Prion-Related Diseases Medication

  • Author: Tarakad S Ramachandran, MBBS, FRCP(C), FACP; Chief Editor: Karen L Roos, MD   more...
 
Updated: Feb 6, 2012
 
 

Medication Summary

All prion diseases are fatal; no effective treatment is available. Patients are currently provided symptomatic treatment. Hence, some patients with CJD who develop seizures should be administered antiepileptic drugs, while those with extrapyramidal symptoms should be administered anti-Parkinson drugs.

A number of medications have been shown in experimental systems to be effective at preventing prion propagation. These have included Congo red and its analogs,[82, 83, 84, 85] anthracyclines[86] , amphotericin B and its analogs,[87, 88, 89, 90, 91] sulfated polyanions,[92, 93, 94] and tetrapyrroles.[95, 96] Some of these have been shown to delay the incubation times of animals infected with scrapie, but these agents have limitations in terms of toxic effects and/or unfavorable pharmacokinetic properties. Of these compounds, amphotericin B failed to ameliorate CJD in a single patient.[97]

In addition, tissue culture studies have shown that acridine and phenothiazine derivatives (eg, quinacrine, chlorpromazine) can inhibit the conversion of PrPC to PrPSc.[98] These types of drugs have been used in humans for many years as antimalarial and antipsychotic drugs; however, recent reports of anecdotal use of these agents in limited numbers of patients with sporadic CJD or vCJD have so far not supported their use,[99] and animal studies have also been negative.[100, 84, 101] An extensive clinical trial (PRION-1) on this approach was initiated in the UK in 2004 (see National Prion Clinic).

Another compound that is being tested in patients is pentosan polysulphate, which seemed promising based on an animal study.[84] This compound does not cross the blood-brain barrier and has been delivered by intraventricular administration to symptomatic patients. In the only reported vCDJ case study using this approach, no obvious side effects were observed, and the clinical symptoms appeared to be slightly attenuated, although brain atrophy progressed based on CT scans.[102]

The author and their colleagues have recently designed a number of compounds that interact with the PrPSc structure and act as beta-sheet breakers,[103, 104, 105] inhibiting the conformation of PrP associated with disease. These compounds were designed by first synthesizing a large number of different PrP homologous peptides. These were then screened for inhibitory activity on the conversion of PrPC to PrPSc using an in vitro system. That synthetic peptides corresponding to PrP residues 109-141 can reproduce some of the properties of PrPSc in vitro is well known.[106, 107, 108] The author's studies determined the ability of these various candidate beta-sheet breaker peptides to inhibit amyloidlike fibril formation of PrP109-141 using a fluorometric assay based on the fluorescence emission of thioflavine T.[109, 110] This assay showed that a 13-residue peptide (iPrP13) had the greatest beta-sheet–breaking capability. Using this peptide,the author and his colleagues were able to show that the proteinase K sensitivity of extracted mouse PrPSc and of human PrPSc extracted from patients with sporadic CJD or from patients with vCJD was increased in a concentration-dependent fashion by iPrP13.[103]

The in vivo effect of iPrP13 was tested by using mouse-adapted scrapie strain 139A. Incubation time assays were performed using 3 different 10-fold dilutions of extracted 139A PrPSc, in the presence or absence of an equimolar concentration of iPrP13. At each dilution, one group of mice was injected with untreated and nonincubated PrPSc, a second group was inoculated with PrPSc that was incubated for 48 hours alone, a third group was inoculated with PrPSc and nonincubated iPrP13, and a fourth group was inoculated with PrPSc and iPrP13 incubated for 48 hours. iPrP13 induced a substantial delay in the appearance of disease. These results suggest that beta-sheet breakers may have therapeutic potential in the prionoses.

This type of therapeutic approach, in which the disease-associated abnormal protein conformation is the target, currently is under extensive investigation for the prionoses as well as for other conformational disorders, such as Alzheimer disease.[111, 112]

Other more recent approaches include chelation therapy. Copper has been implicated in prion propagation,[113] and the authors have demonstrated that a chelator, D-penicillamine, which selectively chelates copper, delays the onset of prion disease in infected mice.[114] In vitro, copper enhanced the proteinase K resistance of the prion protein, which was counteracted by co-incubation with D-penicillamine. Overall, these findings indicate that copper levels can influence the conformational state of PrP, thereby enhancing its infectivity, and this effect can be attenuated by chelator-based therapy.

An additional therapeutic approach that may be of benefit for the prion diseases is immunological.[115] A number of recent reports have shown that immunization with alpha-helix peptides is highly successful at reducing cerebral amyloid accumulation, a key neuropathologic feature in Alzheimer disease, in transgenic mouse models of that disease.[116, 117, 118, 119]

Alpha-helix peptides are normal constituents of biological fluids such as blood and CSF at low concentrations, and they are the major component of the amyloid deposits that characterize Alzheimer disease. Passive immunization studies in the Alzheimer disease model mice suggest that an antibody-mediated clearance of alpha-helix peptides is critical for a therapeutic response.[120] The authors have extended this immunological approach to prion disease and suggest that this approach can be applied to all members of the extended category of neurodegenerative conformational diseases.[121, 122, 123, 124]

Interestingly, prior work has shown that vaccination with an attenuated CJD strain can prevent expression of a more virulent strain.[125] The authors have reported that vaccination with recombinant mouse prion protein (recPrP) delays the onset of prion disease in mice.[121] Vaccination was performed both prior to peripheral prion exposure and after exposure. A delay in disease onset was observed in both groups but was more effective in animals immunized prior to exposure. The increase in the incubation period closely correlated with the anti-PrP antibody titer. The mechanism of the delay with vaccination is not clear, but the correlation of the increased incubation time with antibody titer. The authors subsequently showed that passive immunization in mice using anti-PrP antibodies prolonged the incubation times, which suggests that humoral immunity is critical for a therapeutic response.[124]

Subsequent mouse studies using much higher doses of antibodies completely prevented symptoms of prion disease.[126] Antibody administration is unlikely to be used prophylactically in large populations because of high cost but can potentially be used in humans following accidental exposure.

