Biomarkers of Risk of Parkinson Disease

Objective: This Protocol is to test whether individuals with statistical risk factors for
Parkinson disease (PD) have abnormal values for biomarkers of central or peripheral
catecholaminergic innervation and whether at-risk individuals with positive biomarkers
develop PD within up to 7.5 years of follow-up.

Study Population: The subjects are individuals who may be at risk for developing PD, because
of (a) genetic risk i.e., a family history of PD or genotypic abnormalities known to be
associated statistically with PD; (b) olfactory dysfunction i.e., decreased ability to
distinguish among odors; (c) symptomatic rapid eye movement (REM) sleep behavior disorder
(RBD); or (d) orthostatic hypotension. A total of 200 at-risk subjects undergo
catecholaminergic biomarker testing by (18)F-DOPA brain and (18)F-dopamine cardiac scanning.
At-risk subjects with positive biomarkers are compared to at-risk subjects without positive
biomarkers, in terms of development of PD during follow-up. Up to 20 control subjects are
included, to add to a database of normal values for catecholaminergic biomarkers.

Design: The study includes four phases recruitment, screening, laboratory biomarkers testing,
and follow-up. Recruitment is by advertisement and a web site questionnaire of self-reported
risk. A screening examination is done at the NIH Clinical Center, to confirm risk status.
Based on the screening examination results, subjects undergo inpatient clinical laboratory
testing, to identify central and peripheral catecholaminergic denervation. In the follow-up
phase, subjects are re-tested as inpatients approximately every 18 months for a total of up
to 5 re-evaluations (90 months, or 7.5 years), to detect the onset of the characteristic
movement disorder in PD and follow the status of catecholaminergic innervation.

Outcome Measures:

Primary: Diagnosis of PD by a Board-certified neurologist who is blinded to risk factor
status and the results of catecholaminergic biomarkers testing. If PD diagnosed, time to
diagnosis.

Secondary: UPDRS; (18)F-DOPA brain scanning, (18)F-dopamine cardiac scanning; CSF and plasma
neurochemicals; neuropsychological rating scales; autonomic function testing, retrospective
CSF proteomics; retrospective DNA analyses.

- INCLUSION CRITERIA:

Individuals who report at least 3 of the following 4 risk factors at the protocol-specific
website may be invited to the Screening Examination. All subjects must have ability to
provide their own consent for participation in the study. Otherwise eligible candidate
participants who are taking medications that would interfere with the scientific results
may be included, if (1) the medications are held temporarily or safely substituted for, and
(2) the medications are held while the participants are inpatients. The prescribing
physician will be contacted, with the participant's permission, if withholding or
substituting medication is considered.

1. Genetic Risk: A positive family history (one immediate or more than one non-immediate
family member with PD) or positive genetic testing (e.g., LRRK2, alpha-synuclein,
glucocerebrosidase) satisfies this risk factor criterion.

2. Olfactory Dysfunction: Olfactory dysfunction reported at the protocol-specific website
satisfies this criterion. This may be confirmed by the UPSIT sent by mail prior to the
Screening Examination.

3. REM Behavior Disorder (RBD): To satisfy this risk factor criterion, the individual
must have movements of the body or limbs associated with dreaming and at least one of
the following: potentially harmful sleep behavior, dreams that appear to be acted out,
and sleep behavior that disrupts sleep continuity.

4. Orthostatic Hypotension (OH): To satisfy this risk factor criterion, the individual
reports symptoms of orthostatic hypotension or having orthostatic hypotension at the
protocol-specific website. This may be confirmed by orthostatic vital signs prior to
the Screening Examination.

EXCLUSION CRITERIA:

1. Age: People younger than 18 years old or older than 70 years old are excluded.

2. Risk: A candidate subject is excluded if, in the judgment of the Principal
Investigator, Protocol participation would place the subject at substantially
increased acute medical risk. This includes the risks associated with air travel to
the NIH. A candidate subject may be excluded from the study if, in the opinion of the
Principal Investigator or Clinical Director, the medical risk outweighs the potential
scientific benefit. An example of such risk is inability to travel safely to the NIH
Clinical Center, in Bethesda, Maryland, due to a neurological disorder associated with
frequent falls.

3. Disqualifying Conditions: A candidate subject is excluded if there is a disqualifying
condition. Examples of disqualifying conditions are insulin-dependent diabetes,
hepatic or renal failure, symptomatic congestive heart failure, severe anemia,
psychosis, ventricular arrhythmias, and symptomatic coronary heart disease.

- Unable to Provide Consent: Persons who are unable to provide their own consent
(e.g., due to dementia) are excluded.

- MRI: Persons who are unable to undergo MRI safely, due to implanted metal, are
excluded from the MRI procedure.

- Safe Travel: A candidate participant is excluded if the person is unable to
travel safely to the NIH Clinical Center, in Bethesda, Maryland, such as due to a
neurological disorder associated with frequent falls.

4. Medications: A candidate subject is excluded if clinical considerations require
continued treatment with a drug likely to interfere with the scientific results.
Chronic, ongoing use of drugs such as tricyclic antidepressants that affect the
clinical laboratory results exclude candidate subjects. People with known or suspected
allergy or hypersensitivity to any test drug are excluded. Candidate subjects are not
to discontinue any medications before discussion with the Principal Investigator,
Research Nurse, Nurse Practitioner, or Clinical Fellow. Temporary discontinuation of
serotonin and norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine
(Effexor), duloxetine (Cymbalta), or des-venlafaxine (Pristiq) can result in rapid
rebound of depression or anxiety, and so treatment with SNRIs is exclusionary.

5. Herbal Medicines and Dietary Supplements: If a subject wishes to continue herbal
medicines or dietary supplements while on study, but a search of the available medical
identifies drug effects that are known or expected to interfere with the experimental
results, then the subject may be excluded, at the discretion of Principal Investigator

6. Practical Limitations: People in whom we feel it would be difficult to insert a
catheter into a vein may be excluded. People who are not expected clinically to
tolerate lying still supine during the testing will be excluded.

7. Pregnancy: Pregnant or lactating women are excluded