Skip to main content
SpringerLink
Log in

Neuropathology and Molecular Biology of Variant Creutzfeldt-Jakob Disease

  • Chapter
Mad Cow Disease and Related Spongiform Encephalopathies

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 284))

Abstract

The neuropathological features of human prion diseases are spongiform change, neuronal loss, astrocytic proliferation and the accumulation of PrPSc, the abnormal isoform of prion protein (PrP). The pattern of brain involvement is remarkably variable and is substantially influenced by the host PrP genotype and PrPSc isotype. Variant Creutzfeldt-Jakob disease (vCJD) is a novel human prion disease which results from exposure to the bovine spongiform encephalopathy (BSE) agent. The neuropathology of vCJD shows consistent characteristics, with abundant florid and cluster plaques in the cerebrum and cerebellum, and widespread accumulation of PrPres on immunocytochemistry. These features are distinct from all other types of human prion disease. Spongiform change is most marked in the basal ganglia, while the thalamus exhibits severe neuronal loss and gliosis in the posterior nuclei. These areas of thalamic pathology correlate with the areas of high signal seen in the thalamus on magnetic resonance imaging (MRI) examination of the brain. Western blot analysis of PrPSc in the brain in vCJD tissue shows a uniform isotype, with a glycoform ratio characterized by predominance of the diglycosylated band, distinct from sporadic CJD. PrPSc accumulation in vCJD is readily detectable outside the brain, in contrast with other forms of human prion disease, particularly in the lymphoid system and in parts of the peripheral nervous system. This has raised concern about the possible iatrogenic transmission of vCJD by contaminated surgical instruments, or blood. All cases of vCJD are methionine homozygotes at codon 129 of the prion protein gene (PRNP). Continued surveillance is required to investigate cases of vCJD in the UK and other countries where BSE has been reported, particularly as cases of ‘human BSE’ in individuals who are MV or VV at codon 129 of the PrP gene have not yet been identified. Histological, genetic and biochemical techniques are essential tools for the adequate diagnosis and investigation of human prion diseases.

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

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

References

  • Anderson RM, Donnelly CA, Ferguson NM, Woolhouse ME, Watt CJ, Udy HJ, MaWhinney S, Dunstan SP, Southwood TR, Wilesmith JW, Ryan JB, Hoinville LJ, Hillerton JE, Austin AR, Wells GA (1996) Transmission dynamics and epidemiology of BSE in British cattle. Nature 382: 779–88

    Article  PubMed  CAS  Google Scholar 

  • Bell JE, Gentleman SM, Ironside JW, McCardle L, Lantos PL, Dey L, Lowe J, Fergusson J, Luthert P, McQuaid S (1997) Prion protein immunocytochemistryUK five centre consensus report. Neuropathol Appl Neurobiol 23: 26–35

    Article  PubMed  CAS  Google Scholar 

  • Beekes M, McBride P (2000) Early accumulation of pathological PrP in the enteric nervous system and gut-associated lymphoid tissue of hamsters orally fed with scrapie. Neurosci Lett 278: 81–184

    Article  Google Scholar 

  • Bessen RA, Marsh RF (1994) Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J Virol 68: 7859–7868

    PubMed  CAS  Google Scholar 

  • Brown P, Gibbs CJ Jr, Rodgers-Johnson P, Asher DM, Sulima MP, Bacote A, Goldfarb LG, Gajdusek DC (1994) Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol 35: 513–529

    Article  PubMed  CAS  Google Scholar 

  • Brown P, Preece P, Brandel JP, Sato T, McShane L, Zerr I, Fletcher A, Will RG, Pocchiari M, Cashman NR, d’Aignaux JH, Cervenakova L, Fradkin J, Schonberger LB, Collins SJ (2000) latrogenic Creutzfeldt-Jakob disease at the millennium. Neurology 55: 1075–1081

    Google Scholar 

  • Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, McCardle L, Chree A, Hope J, Birkett C, Cousens S, Fraser H, Bostock C (1997) Transmissions to mice indicate that “new variant” CJD is caused by the BSE agent. Nature 389: 498–501

    Article  PubMed  CAS  Google Scholar 

  • Bruce ME, Chree A, McConnell I, Foster J, Pearson G, Fraser H (1994) Transmission of bovine spongiform encephalopathy and scrapie to mice: strain variation and the species barrier. Philos Trans R Soc Lond B Biol Sci 343: 405–411

