PPMI Prodromal cohort RBD · PPMI Prodromal cohort . RBD . Shirley Lasch . Institute of...
Transcript of PPMI Prodromal cohort RBD · PPMI Prodromal cohort . RBD . Shirley Lasch . Institute of...
PPMI Prodromal cohort RBD
Shirley Lasch Institute of Neurodegenerative disorders
May 7, 2014
PPMI 2014 Annual Meeting
PPMI Sites Recruiting RBD Subjects
PPMI SITES (RBD) IN THE UNITED STATES: Boston University (Boston, MA) Cleveland Clinic (Cleveland, OH) Emory University (Atlanta, GA) Johns Hopkins University (Baltimore ,MD) Northwestern University (Chicago, IL) University of Alabama at Birmingham (Birmingham, AL) University of Pennsylvania (Philadelphia, PA)
PPMI SITES (RBD) IN EUROPE: Foundation for Biomedical Research of the Academy of Athens (Athens, Greece) Innsbruck University (Innsbruck, Austria) Paracelsus-Elena Clinic Kassel/University of Marburg (Kassel and Marburg, Germany) University of Barcelona (Barcelona, Spain)
12 centers recruiting RBD subjects for PPMI
PPMI RBD Site Status RBD Enrollment process Sites Active
Centers/sites participating in RBD recruitment 12
Uploaded data/ test data to central database 11 Consented subject and provided PSG for evaluation 10
PSG meets criteria or subject has clinical and/or clinical diagnosis of RBD by site investigator including existing PSG
10*
Completed SPECT scan sent to Imaging Core for DaTSCAN eligibility evaluation 7
DaTSCAN eligible subjects 6 RBD subjects enrolling in Prodromal Cohort of PPMI 6
*Pending approval of AM7
PPMI RBD Enrollment Status
RBD Screening phase Subjects n (%)
PSG meets criteria or subject has clinical and/or clinical diagnosis of RBD by site investigator including existing PSG
71
Subject consented for screening and DaTSCAN 42 (59%)
Completed SPECT scan sent to Imaging Core for DaTSCAN eligibility evaluation 31 (73%)
PPMI RBD Enrollment Status Criteria Subjects
n (%) Completed SPECT scan sent to Imaging Core for DaTSCAN eligibility evaluation
31
Gender (Male/ Female) 28 (74%) / 8 (26%) Age years (Range) 69 (61-80) / 69 (65-79)
Meet DAT Eligibility 15 (48%) Gender (Male/ Female) 13 (87%) / 2 (13%) Age years (Range) 70 (61-80) / 65 (65)
Enrolled 12 Withdrawn 0
PPMI RBD Summary • Subject enrollment started May 2013 •Approximately 50% of RBD subjects scanned to date meet DAT requirements (moderate to minimal DAT deficit)
• 12 PPMI sites/centers participating with 7 currently completing SPECT scanning
• Identification of RBD subjects and process is individualized based on site resources and set-up
• Every RBD subject is important to developing this cohort and understanding the role of RBD in PD
• Goal is to enroll 50 RBD subjects by end of 2014
P-PPMI NY may 6.-7.2014
RBD
G. Mayer, M. Bitterlich, C. Doerr Schwalmstadt, Marburg University
W. Oertel, Marburg University
K. Kesper, Marburg University
G. Antony, Parkinson Kompetenznetz KNP, Marburg
Classification ICSD 2
A. Violent or injurious behavior in sleep
B. Limb- or body movements that relate to dream contents
behavior:
- Aggressive sleep behavior
- Acting out dream contents
- Fragmentation of sleep continuity
C.Polysomnography
- Excessive increase of chin EMG
- Excessive chin EMG or limb movement
- Complex, aggressive behavior
D. Symptoms must not be caused by psychiatric disorders, association with neurological disorders (no epilepsies!)
E. Other sleep disorders may be present but are not the cause
AASM criteria 2012
ICCN Berlin 2014
F. Scoring PSG Features of RElVJ Sleep Behavior Disorder (RBD)
1. Score i11 accordance with tt1e folJo,ving definitions: RECOMMEHOED
Sustained muscle acth;ty (tonic acthity) in REl\f sleep: An epoch of REM sleep with at least 50% of the duration ofd1e epoch ba''ing a chin £ f\.fG amplitttde greater than the Lninin1t1111 an1plirude den1onstrated in NRE1'.·f sleert
Exces.<ive transient muscle ac6\ity (phasic activity) in REM sleep: Tn a 30..second epoch of REM sleep divided into 10 sequential, 3~second n1ini·epochs, at least) (50%) of the n1.i11i .. e1>0chs contain bursts oftrai1sient 111uscle acti\:ity. Jn RBD, ei!Ccessi·ve transient 11lus.cle activity bitrsts are 0.1- :5.0 second" in duration and at least 4 times as high i11 amplitude as the background EMG activity.
2. The polysomnograpbic characteristics ofRBD are cbarac.terized by EITHER or BOTH ofthefollon;ng featnres:Nl.i."i!,XJ,NA RECOMMEHDEI>
a. Sustained ma<ele activity in REiM sleep i11 the chin EMG b. Excessi\•e transient muscle actj\.ity during P~'f in the chin or limb E?i.·fG
-3 0 3 6 9 12 15 18
50
100
years
0
-6
Disease progression
(modified from Schwarz et al., 2004)
control
7,5 years
De novo 0
2 years
R L
olfactory dysfunction
obstipation
RBD
depression
Disease progression
38%
80%
iRBD 29 pts.
5 y
10 y
RBD and neurodegeneration
• iRBD: conversion into neurodegenerative disease 10-20 years
• Braak model of neurodegeneration
• Olfactory dysfunction in PD 100%
Impaired olfaction (60%)
increases PD risk 5.2 fold (Ross 2008)
Iranzo 2013
RBD criteria ICSD2 and AASM 2007
• Both PSG and videoanalysis required
– Minimal duration of REM sleep: 5 min
PSG (according to Frauscher 2012):
– Cut off (3 s bins): Any EMG activity in mentalis 18%
Any EMG activity mentalis+FDS 32%
- Cut off (30 s bins): Any EMG activity in mentalis 27%
Any EMG activity in mentalis+FDS 32%
Video
– RBDSS: proposed cut-off: 2/1 “0” = no visible movement; “1” = slight movements or jerks “2” = movements involving proximal extremities, including violent behavior; “3” = axial involvement including bed falls. Vocalizations were rated as “1” for present or “0”
New since 2014 https://knp.interactive-systems.de/cgi-bin/WebObjects/EFNS-productive-
% REM sleep
What we see
Please look at comments
P-PPMI
0
5
10
15
20
25
30
35
C 307 C 291 C 290 C 120 C 088 C 057 C 032 C 18 C040
no
pat
ien
ts
Centers
no patients/center
Problems recruiting: depending on decisions of ECs
PSG: SINBAR scoring Phasic muscle activity is higlighted in the chin (red), and tonic muscle activity in the chin and extremities
(blue).
Analysis each center
0
10
20
30
40
50
60
70
C 307 C 291 C 290 C 120 C 088 C 057 C 032 C 018 C040
% R
WA
Centers
RWA/Center, any EMG (3 sec)
0
10
20
30
40
50
60
C 307 C 291 C 290 C 120 C 088 C 057 C 032 C 018 C040
% R
WA
Centers
RWA/Center, any EMG (30 sec)
0
5
10
15
20
25
30
C 307 C 291 C 290 C 120 C 088 C 057 C 032 C 018 C040
% R
EM
Centers
% REM/Center
EMG analysis all centers 69 PSGs, 13 excluded
0
10
20
30
40
50
60
phas. EMG (3s.) any EMG (3s.) ton. EMG (30s.) phas. EMG (30s.) any EMG (30s.) REM%
% R
WA
RWA scoring method
EMG analysis
How to improve?
• Optimise quality of PSGs
• Recruit more patients until end of 2014
• Include patients with clinical RBD
– who do not meet PSG criteria
– Who do not meet DAT scan criteria
this requires repeat PSG
• QC requires repeated measurement
REM sleep atonia index
ICCN Berlin 2014
• 1-sec mini-epochs • average amplitude of rectified mentalis EMG signal for each mini-epoch • EMG atonia amplitude ≤1V ,activation > 2 V
REM sleep and movement throughout the life span Ferri et al. 2011
ICCN Berlin 2014
Variability of muscle activity in REM sleep during 6 consecutive nights
12 iRBD, 8 controls
ICCN Berlin 2014
Any muscle activity/30 sec (Frauscher 2013)
ICCN Berlin 2014
Contents lists available at ScienceDirect
Sleep Medicine
ELSEVIER journ a l home page: www. el s ev ie r.com{locate/s lee p
Original Article
Electroencephalogram slowing in rapid eye movement sleep behavior disorder is associated with mild cognitive impairment
Jessica Rodrigues Brazete a.b. Jacques Montplaisir a.c. Dominique Petit •. Ronald B. Postuma a.ct.
w * w 0 nn nn nn 0 •
! ! ! ! 22 2~ 2 ~ ~ ~ Parietal Tempo iral Oectpimat
CoTd ::!
