determinants of-survival-time-in-human-prion-diseases-1233685082975925-3
TRANSCRIPT
![Page 1: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/1.jpg)
Brian S. Appleby, M.D.
Johns Hopkins Psychiatry Research ConferenceFebruary 3, 2009
![Page 2: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/2.jpg)
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)
![Page 3: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/3.jpg)
![Page 4: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/4.jpg)
Spongiform Encephalopathy
![Page 5: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/5.jpg)
EtiologiesI. Sporadic (85%)II. Genetic (15%)
A. >30 mutations, mostly autosomal dominant
III. Acquired (<1%)A. IatrogenicB. Variant CJD
![Page 6: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/6.jpg)
Age of Onset
Appleby BS, et al. J Neuropsychiatry Clin Neurosci, 2007
vCJDgCJD
sCJD
![Page 7: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/7.jpg)
Survival Curve of Prion Diseases
Pocchiari M, et al. Brain, 2004
![Page 8: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/8.jpg)
Survival Time of Prion Disease Subtypes
Pocchiari M, et al. Brain, 2004
![Page 9: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/9.jpg)
Will RG, et al. In: Prion Biology and Diseases, 2004
Initial Symptoms of sCJD
![Page 10: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/10.jpg)
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
![Page 11: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/11.jpg)
Electroencephalogram (EEG)
Periodic sharp wave complexes (PSWC’s)
![Page 12: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/12.jpg)
Brain MRI (DWI/FLAIR)
Cortical ribbon
Basal ganglia
![Page 13: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/13.jpg)
Discovery of Variant CJD (vCJD)
Will RG, et al. Lancet, 1996
![Page 14: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/14.jpg)
Characteristics of Initial vCJD Cases
Will RG, et al. Lancet, 1996
![Page 15: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/15.jpg)
Psychiatric Symptoms in vCJD
Zeidler M, et al. Lancet, 1997
![Page 16: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/16.jpg)
Symptom Profiles of Prion Disease Mutations
Kovács GG, et al. J Neurol, 2002
![Page 17: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/17.jpg)
Samaia HB, et al. Nature, 1997
![Page 18: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/18.jpg)
Mutation Status, Age, and Anxiety
Gigi A, et al. Dement Geriatr Cogn Disord, 2005
PRNP E200K
![Page 19: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/19.jpg)
Physiological processes involving PrPc
![Page 20: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/20.jpg)
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
![Page 21: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/21.jpg)
CJD Meta-Analysis
Appleby BS et al. J Neuropsychiatry Clin Neurosci, 2007
![Page 22: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/22.jpg)
Study Sample
Appleby BS et al. J Neuropsychiatry Clin Neurosci, 2007
![Page 23: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/23.jpg)
Survival Time by Initial Symptoms
Appleby BS et al. J Neuropsychiatry Clin Neurosci, 2007
![Page 24: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/24.jpg)
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
![Page 25: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/25.jpg)
Survival Time of sCJD Phenotypes
Appleby BS, et al. Arch Neurol , 2009
Log Rank, χ2=25.3, p<0.001
![Page 26: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/26.jpg)
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
![Page 27: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/27.jpg)
Initial Diagnoses of Human Prion Diseases (n=92)
Appleby BS, et al. Prion 2008, Madrid, Spain
![Page 28: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/28.jpg)
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
![Page 29: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/29.jpg)
Safar J et al., Proc Natl Acad Sci USA, 2006
Prions and Lipids
![Page 30: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/30.jpg)
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
![Page 31: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/31.jpg)
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
![Page 32: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/32.jpg)
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
![Page 33: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/33.jpg)
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
![Page 34: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/34.jpg)
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
![Page 35: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/35.jpg)
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
![Page 36: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/36.jpg)
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)
Slideshare : www.slideshare.net/applebyb
![Page 37: Determinants of-survival-time-in-human-prion-diseases-1233685082975925-3](https://reader037.vdocuments.net/reader037/viewer/2022110122/5593501a1a28ab1b3c8b47f3/html5/thumbnails/37.jpg)