PPMI Prodromal cohort RBD · PPMI Prodromal cohort . RBD . Shirley Lasch . Institute of Neurodegenerative disorders . May 7, 2014 . ... –Cut off (3 s bins): Any EMG activity in

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Enrolled 12 Withdrawn 0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


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)



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



535 14% Hyposmics


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%)


unsure 615 16%) 32 (6%) 583 (18%) family history



yes 401 (10%) 64 (12%) 337 (10%) no 3382 (88%) 460 (86%) 2922 (89%)


< 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%)


unsure 32 (6%) 11 (3%) 63 (17%) family history



yes 64 (12%) 6 (9%) 50 (13%) no 460 (86%) 58 (91%) 321 (85%)


< 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%)


unsure 32 (6%) 11 (3%) 63 (17%) family history



yes 64 (12%) 6 (9%) 50 (13%) no 460 (86%) 58 (91%) 321 (85%)


< 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



535 14% Hyposmics


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

mailto:[email protected]

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


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




GCC-WRI website

www.ppmi.iu.edu

http://www.ppmi.iu.edu/

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


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


......... __ ,. .. _ .... _______ _

----.. ·--------·----..... ____ _

== BUSINESS REPLY MAI~, == =

I:::::---.. ----.. --' :::::...------.. -·_ .. __ . :::....""::-----·-·--·-

Who has qualified for a saliva kit?


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


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



~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 ~·



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


1.0 2.0

3.o 4.1

4.2

4.3

4.4

4.5

PPMI


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


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


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)








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






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





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


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!


University of California San Diego

In 2nd place, University of California San Diego!

Over 2,700 pages completed, 93.2% timely!


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

http://www.google.com/url?sa=i&source=images&cd=&cad=rja&docid=LSt6UMWFEE-DsM&tbnid=N1xrt--lNMKGjM:&ved=0CAgQjRwwAA&url=http://www.urmc.rochester.edu/news/story/index.cfm?id=1849&ei=iyAyUpvbMbG44APF3oCYBQ&psig=AFQjCNHc_TnLRqP7Pq7ZyffOprqhT3RUZw&ust=1379103243926906

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


• 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


• 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


• 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.


• 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

Documents

PPMI Prodromal cohort RBD · PPMI Prodromal cohort . RBD . Shirley Lasch . Institute of Neurodegenerative disorders . May 7, 2014 . ... –Cut off (3 s bins): Any EMG activity in