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

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

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Page 1: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3

Brian S. Appleby, M.D.

Johns Hopkins Psychiatry Research ConferenceFebruary 3, 2009

Page 2: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3

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)

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Page 4: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3

Spongiform Encephalopathy

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

A. >30 mutations, mostly autosomal dominant

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

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Age of Onset

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

vCJDgCJD

sCJD

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Survival Curve of Prion Diseases

Pocchiari M, et al. Brain, 2004

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Survival Time of Prion Disease Subtypes

Pocchiari M, et al. Brain, 2004

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

Initial Symptoms of sCJD

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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

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Electroencephalogram (EEG)

Periodic sharp wave complexes (PSWC’s)

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Brain MRI (DWI/FLAIR)

Cortical ribbon

Basal ganglia

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Discovery of Variant CJD (vCJD)

Will RG, et al. Lancet, 1996

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Characteristics of Initial vCJD Cases

Will RG, et al. Lancet, 1996

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Psychiatric Symptoms in vCJD

Zeidler M, et al. Lancet, 1997

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Symptom Profiles of Prion Disease Mutations

Kovács GG, et al. J Neurol, 2002

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Samaia HB, et al. Nature, 1997

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Mutation Status, Age, and Anxiety

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

PRNP E200K

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Physiological processes involving PrPc

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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

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CJD Meta-Analysis

Appleby BS et al. J Neuropsychiatry Clin Neurosci, 2007

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Study Sample

Appleby BS et al. J Neuropsychiatry Clin Neurosci, 2007

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Survival Time by Initial Symptoms

Appleby BS et al. J Neuropsychiatry Clin Neurosci, 2007

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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

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Survival Time of sCJD Phenotypes

Appleby BS, et al. Arch Neurol , 2009

Log Rank, χ2=25.3, p<0.001

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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

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Initial Diagnoses of Human Prion Diseases (n=92)

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

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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

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

Prions and Lipids

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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

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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

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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

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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

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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

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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

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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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