PPMI ANNUAL MEETING

Day 2: May 14, 2015

Genetic Recruitment

Genetic Coordination Core

Genetic Arms • Recruit for:

– LRRK2: G2019S, R1441G, I2020T – SNCA: A53T, G209A – GBA: N370S

• Other mutations can be found in these

genes – Limited the range of mutations – Only mutations that have been shown to

increase the risk of PD – Select mutations that we can find in multiple

families

LRRK2 Testing at PPMI Sites

0 20 40 60 80 100 120

Barcelona San Sebastian

Norway Northwestern

Columbia Beth Israel

Emory USF

Paris Tel Aviv

UAB UPenn

London INDD

BU CCF

Uwash PI

Banner Tuebingen

Salerno

Number of Subjects Tested

LRRK2-

LRRK2+

LRRK2 Testing at PPMI Sites

0 100 200 300 400 500 600

Boca Barcelona

San Sebastian Norway

Northwestern Columbia

Beth Israel Emory

USF Paris

Tel Aviv UAB

UPenn London

INDD BU

CCF Uwash

PI Banner

Tuebingen Salerno

Number of Subjects Tested

LRRK2-

LRRK2+

SNCA Testing at PPMI Sites

0 5 10 15 20 25

Salerno

Greece

Number of Subjects Tested

SNCA- SNCA+

GBA Testing at PPMI Sites

0 10 20 30 40 50 60

Barcelona

Boca

UAB

Northwestern

Number of Subjects Tested

Pending GBA- GBA+

Widespread Recruitment Initiative

0

200

400

600

800

1000

1200

1400

Sent kit Results returned

Positive LRRK2

G2019S

With previous testing

LRRK2+ G2019S

GBA+ N370S

Num

ber o

f Sub

ject

s 134 LRRK2+ individuals identified!

Genetic Counseling in WRI

• Over 975 individuals have received genetic counseling as part of the WRI

Jennifer Verbrugge, MS, CGC Lisa Cushman Spock, MS, PhD, CGC

Widespread Recruitment Initiative

0 10 20 30 40 50

Cohort Unaffected

Cohort with PD

Registry Unaffected

Registry with PD

# of individuals referred

WRI Site Referrals

0 5 10 15 20 25

Northwestern Beth Israel

Columbia UCSD

Banner PI

Upenn BU

Emory Boca

Baylor INDD UCSF

London Oregon

USF Hopkins

UR Uwash

CCF Tel Aviv

# of subjects

Site

Nam

e

0 10 20 30 40 50 60

Greece Tel Aviv Salerno Norway

Barcelona San Sebastian

London Tuebingen

Boca Paris

Banner CCF

UWash Northwestern

Beth Israel UCSF UAB

BU INDD

Emory Johns Hopkins

UCSD USF

Upenn PI

Baylor OHSU

Columbia Rochester

Number of Subjects

Genetic Registry PD Genetic Registry UNAF Genetic Cohort PD Genetic Cohort UNAF

Current Enrollment

3

66

0

69

1

44

0

45

8

70

0

78

2

55

0

57

0

10

20

30

40

50

60

70

80

90

SNCA LRRK2 GBA Total

Num

ber o

f Sub

ject

s Enr

olle

d

Genetic Registry PD

Genetic Registry UNAF

Genetic Cohort PD

Genetic Cohort UNAF

PPMI Goals for Genetics • 600 cohort

– 300 PD – 300 unaffected

• 600 registry

– 300 PD – 300 unaffected

0

50

100

150

Genetic Registry PD Genetic Registry UNAF Genetic Cohort PD Genetic Cohort UNAF

LRRK2

LRRK2 Actual LRRK2 Target

0

20

40

60

Genetic Registry PD Genetic Registry UNAF Genetic Cohort PD Genetic Cohort UNAF

SNCA

SNCA Actual SNCA Target

How will we reach our study recruitment goals?

Working together…

Upcoming Recruitment Plans: 23 and Me

• Sending emails to individuals with positive results for: – LRRK2 G2019S (700-1000 individuals) – GBA N370S (~2500 individuals)

• 23 and Me sending these emails in waves to states with PPMI sites

• Individuals directed to WRI – Rapid referral to sites following confirmation

of genetic test results and genetic counseling

Upcoming Recruitment Plans: WRI

• Newsletter being sent to all WRI LRRK2- individuals (n=820) – Invite individuals to come back to WRI – Sign Informed Consent for GBA N370S

testing – MGH perform genetic testing

• Typical WRI referral – Subjects complete genetic counseling – Subjects referred to PPMI site with typical

paperwork

Don’t stop with one person, recruit families…

At least 1 family member

participating (%)

No other family members participating

currently (% )

Totals

MGH tested 51 (52%) 47 (48%) 98 Previous testing 9 (22%) 31 (78%) 40 totals 60 (43%) 76 (57%) 138

