Creutzfeldt-Jakob Disease and           Other Prion Diseases                        Overview and Research UpdatePresented ...
DisclosuresI. No financial disclosuresII. Off-label uses of:  A. Quinacrine  B. Pentosan Polysulphate  C. Doxycycline
ObjectivesI. Understand the pathogenesis of prion     diseasesII. Demonstrate clinical and diagnostic     knowledge of pri...
What causes prion diseases?A. Eating tainted beefB. Genetic mutationsC. Spontaneous protein misfoldingD. All of the aboveE...
“Pri-on”•   proteinaceous and infectious•   -ion (infectious, e.g. virion)•   No nucleic acid•   Non-degradable by typical...
Copyright 2002, John Wiley & Sons Publishers, Inc.
EtiologyI. Sporadic (85%)II. Genetic (15%)III. Acquired (<1%)  A. Iatrogenic CJD  B. Variant CJD
sCJD                                       gCJD                  vCJDAdapted from: Appleby BS, et al. J Neuropsychiatry Cl...
Sporadic CJD• Spontaneous protein mutation• 1 per million people per year  60% occur in people >65 years  4.8 per millio...
Adapted from: Appleby BS, et al. Arch Neurol, 2009
Clinical Diagnosis (WHO Criteria)•  Absence of alternative diagnosis•  Progressive dementia•  At least two of the followin...
Electroencephalogram (EEG)   Periodic sharp wave complexes (PSWC’s)
CSF markers1.   14-3-32.   Tau (cutoff > 1200 pg/mL)3.   Neuron specific enolase4.   S-100b                      T-tau + 1...
MRI (DWI/FLAIR) Basal ganglia           Cortical ribbon
Definitive DiagnosisSpongiform encephalopathy   Immunohistochemistry
Kovács GG, et al. J Neurol, 2002
Gerstmann-Sträussler-Scheinker Disease             Tranchant C, et al. JNNP, 1997
Fatal Familial Insomnia
Kuru
Iatrogenic CJD• Known causes of transmission:  – Intracerebral inoculation (depth electrodes,    neurosurgical instruments...
Incidence of iCJD from hGHPRNP codon 129 polymorphism     Huillard d’Aignaux J, et al. Neurology, 1999
Variant CJD•   Etiology: Consumption of BSE tainted beef•   Age at onset: 20-30’s•   Survival: 1-2 years•   Presentation: ...
Pulvinar Sign Zeidler M, et al. Lancet, 2000
Sixteenth Annual Report, Creutzfeldt-Jakob Disease Surveillance in the UK, 2007
Ann Neurol, 2008Arch Neurol, 2009
Protease Sensitive Prionopathy Mean age        Mean              Clinical             Abnormal          Family History at ...
Investigational Treatments1. Quinacrine/other tricyclic compounds2. Pentosan polysulphate (PPS)3. Doxycycline
Korth C, et al. Proc Natl Acad Sci USA, 2001
Quinacrine• 30 sCJD and 2 vCJD patients, no sig  difference in survival time (Haik S, et al. Neurology, 2004)• Prion-1 (UK...
Pentosan Polysulphate (PPS)Prion Disease                  Published Survival Time          PPS Treated Survival           ...
“On the basis of the available evidence,the best possible outcome that couldbe expected after treatment withintraventricul...
Doxycycline         Group                   Number of cases                     Median survival timeDoxycycline treated   ...
Johns Hopkins CJD Program• Clinical care: Evaluation & management,• Education: Diagnosis, care & resources,• Research:  – ...
ResourcesCJD Foundation: www.cjdfoundation.orgCJD Insight: www.cjdinsight.orgCJD Aware!: www.cjdaware.comCJD Surveillance ...
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  1. 1. Creutzfeldt-Jakob Disease and Other Prion Diseases Overview and Research UpdatePresented by: Brian S. Appleby, M.D.University of Cincinnati , Department of Neurology, July 22, 2009
  2. 2. DisclosuresI. No financial disclosuresII. Off-label uses of: A. Quinacrine B. Pentosan Polysulphate C. Doxycycline
  3. 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. 4. What causes prion diseases?A. Eating tainted beefB. Genetic mutationsC. Spontaneous protein misfoldingD. All of the aboveE. None of the above
  5. 5. “Pri-on”• proteinaceous and infectious• -ion (infectious, e.g. virion)• No nucleic acid• Non-degradable by typical sterilization
  6. 6. Copyright 2002, John Wiley & Sons Publishers, Inc.