    Article  PubMed  CAS  Google Scholar 

  • Bruce ME, McConnell I, Will RG, Ironside JW (2001) Detection of variant Creutzfeldt-Jakob disease infectivity in extraneural tissues. Lancet 358: 208–209

    Article  PubMed  CAS  Google Scholar 

  • Cervenakova L, Goldfarb LG, Garruto R, Lee H-S, Gajdusek DC, Brown P (1999) Phenotype-genotype studies in kuru: implications for new variant Creutzfeldt-Jakob disease. Proc Natl Acad Sci USA 95: 13239–13241

    Article  Google Scholar 

  • Collinge J, Palmer MS, Sidle KC, Hill AF, Gowkland I, Meads J, Asante E, Bradley R, Doey LJ, Lantos P (1995) Unaltered susceptibility to BSE in transgenic mice expressing human prion protein. Nature 378: 779–783

    Article  PubMed  CAS  Google Scholar 

  • Collinge J, Sidle KCL, Meads J, Ironside J, Hill AF (1996) Molecular analysis of prion strain variation and the aetiology of `new variant’ CJD. Nature 383:685–690 DEFRA;

    Google Scholar 

  • Bovine Spongiform Encephalopathy in the UK: A Progress Report (2002) DEFRA Publications, London

    Google Scholar 

  • Fraser H (1979) The pathogenesis of pathology of scrapie. in: Tyrell DAJ, (Eds.), Aspects of slow and persistent virus infections. Martinus Nijhoff, The Hague, 30–58

    Chapter  Google Scholar 

  • Gajdusek DC, Zigas V (1957) Degenerative disease of the central nervous system in New Guinea: the endemic occurrence of `Kuru’ in the native population. N Engl J Med 257: 974–978

    Article  PubMed  CAS  Google Scholar 

  • Gambetti P, Parchi P, Petersen RB, Chen SG, Lugaresi E (1995) Fatal familial insomnia and familial Creutzfeldt-Jakob disease: clinical, pathological and molecular features. Brain Pathol 5: 43–51

    Article  PubMed  CAS  Google Scholar 

  • Giese A, Kretzschmar HA (2001) Prion-induced neuronal damage. Curr Top Microbiol Immunol 253: 203–217

    PubMed  CAS  Google Scholar 

  • Green AJ, Thompson EJ, Stewart GE, Zeidler M, McKenzie JM, MacLeod MA, Ironside JW, Will RG, Knight RS (2001) Use of 14–3–3 and other brain–specific proteins in CSF in the diagnosis of variant Creutzfeldt–Jakob disease. J Neurol Neurosurg Psychiatry 70: 744 – 748

    Article  PubMed  CAS  Google Scholar 

  • Hainfellner JA, Budka H (1999) Disease associated prion protein may deposit in the peripheral nervous system in human transmissible spongiform encephalopathies. Acta Neuropathol 98: 458–460

    Article  PubMed  CAS  Google Scholar 

  • Hainfellner JA, Parchi P, Kitamoto T, Jarius C, Gambetti P, Budka H (1999) A novel phenotype in familial Creutzfeldt-Jakob disease: Prion protein gene E200 K mutation coupled with valine at codon 129 and type 2 protease-resistant prion protein. Ann Neurol 45: 812–816

    Article  PubMed  CAS  Google Scholar 

  • Head MW, Tissingh G, Uitdehaag BMJ, Barkhof F, Bunn TJB, Ironside JW, Kamphorst W, Scheltens P (2001) Sporadic Creutzfeldt-Jakob disease in a young Dutch valine homozygote: atypical molecular phenotype. Ann Neurol 50: 258–261

    Article  PubMed  CAS  Google Scholar 

  • Head MW, Northcott V, Rennison K, Ritchie D, McCardle L, Bunn TJR, McLennan NF, Ironside JW, Tullo AB, Bonshek RE (2003) Prion protein accumulation in eyes of patients with sporadic and variant Creutzfeldt-Jakob disease. Invest Ophthalmol Vis Sci 44: 342–346

    Article  PubMed  Google Scholar 

  • Hill AF, Butterworth RJ, Joiner S, Jackson G, Rossor M, Thomas DJ, Frosh A, Tolley N, Bell JB, Spencer M, King A, Al-Sarraj S, Ironside JW, Lantos PL, Collinge J (1999) Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet 353: 183–189