• WRI identified LRRK2+ individuals • During counseling, obtain a pedigree • During counseling, discuss opportunity for family members to

participate (including nonclosure of test results) • We reviewed the pedigree and the WRI database to identify

family members who came through WRI

Take home! • LRRK2 recruitment is going well

– Need to keep looking for new probands – Need to try to recruit other family

members • GBA is likely to be very productive

recruitment – Outreach in place to start

• SNCA still challenging – Need to expand recruitment, if possible

Phenoconversion for PPMI Prodromal and Genetic

Cohorts PPMI Prodromal Cohort Training

May 14, 2015

Defining Phenoconversion to PD in the PPMI cohort

• Critical outcome for PPMI cohorts • Established phenoconversion

definition not available • Approach: develop a standardized

diagnosis with minimal interrater variability

• Phenoconversion = motor Parkinsonian syndrome

Phenoconversion Measures • Primary Measure:

– Based on UK Brain Bank Criteria – Data mapped from the ‘Diagnostic

Features Questionnaire’ • 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)

UK PD Society Brain Bank Diagnostic Criteria

PPMI Primary Definition for Phenoconversion

(Based on the ‘Diagnostic Features Questionnaire’)

3/16/2015 5

Bradykinesia and at least one of the following: • Muscular rigidity • Rest tremor (4-6 Hz) • Postural instability unrelated to primary visual,

cerebellar, vestibular or proprioceptive dysfunction

Primary Outcome for Phenoconversion:

‘Diagnostic Features Questionnaire’

Primary Outcome for Phenoconversion:

‘Diagnostic Features Questionnaire’

P-PPMI Primary Definition for Phenoconversion

(Based on the ‘Diagnostic Features Questionnaire’)

3/16/2015 8

Features that could exclude phenoconversion: • History of repeated strokes, excessive stroke risk factors (question 1) • Neuroleptic exposure or history of repeated head injury, definite encephalitis,

MPTP exposure (question 2) • Oculogyric crisis, oculomotor disturbances, or supranuclear gaze palsy

(question 13) • Wide based gait or ataxia (question 8.2) • Other neurological abnormalities atypical of parkinsonism (e.g. hyperreflexia,

Babinski sign, sensory deficit, apraxia, sleep apnea , dsymetria or other cerebellar dysfunction) (question 15)

• Early severe autonomic involvement, unusual or atypical presentation (eg presentation, symptoms, signs, course, response to therapy, etc.), which could indicate an alternative diagnosis to Parkinsonian sndrome, (question 15)

• Early severe dementia with disturbances of memory, language, and praxis; • Mental changes: Cognitive (question 9.2) • Little or no response to levodopa or a dopamine agonist, if applicable (question

16) • Presence of very rapid speech (tachyphemia) (question 17) • Presence of dysphagia or other bulbar dysfunction (question 18) • CT/MRI is suggestive of another cause of parkinsonism (eg vascular) (question

19, 20)

Phenoconversion for PPMI Cohort: Key Points

• Be attentive to the Diagnostic Features Questionnaire

• Ensure completion of the correct Diagnostic Questionnaire (‘Prodromal Diagnostic Questionnaire’)

• Same investigator rating the subject at each visit to reduce variability

• Call/email if there are questions regarding how to best complete the form based on special cases.

Objective measures of PD – smartphones

Acknowledgements

2

Dr. Max Little

Dr. Stephen Friend Dr. Andrew Trister

Dr. Carlie Tanner

Dr. Kevin Biglan Dr. Karl Kieburtz Solomon Abiola Denzil Harris

Dr. Suchi Saria Andong Zhan

Dr. Max Little

Sources: IEEE Transactions on Biomedical Engineering 2009;56:1015-22, IEEE Transactions on Biomedical Engineering 2010;57:884-93

Outline

• Rationale and pilot study

• Android study

• mPower

3

Many of our current outcome measures are subjective and sub-optimal Characteristics of 20th vs 21st century studies Clinical Trials

Source: JAMA Neurol. Published online March 02, 2015. doi:10.1001/jamaneurol.2014.4524. 4

Because of rapid adoption and functionality, smartphones have great research potential

5

Number of U.S. smartphone users, 2010 – 2016

Source: Statista. Available at: http://www.statista.com/statistics/201182/forecast-of-smartphone-users-in-the-us/.

Smartphones can provide objective measures of Parkinson disease

6

Movement disorders have external manifestations suited for assessment

Figure 1: Picture of Android smartphone and software application.

Figure 2: Procedure for collecting voice recordings, finger tapping, and passive sensor data from gait and postural sway test

Source: Parkinsonism & Related Disorders, http://dx.doi.org/10.1016/j.parkreldis.2015.02.026. 7

Source: Parkinsonism and Related Disorders 2015 (epub ahead of print)

Smartphones can distinguish those with PD from those without

Gait and posture tests in Parkinson disease

8

-2 0 2 4 6 8

x 10-4

0.8

1

1.2

1.4

Teager-Kaiser energy operator

Det

rended

flu

ctuat

ion a

nal

ysi

s

a) Gait test

Participant with Parkinson desease

Control participant

0 0.5 1 1.5

0.6

0.8

1

1.2

1.4b) Postural sway test

Teager-Kaiser energy operator

Det

rended

flu

ctuat

ion a

nal

ysi

s

Gait test

-2 0 2 4 6 8

x 10-4

0.8

1

1.2

1.4

Teager-Kaiser energy operator

Det

rended

flu

ctuat

ion a

nal

ysi

s

a) Gait test

Participant with Parkinson desease

Control participant

0 0.5 1 1.5

0.6

0.8

1

1.2

1.4b) Postural sway test

Teager-Kaiser energy operator

Det

rended

flu

ctuat

ion a

nal

ysi

s

Postural sway test

Outline

• Rationale and pilot study

• Android study

• mPower

9

Smartphones allow for global participation anytime anywhere

Geographical representation of study participants (N=653)

