provided written informed consent.

Consent for Publication

Not applicable.

Competing Interests

Dr. Lachmann reports he is a representative of AJ Roboscreen GmbH, Leipzig, Germany.

Supplementary material

12035_2018_1251_Fig6_ESM.png (97 kb)
Supplementary Figure 1

CSF t-PrP levels in gPD associated to E200K, D178N-M and P102L mutations in different cohorts. (A) CSF t-PrP in E200K cases from four cohorts. (B) CSF t-PrP in D178N-M cases from two cohorts. (C) CSF t-PrP in V210I cases from two cohorts. Kruskal-Wallis test followed by Dunn’s post-hoc tests (correction for multiple testing) was applied for multiple comparisons and Mann-Whitney-U test for two group comparisons. No statistical differences were detected for any of the comparisons. (PNG 97 kb)

12035_2018_1251_MOESM1_ESM.tif (527 kb)
High Resolution (TIF 526 kb)
12035_2018_1251_Fig7_ESM.png (99 kb)
Supplementary Figure 2

CSF t-PrP concentrations in asymptomatic PRNP mutant carriers from the UCSF cohort (asymptomatic – UCSF), symptomatic cases from the UCSF cohort (symptomatic – UCSF) and symptomatic cases from all the cases analyzed in the present study (symptomatic - ALL) for the E200K, D178N-M and P102L mutations. Dashed red lines indicate upper and lower 95% CI t-PrP concentrations in ND cases. (PNG 99 kb)

12035_2018_1251_MOESM2_ESM.tif (330 kb)
High Resolution (TIF 330 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Anna Villar-Piqué
    • 1
    Email author
  • Matthias Schmitz
    • 1
    • 2
    Email author
  • Ingolf Lachmann
    • 3
  • André Karch
    • 4
  • Olga Calero
    • 5
    • 6
  • Christiane Stehmann
    • 7
  • Shannon Sarros
    • 7
  • Anna Ladogana
    • 8
  • Anna Poleggi
    • 8
  • Isabel Santana
    • 9
  • Isidre Ferrer
    • 10
    • 11
  • Eva Mitrova
    • 12
  • Dana Žáková
    • 12
  • Maurizio Pocchiari
    • 8
  • Inês Baldeiras
    • 9
  • Miguel Calero
    • 5
    • 6
  • Steven J. Collins
    • 7
    • 13
  • Michael D. Geschwind
    • 14
  • Raquel Sánchez-Valle
    • 15
  • Inga Zerr
    • 1
    • 2
  • Franc Llorens
    • 1
    • 11
    • 16
    Email author
  1. 1.Department of NeurologyUniversity Medical SchoolGöttingenGermany
  2. 2.German Center for Neurodegenerative Diseases (DZNE)GöttingenGermany
  3. 3.AJ Roboscreen GmbHLeipzigGermany
  4. 4.Department of EpidemiologyHelmholtz Centre for Infection ResearchBraunschweigGermany
  5. 5.Alzheimer Disease Research Unit, CIEN Foundation, Queen Sofia Foundation Alzheimer Center, Chronic Disease Programme Carlos III Institute of HealthMadridSpain
  6. 6.Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED)MadridSpain
  7. 7.Australian National Creutzfeldt-Jakob Disease Registry, Florey InstituteThe University of MelbourneMelbourneAustralia
  8. 8.Department of NeurosciencesIstituto Superiore di SanitàRomeItaly
  9. 9.Neurology Department, CHUC - Centro Hospitalar e Universitário de Coimbra, CNC- Center for Neuroscience and Cell Biology, Faculty of MedicineUniversity of CoimbraCoimbraPortugal
  10. 10.Bellvitge University Hospital-IDIBELL, Department of Pathology and Experimental Therapeutics, Hospitalet de LlobregatUniversity of BarcelonaBarcelonaSpain
  11. 11.Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED)BarcelonaSpain
  12. 12.Department of Prion DiseasesSlovak Medical UniversityBratislavaSlovakia
  13. 13.Department of Medicine (RMH)The University of MelbourneMelbourneAustralia
  14. 14.Department of Neurology, Memory and Aging CenterUniversity of CaliforniaSan FranciscoUSA
  15. 15.Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Department, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS)Hospital ClínicBarcelonaSpain
  16. 16.Bellvitge Biomedical Research Institute (IDIBELL)L’Hospitalet de LlobregatSpain

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