1.The Historical Significance ofBiomarkers in Prion DiseasesBiomarkers in Neurodegeneration Seminar Johns Hopkins Bayview Medical CenterPresented by: Brian Appleby, M.D.April 5, 2010

2. History of prion diseasesOne Spongiform encephalopathy and transmissibilityas biomarkers of prion diseaseTwo PrPres as a biomarker of prion diseaseThree Describe biomarkers in different types of prion Four diseases 3. SPONGIFORMENCEPHALOPATHY 4. Brown P, CNS Neurol Disord Drug Targets 2009 5. Brown P, CNS Neurol Disord Drug Targets 2009 6. Creutzfeldt-Jakob diseaseHans Gerhard Creutzfeldt Alfons Maria Jakob 7. this is a disease of middle and late life which beginswithdisturbances of the motor apparatus and of sensationthe patients gait is strikinglyuncoordinatedstriking mental changes appear, in theform of apathy, negativism, and delirious and hallucinatoryconfusional statesThe course of the disease is subacutely progressiveof several weeks to a year. Jakob A. Med Klin 1921 8. Jones DP & Nevin S. JNNP 1954 9. Jones DP & Nevin S. JNNP 1954 10. Brown P, CNS Neurol Disord Drug Targets 2009 11. Gerstmann-Strussler-Scheinker (GSS)Gerstmann J, et al. Z Gesamte Neurol Psych 1935 12. TRANSMISSIBILITY 13. Brown P, CNS Neurol Disord Drug Targets 2009 14. KuruGajdusek DC & Zigas V. NEJM 1957 15. 1958 1959 1960 Hadlow WJ. Lancet 1959 16. 1960 1961 1962 Chandler RL. Lancet 1961 17. 19651966 1967 Gajdusek DC, et al. JAMA 1967 18. 1967 19681969 Gibbs CJ, et al. Science 1968 19. Brown P, CNS Neurol Disord Drug Targets 2009 20. Fatal Familial Insomnia (FFI) 21. Lugaresi E, et al. NEJM 1986 22. Lugaresi E, et al. NEJM 1986 23. Tateishi J, et al. Nature 1995 24. PRIONSProteinaceous and infectious particles 25. the evidence that no inactivation results from exposure to a huge dose of ultraviolet light, of wave- length specifically absorbed by nucleic acids, suggests that the agent may be able to increase in quantity without itselfcontaining nucleic acid. Alper T, et al. Biochem Biophys Res Commun 1966Alper T, et al. Nature 1967 26. S1 + G1 = S1G G0 S2 + G2 = S2G S S1 + G2 = S2S+G=S S2 + G1 = 0 XM M+G=S P1 = normal P2 = normal P1 + P2 = scrapie Griffith JS. Nature 1967 27. 2 + = 3 3 + = 4 422 + 2 2 F1 +2 + F2 2 + = 3 + F3 3 + = 4 + F4 422 + F5F5 = -2F1 + F2- F3 - F4 > 0 28. Prusiner SB. Science 1982 29. for his discovery of Prions - a newbiological principle of infection."Prusiner SB. Science 1982 30. control100 g/mLProteinase K500 g/mLProteinase K McKinley MP, et al. Cell 1983 31. Soto C, et al. Trends Biochem Sci 2006 32. Protein X A. PrPc (blue) and PrPSc(red) undergoendocytosis B. Co-factor (yellow) onlipid raft assistsconversion of PrPc toPrPScTaylor D & Hooper N. Semin Cell Dev Biol, 2007 33. These findings provide strong support for the protein-onlyhypothesis of TSE diseases, as well as argue thatcofactors such as nucleic acids, other polyanions or lipids are nonobligatory for prion protein conversion to the infectious form.Kim J, et al. JBC [In Press] 34. BIOMARKERS IN PRION DISEASE SUBTYPES 35. Importance of donor PrPres strainTelling GC, et al. Science 1996 36. Brown P, CNS Neurol Disord Drug Targets 2009 37. Bovine Spongiform Encephalopathy (BSE)Wells GAH, et al. Vet Rec 1987 Wilesmith JW, et al. Vet Rec 1988 38. Will RG, et al. Lancet 1996 39. Clinical DifferencesWill RG, et al. Lancet 1996 40. Neuropathologic Differences Florid plaquesIronside JW. FEMS Immunol Med Microbiol 1998 41. Neuroradiologic Differencespulvinar signZeidler M, et al. Lancet 2000 42. Met-ValMet-MetVal-Val codon 129PRNP 43. http://www.cjd.ed.ac.uk/vcjdworld.htm 44. Andrews NJ. Incidence of variant Creutzfeldt-Jakob disease deaths in the UK 2010 45. Met-ValThe Transfusion Medicine Epidemiology Review 46. Peden A, et al. Haemophilia 2010 47. estimated prevalence of 237 per million individuals 0/63,007 samples were positiveHilton DA, et al. J Path 2004 Clewley J, et al. BMJ 2009 48. Peripheral tissues shown to contain PrPres in vCJDNotari S, et al. PLoS ONE 2010 49. Synopsis of PrPres analyses in the brain and other tissuesNotari S, et al. PLoS ONE 2010 50. Kaski D, et al. Lancet 2009 51. Strain Individual variability sCJD gCJD *connected circles represent animals inoculated at same timewith identical aliquots Brown P, et al. Ann Neurol 1994 52. Incidence of iCJD cases from hGHHuillard dAignaux J, et al. Neurology 1999 53. Telegraph.co.uk, 18 Dec 2008Nurmi MH, et al. Acta Neurol Scand 2003 54. Protease sensitive prionopathy (PSPr)Gambetti P, et al. Ann Neurol 2008 55. Summary Prion disease cause spongiformencephalopathies and are transmissible* Prion disease are characterized by anabnormal isomer of the native prion proteinthat is incompletely digested by proteinase K Prion disease characteristics are affected byPrPres strain and host genotype. 56. AcknowledgementsPatients and families CJD Foundation, CJD Insight, CJD Aware!Florence KranitzPaul Brown (CEA/DSV/iMETI/SEPIA)Deana SimpsonBob Will (National CJD Surveillance Unit, UK)NPDPSCJohns Hopkins Pierluigi GambettiPeter RabinsSally BerriKostas LyketsosBarbara Crain FTD/YOD ClinicAvi NathChiadi OnyikeMary Anne WylieRebecca RyeKate Hicks