10

Most participants were recently diagnosed

11

Participants produced 46,000 hours of high fidelity and high frequency data

One hundred eighty five instances of active tests collected (black dots in the graph)

One hundred twenty six days of passive monitoring (each blue line segment stands

for one complete passive monitoring)

Instances of active tests collected in each day of a week

Instances of active tests collected in each house of a day

12

The signal from the smartphone could be quite sensitive in response to drugs Sample accelerometry tracing in three dimensions

13 Withdrawn participant

Active participant

Confidential

Outline

• Rationale and pilot study

• Android study – Smartphone-PD

• mPower

14

In March Apple released ResearchKit and five medical research smartphone apps

mPower smartphone application for Parkinson disease

15 Withdrawn participant

ResearchKit is an open source platform empowering patients and providers

It is open source and available to developers globally

Works with Apple’s HealthKit, pooling daily step counts, heart rate, and other health metrics

16

Sage, Apple, Aston University, MJFF and UR collaborated to develop mPower

17

Data • Data are de-identified are

stored on a secure server operated by Sage Bionetworks

• Depending on the preference of the participants, data are available to all researchers or the study’s investigators

• Participants receive real-time feedback on their performance so they can generate their own insights

mPower consist of three main components

Surveys

Structured tasks

Passive measures

18

• Demographics • Co-morbidities • Medications • MDS-UPDRS • Open responses from participants

• Voice recording • Speeded tapping • Gait • Posture • Memory

• GPS • Activity data

mPower surveys provide insight into medication usage and quality of life

19

mPower structured test assess cognitive, speech, and gait function

20

Passive tasks provide additional data and feedback around activities

21

We plan to have new generations of mPower with greater functionality

Pilot

•Differentiate between controls and PD

Android

•Global reach

• Passive monitoring

mPower 1.0

• Participant empowerment and feedback

22

In two months, over 13,000

individuals have enrolled in the study of whom

10% have Parkinson disease

Incorporating mPower into PPMI could support additional insights into PD

mPower • 80+% of those in Fox Trial Finder have Apple smartphones

PPMI • Some PPMI participants may already be enrolled in mPower

mPower + PPMI

• Marriage of PPMI and mPower could add frequent, objective measures of phenotype to detailed neuroimaging, genotyping, and clinical characterization in the study

23

Other wearables can provide additional measures of Parkinson disease

Medication reporting

Medication reminder

Report something

PATIENT REPORTED

OTHER

Configurable data

collections Contribution

score

Integrated Login and

registration Pebble notifications

OBJECTIVE MEASURES

Gait

Sleep

Tremor

Activity Level

Controlled Tests

24 Source: Fox Insight Mobile Overview; slide courtesy of Ken Kubota

The Precision Medicine Initiative aims to incorporate sensors into its efforts

Source: Precision Medicine Initiative http://www.nih.gov/precisionmedicine/ 25

PPMI and new measures could be well positioned for this Initiative

Source: NEJM 2015;372:793-5 26

• “The initiative will encourage and support the next generation of scientists to develop creative new approaches for detecting, measuring, and analyzing a wide range of biomedical information – including … data from mobile devices … Such innovations will first need to be tested in pilot studies.”

• “[The initiative] will also pioneer new models for doing science that

emphasize engaged participants and open, responsible data sharing.” • “The (1 million) research cohort will be assembled in part from some existing

cohort studies ... that have already collected or all well positioned to collect data from participants willing to be involved in the new initiative.”

6/6/2015

1

Motor symptoms in

prodromal Parkinson’s disease

Anat Mirelman PhD Laboratory for Early Markers of Neurodegeneration

Center for the study of Movement , Cognition and Mobility Department of Neurology

Tel Aviv Medical Center Sackler School of Medicine

Tel Aviv University Israel

Rationale

• Gait disturbances play a major role in the motor manifestation of PD.

• Gait changes frequently observed include decreased stride length and an increased stride time variability even early in the disease.