IRBO [·IMCI iRBD[+JMCI
Fig. 2. Group 1comparisons benv1e,en idiopathi1c rapid ey1e mov1ement sleep behavior disorder ( iRBD) with mild cognitive impairm1enr (iRBD ~+) ri.itCI ); iRBD without MCI ( iRB D I- )MCI). and com:rols of log-a-ans formed values of ( o + 19) f( !::t: + p) r a ao for five rortica I regions.
Videometric analysis RBDSS Sixel-Döring et al. , j Clin sleep med 2011
Motor Events 0. = no visible motor activity, RWA present 1. = small movements or jerks 2. = proximal movements including violent behavior 3. = axial movements including bed falls Vocalizations 0. = no vocalization 1. = all sleep associated sounds other than respiratory noises
ICCN Berlin 2014
73 RBD episodes in 20 PD pats.
RBD and 123I-fp-cit-spect iranzo et al. 2011
ICCN Berlin 2014
In 40% of iRBD Pathological in 75% of RBD pts with conversion
Biomarkers RBD
Strong markers • Typical symptoms • RSWA • Olfactory deficits • Cardial MIBG deficits • DAT scan? • PDRP?
Weak markers • Transcranial ultrasound • MCI • EEG slowing
Sensitivity and specificity of most biomarkers depends on time of RBD diagnosis
ICCN Berlin 2014
Videometric analysis RBDSS Sixel-Döring et al. , j Clin sleep med 2011
Motor Events 0. = no visible motor activity, RWA present 1. = small movements or jerks 2. = proximal movements including violent behavior 3. = axial movements including bed falls Vocalizations 0. = no vocalization 1. = all sleep associated sounds other than respiratory noises
ICCN Berlin 2014
73 RBD episodes in 20 PD pats.
Significance of dream recall in RBD Valli et al., JSR 2012
• A link between motor behavior and dreams? • PD+RBD patients • Awakenings 10 min after REM onset • Expert evaluation
• Correctly identified video related dreams 39.5%
ICCN Berlin 2014
Barcelona group work on
IRBD
Alex Iranzo
Neurology Service
Hospital Clinic Barcelona
20/44 (45%) patients with idiopathic RBD developed a
neurological disorder after a median follow-up of 4.5 years
Emerging diagnosis:
Parkinson disease: 9 patients
Dementia with Lewy bodies: 6 patients
Multiple system atrophy-C: 1 patient
Mild cognitive impairment: 4 patients
Iranzo et al. Lancet Neurol 2006;5:572-577
• Patients who developed a neurological disorder had
longer RBD duration and follow-up in our center
The longer you follow them, the
higher rate of conversion
Lancet Neurol 2013;12:443-453
36/44 (82%) developed neurological
disease after 10 years of follow-up
Parkinson disease: 16
Dementia with Lewy bodies: 14
Multiple system atrophy: 1
Mild cognitive impairment: 5
Iranzo et al. Lancet Neurol 2013
Estimated rates of conversion from the
diagnosis of IRBD
17% at 5 y.
35% at 5 years
73% at 10 years
92% at 14 years
Iranzo et al. Lancet Neurol 2013
Iranzo et al. PLOS One 2014;2;e89741
174 patients diagnosed between 1991 and 2013
Median clinical follow up of 4.5 years
65/174 (37%) converted after a
mean follow-up of 4.5 years
Parkinson disease: 22
Dementia with Lewy bodies: 29
Multiple system atrophy: 2
Mild cognitive impairment: 12
(six confirmed by neuropathology)
Iranzo et al. PLOS One 2014
33% at 5 years
76% at 10 years
91% at 14 years
Estimated rates of conversion from the
diagnosis of IRBD (n=174)
Iranzo et al. PLOS One 2014
Conclusions
The majority of IRBD diagnosed in a sleep center
eventually develop PD or other synucleinopathy
IRBD represents the prodromal stage of the
synucleinopathies
This challenges current diagnosis criteria of PD
IRBD is a candidate to test neuroprotective drugs
Iranzo et al. Lancet Neurology 2010;9:1070-1077
Results
43 subjects with IRBD
63% had abnormal DAT-SPECT or/and
hyperechogenicity of the SN in TCS at baseline
COMBINED 123I-FP-CIT SPECT AND TCS
After 2.5 years of follow-up
8 (20%) patients developed a neurological disease
PD in 5 DLB in 2 MSA in 1
All these 8 patients had reduced DAT uptake and/or hyperechogenicity
All 15 patients with normal neuroimaging remained disease-free
SENSTIVITY = 100% SPECIFICITY= 55%
Patients with IRBD, and especially those
with abnormal DAT-SPECT and TCS, are
waiting for being tested with
neuroprotective medications !!!!!!!!
• To evaluate the effect of potential
neuroprotective agents in IRBD, it is
essential to find biomarkers capable of
monitoring the degenerative process
taking place in the brain over time.
In IRBD, olfactory deficits do not
worsen after a 4 year period
In IRBD, serial olfactory
tests may be not useful as an
outcome measure in future
neuroprotective trials
Iranzo et al. Lancet Neurology 2011;10:797-805
Left putamen
Right caudate Left caudate
Right putamen
P= 0.034 P= 0.026
P= 0.044 P= 0.076
Left putamen Right putamen
Left caudate Right caudate
DEVELOPMENT OF PD AT 3 YEAR EVALUATION
BASELINE 1.5 YEARS 3 YEARS
DISEASE FREE AT 3 YEAR EVALUATION
BASELINE 1.5 YEARS 3 YEARS
Conclusions • Most of the patients with RBD will be diagnosed
with a synucleinopathy
• Short-term risk for those with abnormal DAT-
SPECT and TCS.
• Serial DAT- SPECT (but not Olfactory tests and
TCS) can be useful to monitor disease
progression in studies with potential
neuroprotective medications
“Any” EMG activity Mentalis
Cutoff value ≥30% (n=21) <30% (n=27) p
Mean 0.49±0.178 0.15±0.07
Enfermedad neurodegenerativa (n)
PD (12) DLB (7) AMS (2)
PD (8) DLB (7) AMS (0)
0.021
Age PSG review (mean, years) 70.33±5.27 67.81±5.73 0.121
Time PSG to Conversion (years)
3.6±3.9 5.5±3.4 0.046
PPMI Prodromal cohort Hyposmia
Danna Jennings, MD Institute of Neurodegenerative disorders
May 7, 2014
PPMI 2014 Annual Meeting
Prodromal Cohort for PPMI
Hyposmic Subjects RBD Subjects
DAT imaging
Eligible for PPMI Not eligible for PPMI
80% Mild to moderate DAT 20% Min to No-DAT Min to No-DAT
500-700 Subjects scanned
Advantages/Disadvantages of using hyposmia to screen for prodromal PD
Advantages
• Generalizable • Practical • Graspable • Screening at home • Relatively inexpensive • UPSIT is a sensitive for PD • Broad outreach increases
PD awareness
Disadvantages • Requires extensive
outreach • Those willing to do test
at home may not be willing to engage in clinic activities
• UPSIT lacks specificity for PD
Phenoconversion
P A R S
Year 2 Year 4
DAT deficit at BL (n=23, 11%) 7 (30%) 14 (61%)
Indeterminant at BL (n=34) 1 (3%) 2 (6%)
No DAT deficit at BL (n=146) 2 (1%) 4 (3%)
DAT deficit any scan (n=38) 10 (28%) 18 (47%)
Baseline: n=203 Year 2: n=177 (87% retention) Year 4: n=139 (66% retention, so far)
PARS 4 year Longitudinal Hyposmic Data
Surveys completed (mail, on line)
UPSITs mailed to subjects
UPSITs returned, hyposmics identified, referred to sites
Complete Imaging
Enrollment (if deemed eligible)
P-PPMI Hyposmic Cohort:
Process for Identifying Prodromal Subjects
Olfactory Core
PPMI Sites
Site # Site Name Subjects referred Consented Eligible Enrolled
001 Univ of Rochester 0* 006 Oregon Health Sci Univ 26 7 2 2 007 Baylor College of Med 17 012 The Parkinson's Institute 29 3 018 Univ of Pennsylvania 51 6 3 3 019 Univ of S Florida 13 023 Univ Calif San Diego 25 3 028 Johns Hopkins 19 032 Emory 11 1 034 IND 75 24 3 2 040 Boston Univ 16 1 057 Univ of Alabama 21 3 088 Northwestern 20 1 1 089 Univ Cinncinati 0* 096 Univ Washington/VA Puget Sound 0* 120 Cleveland Clinic 17 5 1 1 154 Banner Research Institute 18 9 196 PD and Mov Dis Center of Boca Raton 7 289 University of Tubingen - Germany 1 1 290 Paracelisus-Elena Klinik - Germany 0 291 Univ of Innsbruck - Austria 0 295 Imerial College London -England 11 327 University of Salerno - Italy 3
Hyposmic Enrollment by Site
*recent activation or not yet activated
6296 Eligible Surveys
3820 61% Returned UPSITs
535 14% Hyposmics
64 12% Completed Imaging 8 12% DAT deficit
P-PPMI Olfactory Cohort
Hyposmic Recruitment: How long does it take?
Eligible Survey
Returned UPSIT
Complete Imaging
Hyposmic Recruitment: How long does it take?