The authors were recently able to prevent symptoms in about 30% of infected mice by administering a Salmonella -based prion vaccine,[122] which because of low cost has the potential to be used prophylactically in livestock and perhaps also in high-risk human populations. Antibody binding to PrPC and/or PrPSc may possibly interfere with PrPSc -mediated conversion of PrPC to PrPSc and thereby delay the onset of clinical symptoms. Recent in vitro studies support this view,[127, 128] and immunization with prion peptides of 20 amino acids has been shown to reduce the levels of PrPSc in scrapie-infected mouse tumors[129] without affecting PrPC levels. Hence, epitope mapping of the anti-PrP antibodies produced by immunization may provide insights on which portions of the prion molecule are important for prion replication.

The ultimate goal of such immunological approaches is for human testing; the recent problems with the phase II clinical trial of A-beta1-42 vaccination for Alzheimer disease highlight the difficulties of translating successful therapeutic approaches from mouse models to humans (in this trial of A-beta1-42, a significant number of patients developed encephalitis as a complication). A number of potential toxic side effects of vaccine-based approaches exist in humans; further animal and in vitro experimentation is required. One source of potential toxicity is from the immunogen that is used. In the authors' Alzheimer disease vaccine development studies, the A-beta sequence was altered, making it nonfibrillogenic and nontoxic while maintaining or increasing its immunogenicity, to overcome this source of toxicity.[130, 131]

Similar types of alterations are underway to limit any potential toxicity from using the native PrP sequence as an immunogen. The authors' in vivo findings serve as a starting point for the development of vaccine-based approaches for the prion diseases and suggest that prion-based immunization is promising as a potential therapy.

Proceed to Follow-up
 
 
Contributor Information and Disclosures
Author

Tarakad S Ramachandran, MBBS, FRCP(C), FACP  Professor of Neurology, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Chair, Department of Neurology, Crouse Irving Memorial Hospital

Tarakad S Ramachandran, MBBS, FRCP(C), FACP is a member of the following medical societies: American Academy of Neurology, American Academy of Pain Medicine, American College of Forensic Examiners, American College of International Physicians, American College of Managed Care Medicine, American College of Physicians, American Heart Association, American Stroke Association, Royal College of Physicians, Royal College of Physicians and Surgeons of Canada, Royal College of Surgeons of England, and Royal Society of Medicine

Disclosure: Abbott Labs None None; Teva Marion None None; Boeringer-Ingelheim Honoraria Speaking and teaching

Coauthor(s)

Arun Ramachandran  State University of New York Upstate Medical University

Arun Ramachandran is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Roberta J Seidman, MD  Associate Professor of Clinical Pathology, Stony Brook University; Director of Neuropathology, Department of Pathology, Stony Brook University Medical Center

Roberta J Seidman, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuropathologists, New York Association of Neuropathologists (The Neuroplex), and Suffolk County Society of Pathologists

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Florian P Thomas, MD, MA, PhD, Drmed  Director, Regional MS Center of Excellence, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Director, Neuropathy Association Center of Excellence, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, St Louis University School of Medicine

Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Neurological Association, American Paraplegia Society, Consortium of Multiple Sclerosis Centers, and National Multiple Sclerosis Society

Disclosure: Nothing to disclose.

Selim R Benbadis, MD  Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Pfizer Honoraria Speaking, consulting; Sleepmed/DigiTrace Honoraria Speaking, consulting

Chief Editor

Karen L Roos, MD  John and Nancy Nelson Professor of Neurology, Professor of Neurological Surgery, Department of Neurology, Indiana University School of Medicine

Karen L Roos, MD is a member of the following medical societies: American Academy of Neurology and American Neurological Association

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Thomas Wisniewski, MD and Einar M Sigurdsson, PhD to the development and writing of this article.

References

  1. Sadowski M, Verma A, Wisniewski T. Prion Diseases. In: Bradley WG, Daroff RB, Fenichel GM, Jankovic J, eds. Neurology in Clinial Practice. Philadelphia: Elsevier Inc; 2004:1613-1630.

  2. Gordon WS. Advances in veterinary research. Vet Rec. 1946;58:518-525.

  3. Griffith JS, Hadlow WJ. Scrapie and kuru. Lancet. 1959;11:289-290.

  4. Prusiner SB, Scott MR, DeArmond SJ, Cohen FE. Prion protein biology. Cell. May 1 1998;93(3):337-48. [Medline].

  5. Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science. Apr 9 1982;216(4542):136-44. [Medline].

  6. Weissmann C. The Ninth Datta Lecture. Molecular biology of transmissible spongiform encephalopathies. FEBS Lett. Jun 24 1996;389(1):3-11. [Medline].

  7. Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. Jul 2009;11(7):909-13. [Medline].

  8. Frost B, Jacks RL, Diamond MI. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem. May 8 2009;284(19):12845-52. [Medline].

  9. Ren PH, Lauckner JE, Kachirskaia I, Heuser JE, Melki R, Kopito RR. Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat Cell Biol. Feb 2009;11(2):219-25. [Medline].

  10. Thackray AM, Knight R, Haswell SJ, Bujdoso R, Brown DR. Metal imbalance and compromised antioxidant function are early changes in prion disease. Biochem J. Feb 15 2002;362:253-8. [Medline].

  11. Harris DA, Lele P, Snider WD. Localization of the mRNA for a chicken prion protein by in situ hybridization. Proc Natl Acad Sci U S A. May 1 1993;90(9):4309-13. [Medline].

  12. Windl O, Dempster M, Estibeiro P, Lathe R. A candidate marsupial PrP gene reveals two domains conserved in mammalian PrP proteins. Gene. Jul 4 1995;159(2):181-6. [Medline].

  13. Masison DC, Edskes HK, Maddelein ML, Taylor KL, Wickner RB. [URE3] and [PSI] are prions of yeast and evidence for new fungal prions. Curr Issues Mol Biol. Apr 2000;2(2):51-9. [Medline].

  14. Büeler H, Aguzzi A, Sailer A, et al. Mice devoid of PrP are resistant to scrapie. Cell. Jul 2 1993;73(7):1339-47. [Medline].

  15. Collinge J, Whittington MA, Sidle KC, et al. Prion protein is necessary for normal synaptic function. Nature. Jul 28 1994;370(6487):295-7. [Medline].

  16. Tobler I, Gaus SE, Deboer T, et al. Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature. Apr 18 1996;380(6575):639-42. [Medline].

