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

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Brief Title

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

Official Title

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

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.
    

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 Type

Observational [Patient Registry]


Primary Outcome

Interval change on the Unified Parkinson's disease rating scale (UPDRS) motor rating scale over a 2-yr period


Condition

Parkinson Disease



Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

140

Start Date

March 1, 2022

Completion Date

June 30, 2026

Primary Completion Date

June 30, 2026

Eligibility Criteria

        Inclusion Criteria:

          1. Age ≥21 for normal control subjects (Male/Female) and ≥45 for PD subjects
             (Male/Female).

          2. Parkinson's Disease (PD) diagnosis (with or without Mild Cognitive Impairment) will
             follow the Movement Disorder Society-revised clinical diagnostic criteria for PD.

          3. 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:

          1. Presence of clinically significant dementia.

          2. 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.

          3. 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.**

          4. 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).**

          5. 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.**

          6. Severe claustrophobia precluding MR or PET imaging.**

          7. Subjects limited by previous participation in research procedures involving ionizing
             radiation.**

          8. Pregnancy (test within 48 hours of each PET session) or breastfeeding.**

          9. History of deep brain stimulation surgery.**

         10. 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.

        Inclusion criteria normal control subjects:

        No significant neurological or psychiatric symptoms and normal neuropsychological
        examination for age.
      

Gender

All

Ages

21 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Roger Albin, MD, 734-998-8421, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT05459753

Organization ID

HUM00197590

Secondary IDs

1P50NS123067-01

Responsible Party

Principal Investigator

Study Sponsor

University of Michigan

Collaborators

 National Institute of Neurological Disorders and Stroke (NINDS)

Study Sponsor

Roger Albin, MD, Principal Investigator, University of Michigan


Verification Date

July 2022