Cholinergic Mechanisms of Attentional-motor Integration and Gait Dysfunction in Parkinson Disease (UDALL)

November 27, 2023 updated by: Nicolaas Bohnen, MD, PhD, University of Michigan
To perform a prospective cohort study with [(18)F]fluoroethoxybenzovesamicol (FEOBV) brain PET at baseline and 2-year follow-up in PD subjects at risk of conversion to non-episodic and episodic (falls and FoG) PIGD motor features and cognitive changes at the same time points.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Postural instability and gait difficulty (PIGD) motor and cognitive changer features are common in Parkinson disease (PD), and a significant cause of treatment-refractory disability. Accumulating evidence implicates cholinergic systems dysfunctions as significant contributors to gait and balance and cognitive impairment. During the initial funding period, the investigators established the vesicular acetylcholine transporter (VAChT) ligand FEOBV, which uniquely assesses cholinergic terminal density in high density regions such as the striatum. Recent cross-sectional findings suggest that people with Parkinson's (PwP) participants with isolated falls and those with freezing of gait (FoG) status share common cholinergic deficits in the thalamus (lateral geniculate nucleus (LGN)) and striatum (caudate) with more extensive striatal, limbic, and prefrontal VAChT reductions in PwP with FoG. These data suggest that SChI deficits are a common denominator in the etiology of falls and FoG. These results emphasize the need to understand PIGD, falls, and FoG as products of cholinergic projection dysfunctions within the framework of failing Attentional-Motor Integration (AMI) combined with failures of additional multisensory and cognitive integration.

There is novel preliminary data that cholinergic deficits of the medial geniculate nucleus (MGN) and the entorhinal cortex (ERC) are robustly associated with non-episodic PIGD deficits. These results imply a significant role of impaired sensorimotor integration underlying non-episodic PIGD motor features in PwP. There is also have novel data that cholinergic changes in the cingulo-opercular task control network (COTC) are a robust correlate of cognitive changes in PwP. The overarching goal of this project is to investigate the evolution of cholinergic deficits within multisensory, cognitive and motor integration brain regions and development of PIGD features and cognitive deficits in PwP. This study will perform a prospective cohort study with FEOBV brain PET at baseline and 2-year follow-up.

Study Type

Interventional

Enrollment (Estimated)

125

Phase

  • Not Applicable

Contacts and Locations

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

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Michigan
      • Ann Arbor, Michigan, United States, 48106
        • Recruiting
        • University of Michigan - Michigan Medicine
        • Contact:
        • Principal Investigator:
          • Nicolaas Bohnen, M.D., Ph.D.

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

Ages Eligible for Study

21 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Study Population

Age 21 and over

Description

Inclusion Criteria:

  • Age ≥21 for normal control subjects (Male/Female) and ≥45 for Parkinson's disease (PD), Progressive supranuclear palsy (PSP), or Alzheimer's disease (AD) participants (Male/Female).
  • For normal control subjects, no significant neurological or psychiatric symptoms and normal neuropsychological examination for age.
  • PD diagnosis (with or without Mild Cognitive Impairment/dementia) will follow the Movement Disorder Society-revised clinical diagnostic criteria for PD or Parkinson-PSP patients.
  • Modified Hoehn and Yahr stages 1-4.
  • AD subjects meeting the criteria listed in Guy M. McKhann et al.
  • All PD subjects are required to have nigrostriatal dopaminergic denervation as demonstrated by vesicular monoaminergic transporter type-2 (VMAT) [18F]9-fluoropropyl-(+)-dihydrotetrabenazine (DTBZ) positron emission tomography (PET) imaging. This may be based on a prior DTBZ PET scan or the DTBZ PET scan performed as part of this study.

Exclusion Criteria:

  • Disorders which may resemble PD, such as dementia with Lewy bodies, vascular dementia, normal pressure hydrocephalus, multiple system atrophy, corticobasal ganglionic degeneration, or toxic causes of parkinsonism. The use of the Movement Disorder Society-revised clinical diagnostic criteria will mitigate the inclusion of PD subjects with atypical parkinsonism.
  • Subjects on neuroleptic, anticholinergic (trihexyphenidyl, benztropine), or cholinesterase inhibitor drugs. Subjects with prior exposure to disallowed medications may be eligible if there has been an interval of > 2 months off these medications.** Note that patients on pimavanserin will be eligible.
  • Evidence of a large vessel stroke in a clinically relevant area (cerebral cortex, basal ganglia, thalamus) or mass lesion on structural brain imaging (MRI or CT).**
  • 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, or cochlear implant.**
  • Severe claustrophobia precluding MR or PET imaging.**
  • Subjects limited by previous participation in research procedures involving ionizing radiation.**
  • Pregnancy (test within 48 hours of each PET session) or breastfeeding.**
  • History of deep brain stimulation surgery.**
  • Suicidality (responses 2 or 3 for question 9 on the Beck Depression Inventory).
  • Subjects from the previous U-M Udall Center cohort who have developed a contraindication for neuroimaging procedures (Exclusion criteria #4 - #9) or have started taking cholinergic medications (Exclusion criterion #3) will be eligible to continue their participation in clinical assessments but will not be referred to neuroimaging assessments.

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

  • Primary Purpose: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Parkinson's Disease
Individuals with idiopathic Parkinson's disease.
Radiation: (18)F]fluoroethoxybenzovesamicol ([(18)F (FEOBV) PET
Participants will receive an injection of 8 mCi [18F]FEOBV PET tracer and undergo a CT of the head.
Radiation: Dihydrotetrabenazine (DTBZ) PET
Participants will receive an injection of 15 mCi [11C]DTBZ PET tracer and undergo a CT of the head.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cholinergic brain PET FEOBV PET distribution volume ratio (DVR) interval change over a 2-yr period
Time Frame: At Baseline and at 2-year follow up
Interval change baseline vs 2-yr follow in cholinergic brain FEOBV PET DVR
At Baseline and at 2-year follow up
Interval change on the Unified Parkinson's disease rating scale (UPDRS) motor rating scale over a 2-yr period
Time Frame: At Baseline and at 2-year follow up
Interval change baseline vs 2-yr follow-up on the UPDRS motor score. UPDRS motor section is scored from 0-132, with higher scores indicating more severe motor symptoms.
At Baseline and at 2-year follow up
Cognitive 2-yr interval change on the Montreal Cognitive Assessment (MoCa) cognitive scale
Time Frame: At Baseline and at 2-year follow up
Interval change baseline vs 2-yr follow-up on the Montreal Cognitive Assessment (MoCa) cognitive scale. The MoCa is scored out of 30, with higher scores indicating better cognition.
At Baseline and at 2-year follow up

Collaborators and Investigators

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

Sponsor

University of Michigan

Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

  • Principal Investigator: Roger Albin, MD, University of Michigan

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)

March 1, 2022

Primary Completion (Estimated)

June 30, 2026

Study Completion (Estimated)

June 30, 2026

Study Registration Dates

First Submitted

July 1, 2022

First Submitted That Met QC Criteria

July 12, 2022

First Posted (Actual)

July 15, 2022

Study Record Updates

Last Update Posted (Actual)

November 28, 2023

Last Update Submitted That Met QC Criteria

November 27, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HUM00197590
  • 1P50NS123067-01 (U.S. NIH Grant/Contract)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

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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