• Increased stride time variability has been reported as one of the hallmarks of gait in PD

In a disease diagnosed based on motor symptoms it is unlikely that early motor signs are absent in the

prodromal phase

Pow

er sp

ec

tra

l

de

nsity (p

rs)

Stride time Variability

6/6/2015

2

0

0.5

1

1.5

2

2.5

usual walk dual task walk fast walk

Non-Carriers Carriers

p=0.07

p=0.04

p=0.02

Non carriers = 81, carriers = 72

Stri

de

var

iab

ility

(C

V%

)

Gait variability in healthy subjects at risk

Mirelman et al. Annals of Neurology 2011

Stride time variability under challenging conditions

0.50

1.00

1.50

2.00

2.50

3.00

3.50

4.00

4.50

5.00

NMNC NMC PD- PD+

Stri

de

CV

(%

)

usual walking dual task

P=0.02

P=0.03

Non carriers=61 , carriers =62, PD non-carriers= 50, PD carriers =50

Non carriers carriers PD non- carriers PD carriers

0.0002

0.0003

0.0004

0.0005

Vel

oci

ty (

m/s

)

Mean CoM Velocity Eyes Closed (AP)

NMNC NMC PDnC PDC

p = 0.03

p = 0.02

NS

Postural stability – Sway

Data collected by the ‘gait consortium’

6/6/2015

3

0.01

0.02

0.03

0.04

Sway

Pat

h (

m)

Absolute value of the Sway Path of the CoM Eyes Closed (AP)

NMNC NMC PDnC PDC NMNC NMC PDnC PDC

p = 0.04

p = 0.01 NS

Postural stability – Sway

Data collected by the ‘gait consortium’

Arm swing- PD compared to Healthy

Healthy subject (age=52)

Patient with PD (age =53)

deg

ree

deg

ree

0

0.05

0.1

0.15

0.2

0.25

0.3

Usual walk Dual task walk

Sy

mm

etr

y r

ati

o

NMNC NMC

Group differences in arm swing symmetry between healthy carriers and non-carriers

Non carriers = 61, carriers = 62

p=0.37

p=0.03

Data Analysis –

• Baseline comparison of cohorts • Prediction of disease progression • Rate of disease progression

How to establish PD subsets??

1

Analysis –PD subsets • PD subsets

– Need for DA meds – Subjects with highest change in

UPDRS, DAT, Synuclein – Subjects with low MoCa, low amyloid,

high tau – Subjects with relative hypotension,

RBD on questionnaire, low amyloid, high tau

– Subjects with high depression/anxiety/Reduced SERT

2

Planning for clinical trials

Longitudinal data analysis – sample size estimate • Change in UPDRS • Change in DAT • Change in CSF

3

Longitudinal PD, HS vs SWEDD MDS-UPDRS

PD - Time to Start Dopaminergic Meds

PPMI –UPDRS CHANGE IN UPDRS at 12 months – BY TREATMENT

CHANGE IN UPDRS by TREATMENT

Preliminary Sample Size Estimate - ALL PD

Total number of subjects assume 2 arms

Preliminary Sample Size Estimate - PD

Total number of subjects assume 2 arms

Table 2.Sample Sizes Necessary to Detect Differences in Mean UPDRS Scores in PD subjects who began treatment within one year

Preliminary Sample Size Estimate - PD

Total number of subjects assume 2 arms

Table 3. Sample Sizes Necessary to Detect Differences in Mean UPDRS Scores in PD subjects who did not begin treatment within one year

Preliminary Sample Size Estimate - CSF synuclein

Change from Baseline 50% 30 %

80% power 90% power 80% power 90% power CSF synuclein 45 55 95 110

Total number of subjects assume 2 arms

“Why use a RBD cohort in clinical trials for PD”

New York 2015

Eduardo Tolosa Barcelona, Catalonia, Spain

REM behaviour disorder • Occurs in manifest PD (50%) and in premotor PD (about

15% of cases).

• Idiopathic RBD is associated with subclinical features of manifest PD:

- abnormal DAT SPECT,

- hiperechogenicity of substantia nigra

- abnormal MIBG uptake

- depression, constipation

• In longitudinal studies IRBD patients frequently develop a synucleinopathy (e.g. PD, DLB,MSA)

Rapid eye movement sleep behaviour disorder

Delayed emergence of a parkinsonian disorder in 38% older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder

Shenck, Bundlie and Mahowald. Neurology 1996; 46: 388

Lancet Neurol 2013

• 44 patients with IRBD • After a mean follow up of 10 years, 82% were diagnosed with either PD or DLB or MSA

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

• 69-year-old man was diagnosed as having RBD at age 58 years

• During a ten year follow-up period, development of hyposmia, constipation, depression and mild cognitive changes.

• Parkinsonism was never detected • Serial DAT SPECT imaging showed progressive

subclinical substantia nigra damage. • Diagnosis: Premotor PD • Died at age 77 of lung cancer.

Mov Disord 2014

Neuronal loss + Lewy bodies CNS Olfactory bulb Dorsal motor vagal Subcoeruleus Substantia nigra Amygdala N. basalis of Meynert PNS Stellate ganglia Paravertebral chain Cardiac plexus Myenteric plexus

α-synuclein

Introduction Tissue-based Biomarkers Conclusion Imaging Biomarkers Clinical Biomarkers

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

• 62 patients with iRBD

• 21 converted at follow up

• Compared to those remaining disease free,

patients destined to develop disease had worse baseline olfaction and vision test

Olfaction and color vision identify early-stage synuclein-mediated neurodegenerative diseases

Postuma 2011

Olfactory dysfunction predicts early transition to a Lewy body disorder in idiopathic RBD

