Brian S. Appleby, M.D.Johns Hopkins Psychiatry Research Conference              February 3, 2009
Prion Diseases          Animals                      HumansScrapie (sheep and goats)   KuruTransmissible mink          ...
Spongiform Encephalopathy
EtiologiesI.  Sporadic (85%)II. Genetic (15%)     A.   >30 mutations, mostly autosomal dominantIII. Acquired (<1%)    A. I...
Age of Onset                                      sCJD                                 gCJD                 vCJDAppleby BS...
Survival Curve of Prion Diseases           Pocchiari M, et al. Brain, 2004
Survival Time of Prion Disease Subtypes             Pocchiari M, et al. Brain, 2004
Initial Symptoms of sCJD    Will RG, et al. In: Prion Biology and Diseases, 2004
Diagnostic Criteria: Probable sCJDI.   Absence of alternative diagnosisII. Progressive dementiaIII. At least two of the fo...
Electroencephalogram (EEG)      Periodic sharp wave complexes (PSWC’s)
Brain MRI (DWI/FLAIR)       Basal ganglia                       Cortical ribbon
Discovery of Variant CJD (vCJD)           Will RG, et al. Lancet, 1996
Characteristics of Initial vCJD Cases           Will RG, et al. Lancet, 1996
Psychiatric Symptoms in vCJD        Zeidler M, et al. Lancet, 1997
Symptom Profiles of Prion Disease Mutations             Kovács GG, et al. J Neurol, 2002
Samaia HB, et al. Nature, 1997
Mutation Status, Age, and Anxiety                      PRNP E200K       Gigi A, et al. Dement Geriatr Cogn Disord, 2005
Physiological processes involving PrPc
PrPc and prevention ofAlzheimer’s diseaseIncreased levels of Aβpeptides in Alzheimer’sdisease, particularlyoligomeric and ...
CJD Meta-AnalysisAppleby BS et al. J Neuropsychiatry Clin Neurosci, 2007
Study SampleAppleby BS et al. J Neuropsychiatry Clin Neurosci, 2007
Survival Time by Initial Symptoms      Appleby BS et al. J Neuropsychiatry Clin Neurosci, 2007
Hypothesized Phenotypes1. Affective: depression, anxiety, mood lability2. Cognitive: cognitive impairment only           A...
Survival Time of sCJD Phenotypes         Log Rank, χ2=25.3, p<0.001         Appleby BS, et al. Arch Neurol , 2009
sCJD Phenotype Survival Times                                           95% Confidence Interval    sCJD Variants    Median...
Initial Diagnoses of Human Prion Diseases (n=92)          Appleby BS, et al. Prion 2008, Madrid, Spain
Survival Time of Prion Disease Patients by Initial Diagnosis                           Variables            Sig.   Exp(B) ...
Prions and Lipids Safar J et al., Proc Natl Acad Sci USA, 2006
Retrospective Survival Analysis of sCJD Patients           Table 1. Demographic Data                Characteristic        ...
sCJD Patients and LipidsTable 2. Lipid Characteristics Lipid Characteristics                   Sample (n=21) Time from sym...
sCJD Survival Analysis by Serum Lipid Levels*        Variable                 p value                  Exp(B)            9...
Survival Analysis of Serum LDL Levels in sCJD                                           Sig.    Exp(B)                    ...
Hypothetical Mechanism of Action                                A. PrPc (blue) and PrPSc                                  ...
SummarysCJD phenotypes display differences in clinical course, diagnostic test results, and molecular subtypes  Could th...
AcknowledgementsKristin Appleby, MD (Georgetown)Michael Baier, PhD (Robert-Kock Institute, GER)Paul Brown, MD (CEA/DSV/iME...
Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3
Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3
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Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3

  1. 1. Brian S. Appleby, M.D.Johns Hopkins Psychiatry Research Conference February 3, 2009
  2. 2. Prion Diseases Animals HumansScrapie (sheep and goats) KuruTransmissible mink Creutzfeldt-Jakob disease encephalopathy (CJD)Bovine spongiform Variant CJD (vCJD) encephalopathy (BSE) Fatal familial insomnia (FFI)Chronic wasting disease Gerstmann-Sträussler- (CWD) (deer and elk) Scheinker syndrome (GSS)
  3. 3. Spongiform Encephalopathy
  4. 4. EtiologiesI. Sporadic (85%)II. Genetic (15%) A. >30 mutations, mostly autosomal dominantIII. Acquired (<1%) A. Iatrogenic B. Variant CJD
  5. 5. Age of Onset sCJD gCJD vCJDAppleby BS, et al. J Neuropsychiatry Clin Neurosci, 2007
  6. 6. Survival Curve of Prion Diseases Pocchiari M, et al. Brain, 2004
  7. 7. Survival Time of Prion Disease Subtypes Pocchiari M, et al. Brain, 2004
  8. 8. Initial Symptoms of sCJD Will RG, et al. In: Prion Biology and Diseases, 2004
  9. 9. Diagnostic Criteria: Probable sCJDI. Absence of alternative diagnosisII. Progressive dementiaIII. At least two of the following: A. Myoclonus B. Visual or cerebellar disturbance C. Pyramidal/extrapyramidal dysfunction D. Akinetic mutismIV. At least one of the following: A. Typical CJD EEG findings B. Positive CSF 14-3-3 test and survival time < 2 years World Health Organization, 1998
  10. 10. Electroencephalogram (EEG) Periodic sharp wave complexes (PSWC’s)
  11. 11. Brain MRI (DWI/FLAIR) Basal ganglia Cortical ribbon
  12. 12. Discovery of Variant CJD (vCJD) Will RG, et al. Lancet, 1996
  13. 13. Characteristics of Initial vCJD Cases Will RG, et al. Lancet, 1996
  14. 14. Psychiatric Symptoms in vCJD Zeidler M, et al. Lancet, 1997
  15. 15. Symptom Profiles of Prion Disease Mutations Kovács GG, et al. J Neurol, 2002
  16. 16. Samaia HB, et al. Nature, 1997
  17. 17. Mutation Status, Age, and Anxiety PRNP E200K Gigi A, et al. Dement Geriatr Cogn Disord, 2005
  18. 18. Physiological processes involving PrPc
  19. 19. PrPc and prevention ofAlzheimer’s diseaseIncreased levels of Aβpeptides in Alzheimer’sdisease, particularlyoligomeric and fibrillar forms,cause neuronal cell death anddementia. The normal cellularform of the prion protein,through inhibiting theproduction of the Aβ peptide,might help to prevent thedevelopment of AD. Hooper NM. Trends Biochem Sci, 2008
  20. 20. CJD Meta-AnalysisAppleby BS et al. J Neuropsychiatry Clin Neurosci, 2007
  21. 21. Study SampleAppleby BS et al. J Neuropsychiatry Clin Neurosci, 2007
  22. 22. Survival Time by Initial Symptoms Appleby BS et al. J Neuropsychiatry Clin Neurosci, 2007
  23. 23. Hypothesized Phenotypes1. Affective: depression, anxiety, mood lability2. Cognitive: cognitive impairment only Appleby BS, et al. J Neuropsychiatry Clin Neurosci, 2008 Appleby BS, et al. Alzheimers Dement, 2008
  24. 24. Survival Time of sCJD Phenotypes Log Rank, χ2=25.3, p<0.001 Appleby BS, et al. Arch Neurol , 2009
