Advertisement

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
Article

Abstract

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.

Keywords

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

Abbreviations

GSS-S

Gerstmann–Sträussler–Scheinker syndrome

ROC

Receiver operating characteristic

OPRI

Octapeptide repeat insertion

PRNP

Prion protein gene

gCJD

Genetic Creutzfeldt-Jakob disease

iCJD

Iatrogenic Creutzfeldt-Jakob disease

vCJD

Variant Creutzfeldt-Jakob disease

FFI

Fatal Familial Insomnia

NFL

Neurofilament light

PrPscz

PrPsc: Prion protein scrapie

LP

Lumbar puncture

AUC

Area under the curve

sCJD

Sporadic Creutzfeldt-Jakob disease

CSF

Cerebrospinal fluid

ELISA

Enzyme-linked immunosorbent assays

ND

Neurological diseases

t-PrP

Total prion protein

Notes

Acknowledgements

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.

Funding

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)

References

  1. 1.
    Aguzzi A, Sigurdson C, Heikenwaelder M (2008) Molecular mechanisms of prion pathogenesis. Annu Rev Pathol Mech Dis 3:11–40CrossRefGoogle Scholar
  2. 2.
    Aguzzi A (2006) Prion diseases of humans and farm animals: epidemiology, genetics, and pathogenesis. J Neurochem 97:1726–1739CrossRefGoogle Scholar
  3. 3.
    Chen C, Dong X-P (2016) Epidemiological characteristics of human prion diseases. Infect Dis Poverty [Internet] 5:47. Available from: http://idpjournal.biomedcentral.com/articles/10.1186/s40249-016-0143-8
  4. 4.
    Parchi P, Castellani R, Capellari S, Ghetti B, Young K, Chen SG et al (1996) Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Ann Neurol [Internet] 39:767–78. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8651649
  5. 5.
    Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O et al (1999) Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 46:224–233CrossRefGoogle Scholar
  6. 6.
    Mastrianni JA (2010) The genetics of prion diseases. Genet Med 12:187–95CrossRefGoogle Scholar
  7. 7.
    Lloyd SE, Mead S, Collinge J (2013) Genetics of prion diseases. Curr Opin Genet Dev 345–51CrossRefGoogle Scholar
  8. 8.
    Bonda DJ, Manjila S, Mehndiratta P, Khan F, Miller BR, Onwuzulike K et al (2016) Human prion diseases: surgical lessons learned from iatrogenic prion transmission. Neurosurg Focus 41:E10CrossRefGoogle Scholar
  9. 9.
    Zerr I, Bodemer M, Gefeller O, Otto M, Poser S, Wiltfang J, Windl O, Kretzschmar HA et al (1998) Detection of 14-3-3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt-Jakob disease. Ann Neurol 43:32–40CrossRefGoogle Scholar
  10. 10.
    Otto M, Wiltfang J, Tumani H, Zerr I, Lantsch M, Kornhuber J et al (1997) Elevated levels of tau-protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurosci Lett 225:210–212CrossRefGoogle Scholar
  11. 11.
    Llorens F, Kruse N, Schmitz M, Gotzmann N, Golanska E, Thüne K, Zejneli O, Kanata E et al (2017) Evaluation of α-synuclein as a novel cerebrospinal fluid biomarker in different forms of prion diseases. Alzheimers Dement 13:710–719CrossRefGoogle Scholar
  12. 12.
    Atarashi R, Satoh K, Sano K, Fuse T, Yamaguchi N, Ishibashi D, Matsubara T, Nakagaki T et al (2011) Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking-induced conversion. Nat Med 17:175–178CrossRefGoogle Scholar
  13. 13.
    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 17:863–873CrossRefGoogle Scholar
  14. 14.
    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 72:267–275CrossRefGoogle Scholar
  15. 15.