  17. Riek R, Hornemann S, Wider G, Billeter M, Glockshuber R, Wuthrich K. NMR structure of the mouse prion protein domain PrP(121-321). Nature. Jul 11 1996;382(6587):180-2. [Medline].

  18. Hosszu LL, Baxter NJ, Jackson GS, et al. Structural mobility of the human prion protein probed by backbone hydrogen exchange. Nat Struct Biol. Aug 1999;6(8):740-3. [Medline].

  19. James TL, Liu H, Ulyanov NB, et al. Solution structure of a 142-residue recombinant prion protein corresponding to the infectious fragment of the scrapie isoform. Proc Natl Acad Sci U S A. Sep 16 1997;94(19):10086-91. [Medline].

  20. Knaus KJ, Morillas M, Swietnicki W, Malone M, Surewicz WK, Yee VC. Crystal structure of the human prion protein reveals a mechanism for oligomerization. Nat Struct Biol. Sep 2001;8(9):770-4. [Medline].

  21. Aucouturier P, Geissmann F, Damotte D, et al. Infected splenic dendritic cells are sufficient for prion transmission to the CNS in mouse scrapie. J Clin Invest. Sep 2001;108(5):703-8. [Medline].

  22. Pan KM, Baldwin M, Nguyen J, et al. Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci U S A. Dec 1 1993;90(23):10962-6. [Medline].

  23. Baron T. Identification of inter-species transmission of prion strains. J Neuropathol Exp Neurol. May 2002;61(5):377-83. [Medline].

  24. Kascsak RJ, Rubenstein R, Merz PA, et al. Immunological comparison of scrapie-associated fibrils isolated from animals infected with four different scrapie strains. J Virol. Sep 1986;59(3):676-83. [Medline].

  25. Carp RI, Rubenstein R. Diversity and significance of scrapie strains. Semin Virol. 1991;2:203-13.

  26. Bessen RA, Marsh RF. Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J Virol. Dec 1994;68(12):7859-68. [Medline].

  27. Caughey B, Raymond GJ, Bessen RA. Strain-dependent differences in beta-sheet conformations of abnormal prion protein. J Biol Chem. Nov 27 1998;273(48):32230-5. [Medline].

  28. Parchi P, Castellani R, Capellari S, et al. Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Ann Neurol. Jun 1996;39(6):767-78. [Medline].

  29. Collinge J, Sidle KC, Meads J, Ironside J, Hill AF. Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD. Nature. Oct 24 1996;383(6602):685-90. [Medline].

  30. Kimberlin RH, Walker CA. Evidence that the transmission of one source of scrapie agent to hamsters involves separation of agent strains from a mixture. J Gen Virol. Jun 1978;39(3):487-96. [Medline].

  31. Nicoll AJ, Collinge J. Preventing prion pathogenicity by targeting the cellular prion protein. Infect Disord Drug Targets. Feb 2009;9(1):48-57. [Medline].

  32. Aucouturier P, Carp RI, Carnaud C, Wisniewski T. Prion diseases and the immune system. Clin Immunol. Aug 2000;96(2):79-85. [Medline].

  33. Eklund CM, Kennedy RC, Hadlow WJ. Pathogenesis of scrapie virus infection in the mouse. J Infect Dis. Feb 1967;117(1):15-22. [Medline].

  34. Fraser H, Dickinson AG. Studies of the lymphoreticular system in the pathogenesis of scrapie: the role of spleen and thymus. J Comp Pathol. Oct 1978;88(4):563-73. [Medline].

  35. Kimberlin RH, Walker CA. Pathogenesis of mouse scrapie: dynamics of agent replication in spleen, spinal cord and brain after infection by different routes. J Comp Pathol. Oct 1979;89(4):551-62. [Medline].

  36. Houston F, Foster JD, Chong A, Hunter N, Bostock CJ. Transmission of BSE by blood transfusion in sheep. Lancet. Sep 16 2000;356(9234):999-1000. [Medline].

  37. Klein MA, Frigg R, Flechsig E, et al. A crucial role for B cells in neuroinvasive scrapie. Nature. Dec 18-25 1997;390(6661):687-90. [Medline].

  38. Montrasio F, Frigg R, Glatzel M, et al. Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science. May 19 2000;288(5469):1257-9. [Medline].

  39. Shlomchik MJ, Radebold K, Duclos N, Manuelidis L. Neuroinvasion by a Creutzfeldt-Jakob disease agent in the absence of B cells and follicular dendritic cells. Proc Natl Acad Sci U S A. Jul 31 2001;98(16):9289-94. [Medline].

  40. Beekes M, McBride PA, Baldauf E. Cerebral targeting indicates vagal spread of infection in hamsters fed with scrapie. J Gen Virol. Mar 1998;79 ( Pt 3):601-7. [Medline].

  41. Glatzel M, Heppner FL, Albers KM, Aguzzi A. Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron. Jul 19 2001;31(1):25-34. [Medline].

  42. Meiner Z, Halimi M, Polakiewicz RD, Prusiner SB, Gabizon R. Presence of prion protein in peripheral tissues of Libyan Jews with Creutzfeldt-Jakob disease. Neurology. Jul 1992;42(7):1355-60. [Medline].

  43. Neufeld MY, Josiphov J, Korczyn AD. Demyelinating peripheral neuropathy in Creutzfeldt-Jakob disease. Muscle Nerve. Nov 1992;15(11):1234-9. [Medline].

  44. Holman RC, Khan AS, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States, 1979-1994: using national mortality data to assess the possible occurrence of variant cases. Emerg Infect Dis. Oct-Dec 1996;2(4):333-7. [Medline].

  45. Masters CL, Harris JO, Gajdusek DC, Gibbs CJ Jr, Bernoulli C, Asher DM. Creutzfeldt-Jakob disease: patterns of worldwide occurrence and the significance of familial and sporadic clustering. Ann Neurol. Feb 1979;5(2):177-88. [Medline].

  46. Cathala F, Baron H. Clinical Aspects of Creutzfeldt-Jakob Disease. In: Prusiner SB, McKinley MP, eds. Prions: novel infectious pathogens causing scrapie and Creutzfeldt-Jakob disease. New York, NY: Academic Press; 1987:467-509.

  47. Gajdusek DC, Zigas V. Degenerative disease of the central nervous system in New Guinea: the epidemic occurrence of "kuru" in the native population. N Engl J Med. 1957;257:974-978.

