Amyloidopathy, Cholinopathy, Dopamine Responsiveness and Freezing of Gait in PD (FOG)

March 29, 2023 updated by: VA Office of Research and Development
Early stage Parkinson disease (PD) is characterized by a 'honeymoon' phase in terms of responsiveness of motor symptoms, including gait, to dopaminergic pharmacotherapy. Advancing PD is associated with disabling axial motor complications, such as freezing of gait (FoG), with decreased or even refractory dopamine responsiveness in over 50% of patients. The management of dopamine resistant gait problems represents the most important unmet need in PD. This study will related detailed motor testing to brain PET imaging to see if certain molecules (or lack thereof) involved with neurologic transmission in the brain are involved with FoG.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Early stage Parkinson disease (PD) is characterized by a 'honeymoon' phase in terms of responsiveness of motor symptoms, including gait, to dopaminergic pharmacotherapy. Advancing PD is associated with disabling axial motor complications, such as freezing of gait (FoG), with decreased or even refractory dopamine responsiveness in over 50% of patients. The management of dopamine resistant gait problems represents the most important unmet need in PD. At present, there is no biomarker of FoG in patients with PD as there is a lack of mechanistic understanding of dopamine nonresponsiveness of FoG. The investigators have previously identified cholinergic denervation as a prominent factor related to both falls and gait slowing in PD. The investigators recently identified that cortical -amyloid deposition not only associates with cognitive decline but also with postural instability and gait difficulties in PD. In this proposal, the investigators present preliminary data suggesting that FoG is associated with either cholinopathy, amyloidopathy or both in PD. The investigators propose to test the novel hypothesis that comorbid amyloidopathy may be a possible mechanistic factor underlying the poor response of FoG to dopaminergic therapy in advancing PD. In contrast, isolated cholinopathy would be expected to be associated with preserved dopamine responsiveness of FoG. For this purpose, the investigators propose to perform detailed motor, including FoG, testing in PD patients "on" and "off" their dopaminergic medications and relate this to dopaminergic 11C-dihydrotetrabenazine (DTBZ), vesicular acetylcholine transporter 18F-fluoroethoxybenzovesamicol (FEOBV) and -amyloid 11C-labeled Pittsburgh Compound-B (PIB) brain PET imaging in PD subjects with and without FoG. Furthermore, based on recent clinical observations that serotoninergic drugs, like the popular anti-depressant selective serotonin reuptake inhibitor (SSRI) drugs, are associated with significantly lower build- up of -amyloid plaques in the elderly population, and based on the investigators' subsequent observation of an intriguing inverse relationship between -amyloid plaque deposition and striatal serotoninergic terminal in PD, the investigators propose to perform an exploratory sub-study to test a new hypothesis that PD subjects with FoG will exhibit not only higher striatal -amyloid but also lower striatal serotoninergic innervation (as determined by 11C-DASB serotonin PET imaging) compared to PD subjects without FoG. If confirmed, positive findings in this study would allow the identification of different PD subgroups ('personalized medicine'), such as presence amyloidopathy or cholinopathy, to select patients for targeted pharmacotherapies to potentially prevent the development of FoG (anti-amyloid, such as serotoninergic drugs) or manage its clinical manifestation (cholinergic augmentation therapy) in order to preserve and maintain a good quality of life in individuals with PD.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
53

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Michigan
      • Ann Arbor, Michigan, United States, 48105
        • VA Ann Arbor Healthcare System, Ann Arbor, MI

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

50 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Community sample recruited from the following sources

  1. UMHS Movement Disorders Clinics
  2. VA Ann Arbor HS Movement Disorders Clinic
  3. Existing studies at Functional Neuroimaging, Cognitive, and Mobility Lab at the University of Michigan

Description

Inclusion Criteria:

  • PD based on the United Kingdom Parkinson's Disease Society Brain Bank
  • Diagnostic Research Criteria with or without Freezing of Gait
  • Duration of Disease > 5 years
  • Mini-Mental State Examination (MMSE) > 23

Exclusion Criteria:

  • Dementia
  • Dementia with Lewy Bodies
  • Other disorders which may resemble PD
  • Subjects on neuroleptic, anticholinergic (trihexyphenidyl, benztropine) or cholinesterase inhibitor drugs
  • Evidence of a stroke or mass lesion on structural brain imaging (MRI)

