1. Creutzfeldt-Jakob Disease and
Other Prion Diseases
Overview and Research Update
Presented by: Brian S. Appleby, M.D.
University of Cincinnati , Department of Neurology, July 22, 2009
2. Disclosures
I. No financial disclosures
II. Off-label uses of:
A. Quinacrine
B. Pentosan Polysulphate
C. Doxycycline
3. Objectives
I. Understand the pathogenesis of prion
diseases
II. Demonstrate clinical and diagnostic
knowledge of prion diseases
III. Describe recent developments in the
field of prion diseases
4. What causes prion diseases?
A. Eating tainted beef
B. Genetic mutations
C. Spontaneous protein misfolding
D. All of the above
E. None of the above
5. “Pri-on”
• proteinaceous and infectious
• -ion (infectious, e.g. virion)
• No nucleic acid
• Non-degradable by typical sterilization
10. 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
12. 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
27. Protease Sensitive Prionopathy
Mean age Mean Clinical Abnormal Family History
at onset Duration (mo) Presentation PrP
62 (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
30. 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
31. Pentosan Polysulphate (PPS)
Prion Disease Published Survival Time PPS Treated Survival
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
32. “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
33. Doxycycline
Group Number of cases Median survival time
Doxycycline treated 21 292 days
Untreated 581 169 days
Log 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
34. 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)
