1. Brian S. Appleby, M.D.
Johns Hopkins Psychiatry Research Conference
February 3, 2009

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)

4. Spongiform Encephalopathy

5. Etiologies
I. Sporadic (85%)
II. Genetic (15%)
A. >30 mutations, mostly autosomal dominant
III. Acquired (<1%)
A. Iatrogenic
B. Variant CJD

6. Age of Onset
sCJD
gCJD
vCJD
Appleby BS, et al. J Neuropsychiatry Clin Neurosci, 2007

7. Survival Curve of Prion Diseases
Pocchiari M, et al. Brain, 2004

8. Survival Time of Prion Disease Subtypes
Pocchiari M, et al. Brain, 2004

9. Initial Symptoms of sCJD
Will RG, et al. In: Prion Biology and Diseases, 2004

10. Diagnostic Criteria: Probable sCJD
I. Absence of alternative diagnosis
II. Progressive dementia
III. At least two of the following:
A. Myoclonus
B. Visual or cerebellar disturbance
C. Pyramidal/extrapyramidal dysfunction
D. Akinetic mutism
IV. 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

11. Electroencephalogram (EEG)
Periodic sharp wave complexes (PSWC’s)

12. Brain MRI (DWI/FLAIR)
Basal ganglia
Cortical ribbon

13. Discovery of Variant CJD (vCJD)
Will RG, et al. Lancet, 1996

14. Characteristics of Initial vCJD Cases
Will RG, et al. Lancet, 1996

15. Psychiatric Symptoms in vCJD
Zeidler M, et al. Lancet, 1997

16. Symptom Profiles of Prion Disease Mutations
Kovács GG, et al. J Neurol, 2002

17. Samaia HB, et al. Nature, 1997

18. Mutation Status, Age, and Anxiety
PRNP E200K
Gigi A, et al. Dement Geriatr Cogn Disord, 2005

19. Physiological processes involving PrPc

20. PrPc and prevention of
Alzheimer’s disease
Increased levels of Aβ
peptides in Alzheimer’s
disease, particularly
oligomeric and fibrillar forms,
cause neuronal cell death and
dementia. The normal cellular
form of the prion protein,
through inhibiting the
production of the Aβ peptide,
might help to prevent the
development of AD.
Hooper NM. Trends Biochem Sci, 2008

21. CJD Meta-Analysis
Appleby BS et al. J Neuropsychiatry Clin Neurosci, 2007

22. Study Sample
Appleby BS et al. J Neuropsychiatry Clin Neurosci, 2007

23. Survival Time by Initial Symptoms
Appleby BS et al. J Neuropsychiatry Clin Neurosci, 2007

24. Hypothesized Phenotypes
1. Affective: depression, anxiety, mood lability
2. Cognitive: cognitive impairment only
Appleby BS, et al. J Neuropsychiatry Clin Neurosci, 2008
Appleby BS, et al. Alzheimers Dement, 2008

25. Survival Time of sCJD Phenotypes
Log Rank, χ2=25.3, p<0.001
Appleby BS, et al. Arch Neurol , 2009

26. sCJD Phenotype Survival Times
95% Confidence Interval
sCJD Variants Median SE Lower Upper
Cognitive 214 41.4 132.8 295.2
Heidenhain 104 11.6 81.3 126.7
Affective 421 97.1 230.8 611.2
Classic CJD 66 13.2 40.1 91.9
Oppenheimer-Brownell 147 26.2 95.7 198.3
Indeterminate 119 15.6 88.5 149.5
Overall 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

27. Initial Diagnoses of Human Prion Diseases (n=92)
Appleby BS, et al. Prion 2008, Madrid, Spain

28. 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

29. Prions and Lipids
Safar J et al., Proc Natl Acad Sci USA, 2006

30. 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

31. sCJD Patients and Lipids
Table 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

32. 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

33. 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

34. 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

35. 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

36. Acknowledgements
Kristin 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)
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