Imaging Biomarkers in Parkinson's Disease

Background:

- Parkinson's disease (PD) causes slow movement, stiffness, and tremor. It results from the loss of a brain chemical called dopamine. PD gets worse over time, but researchers do not fully understand why the brain cells that produce dopamine stop working or die in people with PD. This study will use different ways of imaging the brain and brain chemicals to look at PD. It will compare brain imaging in people who definitely have PD to people who might have PD and to people without signs of PD. It will provide more information how the brain in people with PD changes over time.

Objectives:

- To understand the changes that occur in the brains of people with Parkinson's disease.

Eligibility:

• Individuals at least 18 years of age who have definite or possible Parkinson's disease.
• Healthy volunteers at least 18 years of age.

Design:

• Participants will have a screening visit with a physical exam and medical history. Blood and urine samples will be collected.
• Participants will visit the National Institutes of Health Clinical Center once a year for 9 years. There will be 10 total visits. Most visits will last 5 to 6 hours a day for 2 to 3 days. Some or all of the following tests will be performed at each visit:
• Transcranial sonography, which uses sound waves to take pictures of the brain.
• Magnetic resonance imaging to take pictures of the brain. Some of these tests will be done at rest. Others will require participants to perform an activity during the scan.
• Dopamine imaging studies to show how the brain uses the chemical dopamine.
• Magnetoencephaolgraphy to show brain activity.
• Electromyography to show muscle activity.
• Medication withdrawal for 12 hours overnight for people taking PD medications. This may be done before some scans. Participants who feel unwell when they stop taking medications will be allowed to start taking them again.
• Participants will continue with the followup visits until the end of the study.

Objectives:

The purpose of this protocol is to evaluate possible biomarkers for diagnosis and assessment of disease progression in Parkinson disease (PD) through multi-modal neuroimaging studies. The study will have two parts:

1. Part 1: Compare brain images of PD subjects and healthy volunteers (HVs) using various imaging techniques in a case-control analysis.
2. Part 2: Compare findings on serial brain images with clinical assessments of PD subjects, subjects with early parkinsonism and healthy volunteers over the following 9 years. The findings from this exploratory study will help develop additional hypothesis-driven studies investigating PD pathology. PD patients will yield information about how biomarkers change over time; the patients with early parkinsonism will give information as to which biomarkers might predict the development of PD.

Study Population:

Part 1 (Case-control study): We will study 30 patients with well-defined PD, as defined by the UK Parkinson's Society Brain Bank diagnostic criteria [1-3]. We will also study 15 age-matched healthy volunteers (HVs) as controls.

Part 2 (Longitudinal study): We will continue to study all of the subjects from Part 1 periodically over the following 9 years. We will also study 30 subjects with early parkinsonism (EP). EP subjects are defined as individuals who have experienced at least one but fewer than 3 of the cardinal symptoms of PD at the time of enrollment.

Design:

Part 1: (Case-control study). Eligible participants will come for a 2-3 day visit. They will have a clinical assessment, brain ultrasound (transcranial sonography or TCS), dopamine transporter single photon emission computed tomography (DAT SPECT) scan, a magnetic resonance (MR) scan, and magnetoencephalography (MEG). Subjects on Parkinson medications may have 2-3 additional MR scans in the off medications condition as tolerated.

Part 2: (Longitudinal study). PD and EP subjects will be asked to follow-up annually for a total of 10 visits. After a screening visit, HV subjects will be asked to follow up annually for the first 3 years, and then every 3 years for the following 6 years, for a total of 6 visits. Each follow-up will involve a 2-3 day visit and will consist of repeat clinical evaluations and imaging studies (TCS, SPECT, MEG, MR scans).

Outcome Measures:

1. MRI: To measure the difference in susceptibility in iron-rich structures (using susceptibility weighted imaging); the difference in fractional anisotropy between seed and target regions of interest (using DTI); the difference in gray and white mattervolume of brain regions (using VBM); fluctuations of the blood oxygen level dependent (BOLD) signal during resting state (using fMRI); and the signal amplitude of phosphorus-containing compounds and neurotransmitters in brain regions of interest (ROIs) (using MRS).
2. TCS: To measure parameters such as the difference in the area of increased signal (hyperechogenicity) seen in brain structures such as the substantia nigra (SN).
3. SPECT: To measure the amount of dopamine reuptake in the striatal part of the brain.
4. MEG: To quantify measures such as task-related potentials, relative spectral power, and synchronization.

• Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 2010 Jan 26;8(1):e1000298.
• Olanow CW, Stern MB, Sethi K. The scientific and clinical basis for the treatment of Parkinson disease (2009). Neurology. 2009 May 26;72(21 Suppl 4):S1-136. Review.
• Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol. 2008 Jan;7(1):97-109. Review.

• INCLUSION CRITERIA:

For all subjects:

1. Age 18 or older
2. Able to abstain from caffeine and alcohol for 48 hours before each visit.

For PD cohort:

1. Must demonstrate at least 3 of the following features of PD: bradykinesia, resting tremor, cogwheel rigidity or postural reflex impairment.
2. At least one of the 3 clinical features must be resting tremor or bradykinesia.
3. Currently taking or history of taking dopaminergic therapy with symptomatic response.
4. Able to give informed consent or, if there is evidence of cognitive decline, able to appoint a durable power of attorney (DPA) who can give informed consent.

For EP cohort:

1. Have experienced at least one but fewer than three of the cardinal symptoms of PD (rest tremor, bradykinesia, rigidity) at the time of enrollment.
2. Able to give informed consent or, if there is evidence of cognitive decline, able to appoint a durable power of attorney (DPA) who can give informed consent

EXCLUSION CRITERIA:

Exclusion criteria for all subjects:

1. Use of illegal drugs within the past 6 months
2. More than 7 alcoholic drinks a week for females or 14 alcoholic drinks a week for males.
3. History of a neurologic disorder such as a brain tumor, stroke, central nervous system infection, multiple sclerosis, a movement disorder epilepsy or a history of seizures.
4. History of any head injury with loss of consciousness
5. Pregnancy or positive pregnancy test before the research procedure due to the risks associated with MRI and SPECT scans. This would exclude subjects from participating in the protocol.
6. Inability to lie flat on the back for up to 2 hours
7. Claustrophobia or a feeling of discomfort from being in small, enclosed spaces.
8. Surgically or traumatically implanted metallic foreign bodies, such as pacemakers, implanted medical pumps, implanted hearing aids, metal plates in the skull or metal implants in the skull or eyes (other than dental fillings) that may be physically hazardous during an MRI, or might distort the images.
9. Ablative surgery or implanted electrodes and generator for deep brain stimulation
10. Use of the following medications or substances within 6 months of getting DAT SPECT scan: Cocaine, amphetamines, methylphenidate, ephedrine, phentermine, buproprion, fentanyl, ketamine, phencyclidine.
11. Use of the following therapies which may affect mitochondrial function: Coenzyme Q10, vitamin E, vitamin C, anti-retroviral drugs, chemotherapeutic agents, anti-epileptics agents or antibiotics. (Use of these substances will prevent getting MRS scan only).
12. Have uncontrolled head movements that may impair image data collection (for PD and EP cohorts)
13. Have clinically relevant focal neurological findings on exam that suggest cerebral pathology other than that associated with parkinsonism (for PD and EP cohorts)
14. Any abnormal or focal finding on neurological exam (for healthy volunteer cohort only).