  7. 7. EtiologyI. Sporadic (85%)II. Genetic (15%)III. Acquired (<1%) A. Iatrogenic CJD B. Variant CJD
  8. 8. sCJD gCJD vCJDAdapted from: Appleby BS, et al. J Neuropsychiatry Clin Neurosci, 2007
  9. 9. Sporadic CJD• Spontaneous protein mutation• 1 per million people per year 60% occur in people >65 years 4.8 per million people per year in people >65 years World Health Organization, 1998 Holman R, et al. Prion 2009, Madrid, Spain
  10. 10. Adapted from: Appleby BS, et al. Arch Neurol, 2009
  11. 11. Clinical Diagnosis (WHO Criteria)• Absence of alternative diagnosis• Progressive dementia• At least two of the following: A. Myoclonus B. Visual or cerebellar disturbance C. Pyramidal/extrapyramidal dysfunction D. Akinetic mutism• At least one of the following: – Typical CJD EEG findings – Positive CSF 14-3-3 test and survival time < 2 years
  12. 12. Electroencephalogram (EEG) Periodic sharp wave complexes (PSWC’s)
  13. 13. CSF markers1. 14-3-32. Tau (cutoff > 1200 pg/mL)3. Neuron specific enolase4. S-100b T-tau + 14-3-3 96% specificity 84% sensitivity Beaudry P, et al. Dement Geriatr Cogn Disord, 1999 Bahl JM, et al. Neurobiol Aging, 2008
  14. 14. MRI (DWI/FLAIR) Basal ganglia Cortical ribbon
  15. 15. Definitive DiagnosisSpongiform encephalopathy Immunohistochemistry
  16. 16. Kovács GG, et al. J Neurol, 2002
  17. 17. Gerstmann-Sträussler-Scheinker Disease Tranchant C, et al. JNNP, 1997
  18. 18. Fatal Familial Insomnia
  19. 19. Kuru
  20. 20. Iatrogenic CJD• Known causes of transmission: – Intracerebral inoculation (depth electrodes, neurosurgical instruments) – Cadaveric hormones, cornea, dura mater grafts – Blood* (4 cases of vCJD)• NO transmission via casual contact• Universal precautions by healthcare workers
  21. 21. Incidence of iCJD from hGHPRNP codon 129 polymorphism Huillard d’Aignaux J, et al. Neurology, 1999
  22. 22. Variant CJD• Etiology: Consumption of BSE tainted beef• Age at onset: 20-30’s• Survival: 1-2 years• Presentation: sensory and psych symptoms• Brain MRI: “pulvinar sign”
  23. 23. Pulvinar Sign Zeidler M, et al. Lancet, 2000
  24. 24. Sixteenth Annual Report, Creutzfeldt-Jakob Disease Surveillance in the UK, 2007
  25. 25. Ann Neurol, 2008Arch Neurol, 2009
  26. 26. Protease Sensitive Prionopathy Mean age Mean Clinical Abnormal Family History at onset Duration (mo) Presentation PrP62 (48-71) 20 (10-60) Cognitive decline Minimal Dementia (8/10) (8/11) amount of Dementia <61 Mood/Behavioral PK-resistant years (2/4) changes (7/11) PrP Adapted from: Gambetti P, et al. Ann Neurol, 2008
  27. 27. Investigational Treatments1. Quinacrine/other tricyclic compounds2. Pentosan polysulphate (PPS)3. Doxycycline
  28. 28. Korth C, et al. Proc Natl Acad Sci USA, 2001
  29. 29. Quinacrine• 30 sCJD and 2 vCJD patients, no sig difference in survival time (Haik S, et al. Neurology, 2004)• Prion-1 (UK): 45 sCJD, 2 iCJD, 18 vCJD, 42 gCJD, no sig difference in survival time (Collinge J, et al. Lancet Neurol, 2009)• UCSF: midpoint survival analyses showed no sig difference between comparison groups (Log rank, p=0.4)(6 CJD Family Conference, 2008) th
  30. 30. Pentosan Polysulphate (PPS)Prion Disease Published Survival Time PPS Treated Survival TimeGSS Median=48 months Case #3=52 months Range=2-84 months Case #4=60 months N=21 cases, 6 studiesiCJD (hGH) Median=16 months Case#1=30 months Range=3-30 months Case #6=29 months N=111 cases, 3 studiesvCJD Median=14 months Case #2=36 months Range=6-40 months Case #5=42 months N=145 cases, 2 studies Case #7=16 months Case #Y=61 months Bone I, MRC New Therapies Scrutiny Group for Prion Disease, 2006
  31. 31. “On the basis of the available evidence,the best possible outcome that couldbe expected after treatment withintraventricular PPS is that there maybe some temporary slowing or haltingof the disease progression. However,there is little likelihood of significantclinical improvement. Nor is there alikelihood of permanent halting ofdisease progression.” CJD Support Network Newsletter, March 2004
  32. 32. Doxycycline Group Number of cases Median survival timeDoxycycline treated 21 292 daysUntreated 581 169 daysLog Rank test, p<0.001 PRNP Codon 129 Polymorphism MM, p=0.019 MV, p=0.133 VV, p=0.54 Zerr I. 6th CJD Family Conference, 2008
  33. 33. Johns Hopkins CJD Program• Clinical care: Evaluation & management,• Education: Diagnosis, care & resources,• Research: – Clinical: diagnostic, epidemiology, management, therapies – Model for other proteinopathies (e.g. Alzheimer’s and Parkinson’s disease)
  34. 34. ResourcesCJD Foundation: www.cjdfoundation.orgCJD Insight: www.cjdinsight.orgCJD Aware!: www.cjdaware.comCJD Surveillance Center: www.cjdsurveillance.comJH Clinic: www.hopkinsmedicine.org/ftdyoungonsetEmail: bappleb1@jhmi.eduSlideShare: http://www.slideshare.net/applebyb

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