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Non-invasive Markers of Neurodegeneration in Movement Disorders (R01)

David Vaillancourt
PI:
David Vaillancourt, PhD
University of Florida (Gainesville, FL)

Summary

Several movement disorders such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and essential tremor (ET), share many of the signs and symptoms commonly used to diagnosis Parkinson's disease. During the early stages of these diseases and because of the similarities with Parkinson's disease, it is often difficult to accurately diagnose the disorder. Dr. Vaillancourt and his team are using non-invasive imaging techniques that enable them to take snapshots of an individual's brain at different stages of disease. These snapshots not only enable them to look at changes in the appearance of the brain, but also in how the brain is functioning and interacting with its various anatomical regions associated with movement and cognition. By identifying unique changes associated with brain structure and function for these disorders, Dr Vaillancourt's team hopes to provide both a better way for accurate and early diagnosis, as well as a method for tracking the effectiveness of new therapeutics for these disorders as they become available.

Study Information

Title: Non-invasive Markers of Neurodegeneration in Movement Disorders
PI Name: David Vaillancourt
Repository: Parkinson's Disease Biomarker Program
Status: Controlled Access
Funding Source: NIH-NINDS
Abstract: University of Florida, Gainesville, FL; 1 R01 NS075012-01A1; Study Description: Objective, valid, noninvasive, and biologically relevant markers of PD, MSA, PSP, and ET are pivotal for early and accurate diagnosis (trait), and for tracking disease progression (state). Dr. Vaillancourt?s group has recently shown that diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) can be used to identify mechanisms for basal ganglia dysfunction in individuals with Parkinson's disease. Preliminary data indicate that DTI and fMRI measures from the basal ganglia and cerebellum show excellent promise for differentiating PD, MSA, PSP, and ET, and for tracking longitudinal disease-specific changes in neurodegeneration. For fMRI assessment, the proposed study uses a grip force paradigm that has reliably shown reduced activity in all nuclei of the basal ganglia in patients with PD(1), and predicts severity of PD motor symptoms. Each patient will be tested off medication following an overnight withdrawal of medication. If a patient is taking a long-acting dopamine agonist, the patient will be off the specific medication for 72 hours prior to testing. # of subjects planned for enrollment: 150 Patient inclusion criteria: The diagnosis will be one of the following: PD based on the UK PD brain bank criteria; MSA Parkinsonian variant based on the American Academy of Neurology and American Autonomic Society; PSP based on the NINDS-PSP criteria; or ET based on the Consensus Statement from the Movement Disorders Society. Subjects will be recruited in the age range of 50 ? 75 years. Control inclusion criteria: The control subjects will consist of 15 male and 15 female subjects, also in the age range of 50 ? 75 years. All will be recruited by the Movement Disorder physicians and examined neurologically to ensure that they are neurologically healthy. # of PD participants: 30 # of Controls: 30 # of Essential Tremor (ET) participants:30 # of Multisystem Atrophy (MSA) participants: 30 # of Progressive Supranuclear Palsy participants: 30 Clinical Assessments: Baseline and 48 month PDBP visit assessments are collected. In addition, for Essential tremor the Fahn-Tolosa-Marin Tremor Rating Scale (TRS)(2) is collected at baseline and 48 month visits, for Multiple System Atrophy the Unified Multiple System Atrophy Rating Scale (UMSARS)(3) is collected at baseline and 48 month visits and for Progressive Supranuclear Palsy the Progressive Supranuclear Palsy Rating Scale (PSP-RS)(4) is collected for baseline and 48 month visits. PDBP Baseline and 48 month visit assessment ? Behavioral History, Demographics, Epworth Sleepiness Scale, Family History, Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HDRS), Informed Consent and Enrollment, MDS-UPDRS (Movement Disorder Society - Unified Parkinson's Disease Rating Scale), Modified Schwab and England Activities of Daily Living Scale, Montreal Cognitive Assessment (MoCA), Neurological Exam, PDBP Inclusion and Exclusion Criteria, PDQ-39, Prior and Concomitant Medications, Rapid Eye Movement Behavior Disorder Questionnaire, University of Pennsylvania Smell Identification Test (UPSIT) and Vital Signs Imaging Assessments: DTI and fMRI (grip force paradigm) at baseline and 48 month visits Types of biospecimens: DNA at baseline, RNA and serum at baseline visit and 48 month visit
Study ID: PDBP-STUDY0000202
Data Type: Clinical Assessment, Imaging
Study Type: Natural History
Grant ID: R01 NS075012
Study Started On: 2013-01-31
Study Completed On: 2014-11-28
Estimated number of Subjects: 204

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. Other movement disorders that commonly mimic symptoms of PD include the Parkinsonian variant of multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and essential tremor (ET). Taken together, these movement disorders affect over 10 million people in the United States alone. Current diagnostic approaches for PD, MSA, PSP, and ET are based on behavioral signs and clinical judgment, and this can often lead to the incorrect diagnosis, especially early in the course of the disease. In fact, it is estimated that 15% of patients in disease modifying drug trials for early PD do not have PD. Objective, valid, noninvasive, and biologically relevant markers of PD, MSA, PSP, and ET are pivotal for early and accurate diagnosis (trait), and for tracking disease progression (state). Our group has recently shown that diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) can be used to identify mechanisms for basal ganglia dysfunction in individuals with Parkinson's disease. Our preliminary data indicate that DTI and fMRI measures from the basal ganglia and cerebellum show excellent promise for differentiating PD, MSA, PSP, and ET, and for tracking longitudinal disease-specific changes in neurodegeneration. We will recruit 150 individuals for the study: 30 patients with PD, 30 patients with MSA, 30 patients with PSP, 30 patients with ET, and 30 control subjects. In Aim 1, we will use DTI and fMRI of the basal ganglia and cerebellum to focus on the development of a sensitive and specific trait marker for each movement disorder. In Aim 2, we will test the same individuals following 2 years using DTI and fMRI of the basal ganglia and cerebellum to develop state markers of neurodegeneration for each movement disorder. With the large and carefully diagnosed patient population at the Center for Movement Disorders and Neurorestoration and the state-of-the-art MRI facility at the McKnight Brain Institute, our group is uniquely positioned to complete the proposed study. The proposed research is innovative because it will utilize structural and functional imaging modalities with a 32-channel head coil performed on a state-of-the-art 3 Tesla MRI unit. The proposed research is significant because it will be the first study to develop non-invasive trait and state markers for four debilitating movement disorders that affect over 10 million people in the United States.

Goals

Goals of Project

  • Discovery: Establish neural signatures that differentiate MSA, PSP, ET and PD using diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI). Using DTI this study will test the hypothesis that changes in the structural integrity in the basal ganglia and cerebellum differentiate PD, MSA, PSP, ET and healthy controls. Motor fMRI will be used to test the hypothesis that functional changes in the basal ganglia and cerebellum will differentiate PD, MSA, PSP, ET and healthy controls. Advanced statistical methods will be used to combine DTI and fMRI measures to achieve maximum sensitivity and specificity.
  • Discovery: Demonstrate that changes in structural integrity and/or functional activity over a 2 year time period are specific for each movement disorder.

Enrollment Goals

  • 30 Parkinson's diseases participants
  • 30 Multisystem Atrophy particpants
  • 30 Progressive Supranuclear Palsy participants
  • 30 Essential Tremor participants
  • 30 Healthy participants (various ages)

Updates

Congratulations, to the University of Florida for enrolling 205 participants (100% of target enrollment) in their PD biomarkers program as of June 3, 2016, and completing, through the PDBP Data Management Resource, electronic documentation of 202 baseline visits and 95 twelve month visits!

Available Data Types

David Vaillancourt