• 34 PSG confirmed RBD cases studied

• Olfactory testing with Sniffing Stick test

• Prospectively followed for 4.9 years: 9 (26%) developed a Lewy body disorder

• Compared to patients who remained disease free, patients who went on to develop disease had lower olfactory scores at baseline

Mahlknecht et al. Neurology 2015

43 Idiopathic REMs BD

DAT-SPECT +

SN Sonography

27 Individuals with DAT-SPECT and/or Hyperechogenicity

15 Individuals with normal examens

8 Individuals affected by Parkinsonism

NONE affected by Parkinsonism

After 2.5 years Follow-up

Decreased DAT SPECT and TCS as risk markers for PD: a prospective study

Iranzo et al. Lancet Neurol 2010

Parkinson risk in idiopathic RBD

• Test the ability of prodromal markers to identify patients at higher risk

• 30% developed disease at 3 years;66% at 7.5 years

• Advanced age, olfactory loss,abnormal color vision, subtle motor dsyfunction and no use of antidepressants identified higher risk of disease conversion

Postuma 2015

Markers of disease progression in IRBD

• No change with time Olfactory tests

Color vision tests

Hiperechogenicity of the nigra

• Worsens with time

DAT scaning

UPSIT score does not change over a 4 years follow-up

Serial DAT imaging in iRBD

Iranzo et al. Lancet Neurol 2011 20 iRBD, 20 HC, 3 year follow-up

Why use a RBD cohort in clinical trials for PD?

IRBD is a specific prodromal PD marker

IRBD is an indicator of an evolving synucleinopathy.

In iRBD, olfactory and color vision tests, DAT- SPECT

and TCS: markers of short term phenoconversion.

Serial DAT- SPECT (but not serial olfactory and color vision tests): marker of disease progression.

• Thank you very much for your attention!!

The Prospect of Using Genetic Synucleinopathy Cohorts in

Clinical Trials

Leonidas Stefanis

Second Department of Neurology University of Athens Medical School

Foundation of Biomedical Research of the Academy of Athens Athens, Greece

The G209A mutation in the SNCA gene

• First discovered in families of Italian or Greek origin with autosomal dominant PD (Polymeropoulos et al., 1997)

• Has since been described also in families of Northern European and Korean origin (Puschmann et al., 2009; Choi et al., 2008)

• The clinical picture is variable, but generally consistent with PD or PDD (Bostanjopoulou et al., 2001; Papapetropoulos et al., 2001, 2003; Kasten and Klein, 2013), rarely DLB (Morfis and Cordato, 2006)

• Some cases with very prominent autonomic involvement, resembling MSA

• AAO 30s to 60s, mean AAO 45-50 • Approximately 70 cases reported

Other missense point mutations in SNCA leading to familial PD

• Other point mutations identified (A30P, E46K, H50Q, G51D, A53E)

• Autosomal dominant inheritance • Clinical picture PD, PDD, MSA-like, DLB

(rarely) • AAO 50s to 60s, more typical for iPD • Few cases: Approximately 15 reported total

Kasten and Klein, 2013 Kiely et al., 2013 Pasanen et al., 2014

Multiplications in SNCA leading to familial PD

• Duplications and triplications of the SNCA gene

• Autosomal dominant pattern of inheritance • AAO 40s (tri) 50s (di) • Protein levels of ASYN in peripheral tissues

and iPS-derived neurons with commensurate increase

• Dementia dose-dependent in incidence, timing, severity

• Total of around 70 cases reported

Kasten and Klein, 2013

Strategy for recruitment

• Getting in touch with already identified families with carriers of the G209A SNCA mutation (Profs. Athanasiadou, Papadimitriou, Bostanjopoulou)

• PD patients with increased chance of genetic load (AAO<50 and/or family history) presenting to outpatient clinic appointments

• Referrals from other Neurologists

• Systematic genetic analysis of 111 patients with PD with early AOO (<50) or with positive family history

• Subjects with no known link to families with the G209A SNCA mutation

• 5/111 were found positive for the G209A SNCA mutation • In all cases autosomal dominant family pattern of

inheritance • Except for one case, early age of onset • Amongst patients with early age of onset and family history,

frequency at 15%

Bozi et al, 2014

Greek MEFOPA Cohort of G209A SNCA carriers

0

10

20

30

40

50

60

70

80

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age

max age of disease onset

mean age of disease onset

min age of disease onset

Age of Asymptomatic Carriers

Clinical Picture of affected carriers

0

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H&Y

SCAL

E U

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baseline

followup

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UPDRS I UPDRS II UPDRS III UPDRS IV

SCAL

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follow up

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MOCA

units

baseline

follow up

Disease Progression over 2 years

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stic

ks

Sniffin' test

baseline

follow up

* *

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BASELINE FOLLOW UP

SCAL

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Global Impression of Progression: Non-motor Symptoms

