Imaging Biomarkers in Parkinson s Disease

Imaging Biomarkers in Parkinson 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.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease

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.

• Study Type: Observational
• Enrollment (Actual): 62

Contacts and Locations

• Study Contact: Name: Myriam E Martinez Vega, R.N.; Phone Number: (301) 496-9526; Email: myriam.martinez@nih.gov
• Study Contact Backup: Name: Silvina G Horovitz, Ph.D.; Phone Number: (301) 435-2163; Email: silvina.horovitz@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• 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.

Description

• 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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Healthy Volunteers; Subjects without PD diagnosis
Parkinsons Disease subjects; Subjects fitting the MSD Clinical Diagnostic Criteria for PD
Prodromal Parkinson disease; Subjects fitting the MDS prodromal criteria for PD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Using MRI, we will measure signal intensities of iron-rich structures using T2 sequences and calculate phase shift values in these structures with susceptibility weighted sequences. We will also measure clinical symptom severity with the UPDRS s...	-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.	10 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	10 years
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.	10 years
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.	10 years

Collaborators and Investigators

• Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Silvina G Horovitz, Ph.D., National Institute of Neurological Disorders and Stroke (NINDS)

Publications and helpful links

General Publications

• 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. doi: 10.1371/journal.pbio.1000298.
• 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. doi: 10.1212/WNL.0b013e3181a1d44c.
• Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol. 2008 Jan;7(1):97-109. doi: 10.1016/S1474-4422(07)70327-7.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): January 24, 2012

Study Registration Dates

• First Submitted: December 17, 2011
• First Submitted That Met QC Criteria: December 17, 2011
• First Posted (Estimated): December 21, 2011

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: March 4, 2024

More Information

Terms related to this study

• Keywords: HV; Natural History; Healthy Volunteer; Parkinson's Disease; Parkinson Disease; Brain Imaging; PD; Parkinsonism
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease
• Other Study ID Numbers: 120031; 12-N-0031

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: .We will share IPD and data dictionaries that underlie results in a publication. The data sharing will be restricted to those subjects whom have agreed to data sharing, and those authorized by the IRB if re-consenting were not an option.
• IPD Sharing Time Frame: Starting 1 year after publication.
• IPD Sharing Access Criteria: IPD will be shared with qualified investigators, if allowed by IRB@@@@@@Any request for data sharing will be first reviewed by the protocol PI. @@@@@@The request must include the proposed use of the data. When requested data has IRB approval for data sharing, and the PI considers it a reasonable request, a memo of understanding will be signed by the parts, including the allowed use for the data. This will be done in consultation with the office of Tech Transfer.
• IPD Sharing Supporting Information Type: CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No