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

NCT ID: NCT05459753

Last Updated: 2025-10-30

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 125 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-03-01
• Study Completion Date: 2026-06-30

Brief Summary

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.

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.

Conditions

Parkinson Disease; Progressive Supranuclear Palsy

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Parkinson's Disease

Individuals with idiopathic Parkinson's disease.

Group Type: EXPERIMENTAL

(18)F]fluoroethoxybenzovesamicol ([(18)F (FEOBV) PET

Intervention Type: RADIATION

Participants will receive an injection of 8 mCi \[18F\]FEOBV PET tracer and undergo a CT of the head.

Dihydrotetrabenazine (DTBZ) PET

Intervention Type: RADIATION

Participants will receive an injection of 15 mCi \[11C\]DTBZ PET tracer and undergo a CT of the head.

Interventions

(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.

Intervention Type: RADIATION

Dihydrotetrabenazine (DTBZ) PET

Participants will receive an injection of 15 mCi \[11C\]DTBZ PET tracer and undergo a CT of the head.

Intervention Type: RADIATION

Eligibility Criteria

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).

• Minimum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: collaborator

University of Michigan

OTHER

Sponsor Role: lead

Responsible Party

Nicolaas Bohnen, MD, PhD

Professor of Radiology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Roger Albin, MD

Role: PRINCIPAL_INVESTIGATOR

University of Michigan

Locations

University of Michigan - Michigan Medicine

Ann Arbor, Michigan, United States

Countries

United States

References

Barr J, Vangel R, Kanel P, Roytman S, Pongmala C, Albin RL, Scott PJH, Bohnen NI. Topography of Cholinergic Nerve Terminal Vulnerability and Balance Self-Efficacy in Parkinson's Disease. J Integr Neurosci. 2024 Sep 24;23(9):178. doi: 10.31083/j.jin2309178.

Reference Type: DERIVED

PMID: 39344233 (View on PubMed)

Other Identifiers

1P50NS123067-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

HUM00197590

Identifier Type: -

Identifier Source: org_study_id