0

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UPD

RS sc

ore

at q

uest

ion

1.1

cognitive impairment

baseline

follow up

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UPD

RS sc

ore

at q

uest

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psychosis

baseline

follow up

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UPD

RS sc

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baseline

follow up

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UPD

RS sc

ore

at q

uest

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1.11

constipation

baseline

follow up

Impression of Progression confirmed by UPDRS-I subscores

*

* *

Examples of phenotypic variability

Lower levels of a-synuclein in serum of A53T carriers

CTL A53T0

10

20

30

40

50

60

**α

-syn

ucle

in(n

g/m

l)

Emmanouilidou et al., unpublished data

DAT Scans in A53T cohort (PPMI)

asymptomatic Early disease (<3years)

Mid-disease (<7 years)

CONCLUSIONS • 5-8 years after disease onset dementia, psychosis

and autonomic dysfunction may ensue, but are not obligate events

• Unusually severe and early dementia may occur in some cases

• Progression of motor impairment and cognitive and autonomic dysfunction occurs over 2 years

• DAT scans appear to show unusually severe nigrostriatal degenration, and this rapid progression may serve as a good biomarker in this cohort

• There is substantial heterogeneity in clinical manifestations and course of the disease

• Peripheral markers of ASYN may be telling us something and may be useful as biomarkers in this population

The Prospect of Using Genetic Synucleinopathy Cohorts in Clinical Trials:

Pros • Defined pathogenic link of genetic defect to

disease-modifying approach • Possibility of recruiting asymptomatic at risk

individuals (e.g. carriers with abnormal DAT scan)

• Clinical progression is measurable, especially in terms of cognitive function

• DAT scans may serve as a useful biomarker of disease progression in this cohort

• Possibility of useful peripheral a-syn biomarker

• Small number of subjects • Question whether the genetic defects share

the same pathogenic cascade • Heterogeneity in clinical manifestations and

course

The Prospect of Using Genetic Synucleinopathy Cohorts in Clinical Trials: Cons

Recruitment of G209A SNCA carriers into MULTISYN (1)

• Main aim of project is to develop an a-synuclein radiotracer

• This will then be applied to our A53T cohort • 10 subjects (manifesting carriers or non-

manifesting carriers with pathological DAT scan)

• 2 PETs over 6-12 months to assess sensitivity to progression

Recruitment of G209A SNCA carriers into MULTISYN (2)

• Interventional phase • Treatment with PD01A (all subjects) • PETs every 6 months • Clinical follow-up, wet biomarkers • Main outcome: comparison of PETs with

PETs in run-in period • Secondary outcomes: effects on motor,

cognitive, autonomic functions, using rating scales

LRRK2 Trials: Who/ When, and What:

Who/ When: -pre-symptomatic? (gene carriage only) -pre-symptomatic and higher risk? (gene +others) BUT by how many years? very mild motor but not meeting PD criteria? -OR early (<xx years?) PD?

What Outcomes: -Change in surrogate markers? -imaging (which ligand?) -CSF marker -motor prior to PD -Prevention Phenoconversion? -Improvement Motor Features after diagnosis/ (Disease Modifying Design)?

LRRK2 Specific Challenges: -reduced age related G2019S penetrance (approx 26% age 80 AJ, but wide range)

Domain— (Some representative measures)

LRRK2 G2019S PD (vs. control)

LRRK2 G2019SPD vs IPD NMC: vs. NC-F or vs. control (“trait”)

NMC: Subgroup? 30% or fewer? (“state”)

Timing (Phenoconversion-PD)

Motor

UPDRS + = (overall) -4 ?

Gait + + (several measures) + Prior to phenoconvers

Spiral + = (faster dom hand mean speed)

- (NMC vs. NC-F) + (NMC vs. controls)

Yes (two classes) ?Prior (BUT only 2 cases)

Non-motor Symptoms (0verall) NMS

+ = or < ?sl > (const/urg) >>(all >50 y/o)5 ?

Cognitive impairment + <1,2 or = (R1441G)3 (Executive dysfx)/- ? ?

Olfaction + < or = No diff Yes (latent classes) ?Before PD6

RBD (RBD questionnaire polysomnography)

+ (subgroup) <9 (Questionnaire) - no ?Not early <3 yr

Dysautonomia (Questionnaire, MIBG?, colonic biopsy, HRV)

+ =6, or < ? ?Constip/hypos/depression/EDS before PD6

Psychiatric Depression Anxiety

+ =6 (or >?apathy, hallucination)

? - -

(all >50 y/o) +5

?

*Combined Battery (battery derivation on 3 yr or less LRRK2 PD)

vs NC-F:(UPDRS-III, UPSIT, NMS, spiral AUC 0.77) w/out spiral 0.678

??

Selected studies referenced– not complete! (1)Helmich, (2)Alcalay 15, (3) Estanga 14, (4) Somme 15, (5) Mirelman 15, (6) Gaig 14 (7) Mirelman (8) Ortega (9) Trinh 14(10) Tijero 13, (11) Saunders-Pullman 15

Consider imaging (DAT/ fMRI/ TCS and others?); CSF or other biofluid

LRRK2 Trials: Who/ When, and What

Who/ When: -pre-symptomatic(by gene carriage only)? c need longitudinal data -very mild motor but not meeting PD criteria? -early <xx years? (?untreated) PD?