  • Participants in whom MRI is contraindicated including, but not limited to:

    • those with a pacemaker
    • presence of metallic fragments near the eyes or spinal cord
    • cochlear implant
  • Severe claustrophobia precluding MR or PET imaging
  • Subjects limited by participation in research procedures involving ionizing radiation
  • Pregnancy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Parkinson's disease without FoG
Subjects with Parkinson's disease that do not have freezing of gait observed during motor assessment while both on or off dopaminergic medication who have undergone Brain PET imaging of 11C-DBTZ, 18F-FEOBV (vesicular acetylcholine transporter, and 11C-PIB (beta-amyloid).
Other: Detailed motor testing, including FoG, in PD subjects
Subjects with PD with and without freezing of gait (FoG) will undergo a biomechanical assessment during a FoG provocation protocol in both the dopaminergic "on" and "off" state.
Parkinson's disease with FoG only while off-meds
Subjects with Parkinson's disease that have freezing of gait observed during motor assessment only while off dopaminergic medication who have undergone Brain PET imaging of 11C-DBTZ, 18F-FEOBV (vesicular acetylcholine transporter, and 11C-PIB (beta-amyloid).
Other: Detailed motor testing, including FoG, in PD subjects
Subjects with PD with and without freezing of gait (FoG) will undergo a biomechanical assessment during a FoG provocation protocol in both the dopaminergic "on" and "off" state.
Parkinson's disease with FoG worse while off-meds
Subjects with Parkinson's disease that have freezing of gait observed during motor assessment while both on and off dopaminergic medication, but greater severity of FoG under off-med, who have undergone Brain PET imaging of 11C-DBTZ, 18F-FEOBV (vesicular acetylcholine transporter, and 11C-PIB (beta-amyloid).
Other: Detailed motor testing, including FoG, in PD subjects
Subjects with PD with and without freezing of gait (FoG) will undergo a biomechanical assessment during a FoG provocation protocol in both the dopaminergic "on" and "off" state.
Parkinson's disease with FoG equivalent between on and off meds
Subjects with Parkinson's disease that have freezing of gait observed during motor assessment while both on and off dopaminergic medication, with no apparent effect of dopaminergic medication on FoG, who have undergone Brain PET imaging of 11C-DBTZ, 18F-FEOBV (vesicular acetylcholine transporter, and 11C-PIB (beta-amyloid).
Other: Detailed motor testing, including FoG, in PD subjects
Subjects with PD with and without freezing of gait (FoG) will undergo a biomechanical assessment during a FoG provocation protocol in both the dopaminergic "on" and "off" state.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
L-DOPA Insensitivity
Time Frame: through study completion, an average of 6 months
Participants are considered as L-DOPA insensitive if their freezing of gait is not observed to be any different between motor assessment while on dopaminergic medication and off dopaminergic medication.
through study completion, an average of 6 months
Striatal FEOVB PET Binding
Time Frame: through study completion, an average of 6 months
Parametric distribution volume ratio (DVR) of FEOVB, a cholinergic PET tracer, in the striatum.
through study completion, an average of 6 months
Striatal DTBZ PET Binding
Time Frame: through study completion, an average of 6 months
Parametric distribution volume ratio (DVR) of DTBZ, a dopaminergic PET tracer, in the striatum.
through study completion, an average of 6 months
Striatal PIB PET Binding
Time Frame: through study completion, an average of 6 months
Parametric distribution volume ratio (DVR) of PIB, an amyloid PET tracer, in the striatum.
through study completion, an average of 6 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Serotonergic Innervation of Striatum and Freezing
Time Frame: through study completion, an average of 6 months
Serotonergic innervation of striatum as assessed by DASB PET scan across freezer groups.
through study completion, an average of 6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
VA Office of Research and Development

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
University of Michigan

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Nicolaas I Bohnen, MD PhD, VA Ann Arbor Healthcare System, Ann Arbor, MI

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 7, 2016

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
May 26, 2021

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
May 26, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 23, 2018

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 23, 2018

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 27, 2018

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 5, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 29, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • B1631-I
  • HUM00110351 (Other Identifier: University of Michigan)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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