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

Sponsor

University of Michigan (Other)

Overall Status

Recruiting

CT.gov ID

NCT05459753

Collaborator

National Institute of Neurological Disorders and Stroke (NINDS) (NIH)

140

Enrollment

Location

Anticipated Duration (Months)

2.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To perform a prospective cohort study with 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.

Condition or Disease	Intervention/Treatment	Phase
Parkinson Disease Progressive Supranuclear Palsy

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 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 Design

Study Type:

Observational [Patient Registry]

Anticipated Enrollment :

140 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

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

Actual Study Start Date :

Mar 1, 2022

Anticipated Primary Completion Date :

Jun 30, 2026

Anticipated Study Completion Date :

Jun 30, 2026

Outcome Measures

Primary Outcome Measures

Interval change on the Unified Parkinson's disease rating scale (UPDRS) motor rating scale over a 2-yr period [At Baseline and at 2-year follow up]
Interval change baseline vs 2-yr follow-up on the UPDRS motor score
Cholinergic brain PET FEOBV PET distribution volume ratio (DVR) interval change over a 2-yr period [At Baseline and at 2-year follow up]
Interval change baseline vs 2-yr follow in cholinergic brain FEOBV PET DVR
Cognitive 2-yr interval change on the MoCa (Montreal Cognitive Assessment) cognitive scale [At Baseline and at 2-year follow up]
Interval change baseline vs 2-yr follow-up on the MoCa cognitive scale

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Age ≥21 for normal control subjects (Male/Female) and ≥45 for PD subjects (Male/Female).
Parkinson's Disease (PD) diagnosis (with or without Mild Cognitive Impairment) will follow the Movement Disorder Society-revised clinical diagnostic criteria for PD.
All PD subjects are required to have nigrostriatal dopaminergic denervation as demonstrated by vesicular monoaminergic transporter type-2 (VMAT) 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:

Presence of clinically significant dementia.
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 (trihexiphenidyl, 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.**
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. **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.