    Article  PubMed  CAS  Google Scholar 

  • Hill AF, Desbruslais M, Joiner S, Sidle KCL, Gowland I, Collinge J, Doey LJ, Lantos P (1997) The same prion strain causes vCJD and BSE. Nature 389: 448–450

    Article  PubMed  CAS  Google Scholar 

  • Hilton DA, Fathers E, Edwards P, Ironside JW, Zajicek J (1999) Prion immunoreactivity in appendix before clinical onset of variant Creutzfeldt-Jakob disease. Lancet 352: 703–704

    Article  Google Scholar 

  • Hsiao K, Baker HF, Crow TJ, Poulter M,Owen F, Terwilliger JD, Westaway D, Ott J, Prusiner SB (1989) Linkage of a prion protein missense variant to GerstmannStraussler syndrome. Nature 338: 342–345

    CAS  Google Scholar 

  • Hunter N, Foster J, Chong A, McCutcheon S, Parnham D, Eaton S, MacKenzie C, Houston F (2002) Transmission of prion diseases by blood transfusion. J Gen Virol 83: 2897–2905

    PubMed  CAS  Google Scholar 

  • Ironside JW (1998) Prion diseases in man. J Pathol 186: 227–234

    Article  PubMed  CAS  Google Scholar 

  • Ironside JW, Sutherland K, Bell JE, McCardle L, Barrie C, Estebeiro K, Zeidler M, Will RG (1996) A new variant of Creutzfeldt-Jakob disease: neuropathological and clinical features. Cold Spring Harbor Symp Quant Biol LXI: 523–530

    Google Scholar 

  • Ironside JW, Head MW, Bell JE, McCardle L, Will RG (2000a) Laboratory diagnosis of variant Creutzfeldt-Jakob disease. Histopathology 37: 1–9

    Article  PubMed  CAS  Google Scholar 

  • Ironside JW, Hilton DA, Ghani A, Johnston NJ, Conyers L, McCardle LM, Best D (2000b) Retrospective study of prion-protein accumulation in tonsil and appendix tissue. Lancet 355: 1693–1694

    Article  PubMed  CAS  Google Scholar 

  • Lasmezas CI, Fournier JG, Nouvel V, Boe H, Marce D, Lamoury F, Kopp N, Hauw JJ, Ironside J, Bruce M, Dormont D, Deslys JP (2001) Adaptation of the bovine spongiform encephalopathy agent to primates and comparison with Creutzfeldt-Jakob disease: implications for human health. Proc Natl Acad Sci USA 98: 4142–4147

    Article  PubMed  CAS  Google Scholar 

  • Lasmézas CI, Ironside JW, Chiach C, Demaimay R, Adjou KT, Hauw JJ, Dormont D (1996) BSE transmission to macaques. Nature 381: 743–744

    Article  PubMed  Google Scholar 

  • Lorains JW, Henry C, Agbamu DA, Rossi M, Bishop M, Will RG, Ironside JW (2001) Variant Creutzfeldt- Jakob disease in an elderly patient. Lancet 357: 1339–1340

    Article  PubMed  CAS  Google Scholar 

  • Mastrianni JA, Nixon R, Layzer R, Telling G, Han D, DeArmond SJ, Prusiner SB (1999) Prion protein conformation in a patient with sporadic fatal insomnia. New Engl J Med 340: 1630–1638

    Article  PubMed  CAS  Google Scholar 

  • McLean CA, Ironside JW, Masters CL (1997) Comparative neuropathology in kuru and new variant CJD. Brain Pathol 7: 1247–1248

    Article  Google Scholar 

  • Pan T, Colucci M, Wong BS, Ruliang L, Liu T, Petersen RB, Chen S, Gambetti P, Sy M-S (2001) Novel differences between two human prion strains revealed by two-dimensional gel electrophoresis. J Biol Chem 276: 37284–37288

    Article  PubMed  CAS  Google Scholar 

  • Parchi P, Capellari S, Chen SG, Petersen RB, Gambetti P, Kopp N, Brown P, Kitamoto T, Tateishi J, Giese A, Kretzschmar (1997) Typing prion isoforms. Nature 386: 232–233