  48. Gajdusek DC, Zigas V. Clinical, pathological and epidemiological study of an acute progressive degenerative disease of the central nervous system among natives of the eastern highlands of New Guinea. Am J Med. 1959;26:442-469.

  49. Liberski PP, Sikorska B, Lindenbaum S, Goldfarb LG, McLean C, Hainfellner JA, et al. Kuru: Genes, Cannibals and Neuropathology. J Neuropathol Exp Neurol. Feb 2012;71(2):92-103. [Medline].

  50. Gajdusek DC, Gibbs CJ, Alpers M. Experimental transmission of a Kuru-like syndrome to chimpanzees. Nature. Feb 19 1966;209(5025):794-6. [Medline].

  51. Jacob A. Uber eigenaritge erkrankungen des zentral-nervensystems mit bemerkenswertem anatomischen befunde (spastische pseudosklerose-encephalomyelopathie mit disseminierten degenerationsherden). Z Gesamte Neurol Psychiatre. 1921;64:147-228.

  52. Hofmann J, Wolf H, Grassmann A, Arndt V, Graham J, Vorberg I. Creutzfeldt-Jakob disease and mad cows: lessons learnt from yeast cells. Swiss Med Wkly. Jan 24 2012;142:0. [Medline].

  53. Chiofalo N, Fuentes A, Galvez S. Serial EEG findings in 27 cases of Creutzfeldt-Jakob disease. Arch Neurol. Mar 1980;37(3):143-5. [Medline].

  54. Gerstmann J, Straussler E, Scheinker I. Über eine eigenartige hereditar-familiare Erkrankung des Zentralnervensystems zugleich ein Beitrag zür frage des vorzeitigen kokalen Alterns. Z Neurol. 1936;154:736-762.

  55. Ghetti B, Tagliavini F, Giaccone G, et al. Familial Gerstmann-Sträussler-Scheinker disease with neurofibrillary tangles. Mol Neurobiol. Feb 1994;8(1):41-8. [Medline].

  56. Ghetti B, Piccardo P, Spillantini MG, et al. Vascular variant of prion protein cerebral amyloidosis with tau-positive neurofibrillary tangles: the phenotype of the stop codon 145 mutation in PRNP. Proc Natl Acad Sci U S A. Jan 23 1996;93(2):744-8. [Medline].

  57. Medori R, Tritschler HJ, LeBlanc A, et al. Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. N Engl J Med. Feb 13 1992;326(7):444-9. [Medline].

  58. Goldfarb LG, Brown P, Haltia M, et al. Creutzfeldt-Jakob disease cosegregates with the codon 178Asn PRNP mutation in families of European origin. Ann Neurol. Mar 1992;31(3):274-81. [Medline].

  59. Solvason HB, Harris B, Zeifert P, Flores BH, Hayward C. Psychological versus biological clinical interpretation: a patient with prion disease. Am J Psychiatry. Apr 2002;159(4):528-37. [Medline].

  60. Oliveros RG, Saracibar N, Gutierrez M, , Munon T, Gonzalez-Pinto A. Catatonia due to a prion familial disease. Schizophr Res. Mar 2009;108(1-3):309-10. [Medline].

  61. Collinge J. Human prion diseases and bovine spongiform encephalopathy (BSE). Hum Mol Genet. 1997;6(10):1699-705. [Medline].

  62. Collinge J, Rossor M. A new variant of prion disease. Lancet. Apr 6 1996;347(9006):916-7. [Medline].

  63. Bateman D, Hilton D, Love S, Zeidler M, Beck J, Collinge J. Sporadic Creutzfeldt-Jakob disease in a 18-year-old in the UK. Lancet. Oct 28 1995;346(8983):1155-6. [Medline].

  64. Britton TC, al-Sarraj S, Shaw C, Campbell T, Collinge J. Sporadic Creutzfeldt-Jakob disease in a 16-year-old in the UK. Lancet. Oct 28 1995;346(8983):1155. [Medline].

  65. Collee JG, Bradley R. BSE: a decade on--Part I. Lancet. Mar 1 1997;349(9052):636-41. [Medline].

  66. Will RG. Surveillance of prion disease in humans. In: HF Baker, Ridley RM, eds. Methods in Molecular Medicine: Prion Diseases. Totowa, NJ: Humana Press Inc; 1996:119-137.

  67. Liberski PP, Guiroy DC, Williams ES, Walis A, Budka H. Deposition patterns of disease-associated prion protein in captive mule deer brains with chronic wasting disease. Acta Neuropathol. Nov 2001;102(5):496-500. [Medline].

  68. Khan RM, Gunaratne LA, Kinmont JC. Rapid fracture healing in a patient with inherited prion disease. Ann R Coll Surg Engl. Apr 2009;91(3):261-2. [Medline].

  69. Belay ED, Gambetti P, Schonberger LB, et al. Creutzfeldt-Jakob disease in unusually young patients who consumed venison. Arch Neurol. Oct 2001;58(10):1673-8. [Medline].

  70. Raymond GJ, Bossers A, Raymond LD, et al. Evidence of a molecular barrier limiting susceptibility of humans, cattle and sheep to chronic wasting disease. EMBO J. Sep 1 2000;19(17):4425-30. [Medline].

  71. Angers RC, Browning SR, Seward TS, et al. Prions in skeletal muscles of deer with chronic wasting disease. Science. Feb 24 2006;311(5764):1117. [Medline].

  72. Marsh RF, Kincaid AE, Bessen RA, Bartz JC. Interspecies transmission of chronic wasting disease prions to squirrel monkeys (Saimiri sciureus). J Virol. Nov 2005;79(21):13794-6. [Medline].

  73. Hamaguchi T, Noguchi-Shinohara M, Nozaki I, Nakamura Y, Sato T, Kitamoto T. Medical procedures and risk for sporadic Creutzfeldt-Jakob disease, Japan, 1999-2008. Emerg Infect Dis. Feb 2009;15(2):265-71. [Medline].

  74. Seipelt M, Zerr I, Nau R, et al. Hashimoto's encephalitis as a differential diagnosis of Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry. Feb 1999;66(2):172-6. [Medline].