  25. 25. sCJD Phenotype Survival Times 95% Confidence Interval sCJD Variants Median SE Lower UpperCognitive 214 41.4 132.8 295.2Heidenhain 104 11.6 81.3 126.7Affective 421 97.1 230.8 611.2Classic CJD 66 13.2 40.1 91.9Oppenheimer-Brownell 147 26.2 95.7 198.3Indeterminate 119 15.6 88.5 149.5Overall 130 19 92.9 167.1 Cox Proportional Hazards Model 95.0% CI for Exp(B) sCJD Variants Sig. Exp(B) Lower Upper Cognitive (n=26) 0.033 0.406 0.177 0.931 Heidenhain (n=15) 0.492 1.379 0.551 3.450 Affective (n=13) 0.020 0.320 0.122 0.835 Classic CJD (n=11) 0.002 - - - Oppenheimer-Brownell (n=7) 0.064 0.348 0.114 1.062 Indeterminate (n=13) 0.754 0.856 0.324 2.264 Appleby BS, et al. Arch Neurol , 2009
  26. 26. Initial Diagnoses of Human Prion Diseases (n=92) Appleby BS, et al. Prion 2008, Madrid, Spain
  27. 27. Survival Time of Prion Disease Patients by Initial Diagnosis Variables Sig. Exp(B) Prion Disease .152 Non-Prion Dementia .008 .397 Cognitive disorder .352 .607 Mood Disorder .039 .408 Neoplasm .658 .793 Other Psychiatric Disorder .859 .909 Stroke .957 .976 Other Diagnosis .195 .621 Appleby BS, et al. Prion 2008, Madrid, Spain
  28. 28. Prions and Lipids Safar J et al., Proc Natl Acad Sci USA, 2006
  29. 29. Retrospective Survival Analysis of sCJD Patients Table 1. Demographic Data Characteristic Sample (n=21) Age at Onset 67.3 years Center JH 7 (33.3%) VA 14 (66.7%) Sex Male 14 (66.7%) Female 7 (33.3%) Race Caucasian 16 (76.2%) Black 1 (4.8%) Unknown 4 (19%) Diagnostic Criteria Definite (3) 15 (71.4%) Probable (WHO) (3) 5 (23.8%) Probable (UCSF) (4) 1 (4.8%) Appleby BS, et al. Prion 2008, Madrid, Spain
  30. 30. sCJD Patients and LipidsTable 2. Lipid Characteristics Lipid Characteristics Sample (n=21) Time from symptom onset to test 25 ± 54.8 days Total cholesterol 186 ± 23.1 mg/dL Serum LDL 108 ± 21.5 mg/dL Serum HDL 51.5 ± 17.3 mg/dL Serum Triglycerides 131.6 ± 65.8 mg/dL Lovastatin ≤ 1yr disease onset n=10 (47.6%) Duration of use 762.8 ± 750.8 days Coronary Artery Disease n=4 (19%) Appleby BS, et al. Prion 2008, Madrid, Spain
  31. 31. sCJD Survival Analysis by Serum Lipid Levels* Variable p value Exp(B) 95% CI for Exp(B) Cholesterol 0.222 1.013 0.992-1.035 LDL 0.035 1.032 1.002-1.062 HDL 0.361 0.987 0.959-1.015 Triglycerides 0.296 1.005 0.996-1.013*controlled for age at onset, sex, coronary artery disease, statins, and time from onset to test Appleby BS, et al. Prion 2008, Madrid, Spain
  32. 32. Survival Analysis of Serum LDL Levels in sCJD Sig. Exp(B) LDL<90mg/dL 0.017 - LDL=90-107mg/dL 0.404 0.546 LDL=108-126mg/dL 0.605 1.421 LDL>126mg/dL 0.010 7.756 Appleby BS, et al. Prion 2008, Madrid, Spain
  33. 33. Hypothetical Mechanism of Action A. PrPc (blue) and PrPSc (red) undergo endocytosis B. Co-factor (yellow) on lipid raft assists conversion of PrPc to PrPSc Taylor D & Hooper N. Semin Cell Dev Biol, 2007
  34. 34. SummarysCJD phenotypes display differences in clinical course, diagnostic test results, and molecular subtypes Could this reflect different etiologies (e.g. vCJD, gCJD)?Serum LDL predicts survival time in sCJD  ? biomarker and/or treatment target
  35. 35. AcknowledgementsKristin Appleby, MD (Georgetown)Michael Baier, PhD (Robert-Kock Institute, GER)Paul Brown, MD (CEA/DSV/iMETI/SEPIA, FRA)Barbara Crain, MD, PhD (JHH)Pierluigi Gambetti, MD (NPDPSC, Case Western)Deirdre Johnston, MB, BCh, BAO, MRCPsych (JHH)Michelle Mielke, PhD (JHBMC)Chiadi Onyike, MD, MHS (JHH)Peter Rabins, MD, MPH (JHH)Mitchell Wallin, MD, MPH (Georgetown, VA)Robert Will, FRCP (CJD Surveillance Unit, UK)Steven Woods (Howard)Slideshare : www.slideshare.net/applebyb
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