What’s New with CJD and Related Early Onset Prion Dementias?15th Update on the Treatment of Alzheimer’s and

Related Disorders

April 4th, 2009

Presented by: Brian S. Appleby, M.D.

Jack Bauer (“24”)

Bauer Hockey Sticks

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

What are Prion Diseases?

Prion Theory“Protein-Only Hypothesis”

Prion Diseases

Animals• Scrapie (sheep and

goats)• Transmissible mink

encephalopathy• Bovine spongiform

encephalopathy (BSE)• Chronic wasting disease

(CWD) (deer and elk)

Humans• Kuru• Creutzfeldt-Jakob

disease (CJD)• Variant CJD (vCJD)• Fatal familial insomnia

(FFI)• Gerstmann-Sträussler-

Scheinker syndrome (GSS)

Etiology

I. Sporadic (85%)

II. Genetic (15%)A. >30 mutations, mostly autosomal

dominant

III. Acquired (<1%)A. Iatrogenic

B. Variant CJD

Age of Onset

Appleby BS, et al. J Neuropsychiatry Clin Neurosci, 2007

vCJDgCJD

sCJD

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

Initial Symptoms

Definitive Diagnosis

Prion protein confirmation Spongiform encephalopathy

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

Electroencephalogram (EEG)

Periodic sharp wave complexes (PSWC’s)

Other CSF markers

1. Tau

2. Neuron specific enolase-unlikely if <30ng/mL

3. S-100b

Beaudry P, et al. Dement Geriatr Cogn Disord, 1999 and Bahl JM, et al. Neurobiol Aging, 2008

T-tau + 14-3-3

96% specificity

84% sensitivity

MRI (DWI/FLAIR)

Cortical ribbon

Basal ganglia

vCJD Update

Sixteenth Annual Report, Creutzfeldt-Jakob Disease Surveillance in the UK, 2007

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

Incubation

Transfusion Medicine Epidemiology Review, 5 Dec 2008

Met-Val

Blood Transmission

sCJD and Blood Transmission

Dorsey K, et al. Transfusion, 2009

Incubation Modifiers

Strain Individual variability

sCJDgCJD

*connected circles represent animals inoculated at same time with identical aliquots

Brown P, et al. Ann Neurol, 1994

Telegraph.co.uk, 18 Dec 2008

Incidence of iCJD cases from hGH

Huillard d’Aignaux J, et al. Neurology, 1999

South Korea Protests

Ackerman F & Johnecheck WA. New Solut, 2008

U.S.A. BSE Scenarios

King S. Lancet, 2008

Ann Neurol, 2008

Prion 2008, Madrid, Spain

Arch Neurol, 2009

Gambetti P, et al. Ann Neurol, 2008

Protease Sensitive Prionopathy (PSPr)

Investigational Therapies

1. Quinacrine/other tricyclic compounds

2. Pentosan polysulphate (PPS)

3. Doxycycline

4. Simvastatin

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

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)(6th CJD Family Conference, 2008)

Pentosan Polysulphate (PPS)

Prion Disease Published Survival Time

PPS Treated Survival Time

GSS Median=48 monthsRange=2-84 monthsN=21 cases, 6 studies

Case #3=52 monthsCase #4=60 months

iCJD (hGH) Median=16 monthsRange=3-30 monthsN=111 cases, 3 studies

Case#1=30 monthsCase #6=29 months

vCJD Median=14 monthsRange=6-40 monthsN=145 cases, 2 studies

Case #2=36 monthsCase #5=42 monthsCase #7=16 monthsCase #Y=61 months

Bone I, MRC New Therapies Scrutiny Group for Prion Disease, 2006

“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

Doxycycline: human studies

Group Number of cases Median survival time

Doxycycline treated 21 292 days

Untreated 581 169 days

Log Rank test, p<0.001

Observational study

MM, p=0.019MV, p=0.133VV, p=0.54

Zerr I. 6th CJD Family Conference, 2008

Prion 2008, Madrid, Spain

Simvastatin: mouse model

Mean survival time=193 days vs. 183 days, p<0.05

Kempster S, et al. Neuroreport, 2007

LDL and survival time: sCJD patients

Appleby BS, et al. Prion 2008, Madrid, Spain

Thank you!http://www.slideshare.net/applebyb