Imaging Biomarkers in Parkinson s Disease
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.

 -  Participants will visit the National Institutes of Health Clinical Center every 18 month
 or 3 years for up to 9 years. There will be up to 6 total visits. Most visits will last
 5 to 6 hours a day for 1 to 3 days.

 Some or all of the following tests will be performed at each visit:

 -  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.

 -  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 follow up visits until the end of the study.
Objectives:

 The purpose of this protocol is to evaluate possible imaging 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 clinically
 defined PD subjects, subjects with prodromal Parkinson disease, 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 imaging outcomes change over time, and their relationship with
 disease progression; the patients with prodromal symptoms will give information as to
 which imaging modalities/analysis might predict the clinical manifestation of PD,
 healthy volunteers will serve as controls for subjects aging and technological changes
 due to scanner functioning.

 Study Population:

 Part 1 (Case-control study): 38 patients fitting the MSD Clinical Diagnostic Criteria
 for PD, and 38 age-matched healthy volunteers (HVs) as controls.

 Part 2 (Longitudinal study): We will continue to study qualifying subjects from Part 1
 periodically over the following 9 years. We will also study 38 subjects fitting the MDS
 prodromal criteria for PD for up to 9 years.

 Design:

 Part 1: (Case-control study). Eligible participants will come for a 1 to 3 day visit.
 They will have a clinical assessment, and a magnetic resonance (MR) scans.

 Part 2: (Longitudinal study).

 -Participants will be followed up for up to 9 years. Each visit will last 2-3 days,
 during which they will have several outpatient tests done. Visits will be scheduled
 according to the following plan:

 --Subjects without neurological disorder (HV) will be seen every three years for a

 total of 9 years.

 --Subjects with clinical PD for more than 5 years will be seen every three years for a

 total of 9 years.

 -  Subjects with clinical PD for less than 5 years will be seen every 18 months, until
 the 5y of diagnosis, and every three years after, for a total of 9 years.

 -  Subjects assigned to the Prodromal group will be seen will every 18 months, until
 the 5y of diagnosis if symptoms do not progress into neurodegeneration (up to 3
 visits), and until year 9 if symptoms progress towards PD.

 -  Subjects who participated in the cross-sectional part will be included in the
 longitudinal section if they fulfill the inclusion/exclusion criteria. New
 subjects can be enrolled to complete this section.

 Outcome Measures:

 Primary outcome measures:

 -  Structural MRI (SWI images): The primary outcome measure is the difference in
 susceptibility changes in iron-rich structures (ie. The SN, red nucleus, striatum)
 across groups and within groups over time.

 -  Clinical presentation: We will evaluate how the prodromal symptoms influence the
 progression to clinical PD.

 Secondary outcome measures:

 -  Structural MR (morphometry and diffusion analyses): The outcome measures are the
 differences in gray and white matter morphometry across groups and within groups
 over time. We will derive measures such as fractional anisotropy, trace, and
 parenchymal volume fractions as measures of fiber tract integrity, across groups
 and within groups over time.

 -  fMRI: The outcome measure for fMRI is the difference in resting state functional
 connectivity patterns as reflected by BOLD signal fluctuations and their dynamics
 across groups and over time.

 -  MRS: The outcome measure for MRS is the difference in the spectroscopy signal
 amplitude of phosphorus-containing compounds and neurotransmitters in the
 sensorimotor cortices and basal ganglia across groups and over time.
-  INCLUSION CRITERIA:

 For all subjects:

 -  Age 18 or older.

 -  Subjects must fulfill either the clinically defined PD, prodromal PD or not having any
 of the red flags following the MDS criteria for PD.

 -  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:

 -  More than 7 alcoholic drinks a week for females or 14 alcoholic drinks a week for
 males.

 -  History of a neurologic disorder such as a brain tumor, stroke, central nervous system
 infection, multiple sclerosis, a movement disorder other than the ones under study,
 epilepsy or a history of seizures or any abnormal or focal finding on neurological
 exam other than that associated with those studied in this protocol.

 -  History of any head injury with loss of consciousness

 -  Pregnancy or positive pregnancy test before the research procedure due to the risks
 associated with MRI scans. This would exclude subjects from participating in the
 protocol at that time.

 -  Inability to lie flat on the back for up to 2 hours

 -  Claustrophobia or a feeling of discomfort from being in small, enclosed spaces.

 -  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.

 -  Ablative surgery or implanted electrodes and generator for deep brain stimulation

 -  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 ofthese substances will prevent getting MRS scan only).

 -  Have uncontrolled head movements that may impair image data collection