  75. Castillo P, Woodruff B, Caselli R, et al. Steroid-responsive encephalopathy associated with autoimmune thyroiditis. Arch Neurol. Feb 2006;63(2):197-202. [Medline].

  76. Cossu G, Melis M, Molari A, et al. Creutzfeldt-Jakob disease associated with high titer of antithyroid autoantibodies: case report and literature review. Neurol Sci. Oct 2003;24(3):138-40. [Medline].

  77. Young GS, Geschwind MD, Fischbein NJ, et al. Diffusion-weighted and fluid-attenuated inversion recovery imaging in Creutzfeldt-Jakob disease: high sensitivity and specificity for diagnosis. AJNR Am J Neuroradiol. Jun-Jul 2005;26(6):1551-62. [Medline].

  78. Rees HC, Maddison BC, Owen JP, Whitelam GC, Gough KC. Concentration of disease-associated prion protein with silicon dioxide. Mol Biotechnol. Mar 2009;41(3):254-62. [Medline].

  79. Laude H. Beringue V. Newly discovered forms of prion diseases in ruminants. [Review]. Pathologie Biologie. 2009;57(2):117-26.

  80. Sim VL. Caughey B. Recent advances in prion chemotherapeutics. [Review]. Infectious Disorders - Drug Targets. 2009;9(1):81-91.

  81. Relano-Gines A. Gabelle A. Lehmann S. Milhavet O. Crozet C. Gene and cell therapy for prion diseases. [Review]. Infectious Disorders - Drug Targets. 2009;9(1):58-68.

  82. Caspi S, Halimi M, Yanai A, Sasson SB, Taraboulos A, Gabizon R. The anti-prion activity of Congo red. Putative mechanism. J Biol Chem. Feb 6 1998;273(6):3484-9. [Medline].

  83. Demaimay R, Harper J, Gordon H, Weaver D, Chesebro B, Caughey B. Structural aspects of Congo red as an inhibitor of protease-resistant prion protein formation. J Neurochem. Dec 1998;71(6):2534-41. [Medline].

  84. Doh-ura K, Ishikawa K, Murakami-Kubo I, et al. Treatment of transmissible spongiform encephalopathy by intraventricular drug infusion in animal models. J Virol. May 2004;78(10):4999-5006. [Medline].

  85. Demaimay R, Chesebro B, Caughey B. Inhibition of formation of protease-resistant prion protein by Trypan Blue, Sirius Red and other Congo Red analogs. Arch Virol Suppl. 2000;277-83. [Medline].

  86. Tagliavini F, McArthur RA, Canciani B, et al. Effectiveness of anthracycline against experimental prion disease in Syrian hamsters. Science. May 16 1997;276(5315):1119-22. [Medline].

  87. Adjou KT, Demaimay R, Lasmezas CI, Seman M, Deslys JP, Dormont D. Differential effects of a new amphotericin B derivative, MS-8209, on mouse BSE and scrapie: implications for the mechanism of action of polyene antibiotics. Res Virol. Jul-Aug 1996;147(4):213-8. [Medline].

  88. Adjou KT, Demaimay R, Deslys JP, et al. MS-8209, a water-soluble amphotericin B derivative, affects both scrapie agent replication and PrPres accumulation in Syrian hamster scrapie. J Gen Virol. Apr 1999;80 ( Pt 4):1079-85. [Medline].

  89. Adjou KT, Privat N, Demart S, et al. MS-8209, an amphotericin B analogue, delays the appearance of spongiosis, astrogliosis and PrPres accumulation in the brain of scrapie-infected hamsters. J Comp Pathol. Jan 2000;122(1):3-8. [Medline].

  90. Mange A, Milhavet O, McMahon HE, Casanova D, Lehmann S. Effect of amphotericin B on wild-type and mutated prion proteins in cultured cells: putative mechanism of action in transmissible spongiform encephalopathies. J Neurochem. Feb 2000;74(2):754-62. [Medline].

  91. Mange A, Nishida N, Milhavet O, McMahon HE, Casanova D, Lehmann S. Amphotericin B inhibits the generation of the scrapie isoform of the prion protein in infected cultures. J Virol. Apr 2000;74(7):3135-40. [Medline].

  92. Farquhar C, Dickinson A, Bruce M. Prophylactic potential of pentosan polysulphate in transmissible spongiform encephalopathies. Lancet. Jan 9 1999;353(9147):117. [Medline].

  93. Ladogana A, Casaccia P, Ingrosso L, et al. Sulphate polyanions prolong the incubation period of scrapie-infected hamsters. J Gen Virol. Mar 1992;73 ( Pt 3):661-5. [Medline].

  94. Farquhar CF, Dickinson AG. Prolongation of scrapie incubation period by an injection of dextran sulphate 500 within the month before or after infection. J Gen Virol. Mar 1986;67 ( Pt 3):463-73. [Medline].

  95. Priola SA, Raines A, Caughey WS. Porphyrin and phthalocyanine antiscrapie compounds. Science. Feb 25 2000;287(5457):1503-6. [Medline].

  96. Priola SA, Raines A, Caughey W. Prophylactic and therapeutic effects of phthalocyanine tetrasulfonate in scrapie-infected mice. J Infect Dis. Sep 1 2003;188(5):699-705. [Medline].

  97. Masullo C, Macchi G, Xi YG, Pocchiari M. Failure to ameliorate Creutzfeldt-Jakob disease with amphotericin B therapy. J Infect Dis. Apr 1992;165(4):784-5. [Medline].

  98. Korth C, May BC, Cohen FE, Prusiner SB. Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci U S A. Aug 14 2001;98(17):9836-41. [Medline].

  99. Nakajima M, Yamada T, Kusuhara T, et al. Results of quinacrine administration to patients with Creutzfeldt-Jakob disease. Dement Geriatr Cogn Disord. 2004;17(3):158-63. [Medline].

  100. Barret A, Tagliavini F, Forloni G, et al. Evaluation of quinacrine treatment for prion diseases. J Virol. Aug 2003;77(15):8462-9. [Medline].

  101. Collins SJ, Lewis V, Brazier M, Hill AF, Fletcher A, Masters CL. Quinacrine does not prolong survival in a murine Creutzfeldt-Jakob disease model. Ann Neurol. Oct 2002;52(4):503-6. [Medline].

