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Cerebrospinal Fluid Total Prion Protein in the Spectrum of Prion Diseases

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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.

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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

References

  1. Aguzzi A, Sigurdson C, Heikenwaelder M (2008) Molecular mechanisms of prion pathogenesis. Annu Rev Pathol Mech Dis 3:11–40

    Article  CAS  Google Scholar 

  2. Aguzzi A (2006) Prion diseases of humans and farm animals: epidemiology, genetics, and pathogenesis. J Neurochem 97:1726–1739

    Article  CAS  Google Scholar 

  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. 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. 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 46:224–233

    Article  CAS  Google Scholar 

  6. Mastrianni JA (2010) The genetics of prion diseases. Genet Med 12:187–95

    Article  Google Scholar 

  7. Lloyd SE, Mead S, Collinge J (2013) Genetics of prion diseases. Curr Opin Genet Dev 345–51

    Article  CAS  Google Scholar 

  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:E10

    Article  Google Scholar 

  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 43:32–40

    Article  CAS  Google Scholar 

  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 225:210–212

    Article  CAS  Google Scholar 

  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 13:710–719

    Article  Google Scholar 

  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 17:175–178

    Article  CAS  Google Scholar 

  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 17:863–873

    Article  CAS  Google Scholar 

  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 72:267–275

    Article  Google Scholar 

  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 55:1–10

    Article  Google Scholar 

  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 7:383–93

    Article  CAS  Google Scholar 

  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 31:2024–2031

    Article  Google Scholar 

  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:e36159

    Article  CAS  Google Scholar 

  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 35:1177–1188

    Article  CAS  Google Scholar 

  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 132:2659–2668

    Article  CAS  Google Scholar 

  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 124:517–529

    Article  Google Scholar 

  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 118:166–174

    Article  Google Scholar 

  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 105

  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 105:244–252

    Article  CAS  Google Scholar 

  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. 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 12:577–589

    Article  Google Scholar 

  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 256:1620–8

    Article  CAS  Google Scholar 

  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 53:1896–1904

    Article  Google Scholar 

  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 75:1166–1170

    Article  CAS  Google Scholar 

  30. Kovács GG, Trabattoni G, Hainfellner JA, Ironside JW, Knight RSG, Budka H (2002) Mutations of the prion protein gene: phenotypic spectrum. J Neurol 249:1567–1582

    Article  Google Scholar 

  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 54:4138–4149

    Article  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  Google Scholar 

  34. Gambetti P, Kong Q, Zou W, Parchi P, Chen SG (2003) Sporadic and familial CJD: classification and characterisation. Br Med Bull 66:213–239

    Article  CAS  Google Scholar 

  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 254:901–906

    Article  CAS  Google Scholar 

  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 55:2249–2257

    Article  Google Scholar 

  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 8:322ra9

  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 38:21–29

    Article  CAS  Google Scholar 

  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 43:71–80

    Article  CAS  Google Scholar 

  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 14:751–763

    Article  Google Scholar 

  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 25:2417–2436

  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

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Silja Köchy for indispensable technical assistance.

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.

Author information

Author notes

  1. Anna Villar-Piqué and Matthias Schmitz contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, University Medical School, Göttingen, Germany

    Anna Villar-Piqué, Matthias Schmitz, Inga Zerr & Franc Llorens

  2. German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany

    Matthias Schmitz & Inga Zerr

  3. AJ Roboscreen GmbH, Leipzig, Germany

    Ingolf Lachmann

  4. Department of Epidemiology, Helmholtz Centre for Infection Research, Braunschweig, Germany

    André Karch

  5. Alzheimer Disease Research Unit, CIEN Foundation, Queen Sofia Foundation Alzheimer Center, Chronic Disease Programme Carlos III Institute of Health, Madrid, Spain

    Olga Calero & Miguel Calero

  6. Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain

    Olga Calero & Miguel Calero

  7. Australian National Creutzfeldt-Jakob Disease Registry, Florey Institute, The University of Melbourne, Melbourne, Australia

    Christiane Stehmann, Shannon Sarros & Steven J. Collins

  8. Department of Neurosciences, Istituto Superiore di Sanità, Rome, Italy

    Anna Ladogana, Anna Poleggi & Maurizio Pocchiari

  9. Neurology Department, CHUC - Centro Hospitalar e Universitário de Coimbra, CNC- Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    Isabel Santana & Inês Baldeiras

  10. Bellvitge University Hospital-IDIBELL, Department of Pathology and Experimental Therapeutics, Hospitalet de Llobregat, University of Barcelona, Barcelona, Spain

    Isidre Ferrer

  11. Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain

    Isidre Ferrer & Franc Llorens

  12. Department of Prion Diseases, Slovak Medical University, Bratislava, Slovakia

    Eva Mitrova & Dana Žáková

  13. Department of Medicine (RMH), The University of Melbourne, Melbourne, Australia

    Steven J. Collins

  14. Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA

    Michael D. Geschwind

  15. Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Department, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain

    Raquel Sánchez-Valle

  16. Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Spain

    Franc Llorens

Authors
  1. Anna Villar-Piqué
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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.

Corresponding authors

Correspondence to Anna Villar-Piqué, Matthias Schmitz or Franc Llorens.

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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.

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Not applicable.

Competing Interests

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

Additional information

Inga Zerr and Franc Llorens are equal senior contributors.

Electronic Supplementary Material

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)

High Resolution (TIF 526 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)

High Resolution (TIF 330 kb)

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Villar-Piqué, A., Schmitz, M., Lachmann, I. et al. Cerebrospinal Fluid Total Prion Protein in the Spectrum of Prion Diseases. Mol Neurobiol 56, 2811–2821 (2019). https://doi.org/10.1007/s12035-018-1251-1

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