What Outcomes: -Change in surrogate markers? -imaging (which ligand?) -CSF marker -motor prior to PD -Prevention Phenoconversion? -Improvement Motor Features/ (Disease Modifying Design)?

PPMI RETENTION UPDATE & SITE AWARDS

2015 PPMI Annual Meeting

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PPMI STATUS UPDATE

Cohort Enrolled Recruitment Status De Novo PD 423 Complete Controls 196 Complete SWEDDs 64 Complete Prodromal 64 Complete Genetic Cohort 137 Ongoing Genetic Registry 115 Ongoing Total 999 Active=901

Goal: Retain subjects by keeping them engaged to participate in study visits over time Status: Overall study retention is 93%! (Original cohort: 92%)

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RETENTION STRATEGIES Goal: Maintaining the stamina and loyalty of enrolled participants over time

» Site Relationships with Participants – Maintaining relationships 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 (Vol 1 & 2) – 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

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RETENTION STRATEGIES CONT.

» Giveaways – PPMI token of appreciation at each study visit – Thank you Cards

• 60 month visit with pedometer

» PPMI Study Update Calls – Quarterly calls featuring presentation by researcher on PPMI data, Q&A session – Recordings available at www.ppmi-info.org/participants – Next call: June 10 @ 12pm ET

• Brit Mollenhauer will present results form analysis of biospecimens

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»Danna Jennings (Chair) »Carlie Tanner »Daniela Berg »Christine Hunter »Lola Vilas »Katie Forsberg »Cheryl Halter

RECRUITMENT & RETENTION WORKING GROUP

»Tanya Simuni »Cathi Thomas »Hubert Fernandez »Zoltan Mari »Vanessa Arnedo »Karen Williams »Jim Leverenz »Shirley Lasch

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PPMI PATIENT ADVISORY COMMITTEE

»Sheryl Jedlinski »Jean Burns »Peter Burne »Bill Shepard »Carey Christensen »Kevin Kwok »Linda Comerci

PPMI SITE AWARDS Recognizing site teams for outstanding effort

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• The Parkinson's Institute

• Imperial College London

• Macquarie University

SITES WITH 100% RETENTION OF ORIGINAL COHORT PARTICIPANTS

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• OHSU

• UCSD

• Macquarie University

• IND

• Imperial College of London

• Salerno University

SITES WITH 100% OF EXPECTED VISITS OF ORIGINAL COHORT COMPLETED

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PRODROMAL ENROLLMENT Site Name Hyposmic Enrolled RBD Enrolled Total Enrolled Barcelona 0 5 18 UPenn 6 5 11 Kassel/Marburg 0 7 7 OHSU 4 0 4 Northwestern 2 2 4 IND 3 0 3 Cleveland Clinic 1 1 2 Tuebingen 2 0 2 Emory 1 1 2 Athens 0 2 2 UCSD 2 0 2 UAB 0 1 1 U of Washington 1 0 1 The PI 1 0 1 USF 1 0 1 Salerno 1 0 1

Total 26 38 64

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• Hospital Clinic Barcelona

• University of Pennsylvania

• Paracelsus Elena Klinik/Marburg

TOP PRODROMAL ENROLLMENT

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• IND – 26 consented

• Banner – 14 consented

• UCSD – 13 consented

• OHSU – 10 consented

• Cleveland - 10 consented

HONORABLE MENTION Sites with high number of consented participants for Prodromal cohort

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GENETIC ENROLLMENT Site Name Cohort

Enrolled Registry Enrolled

Total Enrolled

UPenn 2 6 8

Baylor 2 1 3

Imperial 2 0 2

The PI 1 5 6

USF 1 0 1

Emory 1 5 6

Boston University

1 6 7

Cleveland Clinic

1 0 1

Pitie-Salpetriere

0 8 8

OHSU 0 3 3

IND 0 1 1

Tuebingen 0 1 1

Site Name Cohort Enrolled

Registry Enrolled

Total Enrolled

St. Olavs Hospital

25 4 29

Hospital Clinic Barcelona

23 11 14

Hospital U. Donostia

17 3 20

Tel Aviv Sourasky

13 0 13

PD & Mov Dis - Boca

11 25 36

Beth Israel 9 5 14

Athens 9 3 12

Northwestern 8 4 12

Columbia 3 4 7

Banner 3 0 3

UCSD 3 1 4

Salerno 2 1 3

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• St. Olavs Hospital

• Hospital Clinic Barcelona

• Hospital Universitario Donostia

TOP GENETIC COHORT ENROLLMENT

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TIMELY DATA ENTRY (OVER 85%)

Site Name % Timely Data Entry Barcelona 98 IND 94 UCSD 93 Kassel/Marburg 92 Innsbruck 91 Upenn 89 OHSU 86 Salerno 86 Boston 85

*Data is considered to be entered ‘timely’ if entered within 14 days of assessment

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• Hospital Clinic Barcelona

• Institute for Neurodegenerative Disorders

• University of California, San Diego

TOP 3 SITES WITH TIMELIEST DATA ENTRY…

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EXCELLENCE IN DEVELOPING AND IMPLEMENTING RECRUITMENT STRATEGIES

This site has gone the extra mile to recruit for the SNCA cohort by traveling great distances and engaging families

University of Athens

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MOST COMMITTED TO SITE OPTIMIZATION These coordinators new to PPMI have worked diligently to get up to speed on the study and to better optimize operations at their sites

Gretchen Todd Leigh Donharl

THANK YOU FOR YOUR CONTINUED HARD WORK!