  102. Todd NV, Morrow J, Doh-ura K, et al. Cerebroventricular infusion of pentosan polysulphate in human variant Creutzfeldt-Jakob disease. J Infect. Jun 2005;50(5):394-6. [Medline].

  103. Soto C, Kascsak RJ, Saborio GP, et al. Reversion of prion protein conformational changes by synthetic beta-sheet breaker peptides. Lancet. Jan 15 2000;355(9199):192-7. [Medline].

  104. Wisniewski T, Aucouturier P, Soto C, Frangione B. The prionoses and other conformational disorders. Amyloid. Sep 1998;5(3):212-24. [Medline].

  105. Wisniewski T, Sigurdsson EM, Aucouturier P, et al. Conformation as a therapeutic target in the prionoses and other neurodegenerative conditions. In: Molecular and Cellular Pathology in Prion Disease. 2001.

  106. De Gioia L, Selvaggini C, Ghibaudi E, et al. Conformational polymorphism of the amyloidogenic and neurotoxic peptide homologous to residues 106-126 of the prion protein. J Biol Chem. Mar 18 1994;269(11):7859-62. [Medline].

  107. Nguyen J, Baldwin MA, Cohen FE, Prusiner SB. Prion protein peptides induce alpha-helix to beta-sheet conformational transitions. Biochemistry. Apr 4 1995;34(13):4186-92. [Medline].

  108. Zhang H, Kaneko K, Nguyen JT, et al. Conformational transitions in peptides containing two putative alpha-helices of the prion protein. J Mol Biol. Jul 21 1995;250(4):514-26. [Medline].

  109. Naiki H, Higuchi K, Nakakuki K, Takeda T. Kinetic analysis of amyloid fibril polymerization in vitro. Lab Invest. Jul 1991;65(1):104-10. [Medline].

  110. Wisniewski T, Castano EM, Golabek A, Vogel T, Frangione B. Acceleration of Alzheimer's fibril formation by apolipoprotein E in vitro. Am J Pathol. Nov 1994;145(5):1030-5. [Medline].

  111. Sigurdsson EM, Permanne B, Soto C, Wisniewski T, Frangione B. In vivo reversal of amyloid-beta lesions in rat brain. J Neuropathol Exp Neurol. Jan 2000;59(1):11-7. [Medline].

  112. Soto C, Sigurdsson EM, Morelli L, Kumar RA, Castano EM, Frangione B. Beta-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: implications for Alzheimer's therapy. Nat Med. Jul 1998;4(7):822-6. [Medline].

  113. Vidal R, Ghiso J, Wisniewski T, Frangione B. Alzheimer's presenilin 1 gene expression in platelets and megakaryocytes. Identification of a novel splice variant. FEBS Lett. Sep 9 1996;393(1):19-23. [Medline].

  114. Sigurdsson EM, Brown DR, Alim MA, Scholtzova H, Carp R, Meeker HC, et al. Copper chelation delays the onset of prion disease. J Biol Chem. Nov 21 2003;278(47):46199-202. [Medline].

  115. Sigurdsson EM. Immunotherapy for conformational diseases. Curr Pharm Des. 2006;12(20):2569-85. [Medline].

  116. Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. Jul 8 1999;400(6740):173-7. [Medline].

  117. Weiner HL, Lemere CA, Maron R, et al. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease. Ann Neurol. Oct 2000;48(4):567-79. [Medline].

  118. Janus C, Pearson J, McLaurin J, et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature. Dec 21-28 2000;408(6815):979-82. [Medline].

  119. Morgan D, Diamond DM, Gottschall PE, et al. Arendash GW Ab peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature. 2001;408:982-985.

  120. Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med. Aug 2000;6(8):916-9. [Medline].

  121. Sigurdsson EM, Brown DR, Daniels M, et al. Immunization delays the onset of prion disease in mice. Am J Pathol. Jul 2002;161(1):13-7. [Medline].

  122. Goni F, Knudsen E, Schreiber F, et al. Mucosal vaccination delays or prevents prion infection via an oral route. Neuroscience. 2005;133(2):413-21. [Medline].

  123. Pankiewicz J, Sadowski M, Kascsak R, et al. Therapeutic mechanisms of anti-prion antibodies in a tissue culture model of prion infection. Soc Neurosci Abst. 2005.

  124. Sigurdsson EM, Sy MS, Li R, Scholtzova H, Kascsak RJ, Kascsak R, et al. Anti-prion antibodies for prophylaxis following prion exposure in mice. Neurosci Lett. Jan 23 2003;336(3):185-7. [Medline].

  125. Manuelidis L. Vaccination with an attenuated Creutzfeldt-Jakob disease strain prevents expression of a virulent agent. Proc Natl Acad Sci U S A. Mar 3 1998;95(5):2520-5. [Medline].

  126. White AR, Enever P, Tayebi M, et al. Monoclonal antibodies inhibit prion replication and delay the development of prion disease. Nature. Mar 6 2003;422(6927):80-3. [Medline].

  127. Enari M, Flechsig E, Weissmann C. Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody. Proc Natl Acad Sci U S A. Jul 31 2001;98(16):9295-9. [Medline].

  128. Peretz D, Williamson RA, Kaneko K, et al. Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature. Aug 16 2001;412(6848):739-43. [Medline].

  129. Souan L, Tal Y, Felling Y, Cohen IR, Taraboulos A, Mor F. Modulation of proteinase-K resistant prion protein by prion peptide immunization. Eur J Immunol. Aug 2001;31(8):2338-46. [Medline].

  130. Sigurdsson EM, Scholtzova H, Mehta PD, Frangione B, Wisniewski T. Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice. Am J Pathol. Aug 2001;159(2):439-47. [Medline].

  131. Sigurdsson EM, Knudsen E, Asuni A, Fitzer-Attas C, Sage D, Quartermain D, et al. An attenuated immune response is sufficient to enhance cognition in an Alzheimer's disease mouse model immunized with amyloid-beta derivatives. J Neurosci. Jul 14 2004;24(28):6277-82. [Medline].

  132. Coste J. Prowse C. Eglin R. Fang C. Subgroup on TSE. A report on transmissible spongiform encephalopathies and transfusion safety. [Review]. Vox Sanguinis. 2009;96(4):284-291.