    Rumeileh SA, Lattanzio F, Maserati MS, Rizzi R, Capellari S, Parchi P (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 55:1–10CrossRefGoogle Scholar
  16. 16.
    Llorens F, Ansoleaga B, Garcia-Esparcia P, Zafar S, Grau-Rivera O, López-González I, Blanco R et al (2013) PrP mRNA and protein expression in brain and PrP(c) in CSF in Creutzfeldt-Jakob disease MM1 and VV2. Prion 7:383–93CrossRefGoogle Scholar
  17. 17.
    Schmitz M, Schlomm M, Hasan B, Beekes M, Mitrova E, Korth C, Breil A, Carimalo J et al (2010) Codon 129 polymorphism and the E200K mutation do not affect the cellular prion protein isoform composition in the cerebrospinal fluid from patients with Creutzfeldt-Jakob disease. Eur J Neurosci 31:2024–2031CrossRefGoogle Scholar
  18. 18.
    Torres M, Cartier L, Matamala JM, Hernández N, Woehlbier U, Hetz C (2012) Altered prion protein expression pattern in CSF as a biomarker for Creutzfeldt-Jakob disease. PLoS One 7:e36159CrossRefGoogle Scholar
  19. 19.
    Schmitz M, Lüllmann K, Zafar S, Ebert E, Wohlhage M, Oikonomou P, Schlomm M, Mitrova E et al (2014) Association of prion protein genotype and scrapie prion protein type with cellular prion protein charge isoform profiles in cerebrospinal fluid of humans with sporadic or familial prion diseases. Neurobiol Aging 35:1177–1188CrossRefGoogle Scholar
  20. 20.
    Zerr I, Kallenberg K, Summers DM, Romero C, Taratuto A, Heinemann U, Breithaupt M, Varges D et al (2009) Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Brain 132:2659–2668CrossRefGoogle Scholar
  21. 21.
    Parchi P, De Boni L, Saverioni D, Cohen ML, Ferrer I, Gambetti P 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 124:517–529CrossRefGoogle Scholar
  22. 22.
    Kovács GG, Puopolo M, Ladogana A, Pocchiari M, Budka H, van Duijn C, Collins SJ, Boyd A et al (2005) Genetic prion disease: the EUROCJD experience. Hum Genet 118:166–174CrossRefGoogle Scholar
  23. 23.
    World Health Organisation (2003) WHO manual for surveillance of human transmissible spongiform encephalopathies including variant Creutzfeldt-Jakob disease. WHO Man. Surveill. Hum. Transm. spongiform Enceph 105Google Scholar
  24. 24.
    Windl O, Giese A, Schulz-Schaeffer W, Zerr I, Skworc K, Arendt S, Oberdieck C, Bodemer M et al (1999) Molecular genetics of human prion diseases in Germany. Hum Genet 105:244–252CrossRefGoogle Scholar
  25. 25.
    Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez JC, Müller M (2011). pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics 12:77.  https://doi.org/10.1186/1471-2105-12-77
  26. 26.
    Llorens F, Schmitz M, Karch A, Cramm M, Lange P, Gherib K, Varges D, Schmidt C et al (2016) Comparative analysis of cerebrospinal fluid biomarkers in the differential diagnosis of neurodegenerative dementia. Alzheimers Dement 12:577–589CrossRefGoogle Scholar
  27. 27.
    Ladogana A, Sanchez-Juan P, Mitrova E, Green A, Cuadrado-Corrales N, Sanchez-Valle R et al (2009) Cerebrospinal fluid biomarkers in human genetic transmissible spongiform encephalopathies. J Neuro 256:1620–8CrossRefGoogle Scholar
  28. 28.
    Cramm M, Schmitz M, Karch A, Mitrova E, Kuhn F, Schroeder B, Raeber A, Varges D et al (2016) Stability and reproducibility underscore utility of RT-QuIC for diagnosis of Creutzfeldt-Jakob disease. Mol Neurobiol 53:1896–1904CrossRefGoogle Scholar
  29. 29.
    Croes EA, Theuns J, Houwing-Duistermaat JJ, Dermaut B, Sleegers K, Roks G, van den Broeck M, van Harten B et al (2004) Octapeptide repeat insertions in the prion protein gene and early onset dementia. J Neurol Neurosurg Psychiatry 75:1166–1170CrossRefGoogle Scholar