PPMI – Post 5 year Plans – Amendment 10

Current Plan for Existing Cohorts (PD, Healthy, SWEDD)

• PPMI Early PD and Healthy subjects – All followed for 5 years using current protocol – First subject to reach 5 year June 2015 – All subjects reach 5 yr follow-up in June 2018 – Range of follow-up 5-7+ years

• PPMI – SWEDD – Most will end PPMI participation after 2 year f/u – All Swedd subjects reach 2 yr follow-up in June

2015

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Why f/u 5 years

• Assess long-term PD progression outcomes – Focus on progression of identifed PD subsets – Focus on dopa non-responsive milestones

• Assess predictability of biomarkers identified at earlier stage

• Comparison of PD and Genetic outcomes • Integration of new markers

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PPMI PD and HV Follow-up post 5 years

• Focus on retention – • Reduce frequency of clinic visits • Focus assessments based on existing data

and disease stage • Add options for remote visits to encourage

retention – FOUND/Fox Insight • Customize assessments for different cohorts • Need for path core

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PD subjects p 5 year f/u

• q 12 months clinic visits • In clinic

– UPDRS on/off – Cognition – any change – Focus on gait – Non –motor – Blood – CSF q 2 years – DAT imaging at year 9

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PD subjects p 5 year f/u

• q 12 month remote visit – Found – Fox Insight

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SOE – post 5 year - PD, HV Visit Number SC/BL (year 5) Year 6 Year 7 Year 8 Year 9 Year 10 Visit Description Months (+30 days) -45 days 12 24 36 48 60 Written Informed Consent X Review Inclusion/Exclusion Criteria X Medical & Family History/Demographics X Physical Examination X Neurological Examination X X Vital Signs X X X X Xc X Clinical Laboratory Assessments X X Biomic blood sample X X Xf X Xf X MDS-UPDRS (including Hoehn & Yahr)h X X X X X X Modified Schwab & England ADL X X X X X X Clinical Diagnosis Assessment(s) X X X X X X MDS-UPDRS Repeat Part III/Hoehn & Yahrj X X X X X X

Physical Activity Scale for the Elderly (PASE) X X

Hopkins Verbal Learning Test – Revised X X X X X X Benton Judgment of Line Orientation X X X X X X Semantic Fluency X X X X X X Letter Number Sequencing X X X X X X Symbol Digit Modalities Test X X X X X X Montreal Cognitive Assessment (MoCA) X X X X X X Epworth Sleepiness Scale X X X X X X REM Sleep Behavior Questionnaire X X X X X X Geriatric Depression Scale (GDS-15) X X X X X X State-Trait Anxiety Inventory for Adults X X X X X X QUIP X X X X X X SCOPA-AUT X X X X X X Cognitive Categorization X X X X X X MRI (DTI)e X DAT imagingm,o X VMAT-2 imagingm,o, r (see companion protocol) X

Lumbar puncture (CSF collection) X X X Adverse Eventsa X X X X X X Current Medical Conditions Review X X X X X Concomitant Medication Review X X X X X X assessment of Falls X X X X X X Gait assessment X X X X X X Synucelin imaging X X X X

Current Plan for Existing Cohorts through 2018 (Prodromal, Genetic)

• Prodromal - RBD/olfactory – Enrollment complete Jan 2015 – All followed for 3+ to 5 years in June 2018

• Genetic -PD – Enrollment complete Jan 2016 – All followed for 2+ to 4 years in June 2018

• Genetic Unaffected – Enrollment complete Jan 2016 – All followed for 2+ to 4 years in June 2018

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Prodromal subjects p 2018 -

• Timing of clinic vs remote vs wearables • Suggest in clinic q 12 months for 5 years • Possibility for Milestone

driven/Phenoconversion visit? • In clinic

– UPDRS on/off – Cognition – UPSIT – as precursor to motor – Non –motor – Blood – CSF q 2 years? – DAT imaging at year 6,8 – Synuclien imaging

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Cohort specific f/u

• PD vs Prodromal/unaffected • Genetic Cohort specific

assessments • Flexibility – Identify cohort

specific milestones – phenoconversion, treatment, dyskinesia, falls, dementia,

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PPMI Future plans

Ken Marek

Challenges for 2015/2016

• Subject Retention – Longitudinal assessment • Enroll Genetic cohort • Data Quality/Data Entry • PPMI fatigue • Increase industry sponsorship

PPMI Goals for 2015/16

• Novel analytes, imaging tools, clinical assessments, analyses • Focus on PPMI data analyses – longitudinal data, PD subsets, prodromal data • Develop tools for Prodromal assessments – Phenoconversion • Focus on genetic enrollment/retention • Implement pathology core • Long-term PPMI follow-up • How can PPMI inform clinical trials