Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3

Brian S. Appleby, M.D.

Johns Hopkins Psychiatry Research ConferenceFebruary 3, 2009

Prion DiseasesAnimals Humans

Scrapie (sheep and goats)

Transmissible mink encephalopathy

Bovine spongiform encephalopathy (BSE)

Chronic wasting disease (CWD) (deer and elk)

KuruCreutzfeldt-Jakob

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

(FFI)Gerstmann-Sträussler-

Scheinker syndrome (GSS)

Spongiform Encephalopathy

EtiologiesI. Sporadic (85%)II. Genetic (15%)

A. >30 mutations, mostly autosomal dominant

III. Acquired (<1%)A. IatrogenicB. Variant CJD

Age of Onset

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

vCJDgCJD

sCJD

Survival Curve of Prion Diseases

Pocchiari M, et al. Brain, 2004

Survival Time of Prion Disease Subtypes

Pocchiari M, et al. Brain, 2004

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

Initial Symptoms of sCJD

Diagnostic Criteria: Probable sCJDI. Absence of alternative diagnosisII. Progressive dementiaIII. At least two of the following:

A. MyoclonusB. Visual or cerebellar disturbanceC. Pyramidal/extrapyramidal dysfunctionD. Akinetic mutism

IV. At least one of the following:A. Typical CJD EEG findingsB. Positive CSF 14-3-3 test and survival time < 2 years

World Health Organization, 1998

Electroencephalogram (EEG)

Periodic sharp wave complexes (PSWC’s)

Brain MRI (DWI/FLAIR)

Cortical ribbon

Basal ganglia

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

Gigi A, et al. Dement Geriatr Cogn Disord, 2005

PRNP E200K

Physiological processes involving PrPc

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

CJD Meta-Analysis

Appleby BS et al. J Neuropsychiatry Clin Neurosci, 2007

Study Sample

Appleby 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

Appleby BS, et al. J Neuropsychiatry Clin Neurosci, 2008 Appleby BS, et al. Alzheimers Dement, 2008

Survival Time of sCJD Phenotypes

Appleby BS, et al. Arch Neurol , 2009

Log Rank, χ2=25.3, p<0.001

Median SE95% Confidence Interval

sCJD Variants 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

sCJD Variants Sig. Exp(B)95.0% CI for Exp(B)Lower Upper

Cognitive (n=26) 0.033 0.406 0.177 0.931Heidenhain (n=15) 0.492 1.379 0.551 3.450Affective (n=13) 0.020 0.320 0.122 0.835Classic CJD (n=11) 0.002 - - -Oppenheimer-Brownell (n=7) 0.064 0.348 0.114 1.062Indeterminate (n=13) 0.754 0.856 0.324 2.264

sCJD Phenotype Survival Times

Cox Proportional Hazards Model

Appleby BS, et al. Arch Neurol , 2009

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)Prion Disease .152

Non-Prion Dementia .008 .397

Cognitive disorder .352 .607

Mood Disorder .039 .408

Neoplasm .658 .793

Other Psychiatric Disorder .859 .909Stroke .957 .976

Other Diagnosis .195 .621

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

Safar J et al., Proc Natl Acad Sci USA, 2006

Prions and Lipids

Retrospective Survival Analysis of sCJD Patients

Characteristic Sample (n=21)Age at Onset 67.3 yearsCenter

JH 7 (33.3%)VA 14 (66.7%)

SexMale 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%)

Table 1. Demographic Data

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

sCJD Patients and Lipids

Lipid Characteristics Sample (n=21)Time from symptom onset to test 25 ± 54.8 daysTotal cholesterol 186 ± 23.1 mg/dLSerum LDL 108 ± 21.5 mg/dLSerum HDL 51.5 ± 17.3 mg/dLSerum Triglycerides 131.6 ± 65.8 mg/dLLovastatin ≤ 1yr disease onset n=10 (47.6%)

Duration of use 762.8 ± 750.8 daysCoronary Artery Disease n=4 (19%)

Table 2. Lipid Characteristics

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

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

Survival Analysis of Serum LDL Levels in sCJDSig. 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

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

Hypothetical Mechanism of Action

SummarysCJD phenotypes display differences in clinical

course, diagnostic test results, and molecular subtypesCould this reflect different etiologies (e.g. vCJD,

gCJD)?Serum LDL predicts survival time in sCJD

? biomarker and/or treatment target

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)

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