Developing a Translational Toolbox for Parkinson disease: The Parkinson Progression Marker Initiative Keystone March 2014
Disclosure • Co-founder on Molecular Neuroimaging LLC – PET and SPECT imaging services • Consultant –BMS, GEHC, Lilly, Merck, Navidea, Piramal Pfizer, Sanofi,
• PPMI Study Rationale/Infrastructure • Baseline PPMI data (baseline cohorts) • PPMI new cohorts - Prodromal/Genetics • Utility of Biomarkers prior to symptoms
PD patient vignette • 67 yo right handed WF in excellent general health • History Noted could not coordinate polls when skiing Note 1-2 years – mild constipation 2 months intermittent R UE tremor while reading the newspaper, or if in stressful situation • Exam Mild R UE resting tremor Reduced R arm swing • PD DIAGNOSIS – 1 MONTH AGO • “ IF THE SYMPTOMS REMAIN AS THEY ARE NOW – I COULD DEAL WITH THIS ”
Natural History of PD Symptomatic Neuron Function Diagnosis Prodromal Time
Neuroprotection Studies UNSUCCESSFUL UNCERTAIN • DATATOP – ROPINIROLE SELEGILINE/VIT • • ELLDOPA ADAGIO – TEVA E • • ASA/NSAID ISRADIPINE • LAZABEMIDE • • SR57667B INOSINE • RULIZOLE • PRECEPT – • TCH-346 CEP1347 • NEURO- • GREEN TEA IMMUNOPHILIN • PROUD – • GPI 1485 PRAMIPEXOLE • CALM-PD • QE-2/CO-Q10/QE3 • MINOCYCLINE • NET PS LS1 – • CAFFEINE CREATINE • REAL-PET –
Parkinson Progression Marker Initiative • Disease modifying PD therapeutics remain a major unmet need • A major obstacle to current phase 2/3 neuroprotection studies is the lack of biomarkers for – Disease mechanism – Drug mechanism – Dosage determination – Study eligibility – Stratification into PD sub-types – Correlation with clinical signals – Prodromal PD detection and progression Requirements for Biomarker •Appropriate population (early stage PD and controls) Specific Data •Clinical (motor/non-motor) and imaging data Set •Corresponding biologic samples (DNA, blood, CSF) Infrastructure •Uniform collection of data and samples Standardization •Uniform storage of data and samples •Strict quality control/quality assurance •Data available to research community data mining, hypothesis generation & Access/Sharing testing •Samples available for studies
Olfaction
PPMI funding partners PPMI is sponsored and partially funded by The Michael J. Fox Foundation for Parkinson’s Research. Other funding partners include a consortium of industry players, non-profit organizations and private individuals.
PPMI Sites PPMI SITES IN THE UNITED STATES: Arizona PD Consortium (Sun City, AZ) PPMI SITES IN EUROPE: Beth Israel Medical Center (NY, NY) Foundation for Biomedical Research of the Baylor College of Medicine (Houston, TX) Academy of Athens (Athens, Greece) Boston University (Boston, MA) Imperial College (London, UK) Cleveland Clinic (Cleveland, OH) Innsbruck University (Innsbruck, Austria) Columbia University (NY, NY) Norwegian University of Science and Technology Emory University (Atlanta, GA) (Trondheim, Norway) Institute of Neurodegenerative Disorders (New Paracelsus-Elena Clinic Kassel/University of Haven, CT) Marburg (Kassel and Marburg, Germany) Johns Hopkins University (Baltimore ,MD) Pitié-Salpêtrière Hospital (Paris, France) Northwestern University (Chicago, IL) University of Barcelona (Barcelona, Spain) Oregon Health and Science University (Portland, University of Donostia (San Sebastien, Spain) OR) University of Salerno (Salerno, Italy) The Parkinson’s Institute (Sunnyvale, CA) University of Tübingen (Tübingen, Germany) PD & Movement Disorders Center at Boca Raton (Boca Raton, FL) PPMI SITES IN AUSTRALIA: University of Alabama at Birmingham (Birmingham, Macquarie University (Sydney, Australia) AL) University of California at San Diego PPMI SITES IN Israel: (San Diego, CA) Tel Aviv Sourasky Medical Center (Tel Aviv, Israel) University of Cincinnati (Cincinnati, OH) University of Pennsylvania (Philadelphia, PA) University of Rochester (Rochester, NY) University of South Florida (Tampa, FL) University of Washington (Seattle, WA)
