1.Creutzfeldt-Jakob Disease and Other Prion DiseasesOverview and Research UpdatePresented by: Brian S. Appleby, M.D.University of Cincinnati , Department of Neurology, July 22, 2009

2. DisclosuresI. No financial disclosuresII. Off-label uses of:A. QuinacrineB. Pentosan PolysulphateC. Doxycycline 3. ObjectivesI. Understand the pathogenesis of prion diseasesII. Demonstrate clinical and diagnostic knowledge of prion diseasesIII. Describe recent developments in the field of prion diseases 4. What causes prion diseases?A. Eating tainted beefB. Genetic mutationsC. Spontaneous protein misfoldingD. All of the aboveE. None of the above 5. Pri-on proteinaceous and infectious -ion (infectious, e.g. virion) No nucleic acid Non-degradable by typical sterilization 6. Copyright 2002, John Wiley & Sons Publishers, Inc. 7. EtiologyI. Sporadic (85%)II. Genetic (15%)III. Acquired (65 years4.8 per million people per year in people >65 yearsWorld Health Organization, 1998Holman R, et al. Prion 2009, Madrid, Spain 10. Adapted from: Appleby BS, et al. Arch Neurol, 2009 11. Clinical Diagnosis (WHO Criteria)Absence of alternative diagnosisProgressive dementiaAt least two of the following:A. MyoclonusB. Visual or cerebellar disturbanceC. Pyramidal/extrapyramidal dysfunctionD. Akinetic mutism At least one of the following: Typical CJD EEG findings Positive CSF 14-3-3 test and survival time < 2 years 12. Electroencephalogram (EEG) Periodic sharp wave complexes (PSWCs) 13. CSF markers1. 14-3-32. Tau (cutoff > 1200 pg/mL)3. Neuron specific enolase4. S-100bT-tau + 14-3-3 96% specificity 84% sensitivityBeaudry P, et al. Dement Geriatr Cogn Disord, 1999Bahl JM, et al. Neurobiol Aging, 2008 14. MRI (DWI/FLAIR) Basal ganglia Cortical ribbon 15. Definitive DiagnosisSpongiform encephalopathy Immunohistochemistry 16. Kovcs GG, et al. J Neurol, 2002 17. Gerstmann-Strussler-Scheinker Disease Tranchant C, et al. JNNP, 1997 18. Fatal Familial Insomnia 19. Kuru 20. Iatrogenic CJD Known causes of transmission: Intracerebral inoculation (depth electrodes,neurosurgical instruments) Cadaveric hormones, cornea, dura matergrafts Blood* (4 cases of vCJD) NO transmission via casual contact Universal precautions by healthcare workers 21. Incidence of iCJD from hGHPRNP codon 129 polymorphism Huillard dAignaux J, et al. Neurology, 1999 22. Variant CJD Etiology: Consumption of BSE tainted beef Age at onset: 20-30s Survival: 1-2 years Presentation: sensory and psych symptoms Brain MRI: pulvinar sign 23. Pulvinar Sign Zeidler M, et al. Lancet, 2000 24. Sixteenth Annual Report, Creutzfeldt-Jakob Disease Surveillance in the UK, 2007 25. Ann Neurol, 2008Arch Neurol, 2009 26. Protease Sensitive Prionopathy Mean ageMeanClinical AbnormalFamily History at onsetDuration (mo) Presentation PrP62 (48-71) 20 (10-60)Cognitive declineMinimal Dementia (8/10) (8/11) amount of Dementia