  30. 30.
    Kovács GG, Trabattoni G, Hainfellner JA, Ironside JW, Knight RSG, Budka H (2002) Mutations of the prion protein gene: phenotypic spectrum. J Neurol 249:1567–1582CrossRefGoogle Scholar
  31. 31.
    Schmitz M, Dittmar K, Llorens F, Gelpi E, Ferrer I, Schulz-Schaeffer WJ et al (2016) Hereditary human prion diseases: an update. Mol Neurobiol 54:4138–4149CrossRefGoogle Scholar
  32. 32.
    Beck JA, Poulter M, Campbell TA, Adamson G, Uphill JB, Guerreiro R, Jackson GS, Stevens JC, Manji H, Collinge J, Mead S (2010) PRNP allelic series from 19 years of prion protein gene sequencing at the MRC Prion Unit. Hum Mutat 31(7):E1551–15563.  https://doi.org/10.1002/humu.21281 CrossRefGoogle Scholar
  33. 33.
    Montagna P, Cortelli P, Avoni P, Tinuper P, Plazzi G, Gallassi R et al (1998) Clinical features of fatal familial insomnia: phenotypic variability in relation to a polymorphism at codon 129 of the prion protein gene. Brain Pathol [Internet] 8:515–20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9669701 CrossRefGoogle Scholar
  34. 34.
    Gambetti P, Kong Q, Zou W, Parchi P, Chen SG (2003) Sporadic and familial CJD: classification and characterisation. Br Med Bull 66:213–239CrossRefGoogle Scholar
  35. 35.
    Sanchez-Juan P, Sánchez-Valle R, Green A, Ladogana A, Cuadrado-Corrales N, Mitrová E, Stoeck K, Sklaviadis T et al (2007) Influence of timing on CSF tests value for Creutzfeldt-Jakob disease diagnosis. J Neurol 254:901–906CrossRefGoogle Scholar
  36. 36.
    Llorens F, Kruse N, Karch A, Schmitz M, Zafar S, Gotzmann N, Sun T, Köchy S et al (2018) Validation of α-synuclein as a CSF biomarker for sporadic Creutzfeldt-Jakob disease. Mol Neurobiol Mol Neurobiol 55:2249–2257CrossRefGoogle Scholar
  37. 37.
    Minikel EV, Vallabh SM, Lek M, Estrada K, Samocha KE, Sathirapongsasuti JF, McLean CY, Tung JY et al (2016) Quantifying prion disease penetrance using large population control cohorts. Sci Transl Med 8:322ra9Google Scholar
  38. 38.
    Parchi P, Castellani R, Cortelli P, Montagna P, Chen SG, Petersen RB, Manetto V, Vnencak-Jones CL et al (1995) Regional distribution of protease-resistant prion protein in fatal familial insomnia. Ann Neurol 38:21–29CrossRefGoogle Scholar
  39. 39.
    Llorens F, Karch A, Golanska E, Schmitz M, Lange P, Sikorska B et al (2017) Cerebrospinal fluid biomarker-based diagnosis of sporadic Creutzfeldt-Jakob disease: a validation study for previously established cutoffs. Dement Geriatr Cogn Disord 43:71–80CrossRefGoogle Scholar
  40. 40.
    Zerr I, Schmitz M, Karch A, Villar-Piqué A, Kanata E, Golanska E et al (2018) Cerebrospinal fluid neurofilament light levels in neurodegenerative dementia: evaluation of diagnostic accuracy in the differential diagnosis of prion diseases. Alzheimer’s Dement 14:751–763CrossRefGoogle Scholar
  41. 41.
    Llorens F, Thüne K, Schmitz M, Ansoleaga B, Frau-Méndez MA, Cramm M et al (2016) Identification of new molecular alterations in fatal familial insomnia. Hum Mol Genet 25:2417–2436Google Scholar
  42. 42.
    Llorens F, Barrio T, Correia Â, Villar-Piqué A, Thüne K, Lange P et al (2018) Cerebrospinal fluid prion disease biomarkers in pre-clinical and clinical naturally occurring scrapie. Mol Neurobiol.  https://doi.org/10.1007/s12035-018-1014-z CrossRefGoogle Scholar

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

Personalised recommendations