1. What’s New with CJD and Related
Early Onset Prion Dementias?
15th Update on the Treatment of Alzheimer’s and
Related Disorders
Presented by: Brian S. Appleby, M.D.
April 4th, 2009

2. Jack Bauer (“24”)

3. Bauer Hockey Sticks

4. Objectives
1. Understand the basic concepts of
human prion diseases
2. Demonstrate diagnostic strategies for
prion diseases
3. Describe recent discoveries in the field
of prion disease

5. What are Prion Diseases?

6. Prion Theory
“Protein-Only Hypothesis”

7. Prion Diseases
Animals Humans
• Scrapie (sheep and • Kuru
goats) • Creutzfeldt-Jakob
• Transmissible mink disease (CJD)
encephalopathy • Variant CJD (vCJD)
• Bovine spongiform • Fatal familial insomnia
encephalopathy (BSE) (FFI)
• Chronic wasting disease • Gerstmann-Sträussler-
(CWD) (deer and elk) Scheinker syndrome
(GSS)

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

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

10. Initial Symptoms
Will RG, et al. In: Prion Biology and Diseases, 2004

11. Definitive Diagnosis
Prion protein confirmation Spongiform encephalopathy

12. Probable Diagnosis
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

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

14. Other CSF markers
1. Tau
2. Neuron specific enolase-unlikely if
<30ng/mL
3. S-100b
T-tau + 14-3-3
96% specificity
84% sensitivity
Beaudry P, et al. Dement Geriatr Cogn Disord, 1999 and Bahl JM, et al. Neurobiol Aging, 2008

15. MRI (DWI/FLAIR)
Basal ganglia
Cortical ribbon

16. vCJD Update
Sixteenth Annual Report, Creutzfeldt-Jakob Disease Surveillance in the UK, 2007

17. Incubation
“…estimated prevalence of 237 per million individuals…”
J Pathol, 2004

18. Blood Transmission
Met-
Val
Transfusion Medicine Epidemiology Review, 5 Dec 2008

19. sCJD and Blood Transmission
Dorsey K, et al. Transfusion, 2009

20. Incubation Modifiers
Strain Individual variability
sCJD
gCJD
*connected circles represent animals inoculated at same time
with identical aliquots
Brown P, et al. Ann Neurol, 1994

21. Telegraph.co.uk, 18 Dec 2008
Incidence of iCJD cases from hGH
Huillard d’Aignaux J, et al. Neurology, 1999

22. South Korea Protests

23. U.S.A. BSE Scenarios
Ackerman F & Johnecheck WA. New Solut, 2008

24. King S. Lancet, 2008

25. Ann Neurol, 2008
Prion 2008, Madrid, Spain
Arch Neurol, 2009

26. Protease Sensitive Prionopathy (PSPr)
Gambetti P, et al. Ann Neurol, 2008

27. Investigational Therapies
1. Quinacrine/other tricyclic compounds
2. Pentosan polysulphate (PPS)
3. Doxycycline
4. Simvastatin

28. Korth C, et al. Proc Natl Acad Sci USA, 2001

29. Quinacrine: human studies
1. Haik S, et al. 30 sCJD and 2 vCJD
patients, no sig difference in survival time
(Neurology, 2004)
2. UK Prion-1: only recruited 81/160
patients, results unpublished (Stewart L, et al.
Neurology, 2008)
3. CJD quinacrine study (UCSF): study
midpoint survival analyses showed no sig
difference between comparison groups
(Log rank, p=0.4)(6 CJD Family Conference, 2008)
th

30. Pentosan Polysulphate (PPS)
Prion Disease Published Survival PPS Treated Survival
Time Time
GSS Median=48 months Case #3=52 months
Range=2-84 months Case #4=60 months
N=21 cases, 6 studies
iCJD (hGH) Median=16 months Case#1=30 months
Range=3-30 months Case #6=29 months
N=111 cases, 3 studies
vCJD 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. “On the basis of the available evidence,
the best possible outcome that could
be expected after treatment with
intraventricular PPS is that there may
be some temporary slowing or halting
of the disease progression. However,
there is little likelihood of significant
clinical improvement. Nor is there a
likelihood of permanent halting of
disease progression.”
CJD Support Network Newsletter, March 2004

32. Doxycycline: human studies
Observational study
Group Number of cases Median survival time
Doxycycline treated 21 292 days
Untreated 581 169 days
Log Rank test, p<0.001 Zerr I. 6th CJD Family Conference, 2008
MM, p=0.019
MV, p=0.133
VV, p=0.54
Prion 2008, Madrid, Spain

33. Simvastatin: mouse model
Mean survival time=193 days vs. 183 days, p<0.05
Kempster S, et al. Neuroreport, 2007

34. LDL and survival time: sCJD patients
Appleby BS, et al. Prion 2008, Madrid, Spain

35. Thank you!
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