Imaging Biomarkers in Parkinson s Disease

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.