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