    CAS  Google Scholar 

  • Parchi P, Castellani R, Capellari S, Ghetti B, Young K, Chen SG, Farlow M, Dickson DW, Sima AAF, Trojanowski JQ, Petersen RB, Gambetti P (1996) Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Ann Neurol 39: 767–778

    Article  PubMed  CAS  Google Scholar 

  • Parchi P, Chen SG, Brown P, Zou W, Capellari S, Budka H, Hainfellner J, Reyes PF, Golden GT, Hauw JJ, Carlton Gajdusek D, Gambetti P (1998b) Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann-Straussler-Scheinker disease. Proc Natl Acad Sci USA 95: 8322–8327

    Article  PubMed  CAS  Google Scholar 

  • Parchi P, Gambetti P, Piccardo P, Ghetti B (1998c) Human prion diseases. in: ( Kirkham N, Lemoine NR, Eds) Progress in Pathology, Edinburgh, Churchill Livingstone 39–78

    Google Scholar 

  • Parchi P, Petersen RB, Chen SG, Autillio-Gambetti L, Capellari S, Monari L, Cortelli P, Montagna P, Lugaresi E, Gambetti P (1998a) Molecular pathology of fatal familial insomnia. Brain Pathol 8: 539–548

    Article  PubMed  CAS  Google Scholar 

  • Parchi P, Zou W, Wang W, Brown P, Capellari S, Ghetti B, Kopp N, Schulz Schaefer WJ, Krerscmar HA, Head MW, Ironside JW, Gambetti P, Chen SC (2000) Genetic influence on the structural variation of the abnormal prion protein. Proc Natl Acad Sci USA 97: 10168–10172

    Article  PubMed  CAS  Google Scholar 

  • Parchi P, Castellani R, Cortelli P, Montagna P, Chen SG, Petesen RB, Manetto V, Vnecak-Jones CL, McLean MJ, Sheller JR, Lugaresi E, Gambetti L, Gambetti P (1995) Regional distribution of protease-resistant prion protein in fatal familial insomnia. Ann Neurol 38: 21–29

    Article  PubMed  CAS  Google Scholar 

  • Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer WJ, Windle O, Zerr I, Budka H, Kopp N, Piccardo P, Poser S, Rojiani A, Streichenebrger N, Julien J, Vital C, Ghetti B, Gambetti P, Kretzschmar HA (1999) Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 46: 224–233

    Article  PubMed  CAS  Google Scholar 

  • Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95: 13363–13383

    Article  CAS  Google Scholar 

  • Prusiner SB (1993) Genetic and infectious prion diseases. Arch Neurol 50:1129–1153 Scott MR, Will R, Ironside J, Nguyen HO, Tremblay P, DeArmond SJ, Prusiner SB (1999) Compelling transgenic evidence for transmission of bovine spongiform encephalopathy prions to humans. Proc Nat Acad Sci USA 96: 15137–15142

    Google Scholar 

  • Shimizu S, Hoshi K, Muramoto T, Homma M, Ironside JW, Kuzuhara S, Sato T, Yamamoto T, Kitamoto K (1999) Creutzfeldt-Jakob disease with florid-type plaques after cadaveric dura mater grafting. Arch Neurol 56: 357–363

    Article  PubMed  CAS  Google Scholar 

  • Somerville RA (1999) Host and transmissible spongiform encephalopathy agent strain control glycosylation of PrP. J Gen Virol 80: 1865–1872

    PubMed  CAS  Google Scholar 

  • Spence MD, Knight RSG, Will RG (2002) First one hundred cases of variant Creutzfeldt-Jakob disease: retrospective case note review of early psychiatric and neurological features. Brit Med J 324: 1479–1482

    Article  Google Scholar 

  • Telling GC, Parchi P, DeArmond SJ, Cortelli P, Montagna P, Gabizon R, Mastrianni J, Lugaresi E, Gambetti P, Prusiner SB (1996) Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 274: 2079–2082

    Article  PubMed  CAS  Google Scholar 

  • The BSE Inquiry (2000) Vol 1: Findings and Conclusions. London, The Stationery Office

    Google Scholar 

  • Turner M (2001) Variant Creutzfeldt-Jakob disease and blood transfusion. Curr Opin Haematol 8: 372–379

    Article  CAS  Google Scholar 

  • Wadsworth JD, Joiner S, Hill AF, Campbell TA, Desbruslais M, Luthert PJ, Collinge J (2001) Tissue distribution of protease resistant prion protein in variant Creutzfeldt-Jakob disease using a highly sensitive immunoblotting assay. Lancet 358: 171–180