Eligible Survey
Returned UPSIT
Complete Imaging
• 28 days (range 1-453, median 21)
• 77 days (range 22-207, median 64)
6296 Eligible Surveys
3820 61% Returned UPSITs
535 14% Hyposmics
64 12% Completed Imaging
8 12% DAT deficit
P-PPMI Olfactory Cohort : Surveys
0
200
400
600
800
1000
1200
1400
Paper
Online
68% online surveys 32% paper surveys
All Eligible Ineligible n=7365 n=6439 n=926 MJFF 2861 2626 (92%) 235 (8%) Friend/Family 2196 1746 (80%) 450 (20%) Site Activities 1109 1006 (91%) 103 (9%) Mailing 121 111 (92%) 10 (8%) Other/unknown 1341 950 (71%) 391 (29%)
MJFF
Friend/Family
Site Activities
Mailing
Other/unnknown
0
500
1000
1500
2000
newsletters, emails, events
FTF MJFF website
Smell Surveys – Referral Sources
Reason ineligible zip code 488 (53%) diagnosis of PD 197 (21%) incomplete survey 142 (15%) age <60 85 (9%) diagnosis of AD 14 (2%)
MJFF Referrals
Site Referrals
Referral sources for all returning a survey
0
500
1000
1500
2000
Doctor or HC provider
Site Local media
6296 Eligible Surveys
3820 61% Returned UPSITs
535 14% Hyposmics
64 12% Completed Imaging 8 12% DAT deficit
P-PPMI Olfactory Cohort: Returned UPSITs
0
100
200
300
400
500
600
700
800
all hyposmic normosmics (n=3820) (n=535) (n=3285) age (range) 67.9 (60-94) 69.7 (60-92) 67.6 (60-94) gender
male 1284 (34%) 214 (40%) 1070 (33%) female 2536 (66%) 321 (60%) 2215 (67%)
race caucasian 3737 (98%) 531 (99%) 3225 (98%)
asian 27 (<1%) 3 (<1%) 24 (<1%) black/AA 27 (<1%) 0 27 (1%)
Amer Indian 9 (<1%) 1 (<1%) 9 (<1%)
loss of sense of smell yes 823 (22%) 419 (78%) 404 (13%) no 2382 (62%) 84 (16%) 2298 (70%)
unsure 615 16%) 32 (6%) 583 (18%) family history
1st degree 980 (26%) 131 (24%) 849 (26%) 2nd degree 227 (6%) 33 (6%) 194 (6%) any relative 1165 (31%) 122 (23%) 1043 (32%)
none/unknown 2613 (68%) 371 (69%) 2242 (68%) laxatives
yes 401 (10%) 64 (12%) 337 (10%) no 3382 (88%) 460 (86%) 2922 (89%)
unsure 37 (2%) 11 (2%) 26 (1%) BM frequency
< 1 /day 721 (19%) 129 (24%) 5921 (18%) once/day 1953 (51%) 266(50%) 1687 (51%) twice/day 877 (23%) 112 (21%) 765 (23%)
three or more/day 269 (7%) 28 (5%) 241 (7%)
UPSIT Completers: Demographics
all hyposmic normosmics (n=3820) (n=535) (n=3285) age (range) 67.9 (60-94) 69.7 (60-92) 67.6 (60-94) gender
male 1284 (34%) 214 (40%) 1070 (33%) female 2536 (66%) 321 (60%) 2215 (67%)
race caucasian 3737 (98%) 531 (99%) 3225 (98%)
asian 27 (<1%) 3 (<1%) 24 (<1%) black/AA 27 (<1%) 0 27 (1%)
Amer Indian 9 (<1%) 1 (<1%) 9 (<1%)
loss of sense of smell yes 823 (22%) 419 (78%) 404 (13%) no 2382 (62%) 84 (16%) 2298 (70%)
unsure 615 16%) 32 (6%) 583 (18%) family history
1st degree 980 (26%) 131 (24%) 849 (26%) 2nd degree 227 (6%) 33 (7%) 194 (6%) any relative 1165 (31%) 122 (30%) 1043 (32%)
none/unknown 2613 (68%) 371 (69%) 2242 (68%) laxatives
yes 401 (10%) 64 (12%) 337 (10%) no 3382 (88%) 460 (86%) 2922 (89%)
unsure 37 (2%) 11 (2%) 26 (1%) BM frequency
< 1 /day 721 (19%) 129 (24%) 5921 (18%) once/day 1953 (51%) 266(50%) 1687 (51%) twice/day 877 (23%) 112 (21%) 765 (23%)
three or more/day 269 (7%) 28 (5%) 241 (7%)
UPSIT Completers: Demographics
hyposmic consented declined (n=535) (n=64) (n=379) age (range) 69.7 (60-92) 69.7 (60-82) 70.6 (60-92) gender
male 214 (40%) 24 (36%) 138 (36%) female 321 (60%) 40 (64%) 241 (64%)
race caucasian 531 (99%) 64 (100%) 364 (96%)
asian 3 (<1%) 0 (0%) 9 (2%) black/AA 0 (0%) 0 (0%) 3 (1%)
Amer Indian 1 (<1%) 0 (0%) 2 (<1%)
loss of sense of smell yes 419 (78%) 33 (51%) 128 (34%) no 84 (16%) 20 (31%) 165 (44%)
unsure 32 (6%) 11 (3%) 63 (17%) family history
1st degree 131 (24%) 18 (28%) 86 (23%) 2nd degree 33 (6%) 6 (9%) 27 (7%) any relative 122 (23%) 24 (37%) 113 (30%)
none/unknown 371 (69%) 40 (63%) 266 (70%) laxatives
yes 64 (12%) 6 (9%) 50 (13%) no 460 (86%) 58 (91%) 321 (85%)
unsure 11 (2%) 0 (0%) 8 (2%) BM frequency
< 1 /day 129 (24%) 14 (22%) 90 (24%) once/day 266 (50%) 37 (57%) 180 (47%) twice/day 112 (21%) 10 (16%) 79 (21%)
three or more/day 28 (5%) 3 (5%) 30 (8%)
Hyposmic (Consent and declined): Demographics
hyposmic consented declined (n=535) (n=64) (n=379) age (range) 69.7 (60-92) 69.7 (60-82) 70.6 (60-92) gender
male 214 (40%) 24 (36%) 138 (36%) female 321 (60%) 40 (64%) 241 (64%)
race caucasian 531 (99%) 64 (100%) 364 (96%)
asian 3 (<1%) 0 (0%) 9 (2%) black/AA 0 (0%) 0 (0%) 3 (1%)
Amer Indian 1 (<1%) 0 (0%) 2 (<1%)
loss of sense of smell yes 419 (78%) 33 (51%) 128 (34%) no 84 (16%) 20 (31%) 165 (44%)
unsure 32 (6%) 11 (3%) 63 (17%) family history
1st degree 131 (24%) 18 (28%) 86 (23%) 2nd degree 33 (6%) 6 (9%) 27 (7%) any relative 122 (23%) 24 (37%) 113 (30%)
none/unknown 371 (69%) 40 (63%) 266 (70%) laxatives
yes 64 (12%) 6 (9%) 50 (13%) no 460 (86%) 58 (91%) 321 (85%)
unsure 11 (2%) 0 (0%) 8 (2%) BM frequency
< 1 /day 129 (24%) 14 (22%) 90 (24%) once/day 266 (50%) 37 (57%) 180 (47%) twice/day 112 (21%) 10 (16%) 79 (21%)
three or more/day 28 (5%) 3 (5%) 30 (8%)
Hyposmic (Consent and declined): Demographics
6296 Eligible Surveys
3820 61% Returned UPSITs
535 14% Hyposmics
64 12% Completed Imaging 8 12% DAT deficit
P-PPMI Olfactory Cohort: Imaging Visits
0
2
4
6
8
10
12
14
P-PPMI Olfaction compared to PARS
P-PPMI PARS 6296 Eligible Surveys 9398
3820 61% Returned UPSITs 53% 4999
535 14% Hyposmics 13% 669
64 12% Completed Imaging 30% 203 8 12% DAT deficit 11% 23
P-PPMI PARS 6296 Eligible Surveys 9398
3820 61% Returned UPSITs 53% 4999
535 14% Hyposmics 13% 669
64 12% Completed Imaging 30% 203 8 12% DAT deficit 11% 23
P-PPMI Olfaction compared to PARS
Differences between PPMI Olfaction and PARS
• Outreach more centralized by email, social media
• LPs required • Visits 3-4 times/yr • Provide info about risk
(80% with DAT deficit scan)
• Outreach by local mailings and site recruitment
• LPs optional • Annual Visits • Little info about risk
PPMI PARS
Where are all the hyposmics?
Hyposmics N=535
Consented and
imaged n=64
Declined site referral/no response
n=160
Females not referred n=76
Declined participation at site n=219
(65 were contacted w/ no response)
In process N=16
28% (7/2) of mailing responders* 25% (8/2) support group* 20% (13/62) of those from local media 19% (12/119) of friends and family 8% (6/74) of those from site 7% (21/310) of those from MJFF
Referral Source All eligible
(n=535) Consented to
Imaging (n=64)
Declined (at any point in process)
(n=379) MJFF 310 (58%) 21 (33%) 158 (42%) Friends/Family 119 (22%) 12 (19%) 84 (22%) Local media 62 (12%) 13 (20%) 49 (13%) Site 74( 14%) 6 (9%) 49( 13%) Mailing 7 (1%) 2 (3%) 5 (1%) Support group 8 (1%) 2 (3%) 5 (1%) Unknown 48 (9%) 6 (9%) 29 (8%)
Hyposmic Referral Sources
Referral Sources of subjects most likely to consent
Reasons for Decline – at the Site Level (n=219)
Reason for decline # declined Contact attempted, no response 65 (30%) Lumbar puncture** 34 (16%) Not interested 29 (14%) Time commitment 30 (14%) Exclusionary medical condition 24 (11%) Travel/transportation 19 (9%) Other 11 (5%) Datscan 6 (3%)
**If LP were not required there would be roughly 30 less decliners and 1.5 times more subjects who would have been eligible (estimate 15 eligible vs 10).
Contact attempted, no response Lumbar puncture
Not interested
Time commitment
Exclusionary medical condition Travel/transportation Other
0
20
40
60
80
100
120
140
Phone Clinic visit Email Mail
Method of Contact for Decliners
Eligible Subjects (n=10)
Site Age Gender Referral Source Race PD Family Hx
Laxative/Stool
softener use
Bowel Movement Frequency
Notes decreased sense of
smell
UPSIT - total
correct UPSIT
percentile
006 OHSU 73 M MJFF Website White/Caucasian Unsure No Once per day Yes 19 6
006 OHSU 62 F Local news article
White/Caucasian None No Three per day Unsure 22 2
018 UPENN 66 F ABC Philadelphia
White/Caucasian
Biological Father No Less than once
per day Yes 23 5
018 UPENN 66 F MJFF
Newsletter;Email or Event
White/Caucasian None No Once per day No 22 5
018 UPENN 74 F Local Newspaper
White/Caucasian None No Once per day Yes 12 3
034 IND 63 M Local Newspaper
White/Caucasian None No Once per day No 16 2
034 IND 81 M Google/Website
White/Caucasian None No Once per day Yes 12 5
034 IND 82 M Friend or Family Member
White/Caucasian None Yes Once per day No 18 10
088 Northwestern 68 F MJFF Website White/Caucasia
n None No Less than once per day Yes 13 1
120 Cleve Clinic 60 M
Doctor or Medical Care
Provider
White/Caucasian
Biological Father,Paternal
Aunts and Uncles
No Once per day Yes 18 4
Olfactory Recruitment…it’s all about the numbers
P-PPMI Triple surveys
Triple surveys, increase consent rate to 17%
Triple surveys, remove LP requirement
Double surveys, consent rate to 20%
Double surveys, consent rate to 20%, remove LP requirement
6296 18,000 18,000 18,000 12,000 12,000
3820 61% Returned UPSITs 10980 10980 10980 7320 7320
535 14% Hyposmics 1537.2 1537.2 1537.2 1024.8 1024.8
64 12% Completed
Imaging 184.5 261.3 276.7 205.0 307.4 8 12% DAT deficit 22.1 31.4 33.2 24.6 36.9
Reaching the Olfactory Destination
• 30 subjects (24 DAT deficit, 6 no DAT deficit) and enrolled by end of 2014 (60% males)
• Increase percent of individuals willing to consent – Modify an aspect of the protocol – re-contact declining
subjects – Additional support to sites to reach out to subjects – Modify messaging at initial visit/phone call
• Double the number of surveys – Local media – Engage existing cohorts (Alz Prevention Registry; genetics
gene negative individuals) – Focused mailings with local references – Complete surveys at the clinic/event
• Increase Percentage of Eligible subjects – Increase male:female ratio by monitoring female referrals to
site
“You can’t change the wind, but you can adjust the sails.” Jimmy Dean
Genetic Coordination Center (GCC)
Tatiana Foroud
Indiana University
Genetic Coordination Center (GCC) Team
• Jacqueline Jackson
– overall coordination of project team
• Cheryl Halter
– PPMI site recruitment
– Family History Substudy
• Danielle Smith
– Widespread Recruitment Initiative (WRI)
• Jennifer Verbrugge
– Genetic counselor for WRI subjects
GCC Roles
• Coordinate the efforts for the Genetics-PPMI initiative
– Facilitate screening for LRRK2 or SNCA mutations
– Facilitate distribution and collection of family history information (Family History Substudy)
Screening for Mutations
• Blood kits for genetic testing
– GCC provides kits for blood collection
– Kits sent to MGH for testing
– Contact GCC to replenish supplies
Contact: Cheryl Halter for kit replenishment [email protected]
Tracking Genetic Testing
• PPMI sites fax the GCC copies of the Genetic Mutation Testing Form (GMU)
– Allows GCC to track testing at MGH
– Reports now allow GCC to identify missing GMU forms
Receiving Genetic Results
MGH Non-MGH Previous testing
GCC enters genetic test result into eClinical
Triggers study arm assignment to PPMI site
Genetic Testing Results Site # Individuals
Tested # Positive
Tests
University of Barcelona – Hospital Clinic of Barcelona 62 40
PD and Movement Disorders Center of Boca Raton 308 46
Boston University 1 0
Cleveland Clinic 3 1
Emory University 10 4
Foundation for Biomedical Research of the Academy of Athens 3 3
Institute for Neurodegenerative Disorders 3 0
Northwestern University 13 2
Norwegian University of Science and Technology 11 11
University of Donostia – Service of Neurology Hospital 9 9
University of Alabama 2 0
University of Pennsylvania 7 3
Total 432 119
Study Arm Assignment
Genetic Cohort
• Unaffected individuals
– ≥ 50 years for LRRK2
– ≥ 30 years for SNCA
• PD individuals
– Within 7 years of onset
Genetic Registry
• Unaffected individuals
– < 50 years for LRRK2
– < 30 years for SNCA
• PD individuals
– > 7 years from onset
Randomization
• Unaffected individuals who do not want genetic testing results - Genetic Cohort - Genetic Registry
Status of LRRK2+ Individuals
Study Arm Consented Enrolled Active
Cohort PD 14 4 4
Cohort Unaffected 14 7 7
Registry PD 19 17 17
Registry Unaffected 10 10 10
57 38 38
119 LRRK2+ already identified
Subjects Consented in Genetics PPMI Site # Genetic Cohort # Genetic Registry
PD Unaffected PD Unaffected
University of Barcelona – Hospital Clinic of Barcelona
5 2 5 7
PD and Movement Disorders Center of Boca Raton
3 6 10 2
Emory University 0 0 2 1
The Parkinson’s Institute 0 0 1 0
University of Pennsylvania 0 0 1 0
Northwestern University 0 1 0 0
Norwegian University of Science and Technology
2 3 0 0
University of Donostia – Service of Neurology Hospital
4 0 0 0
Cleveland Clinic 0 1 0 0
Sun Health Research Institute 0 1 0 0
Total 14 14 19 10
Subjects Enrolled for Genetics PPMI
Site # Genetic Cohort # Genetic Registry
PD Unaffected PD Unaffected
University of Barcelona – Hospital Clinic of Barcelona
5 2 5 7
PD and Movement Disorders Center of Boca Raton
3 6 10 2
Emory University 0 0 2 1
The Parkinson’s Institute 0 0 1 0
Northwestern University 0 1 0 0
Total 4 7 17 10
119 LRRK2+ identified 57 consented
38 enrolled (cohort/registry)
Chicago G-PPMI Recruitment Plan
Tiered approach
• Tier 1- clinic – In-service of all PD faculty, availability of all
recruitment materials and kits on site
• Tier 2- institution wide – Publicity !!!
• Tier 3- city wide recruitment – Identification of the key targets (CJE, JCC,
Hillels)
• Tier 4- population specific recruitment – Russian Jewish population
Emory G-PPMI Experience
1. Contacted known LRRK2 from prior genetics study
2. Contacted their families
3. Clinic (and family) volunteers through brochures/sign in waiting room
4. Subjects (and families) referred through the Fox Foundation web site
5. Jewish newspaper stories
6. Using the Emory Lifelong Learning Institute:
– Contacted Program coordinators of two Retirement Communities
– Jewish Family and Career Services
• Provided brochures/Talk scheduled for May 14
Subjects Enrollment goals for Genetics PPMI
Almost all PPMI sites are activated to enroll subjects with LRRK2 or SNCA mutations Recruitment challenge for Genetic Cohort is to enroll by the end of 2014:
•120 Unaffected LRRK2 subjects •120 LRRK2 PD subjects
•15 subjects/group per month •20 Unaffected SNCA subjects •20 SNCA PD subjects
• 3 subjects/group per month
Family History Substudy
• GCC will be coordinating the Family History Substudy (Amendment 8)
– For those participants recruited through the Widespread Recruitment Initiative (WRI), GCC will send the Family History substudy information to subject
– For those participants recruited by the site, the site will distribute the Family History Substudy packet
Family History Substudy
• GCC handles Informed Consent and the Family History Questionnaire
• All site has to do is give the subject the Family History Substudy Packet
• All materials are returned to the GCC
• GCC will let sites know when the packet is returned
GCC Operations Manual
• GCC has updated our operations manual
• Download or view at the CTCC portal
• Questions: Contact Cheryl Halter at [email protected] or 888-830-6299
Overview of the PPMI Widespread Recruitment
Initiative
Tatiana Foroud Indiana University
Genetic Coordination Center (GCC)
G-PPMI: Widespread Recruitment
• MJFF and the Genetic Coordination Core (GCC) developed paired websites to screen large numbers of individuals for the key LRRK2 mutations
G-PPMI: Widespread Recruitment
Individuals pre-screened on MJFF website
Read basic information about LRRK2 and PD
Sent to IU website to complete IU Informed
Consent Process
https://www.michaeljfox.org/page.html?ppmi-genetics
MJFF website
PARTICIPATE IN PPMI: FOCUS ON GENETICS Over the past decade. s tudies of the genetics of Pa,-kin son' s disease hav e r-evolutionized the pur-suit o f a - disease-modifying .. t reatment - a therapy that can s low or stop the progre ssion of PD. St u dying people
with Parkins on's and their families is essential to help .-esearcher-s identify genetic t r-a its t h at may c o ntr ibute
to the onset and progressio n o f PD.