  133. Lefrere JJ, Hewitt P. From mad cows to sensible blood transfusion: the risk of prion transmission by labile blood components in the United Kingdom and in France. Transfusion. Apr 2009;49(4):797-812. [Medline].

  134. Brown P, Wolff A, Gajdusek DC. A simple and effective method for inactivating virus infectivity in formalin-fixed tissue samples from patients with Creutzfeldt-Jakob disease. Neurology. Jun 1990;40(6):887-90. [Medline].

  135. Ironside JW, Bell JE. The 'high-risk' neuropathological autopsy in AIDS and Creutzfeldt-Jakob disease: principles and practice. Neuropathol Appl Neurobiol. Oct 1996;22(5):388-93. [Medline].

  136. Budka H, Aguzzi A, Brown P, et al. Tissue handling in suspected Creutzfeldt-Jakob disease (CJD) and other human spongiform encephalopathies (prion diseases). Brain Pathol. Jul 1995;5(3):319-22. [Medline].

  137. Castilla J, Saa P, Soto C. Detection of prions in blood. Nat Med. Sep 2005;11(9):982-5. [Medline].

  138. Chang B, Cheng X, Pan T, et al. An ultra-sensitive assay for detecting prions in blood. Proc Natl Acad Sci (USA) in press. 2006.

  139. Aucouturier P, Kascsak RJ, Frangione B, Wisniewski T. Biochemical and conformational variability of human prion strains in sporadic Creutzfeldt-Jakob disease. Neurosci Lett. Oct 15 1999;274(1):33-6. [Medline].

  140. Brown P, Rau EH, Johnson BK, Bacote AE, Gibbs CJ Jr, Gajdusek DC. New studies on the heat resistance of hamster-adapted scrapie agent: threshold survival after ashing at 600 degrees C suggests an inorganic template of replication. Proc Natl Acad Sci U S A. Mar 28 2000;97(7):3418-21. [Medline].

  141. Bueler H, Fischer M, Lang Y, et al. Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature. Apr 16 1992;356(6370):577-82. [Medline].

  142. Citron M, Vigo-Pelfrey C, Teplow DB, et al. Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proc Natl Acad Sci U S A. Dec 6 1994;91(25):11993-7. [Medline].

  143. Collinge J, Palmer MS, Dryden AJ. Genetic predisposition to iatrogenic Creutzfeldt-Jakob disease. Lancet. Jun 15 1991;337(8755):1441-2. [Medline].

  144. Collins SJ, Lawson VA, Masters CL. Transmissible spongiform encephalopathies. Lancet. Jan 3 2004;363(9402):51-61. [Medline].

  145. Dlouhy SR, Hsiao K, Farlow MR, et al. Linkage of the Indiana kindred of Gerstmann-Sträussler-Scheinker disease to the prion protein gene. Nat Genet. Apr 1992;1(1):64-7. [Medline].

  146. Dominguez DI, De Strooper B, Annaert W. Secretases as therapeutic targets for the treatment of Alzheimer's disease. Amyloid. Jun 2001;8(2):124-42. [Medline].

  147. Dropcho EJ. Update on paraneoplastic syndromes. Curr Opin Neurol. Jun 2005;18(3):331-6. [Medline].

  148. Finkenstaedt M, Szudra A, Zerr I, et al. MR imaging of Creutzfeldt-Jakob disease. Radiology. Jun 1996;199(3):793-8. [Medline].

  149. Foster PR. Prions and blood products. Ann Med. Oct 2000;32(7):501-13. [Medline].

  150. Gabizon R, Rosenmann H, Meiner Z, et al. Mutation and polymorphism of the prion protein gene in Libyan Jews with Creutzfeldt-Jakob disease (CJD). Am J Hum Genet. Oct 1993;53(4):828-35. [Medline].

  151. Goldfarb LG, Brown P, Goldgaber D, et al. Creutzfeldt-Jakob disease and kuru patients lack a mutation consistently found in the Gerstmann-Sträussler-Scheinker syndrome. Exp Neurol. Jun 1990;108(3):247-50. [Medline].

  152. Goldfarb LG, Brown P, McCombie WR, et al. Transmissible familial Creutzfeldt-Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the PRNP gene. Proc Natl Acad Sci U S A. Dec 1 1991;88(23):10926-30. [Medline].

  153. Goldfarb LG, Haltia M, Brown P, et al. New mutation in scrapie amyloid precursor gene (at codon 178) in Finnish Creutzfeldt-Jakob kindred. Lancet. Feb 16 1991;337(8738):425. [Medline].

  154. Goldfarb LG, Mitrova E, Brown P, Toh BK, Gajdusek DC. Mutation in codon 200 of scrapie amyloid protein gene in two clusters of Creutzfeldt-Jakob disease in Slovakia. Lancet. Aug 25 1990;336(8713):514-5. [Medline].

  155. Goldfarb LG, Petersen RB, Tabaton M, et al. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. Science. Oct 30 1992;258(5083):806-8. [Medline].

  156. Goldgaber D, Goldfarb LG, Brown P, et al. Mutations in familial Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker's syndrome. Exp Neurol. Nov 1989;106(2):204-6. [Medline].

  157. Haass C, Hung AY, Schlossmacher MG, Teplow DB, Selkoe DJ. beta-Amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms. J Biol Chem. Feb 15 1993;268(5):3021-4. [Medline].

  158. Head MW, Bunn TJ, Bishop MT, et al. Prion protein heterogeneity in sporadic but not variant Creutzfeldt-Jakob disease: UK cases 1991-2002. Ann Neurol. Jun 2004;55(6):851-9. [Medline].

  159. Hetz C, Soto C. Protein misfolding and disease: the case of prion disorders. Cell Mol Life Sci. Jan 2003;60(1):133-43. [Medline].

  160. Hill AF, Zeidler M, Ironside J, Collinge J. Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy. Lancet. Jan 11 1997;349(9045):99-100. [Medline].

  161. Hsiao K, Baker HF, Crow TJ, et al. Linkage of a prion protein missense variant to Gerstmann-Sträussler syndrome. Nature. Mar 23 1989;338(6213):342-5. [Medline].

  162. Hsiao K, Dlouhy SR, Farlow MR, et al. Mutant prion proteins in Gerstmann-Sträussler-Scheinker disease with neurofibrillary tangles. Nat Genet. Apr 1992;1(1):68-71. [Medline].

