Imaging Biomarkers in Parkinson s Disease
Condition: Parkinson Disease
MeSH terms: Parkinson Disease
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
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 (Hughes et al., 1992, Olanow et
        al., 2009, Defer et al., 1999). We will also study 15 age-matched healthy volunteers (HVs)
        as controls. Part 2 (Longitudinal study): We will continue to study 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.
      
Keywords: Brain Imaging; Parkinson's Disease; Parkinsonism; Natural History; Parkinson Disease; PD; Healthy Volunteer; HV