The Parkinson's Progression Markers Initiative ( PPMI) is The Mic hael J. Fox Foundat io n ' s flags hip biomarkers study seeking to learn more about the genetics o f Parkinson's disease. PPMI is c un-ently studying the connection between PD and having a mutation in the LRRK2 gene - the sing le mos t c ommon
genetic c ontributor to PD.
HOW YOU CAN PARTICIPATE Whether you hav e PD or n o t . y ou may be eligible t o receiv e genetic c ounsel ing and t e st ing a t n o c o st to determine if y ou qualify to participate in PPMI.
NEVER BEEN GENETICALLY TESTED? PPMI is seeking individu a ls who meet either of t he following criteria:
• People vvith Parkin son •s who a re o f Eastern European (Ash kenazi) Jewish, North Afric an Berber, or Basque anc estry.
• Indiv i duals w ithout PD who a re relat ed t o someone wit h PD AND who a re of Easter-n Eur-opean
(Ashkenazi) Jew ish, N o rth Afric an Ber-ber-, or- Basque ancestry.
•
HAVE YOU ALREADY BEEN TESTED? If you know you have a LRRK2 mutation:
Select PPMI sites ar-e a lso study ing the c onnection between Parkinson' s and the SNCA gene. If y ou hav e been tes ted and know t h a t y ou hav e a mut atio n in y our- S NCA gene, c ontact a PPMJ site.
a LEARN MORE ABOUT THE GENETIC TESTING PROCESS IN PPMI
PARKINSON'S PROGRESSION MARKERS INITIATIVE
Play a Part in Parkinson's Research
PPMI SCREENING FOR GENETIC TESTING Tha nk you fOf" you,.. inte ,..cst. i n PPMI. Ove,.. the past decade , stu dies of the g e net ics o f Po ,.-kin.son".s di.seo se hove ,.-evolutionizcd the p u rsu it o f o '"'d isea5c--modi ty;ng "' tr-cotment~ t hensp y that can .slow Of" st.op th e p ,..og,..ession of PD.
Please comple te this form to find o u t if you may be elig ible for g e n etic counselin g and testing a t no cost to det e ,..m in e if you q ualify for pal"ticipatio n in this st:udy. Ciiek here to l e a rn mOf"e a bout t h e g e net ic
counseling o nd tcst:ing p ,..oces.s i n PPMI.
F irnName *
Lan Name *
Age *
G ende r *
E mai l Addr-ess ,..
Ci~: *
Sta1:e : ,..
c.ount~: ..
Ponal C ode: *
I STATE 1- 1 ~Stau.s =8
Do you currently h a ve a d iagnosis of Pa ,.-kin.son•s di,sea.se o,.. Padcin .sonia n .syn d,..ome? "'
0 Yes 0 N o 0 N ot Su ,..e
'"" Requ i ,.-cd
Do you hove .a first.-degrec r-clotivc (foth ef°, moth e ,.-, f u ll .sib l ing, c hild ) with o positive LRRK2 gene test? "'
f:> Ye s 0 N o 0 N ot Su,.-e
Are you of Ea5tern Eu,.-opea n (As.hkenazi) Jewish o ,.. Basque desce nt? "'
C> Yes <t) N o e N ot Sur e
Do you h ave any family m embers (alive or d ecea .s.e-d) w ho have/ had Pad ocin.son •s dis.ease? •
0 Yes 0 N o f:> N o t Su,.-e
~hear .about this .s-.:u dy?
C hoose One 1- 1
SUBMIT
Who has completed the WRI screening process?
WRI–Screening Questions Yes: 265 No: 259
Yes: 53 No: 432 Unknown: 39 Yes: 415 No: 73 Unknown: 36 Yes: 1 No: 92 Unknown: 4 (newer question)
Father: 151 Mother: 120 Sibling: 65 Children: 10 Yes: 43 No: 126 Unknown: 355
G-PPMI: Widespread Recruitment
Individuals pre-screened on Fox website
Read basic information about LRRK2 and PD
Sent to IU website to complete IU Informed
Consent Process
Provide basic demographic information
Complete screening questions
↑ risk for
LRRK2 mutation: qualify for saliva kit
↓ risk for
LRRK2 mutation:
do not qualify for saliva kit
WRI- Saliva kit
--....--
_ ,... .... ___ .. _______ _ =:::":.:::-"..::"'.,.. ______ .......
PA RKINSON'S PROGRESSION MA RKERS INITIATIVE
Play a Part in Parkinson's Research
......... __ ,. .. _ .... _______ _
----.. ·--------·----..... ____ _
== BUSINESS REPLY MAI~, == =
I:::::---.. ----.. --' :::::...------.. -·_ .. __ . :::....""::-----·-·--·-
Who has qualified for a saliva kit?
G-PPMI: Widespread Recruitment
Saliva kit sent by GCC to those at ↑ risk for LRRK2
mutation
Subject fills saliva kit and mails back to GCC at Indiana University
Saliva kit sent by GCC to MGH for testing
Results returned to GCC; GCC Genetic Counselor
counsels subject by phone
LRRK2+ subjects referred to PPMI site for
screening
WRI Update
Qualified and Confirmed 381
Sent Kit 381
Kit returned and sent to MGH 281
Kits outstanding 100
Results returned 229
Positive 28
Negative 201
Pending 52
Pending confirmation of qualification 22
Do not qualify 90
Currently, we have identified 28 LRRK2+ individuals from the 229
subjects who have results
12.2% rate of LRRK2+
(12.1% in PD, 12.4% in unaffected)
Who is testing positive for a LRRK2 mutation?
• In the WRI recruitment, of the 28 LRRK2+ individuals
– 96.4% AJ
– 23 (82.1%) have 1 relative with PD
• For 20 of the 23, the relative is a parent
• At the PPMI site, PD and Movement Disorders Center of Boca Raton:
– 8% of unaffected AJ subjects with a 1st degree relative with PD are LRRK2+
Previous Genetic Testing
• Individuals can also come to the WRI website if they have previous genetic testing
• There is a question in the survey asking if genetic testing has been done
• Individuals who respond affirmatively are asked to send in their results
• Genetic counseling is offered
Previous Genetic Testing
Number of individuals reporting previous genetic testing results
53
Number of individuals who have sent in their genetic testing results so far
37
Number of individuals who after review were confirmed to be LRRK2+
22
Number of individuals already referred to or waiting for a PPMI site
12
Waiting to refer to a PPMI site 4
WRI Referrals to PPMI Sites
Site # WRI
Referred Cohort
PD* Cohort
Unaffected* Registry
PD* Registry
Unaffected*
Columbia University 4 2 1 1
Baylor College of Medicine 2 1 1
The Parkinson’s Institute 5 1 2 1 1
University of Pennsylvania 1 1
University of California – San Diego
4 1 2 1
Boston University 3 2 1
Northwestern University 5 2 3
Sun Health Research Institute
3 1 1 1
Total 27 10 11 2 4
* Subject referred for this arm; enrollment pending for most
44 LRRK2+ individuals identified through WRI • 16 with previous LRRK2+ test • 28 found through genetic testing
Subject participates in Widespread Recruitment Initiative at GCC
Subject LRRK2+ Subject LRRK2-
GCC completes referral to PPMI site:
• Cover sheet • Subject information & unofficial
study arm assignment • GCC genetic counseling checklist • Genetic mutation testing form
(GMU)
The Successful Transfer to a Site is Key!
The Successful Transfer to a Site is Key!
Funnel Filling through WRI
MJFF Website: 1329 Complete the online survey • 581 meet initial criteria
GCC-WRI Website: 493 complete the online survey • 381 meet the criteria to receive a saliva kit
281 return the filled saliva kit
28 LRRK2+
15* referred to
site *+16 with previous genetic test
What next for the PPMI site?
• The PPMI site enters the Genetic Mutation Testing form into eClinical
– GCC enters genetic testing result into eClinical
– Study arm assignment algorithm runs
– Site receives an automated email confirming the study arm assignment
What next for the PPMI site?
• PPMI site contacts the subject
– Discusses the study and study arm assignment
– Schedules screening visit
• After speaking with the subject, the PPMI site
– Completes the bottom portion of the Genetics Referral form
– PPMI site faxes the Genetics Referral form back to the GCC
What’s next for the GCC and WRI?
• Family History Substudy
– Identify related individuals participating in PPMI
• GCC sends Family History Substudy packet to all WRI LRRK2+ individuals
– Reduces the burden on the site
– Allows GCC to ask the subject to share LRRK2 family brochure with family members
Subject participates in Widespread Recruitment Initiative
Subject LRRK2+ Subject LRRK2-
GCC completes referral
to PPMI site: • Cover sheet • Subject information &
study arm assignment • GCC genetic counseling
checklist • GMU
GCC sends Family History Substudy packet and LRRK2 Family Brochures
Subject sends Family History Questionnaire back to GCC; Subject sends LRRK2 Family Brochures to
relatives
PPMI Genetics Operations Manual
• The updated manual is now available and includes:
– Widespread Recruitment Initiative (pages 10 and 11)
– Updated procedures and forms
Enrolling At-Risk Subjects Lessons Learned from PPMI Site teams
Annual Investigators Meeting
May 7th, 2014
Potential Subjects At-Risk for PD: A Unique Group
• Individuals who have recently learned they might be at risk for
developing PD o Potentially limited knowledge of PD
• Likely do not know much about rationale for PPMI • Could be hesitant about LP • Likely unaware of how important they are to this research • May have more questions than other potential participants
Need more time for consent process
Case Study: IND • Schedule an initial visit
o Ideally in person, not always practical o ‘Meet & Greet’ should include time with the
investigator
• Goal of Meet & Greet: o Talk about they study, importance of the research
before presenting ICF
• Next step: schedule screening visit o Consent, imaging, other screening activities
Meet & Greet Discussion • Find out some basic info:
– How did they hear about the study, do they have a family member/know anyone with PD
• Provide info about Hyposmia – Learn more about what they think of their sense of smell, affect on daily living
– Nearly all people with PD have a decrease in sense of smell
– Hyposmia appears to occur prior to the onset of typical PD and may predate it by years
– We expect only 10-15% of people with hyposmia may be at-risk for PD
• Provide info about RBD – Learn more about their RBD, how it was diagnosed, affect on their life – RBD is often a precursor for PD – More than 50% of individuals with RBD appear to be at risk for PD
• Discuss importance of identifying individuals at risk for PD – Major unmet need in PD is lack of medication to slow progression
– Loss of dopamine producing cells at diagnosis is about 50%
– We have likely been testing neuroprotective agents at too late a stage
• Review study procedures – First step, DaTscan: 80% eligible have scan suspicious
for DAT deficit, 20% with normal DAT scan included as a control group
– If eligible, describe visit schedule • Describe why collection of spinal fluid is so important • If they are hesitant about LP, but have a sense they
would consider it if in the eligible category, encourage them to move forward with the DaTScan
• At the end of Meet & Greet, provide ICF and schedule imaging visit
Meet & Greet Discussion
Models from PPMI Sites
• Different sites have different ways of doing this
• Please share your feedback!
P-PPMI Eligible Algorithm 2014
John Seibyl
IND Imaging Core
P-PPMI Eligible DATScan
Eligible? Eligible?
Premotor screening for eligibility
Eligible if at least one visual read is positive AND lowest putamen or average putamen SBR ratio < 0.80 age-expected value Reviewed if both visual reads are negative AND lowest putamen or average putamen SBR ratio <= 0.60 Reviewed if both visual reads are positive AND owest putamen or average putamen SBR ratio >= 0.80 Otherwise Not Eligible
Premotor screening for eligibility
Hyposmic
SB
R m
ean
% A
ge ex
pect M
EAN P
UT E
ligib
le
% A
ge ex
pect L
owes
t PUT E
ligib
le
% A
ge ex
pect M
EAN P
UT N
ot elig
% A
ge ex
pect L
owes
t PUT N
ot elig
0.0
0.5
1.0
1.5
2.0
Not eligibleN= 54
EligibleN= 10
RBD
% A
ge ex
pect M
EAN P
UT E
ligib
le
% A
ge ex
pect L
owes
t PUT E
ligib
le
% A
ge ex
pect M
EAN P
UT N
ot elig
% A
ge ex
pect L
owes
t PUT N
ot elig
0.0
0.5
1.0
SB
R
Not eligibleN= 16
EligibleN= 15
Phenoconversion
Danna Jennings, MD Institute of Neurodegenerative disorders
May 7, 2014
PPMI 2014 Annual Meeting
Defining Phenoconversion to PD in the P-PPMI cohort
• Critical outcome for P-PPMI cohort • Established phenoconversion
definition not available • Approach: develop a standardized
diagnosis with minimal inter-rater variability
Phenoconversion Measures • Primary Measure:
– Based on UK Brain Bank Criteria – Data mapped from the ‘Diagnostic Features
Questionnaire’ – Instruction document to be distributed to sites
shortly after meeting • Secondary Measures:
– Prodromal Diagnostic Questionnaire • Current most likely clinical diagnosis (Q#1) • Confidence level regarding motor symptoms c/w a
diagnosis of Parkinsonian syndrome (Q#2)
nu
PARKINSON'S PROGRESSION MARKERS INITIATIVE
Play a Part in Parkinson's Research
~1
PRODROMAL DIAGNOSTIC QUESTIONNAIRE
10 ~ I I ] I I V.!JJIT I I I I I I ~rn! I I l=Jvl~rr [)ni rnrn1 I I I
CCI
D..Jrren't r11m1 I Efy CilniOOJ (thxJriEI ~·
PARKINSON'S PROGRESSION MARKERS INITIATIVE
Play a Part in Parkinson's Research
lt"t"MI
PRODROMAL DIAGNOSTIC QUESTIONNAIRE
10 I I I I \llOITT"' I ~ [ I I I ~ITE NO I..__.._...__..] v1~rr DATE I I I I I
I I I I I I
'tyY'f
D
UK PD Society Brain Bank Diagnostic Criteria
PPMI
DIAGNOSTIC FEATURES (PD)
SUBJECT ID l~I~~~ VISIT NO ~I ~~~
INITIALS l~~I ~I SITE NO _I ~~I VISIT DATE [IJ [IJ _I ~~~ MM DD YYYY
Factors Suggesting a Diagnosis: Questions below are based on the INVESTIGATOR'S opinion. Which of the following features are present and therefore might have an impact on the correct diagnosis? Answer 0 = No or 1 = Yes for each item.
1.
2.
3.
4.
Excessive stroke risk factors (e.g., diabetes, hypertension, cardiovascular disease) or past symptoms suggestive of cerebrovascular disease
Unusual or atypical risk factors, exposure, or past history (e.g., drug exposure, acute or chronic toxin exposure, acute infection preceding parkinsonism, repeated head trauma, boxer)
Unusual or atypical presenting features or symptoms
Unusual or atypical course of disease: 4.1 Very rapid progression
4.2 Static or little change
4.3 Hemiparkinsonism longer than 6 years
4.4 Onset before age 30
4.5 Other, specify: _______________ _
M-ARKERS INITIATIVE
Play a Part in Parkinson's Research
1.0 2.0
3.o 4.1
4.2
4.3
4.4
4.5
PPMI
DIAGNOSTIC FEATURES (PD)
SUBJECT ID l~I~~~ VISIT NO ~I ~~~
INITIALS l~~I ~I SITE NO _I ~~I VISIT DATE [IJ [IJ _I ~~~ MM DD YYYY
Factors Suggesting a Diagnosis: Questions below are based on the INVESTIGATOR'S opinion. Which of the following features are present and therefore might have an impact on the correct diagnosis? Answer 0 = No or 1 = Yes for each item.
1.
2.
3.
4.
Excessive stroke risk factors (e.g., diabetes, hypertension, cardiovascular disease) or past symptoms suggestive of cerebrovascular disease
Unusual or atypical risk factors, exposure, or past history (e.g., drug exposure, acute or chronic toxin exposure, acute infection preceding parkinsonism, repeated head trauma, boxer)
Unusual or atypical presenting features or symptoms
Unusual or atypical course of disease: 4.1 Very rapid progression
4.2 Static or little change
4.3 Hemiparkinsonism longer than 6 years
4.4 Onset before age 30
4.5 Other, specify: _______________ _
M-ARKERS INITIATIVE
Play a Part in Parkinson's Research
1.0 2.0
3.o 4.1
4.2
4.3
4.4
4.5
PPMI
D1IAGN 10STIC· FEATURES, (PD)
8U BJ ECT ID .__I _____. _ __._______._________.
g_ Mental Changes: 9.1 Psydhiatri:C
9_2 Oognitive
10_ Other hyperkinesias (not re,lated to levodopa or agonists):
10.1 Dystonia
10.2 Chorea
10.3 Myoclonus (indllude stimulus-induced)
v IS IT NO .__I ______._ _ _.__________.
H.1 0 9_20
10.4 O~her (e.g., al'ien llimbs): _______________ _
10.1 o 10.2 0
10.3 0
10.4 0
Play a P
11 . Presenoe of body hemiatrophy
12. Autonomic di:Stutbanoes: 12.1 Postural hypotension
12.2 Sexual dysfunction
12.3 Uriinary dysfunction
12.4 Bowel dysfunction
1tO 12.1
12.2
12.3
12.4 0
Play a Part in I
PPMI
DIAGNOSTIC FEATURES (PD)
SUBJECT ID I VISIT NO I Specific Clinical! Features: Answer 0 = No or 1 = Yes for each iitem _
13_
14_
15_
16_
17-
18_
19_
20_
21-
Oculomotor disturbances
Eyelid disturbances (e_g_, "'apraxia" of lid opening, lllephamspasm)
Other neurologica,1 abnormalities atypical of parkinsoniism (1e_g_, hyperreflexia, Babinski sign, sensory deficit , amyotrophy, limb apraxiia, sleep apnea, dysmetria or other cerebellar dysfunctJion)
Little or no response to llevodopa or a dopamine agonist (Enter N if never trieated with dop1aminergic medications)
Presence of v.ery rapid speech (tachyphemia)
Presence of dysphagia or other bulbar dysfunction
CT is sugyestive of another cause of parkinsonism (Enter N if GT not done)
MRI is suggestive of another caus.e of parkinsonism (Enter N if MRI no1: done)
Is there anything unusual or atypical about this subject's disease (e_g_, presentation, symptoms. signs, course, response to therapy, etc_) which could indicate an alternative diagnosis to Parkinson's disease (li_e_, idiopa~h ic parkinsonism with the presence of Lewy bodies in the substantia nigra), no matter how remote?
13 _ D 14_ D 15_ D 16 _ D 1z D 18- D 19_ D 20_ D 21_0
PPMI Annual Meeting-Breakout Groups Wednesday May 7, 2014
• Participate in one of the 5 different groups • Each session is 1 hour • Summary and discussion of breakout session after lunch
Topic Room Chair
Biologics Old Slip Studio Mollenhauer, Galasko, Frasier, Singleton,
Imaging Front Studio Seibyl, Schuff
Neuropsych/Neurobehavior Riverview Dining Area
Weintraub, Simuni
Sleep Water Studio Meyer, Oertel, Lasch
Providing Clinical Gentic Info/Counseling to Expand Families The Forum Foroud
Goals of PPMI Breakout Groups
• Review current PPMI data
• Discuss methods for analyzing longitudinal data
• Consider new analyses and markers
PPMI Longitudinal Data Analyses
Christopher S. Coffey The University of Iowa
PPMI Investigators Meeting May 6-7, 2014 New York, NY
Source of data for this presentation:
All data comes from a data freeze based on data obtained from the LONI website on 04/15/2014
OVERVIEW
2
Early PD
Healthy Controls
SWEDD Subjects
Prodromal Subjects
PD with and without LRRK2 or SNCA mutation
Unaffected LRRK2 or SNCA mutation carriers
Primary Objective #1: Estimate mean rates of change and variability of clinical, imaging, and biomic outcomes at study intervals ranging from baseline to 36 months in various subsets:
PRIMARY OBJECTIVES
3
Early PD vs. Healthy Controls
Early PD vs. SWEDD
Early PD vs. Prodromal Subjects
PD with LRRK2 or SNCA mutation vs. PD without LRRK2 or SNCA mutation
Unaffected LRRK2 or SNCA mutation carriers vs. Healthy Controls
Primary Objective #2: Comparison between rates of change in mean of clinical, imaging, and biomic outcomes at study intervals ranging from 3 to 36 months in various subsets:
PRIMARY OBJECTIVES
4
Secondary Objective #1: Examine predictive value of early clinical non-motor features, imaging, and biomic outcomes for future course of disease.
SECONDARY OBJECTIVES
Examine short-term change during first six months / 1 year for each progression endpoint using mixed model (continuous endpoints) or logistic regression (dichotomous endpoints)
Initial model will consider all baseline characteristics, and all possible two-way interactions
Will utilize backwards selection to build a model for each progression endpoint
5
UPDRS OVER TIME
6
Group
Baseline Median (N) (Min, Max)
Month 3 Median (N) (Min, Max)
Month 6 Median (N) (Min, Max)
Month 9 Median (N) (Min, Max)
Month 12 Median (N) (Min, Max)
Month 18 Median (N) (Min, Max)
Month 24 Median (N) (Min, Max)
Month 30 Median (N) (Min, Max)
Month 36 Median (N) (Min, Max)
PD 31 (422) (7, 72)
33 (408) (5, 89)
37 (386) (4, 94)
35 (343) (2, 89)
37.5 (346) (8, 113)
40 (269) (6, 101)
43 (156) (15, 96)
38.5 (96) (10, 90)
48 (36) (17, 87)
HC 3 (195) (0, 20)
N/A N/A N/A 4 (173) (0, 25)
N/A 4 (125) (0, 26)
N/A 4 (24) (0, 12)
SWEDD 26 (64) (4, 91)
24 (57) (6, 113)
23 (55) (4, 105)
22 (56) (2, 91)
23 (55) (3, 78)
24.5 (38) (3, 106)
25 (21) (3, 122)
N/A N/A
SCOPA-AUT OVER TIME
7
Group
Baseline Median (N) (Min, Max)
Month 6 Median (N) (Min, Max)
Month 12 Median (N) (Min, Max)
Month 24 Median (N) (Min, Max)
Month 36 Median (N) (Min, Max)
PD 8 (423) (0, 39)
9 (388) (0, 40)
10 (349) (0, 45)
11 (157) (0, 39)
15 (37) (3, 29)
HC 5 (195) (0, 20)
N/A 5 (172) (0, 22)
5 (125) (0, 22)
6 (25) (2, 15)
SWEDD 11.5 (64) (2, 44)
10 (55) (0, 44)
12 (54) (2, 42)
10 (21) (0, 41)
N/A
MOCA OVER TIME
8
Group
Baseline Median (N) (Min, Max)
Month 12 Median (N) (Min, Max)
Month 24 Median (N) (Min, Max)
Month 36 Median (N) (Min, Max)
PD 28 (423) (17, 30)
27 (350) (15, 30)
27 (156) (14, 30)
26 (36) (13, 30)
HC 28 (196) (26, 30)
28 (174) (20, 30)
28 (125) (21, 30)
28 (25) (25, 30)
SWEDD 27 (64) (17, 30)
26 (55) (20, 30)
26.5 (20) (16, 30)
N/A
ALPHA-SYNUCLEIN OVER TIME
9
Group
Baseline N
Mean (SD)
Month 6 N
Mean (SD)
Month 12 N
Mean (SD)
PD 412 1845 (786)
175 1882 (741)
175 1875 (806)
HC 189 2204 (1089)
114 2188 (917)
114 2155 (956)
P-value < 0.001 0.002 0.009
T-TAU OVER TIME
10
Group
Baseline N
Mean (SD)
Month 6 N
Mean (SD)
Month 12 N
Mean (SD)
PD 408 44.7 (18.3)
176 42.2 (16.9)
174 42.9 (17.4)
HC 187 52.5 (27.2)
114 51.0 (23.8)
114 52.9 (27.0)
P-value 0.001 < 0.001 < 0.001
P-TAU OVER TIME
11
Group
Baseline N
Mean (SD)
Month 6 N
Mean (SD)
Month 12 N
Mean (SD)
PD 410 15.6 (10.1)
176 15.4 (9.8)
174 18.5 (11.7)
HC 189 18.3 (11.7)
114 15.7 (8.4)
114 19.6 (12.7)
P-value < 0.001 0.19 0.34
A-BETA OVER TIME
12
Group
Baseline N
Mean (SD)
Month 6 N
Mean (SD)
Month 12 N
Mean (SD)
PD 412 370.6 (100.4)
176 364.4 (98.3)
175 377.3 (103.5)
HC 189 377.8 (113.6)
114 373.2 (98.6)
114 387.0 (105.3)
P-value 0.39 0.16 0.22
Longitudinal DAT Imaging
Mean -10.84 -13.88 SD 15.03 22.13
PD - Time to Start Dopaminergic Meds
::::: 0 ..... 1) §
µ..
1.0
0.8
::::: 0.6 0 ..... -a ~ ..... ~ 00 ..... a .......... ~ > .....
0.4
Kaplan-Meier Curve for Time to Start PD Meds
Percentage Free of
~ Symptomatic Treatment Cl'.l 6Mo 79%
0.2 9Mo 59% 12Mo 53% 18 Mo 43%
Report generated on data submitted as of: 01Apr2014 24Mo 34% 0.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Months
Report Generated on Data Submitted as of: 01Apr2014
Play a Part in Parkinson's Research
Critical review of data
Sensitivity of assay – TAP data
Assay variability – CSF data
Floor effect – DAT data
How to initiate new assessment – synuclein ligand
Longitudinal data considerations
15
Goal to establish subset of PD based on clincal, biomarker data
Fast progressors
Cognitive impairment
Clinical milestone – need for treatment
Biomarker outcome(s)
Genetics
Longitudinal data considerations
16
Opportunities to suggest analyses -
PPMI Retention Update
Annual Investigators Meeting May 7th, 2014
Danna Jennings, R&R Working Group Chair, PPMI Site PI
Vanessa Arnedo, MJFF
PPMI Status Update
Cohort Enrolled Recruitment Status
De Novo PD 423 Complete
Controls 196 Complete
SWEDDs 64 Complete
Hyposmia 7 Ongoing
RBD 11 Ongoing
Genetic Cohort 8 Ongoing
Genetic Registry 24 Ongoing
Total 733 Active=710
Goal: Retain subjects by keeping them engaged to participate in study visits over time – cultivate volunteers as key partners in the study
Retention Progress to Date
• Overall study retention is 95%!