  163. Hsiao K, Doh-ura K, KitamotoT. A prion protein amino acid substitution in ataxic Gerstmann-Straussler syndrome. Ann Neurol. 1989;26:137.

  164. Hsiao K, Meiner Z, Kahana E, et al. Mutation of the prion protein in Libyan Jews with Creutzfeldt-Jakob disease. N Engl J Med. Apr 18 1991;324(16):1091-7. [Medline].

  165. Kitamoto T, Ohta M, Doh-ura K, Hitoshi S, Terao Y, Tateishi J. Novel missense variants of prion protein in Creutzfeldt-Jakob disease or Gerstmann-Sträussler syndrome. Biochem Biophys Res Commun. Mar 15 1993;191(2):709-14. [Medline].

  166. Kovacs GG, Voigtlander T, Gelpi E, Budka H. Rationale for diagnosing human prion disease. World J Biol Psychiatry. Apr 2004;5(2):83-91. [Medline].

  167. Maness LM, Banks WA, Podlisny MB, Selkoe DJ, Kastin AJ. Passage of human amyloid beta-protein 1-40 across the murine blood-brain barrier. Life Sci. 1994;55(21):1643-50. [Medline].

  168. Miyazono M, Kitamoto T, Doh-ura K, Iwaki T, Tateishi J. Creutzfeldt-Jakob disease with codon 129 polymorphism (valine): a comparative study of patients with codon 102 point mutation or without mutations. Acta Neuropathol. 1992;84(4):349-54. [Medline].

  169. Nochlin D, Sumi SM, Bird TD, et al. Familial dementia with PrP-positive amyloid plaques: a variant of Gerstmann-Sträussler syndrome. Neurology. Jul 1989;39(7):910-8. [Medline].

  170. Owen F, Poulter M, Lofthouse R, et al. Insertion in prion protein gene in familial Creutzfeldt-Jakob disease. Lancet. Jan 7 1989;1(8628):51-2. [Medline].

  171. Owen F, Poulter M, Shah T, et al. An in-frame insertion in the prion protein gene in familial Creutzfeldt-Jakob disease. Brain Res Mol Brain Res. Apr 1990;7(3):273-6. [Medline].

  172. Quadrio I, Ugnon-Cafe S, Dupin M, Esposito G, Streichenberger N, Krolak-Salmon P. Rapid diagnosis of human prion disease using streptomycin with tonsil and brain tissues. Lab Invest. Apr 2009;89(4):406-13. [Medline].

  173. Ripoll L, Laplanche JL, Salzmann M, et al. A new point mutation in the prion protein gene at codon 210 in Creutzfeldt-Jakob disease. Neurology. Oct 1993;43(10):1934-8. [Medline].

  174. Sakaguchi S. Prospects for preventative vaccines against prion diseases. Protein & Peptide Letters. 2009;16(3):260-70.

  175. Soto C, Saborio GP, Anderes L. Cyclic amplification of protein misfolding: application to prion-related disorders and beyond. Trends Neurosci. Aug 2002;25(8):390-4. [Medline].

  176. Weissmann C. Molecular genetics of transmissible spongiform encephalopathies. J Biol Chem. Jan 1 1999;274(1):3-6. [Medline].

  177. Will RG, Ironside JW, Zeidler M, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet. Apr 6 1996;347(9006):921-5. [Medline].

 
Previous
Next
 
Prion-related diseases. Spongiform change in prion disease. This section shows mild parenchymal vacuolation and prominent reactive astrocytosis.
Prion-related diseases. A representation of the human proteinaceous infectious particle, or PrP, gene. Mutations associated with inherited prionoses are shown above the gene, while polymorphisms are shown below the gene. A polymorphism at codon 129 (M versus V) is common in white populations, while a polymorphism at codon 219 (E versus K) is common in Japanese populations. The locations of the 4 putative helical regions, H1-H4, correspond to residues 109-122, 129-141, 178-191, and 202-218, respectively. This diagram does not illustrate all of the alpha-helical regions. A diagonal striped area represents the region of octarepeats, spanning residues 51-91. Octarepeats of 16, 32, 40, 48, 56, 64, or 72 amino acids at codons 67, 75, or 83 are indicated by the rectangle above the octarepeat region. These inserts are associated with familial Creutzfeldt-Jakob disease (CJD).
Shows characteristic signal changes of an MRI taken from a patient with sporadic CJD, using diffusion-weighted imaging (DWI). An abnormal signal is shown in both the basal ganglia (red arrows) and the cortical ribbon (yellow arrow).
Table 1. Prion-Related Diseases, Hosts, and Mechanism of Transmission
DiseaseHostMechanism
KuruHumanCannibalism
Sporadic CJDHumanSpontaneous PrPC to PrPSc conversion or somatic mutation
Iatrogenic CJDHumanInfection from prion-containing material, eg, dura mater, electrode
Familial CJDHumanMutations in the PrP gene
vCJDHumanInfection from BSE
GSSHumanMutations in the PrP gene
FFIHumanD178N mutation in the PrP gene, with M129 polymorphism
Sporadic fatal insomniaHumanSpontaneous PrPC to PrPSc conversion or somatic mutation
ScrapieSheepInfection in susceptible sheep
BSECattleInfection from contaminated food
TMEMinkInfection from sheep or cattle in food
CWDMule, deer, elkUnclear
Feline spongiform encephalopathyCatsInfection from contaminated food
Exotic ungulate encephalopathyNyala, oryx, kuduInfection from contaminated food
Table 2. Paraneoplastic Syndromes, Associated Tumors, and Autoantibodies
Clinical SyndromeNeoplasmAutoantibodies
Limbic encephalitisSmall cell lung carcinoma



Testicular/breast, thymoma



Anti-Hu, antiCV2,PCA-2, ANNA-3



Anti-Ma2 Anti-VGKC, anti-CV2



Cerebellar degenerationBreast, ovary, lung, othersAnti-Yo, anti-Ma, anti-Ri



Anti-Hu, anti-CV2



Opsoclonus myoclonusBreast, ovarian, small cell carcinoma of lung



Neuroblastoma



Anti-Ri, anti-Yo, Anti-Hu,



Anti-amphiphysin Anti-Hu



Previous
Next
 
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.