Study to Identify Clinical, Imaging and Biologic Markers of Parkinson Disease Progression

PPMI will be a five-year natural history study (a minimum of 3-year involvement for each
subject) of de novo idiopathic PD patients and healthy controls. This study will also include
a SWEDD (subjects without evidence of dopaminergic deficit)and Prodromal populations.

All subjects will be comprehensively assessed at baseline and every three to six months
thereafter. Subjects will undergo clinical (motor, neuropsychiatric and cognitive) and
imaging assessments and will donate blood, urine, and cerebral spinal fluid (CSF). A blood
sample for DNA will be collected. Data will be collected by each site under uniformly
established protocols and data will be analyzed and stored at designated core facilities.

Inclusion Criteria:

Parkinson Disease (PD) Subjects:

- A diagnosis of Parkinson disease for 2 years or less at Screening.

- Confirmation from imaging core that screening DAT scan is consistent with dopamine
transporter deficit, or if applicable a VMAT-2 PET scan consistent with vesicular
monoamine transporter deficit.

- Not expected to require PD medication with at least 6 months from Baseline.

- Male or female age 30 years or older at time of PD diagnosis.

Healthy Control (HC) Subjects:

• Male or female age 30 years or older at Screening.

Exclusion Criteria:

Parkinson Disease (PD) Subjects:

- Currently taking levodopa, dopamine agonists, MAO-B inhibitors, amantadine or other PD
medication.

- Has taken levodopa, dopamine agonists, MAO-B inhibitors or amantadine within 60 days
of Baseline.

- Has taken levodopa or dopamine agonists prior to Baseline for more than a total of 60
days.

- Received any of the following drugs that might interfere with DAT imaging:
Neuroleptics, metoclopramide, alpha methyldopa, methylphenidate, reserpine, or
amphetamine derivative, within 6 months of Screening.

- Current treatment with anticoagulants (e.g., coumadin, heparin) that might preclude
safe completion of the lumbar puncture.

If applicable, currently taking medications that are known to cause QT-prolongation, or are
currently taking tetrabenazine (TBZ or amphetamine type medications.

- Condition that precludes the safe performance of routine lumbar puncture, such as
prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant
coagulopathy or thrombocytopenia.

- Use of investigational drugs within 60 days prior to Baseline (dietary supplements
taken outside of a clinical trial are not exclusionary, e.g., coenzyme Q10).

Healthy Control (HC) Subjects:

- Current or active neurological disorder.

- First degree relative with idiopathic PD (parent, sibling, child).

- MoCA score < 26.

- Received any of the following drugs that might interfere with DAT imaging:
Neuroleptics, metoclopramide, alpha methyldopa, methylphenidate, reserpine, or
amphetamine derivative, within 6 months of Screening.

If applicable, currently taking medications that are known to cause QT-prolongation, or are
currently taking tetrabenazine (TBZ) or amphetamine type medications.

- Current treatment with anticoagulants (e.g., coumadin, heparin) that might preclude
safe completion of the lumbar puncture.

- Condition that precludes the safe performance of routine lumbar puncture, such as
prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant
coagulopathy or thrombocytopenia.

- Use of other investigational drugs within 60 days prior to baseline (dietary
supplements taken outside of a clinical trial are not exclusionary, e.g., coenzyme
Q10).

SWEDD Subjects:

All PD criteria apply, as above, except a SWEDD subject must have confirmation from imaging
core that screening dopamine transporter SPECT scan shows no evidence of dopamine
transporter deficit or if applicable a VMAT-2 PET scan shows no evidence of vesicular
monoamine transporter deficit.

Prodromal Subjects:

Inclusion Criteria (Prodromal Subjects) 4.2.7.1. Subjects must have at least one of the
following characteristics:

Hyposmia:

1. Male or female age 60 years or older

2. Confirmation from olfactory core that olfaction as determined by UPSIT is at or below
the 10th percentile by age and gender

REM Behavior Disorder (RBD):

1. Male or female age 60 years or older

2. Confirmation from sleep core that subject's Polysomnography (PSG) meets criteria for
RBD

LRRK2:

1. Male or female age 60 years or older

2. Written confirmation or documentation from testing facility that the individual is
LRRK2 mutation positive 4.2.7.2. Confirmation from imaging core that screening
dopamine transporter SPECT scan is read as eligible (see below). About 80 subjects
will have a range of DAT deficit similar to subjects with early PD (mild to moderate
DAT deficit). About 20 subjects will be selected with no DAT deficit or minimal DAT
deficit similar in age, gender, and risk profile to those with mild to moderate DAT
deficit. 4.2.7.3. Ability to provide written informed consent in accordance with Good
Clinical Practice (GCP), International Conference on Harmonization (ICH), and local
regulations. 4.2.7.4. Willing and able to comply with scheduled visits, required study
procedures and laboratory tests. 4.2.7.5. Women may not be pregnant, lactating or
planning pregnancy during the course of the study. Includes a negative urine pregnancy
test on day of screening scan prior to injection (DaTSCAN).

Exclusion Criteria (Prodromal Subjects)

1. Current or active clinically significant neurological disorder or psychiatric disorder
(in the opinion of the Investigator).

2. GDS score greater than or equal to 10 (GDS score of 5 - 9 requires Investigator
discretion to enter study).

3. STAI Form Y-1 greater than or equal to 54 requires Investigator discretion to enter
study.

4. A clinical diagnosis of dementia63 as determined by the investigator (Appendix 1).

5. A clinical diagnosis of Parkinson disease at the Screening visit as determined by the
Investigator.

6. Received any of the following drugs that might interfere with dopamine transporter
SPECT imaging: Neuroleptics, metoclopramide, alpha methyldopa, methylphenidate,
reserpine, or amphetamine derivative, within 6 months of Screening.

7. Current treatment with anticoagulants (e.g., coumadin, heparin) that might preclude
safe completion of the lumbar puncture.

8. Condition that precludes the safe performance of routine lumbar puncture, such as
prohibitive lumbar spinal disease, bleeding diathesis, or clinically significant
coagulopathy or thrombocytopenia.

9. Any other medical or psychiatric condition or lab abnormality, which in the opinion of
the investigator might preclude participation.

10. Use of investigational drugs or devices within 60 days prior to Baseline (dietary
supplements taken outside of a clinical trial are not exclusionary, e.g., coenzyme
Q10).

11. Previously obtained MRI scan with evidence of clinically significant neurological
disorder (in the opinion of the Investigator).