• 10 sites with 100% retention: – Oregon Health & Science University
– University of Washington
– The Parkinson’s Institute
– Baylor College of Medicine
– University of South Florida
– Johns Hopkins University
– University of Cincinnati
– Imperial College London
– PD & Movement Disorders Center of Boca Raton
– Macquarie University
Retention Strategies
Goal: Maintaining the stamina and loyalty of enrolled subjects over time
• Site Relationship with Subjects – maintaining relationship with participants, accommodating
their needs
• Annual Retention Events – Participant appreciation lunch/dinner – Opportunity to update participants on study status and
published data
• Scientific Update packet – Packet of lay abstracts of results using PPMI data to be handed
out at Retention Events
• Participant Newsletters – 2x per year – study updates and special profiles
Retention Strategies Cont.
• Giveaways – PPMI token of appreciation at
each study visit – T-shirts, thera-putty, umbrellas,
etc. – Thank you book
• 42 month giveaway, collection of Thank you letters
• PPMI Study Update Calls – Quarterly calls featuring
presentation by researcher on PPMI data, and Q&A session
– Recordings available at www.ppmi-info.org/participants/
– Next call: May 15th @ 1pm EST
PPMI Recruitment & Retention Working Group
• Danna Jennings
(Chair)
• Alexandra Gaenslen
• Carey Christiansen
• Carlie Tanner
• Daniela Berg
• Christine Hunter
• Tanya Simuni
• Cathi Thomas
• Hubert Fernandez
• Zoltan Mari
• Vanessa Arnedo
• Karen Williams
• Jim Leverenz
• Claire Meunier
PPMI Patient Committee
• Sheryl Jedlinski
• Jean Burns
• Peter Burne
• Bill Shepard
• Carey Christensen
PPMI Site Awards
Recognizing site teams for outstanding effort
Prodromal Enrollment
Site Name Hyposmic Enrolled
RBD Enrolled Total Enrolled
Barcelona 0 5 5
UPenn 3 2 5
OHSU 2 0 2
Northwestern 0 2 2
Kassel/Marburg 0 2 2
IND 1 0 1
Cleveland Clinic 1 0 1
UAB 0 1 1
Top Prodromal Enrollment We have a tie!
Hospital Clinic de Barcelona University of Pennsylvania
Both sites have enrolled 5 Prodromal participants…Great Job!
Genetic Enrollment Site Name LRRK2
Cohort Consented
LRR2 Registry Consented
LRRK2 Cohort Enrolled
LRRK2 Registry Enrolled
Total Enrolled
Boca Raton 9 12 7 12 19
Barcelona 7 12 3 11 14
Emory 0 3 0 3 3
Northwestern 1 0 1 0 1
The PI 0 1 0 1 1
Trondheim 5 0 0 0 0
San Sebastian 4 0 0 0 0
Cleveland Clinic 1 0 0 0 0
Banner 1 0 0 0 0
Upenn 0 1 0 0 0
Top Genetic Enrollment
PD & Movement Disorders Center of Boca Raton
7 enrolled in LRRK2 Genetic Cohort, 12 enrolled in LRRK2 Genetic Registry!
Top Rate of Genetic Enrollment
Hospital Clinic de Barcelona
3 enrolled in LRRK2 Genetic Cohort, 11 enrolled in LRRK2 Genetic Registry in 4 months!
Timely Data Entry (Over 85%)
Site Name Pages Completed % Timely
Barcelona 449 99.6
IND 12,502 95.1
UCSD 2,738 93.2
Boston University 4,414 92.1
Kassel/Marburg 4,954 90.9
UAB 5,578 89.6
Innsbruck 2,805 89.5
The PI 4,595 89.2
Upenn 5,038 88.3
*Data is considered to be entered ‘timely’ if entered within 14 days of assessment
Top 3 Sites with Timeliest Data Entry
Boston University
In 3rd place, Boston University!
Over 4,400 pages completed, 92.1% timely!
Top 3 Sites with Timeliest Data Entry
University of California San Diego
In 2nd place, University of California San Diego!
Over 2,700 pages completed, 93.2% timely!
Top 3 Sites with Timeliest Data Entry
Institute for Neurodegenerative Disorders
In 1st place…we have a tie!
Over 12,000 pages completed, over 95% timely!
Hospital Clinic de Barcelona
Of almost 450 pages completed, 99.6% were entered timely!
Expected Completion of Scheduled Assessments
Site Name # LPs completed
% Expected LPs Completed
Macquarie 12 100
Emory 77 99
Cincinnati 25 96
UPenn 82 94
IND 191 93
Imperial 24 92
Banner 40 91
Boca Raton 10 91
Site Name % Expected Visits Completed
IND 100
OHSU 100
Imperial 100
Salerno 100
Northwestern 98
Cleveland Clinic 98
UCSD 98
The PI 98
Baylor 98
Upenn 97
Tuebingen 97
Kassel/Marburg 97
Innsbruck 96
Boston 96
Sites with over 90% of Expected LPs Completed! Sites with over 95% of Expected Visits Completed!
Sites with 100% of Expected Visits Completed
• Institute for Neurodegenerative Disorders
• Oregon Health & Science University
• Imperial College of London
• University of Salerno
Excellence in Hyposmia Recruitment
Banner Sun Health Research Institute
This site has consented 50% of all referrals, and is a top site for number of surveys returned to the Olfactory Core
Most Likely to Contribute
Karen Williams Northwestern University
This site team member has been the most likely to contribute ideas and suggestions to the Monthly PPMI Operations/Recruitment and Retention Calls
Top Advocate for WRI
Linda Rees Parkinson’s Institute
This site team member has been the top advocate for the PPMI Genetic Widespread Recruitment Initiative in collaboration with the GCC team
PPMI Amendment 8
Renee Wilson MA Sr. Clinical Project Manager
Clinical Trials Coordination Center/ Center for Human Experimental Therapeutics
University of Rochester Medical Center
Aims of the Amendment
• Further promote retention
• Explore objective measure of movement
• Investigate an amyloid imaging agent
• Expand understanding of genetics
• Develop induced pleuripotent stem cell lines
Key Components
• Amended PPMI Protocol
• Addition of Companion Protocols
– Family History Substudy
– FOUND in PPMI
– Skin Biopsy for Stem Cell Lines
– Amyloid Imaging Tracer (18F-Florbetaben)
• Amended AV-133 Protocol
Advance Directive for Clinical Research Participation/Continuing
Ability to Consent
• All subjects, all cohorts
• Mechanism to retain subjects by engaging surrogate decision maker in the event subject can no longer consent to participation
• Aligns with good clinical practice for investigator to ensure continuing consent at each visit
Advance Directive/Continuing Ability to Consent
• The potential for development of cognitive impairment in PPMI subjects is recognized
• In accordance with GCP, we want to ensure each subject’s ability to give ongoing informed consent over the course of study participation
• Advance directive is one way to enable continued participation in subjects whose ability to consent becomes compromised and enables subjects to clarify their preferences
Advance Directive/Continuing Ability to Consent
• During the consenting process, subjects will be encouraged to identify a substitute decision maker who they will permit to carry out the subject’s wishes regarding continued participation (or not) in PPMI should the subject lose the ability to make his own decision.
• Completion of the advance directive is voluntary; identification of a substitute decision maker (research proxy) is not required in order for the subject to participate in PPMI
Advance Directive/Continuing Ability to Consent
• However, in the absence of an advance directive, if the Investigator deems the subject no longer able to provide consent- the subject will be withdrawn from the study
• Important to note- if at any time subject tells research team they do not want to be in the study, the site investigator will respect their wishes and withdraw subject
Advance Directive/Continuing Ability to Consent
• Investigator will evaluate ability to consent and subject’s thinking abilities at each follow-up visit.
• If the Site Investigator feels subject can no longer make decisions about participation, investigator will inform subject of that decision and contact the Substitute Decision Maker.
• The Site Investigator will then discuss with Substitute Decision Maker whether subject should continue in the study or be withdrawn from the study.
Advance Directive/Continuing Ability to Consent
• Documentation of completion of the advance directive, routine review of the subject’s continuing ability to give informed consent at each visit, and any discussion with the subject’s substitute decision maker, will be noted on in the subject source and eCRF
• For subjects already enrolled prior to implementation of this amendment, the advance directive should be introduced and obtained at the next possible in-person visit
Advance Directive for Clinical Research Participation Form
• Introduction and instructions
• Part 1: Choice for a Substitute Decision Maker
• Part 2: Your wishes About Medical Research Participation