PPMI SC and Study Cores PI-K Marek, C Tanner, T Foroud, D Jennings, K Kieburtz, W Poewe, B Mollenhauer, Steering Committee T Simuni, (core leaders, MJFF, ISAB), S Lasch University of Rochester’s Clinical Trials Coordination Center Clinical Coordination Core • PI: Karl Kieburtz, Ray Dorsey, Renee Wilson • Institute for Neurodegenerative Disorders; Imaging Core • PI: John Seibyl, Norbert Schuff, University of Iowa Statistics Core • PI: Chris Coffey Laboratory of Neuroimaging (LONI) at UCLA Bioinformatics Core • PI: Arthur Toga, Karen Crawford Coriell/BioRep BioRepository • PI: Alison Ansbach, Paola Casalin, University of Pennsylvania Bioanalytics Core • PI: John Trojanowski, Les Shaw National Institute on Aging/NIH Genetics Core • PI: Andy Singleton Hephata Hessisches Diakoniezentrum e. V. RBD Core PI: Geert Mayer Institute for Neurodegenerative Disorders Olfactory Core • PI: Danna Jennings Indiana University Genetics Coordinating Core • PI: Tatiana Foroud
PPMI Study Details: Synopsis 400 de novo PD subjects (newly diagnosed and unmedicated) Study population 200 age- and gender-matched healthy controls 70 SWEDD 100 Prodromal - Olfactory/RBD/LRRK2 500 LRRK2 - PD manifest and non-manifesting family members 100 Synuclein - PD manifest and non-manifesting family members Subjects will be followed for 3 to 5 years Motor assessments Assessments/ Clinical Neurobehavioral/cognitive testing data collection Autonomic, Olfaction, Sleep DaTSCAN, AV133, Amyloid, DTI/RS MRI DNA, RNA Biologic collection/ Serum and plasma collected at each visit; urine collected annually CSF collected at baseline, 6mo 12 mo and then annually Samples aliquotted and stored in central biorepository >160,000 Data downloads Data and Biosamples > 35 Sample requests via BRC shared on website - Ancillary study development www.ppmi-info.org
Pre-synaptic Dopaminergic Imaging 123 I ß-CIT- DAT 18 F AV-133- VMAT2 18 F-DOPA- AADC Parkinson disease Healthy
DAT Deficit Scans without evidence of dopaminergic deficit SWEDD
PRECEPT study - FOLLOWUP IMAGING AND CLINICAL OUTCOMES BY SWEDD STATUS AT BASELINE Mean (SD) for Change in [ 123 I] ß-CIT and UPDRS, Percent (CI) for need for DA treatment. * indicates p < 0.01
SWEDD (Scans Without Evidence of Dopaminergic Deficit) in PD Trials Study Stage –PD Dur DX at % SWEDD Baseline (mo) Elldopa-CIT Denovo 6 21/142 (14%) PRECEPT Denovo 8 91/799 (12%) REAL-PET Denovo 9 21/186 (11%) Calm-CIT Start of 18 3/82 (5%) DA Rx GPI1485 Treated 23 3/212 (1.4%) Stable responder
Natural History of Parkinson disease Symptomatic Neuron Function Diagnosis PPMI Pre-diagnostic Time
Baseline Dem ographics and Motor Characteristics PD PD Subjects Healthy Controls SW EDD Subjects PD p-value p-value Baseline Assessm ent relative to ( N = 4 2 3 ) ( N = 1 9 6 ) ( N = 6 4 ) relative to SW EDD HC Mean Age ( Range) 6 1 .7 ( 3 3 - 8 5 ) 6 0 .8 ( 3 1 - 8 4 ) 6 0 .9 ( 3 8 - 7 9 ) 0.33 0.58 2 7 7 ( 6 5 % ) / 1 2 6 ( 6 4 % ) / 4 0 ( 6 3 % ) / Gender ( M % / F % ) 0.79 0.67 1 4 6 ( 3 5 % ) 7 0 ( 3 6 % ) 2 4 ( 3 7 % ) MDS-UPDRS Mean Score & Sub Scores MDS-UPDRS Total Score 3 2 .4 4 .8 2 8 .2 < 0.01 0.03 MDS-UPDRS Part I 5 .6 2 .9 8 .3 < 0.01 < 0.01 MDS-UPDRS Part I I 5 .9 0 .5 5 .7 < 0.01 0.67 MDS-UPDRS Part I I I ( Motor Exam ) 2 0 .9 1 .2 1 4 .3 < 0.01 < 0.01 Hoehn & Yahr N( % ) Stage 0 0 ( 0 % ) 1 9 3 ( 9 8 % ) 0 ( 0 % ) Stage 1 1 8 6 ( 4 4 % ) 2 ( 1 % ) 3 7 ( 5 8 % ) < 0.01 0.11 Stage 2 2 3 5 ( 5 6 % ) 0 ( 0 % ) 2 7 ( 4 1 % ) Stage 3 -5 2 ( 1 % ) 0 ( 0 % ) 0 ( 0 % ) Modified Schw ab & England ( m ean) 9 3 .2 NA 9 4 .8 NA 0.03 First degree fam ily Mem ber w ith PD ( % ) 5 5 ( 1 3 % ) 0 ( 0 % ) 1 5 ( 2 3 % ) < 0.01 0.14 Mean Duration of Disease ( m onths) 6 .7 ( 0 .4 - 3 5 .8 ) NA 7 .4 ( 0 .5 - 3 7 ) NA 0.38 I nitial Sym ptom s* Resting Trem or 3 3 1 ( 7 8 % ) NA 5 3 ( 8 3 % ) NA 0.40 Rigidity 3 2 1 ( 7 6 % ) NA 3 7 ( 5 8 % ) NA < 0.01 Bradykinesia 3 4 8 ( 8 2 % ) NA 5 1 ( 8 0 % ) NA 0.62 Postural I nstability 2 9 ( 7 % ) NA 8 ( 1 3 % ) NA 0.11 Other 7 1 ( 1 7 % ) NA 9 ( 1 4 % ) NA 0.58
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