    Article  PubMed  CAS  Google Scholar 

  • Wadsworth JDF, Hill AF, Joiner S, Jackson GS, Clarke AR, Collinge J (1999a) Strain-specific prion-protein conformation determined by metal ions. Nature Cell Biol 1: 55–59

    Article  PubMed  CAS  Google Scholar 

  • Wadsworth JDF, Jackson GS, Hill AF, Collinge J (1999b) Molecular biology of prion propagation. Curr Opin Genetics Develop 9: 338–345

    Article  CAS  Google Scholar 

  • Wells GA, Scott AC, Johnson CT, Gunning RF, Hancock RD, Jeffrey M, Dawson M, Bradley R (1987) A novel progressive spongiform encephalopathy in cattle. Vet Rec 121: 419–20

    Article  PubMed  CAS  Google Scholar 

  • Wilesmith JW, Wells GA, Cranwell MP, Ryan JB (1988) Bovine spongiform encephalopathy: epidemiological studies. Vet Rec 123: 638–44

    PubMed  CAS  Google Scholar 

  • Will RG, Ironside JW, Zeidler M, Cousens S, Estebeiro K, Alperovitch A, Poser S, Pocchiari M, Hofmann B, Smith PG (1996) A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 347: 921–925

    Article  PubMed  CAS  Google Scholar 

  • Will RG, Alpers MP, Dormont D, Schonberger LB, Tateishi J (1999) Infectious and sporadic prion diseases. Prion Biology and Diseases ch12: 465–507

    Google Scholar 

  • Will RG, Matthews WB (1984) A retrospective study of Creutzfeldt-Jakob disease in England and Wales 1970–79 I: Clinical features. J Neurol Neurosurg Psych 47: 134–140

    Google Scholar 

  • Will RG, Zeidler M, Stewart GE, Macleod MA, Ironside JW, Cousens SN, Mackenzie J, Estibeiro K, Green AJE, Knight RSG (2000) Diagnosis of new variant Creutzfeldt-Jakob disease. Ann Neurol 47: 575–582

    Article  PubMed  CAS  Google Scholar 

  • Williams ES, Young S (1993) Neuropathology of chronic wasting disease of mule deer (odocoileus hemionus) and elk ( Cervus elaphus nelsoni ). Vet Pathol 30: 36–45

    Google Scholar 

  • World Health Organization (1996) Report of a WHO consultation on clinical and neuropathological characteristics of the new variant of CJD and other human and animal transmissible spongiform encephalopathies. World Health Organization, Geneva

    Google Scholar 

  • Zanusso G, Farinazzo A, Fiorini M, Gelati M, Castagna A, Righetti PG, Rizzuto N, Monaco S (2001) pH-dependent prion protein conformation in classical Creutzfeldt-Jakob disease. J Biol Chem 276: 40377–40380

    Google Scholar 

  • Zanusso G, Righetti PG, Ferrari S, Terrin L, Farinazzo A, Cardone F, Pocchiari M, Rizzuto N, Monaco S (2002) Two-dimensional mapping of three phenotype associated isoforms of the prion protein in sporadic Creutzfeldt-Jakob disease. Electrophoresis 23: 347–355

    Article  PubMed  CAS  Google Scholar 

  • Zeidler M, Sellar RJ, Collie DA, Knight R, Stewart G, Macleod M-A, Ironside JW, Cousens S, Colchester ACF, Hadley DM, Will RG (2000) The pulvinar sign on magnetic resonance imaging in variant Creutzfeldt-Jakob disease. Lancet 355: 1412–1418

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. National Creutzfeldt-Jakob Disease Surveillance Unit, Department of Pathology, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK

    J. W. Ironside & M. W. Head

Authors
  1. J. W. Ironside
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. W. Head
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Ave, 63110, St. Louis, MO, USA

    David A. Harris MD, PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Ironside, J.W., Head, M.W. (2004). Neuropathology and Molecular Biology of Variant Creutzfeldt-Jakob Disease. In: Harris, D.A. (eds) Mad Cow Disease and Related Spongiform Encephalopathies. Current Topics in Microbiology and Immunology, vol 284. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-08441-0_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-08441-0_6

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-05756-4

  • Online ISBN: 978-3-662-08441-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation