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

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: Completed
• Conditions: Parkinson's Disease
• Intervention / Treatment: Other: Detailed motor testing, including FoG, in PD subjects

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: Observational
• Enrollment (Actual): 53

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• 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

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
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

Outcome Measure	Measure Description	Time Frame
L-DOPA Insensitivity	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	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	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	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

Outcome Measure	Measure Description	Time Frame
Serotonergic Innervation of Striatum and Freezing	Serotonergic innervation of striatum as assessed by DASB PET scan across freezer groups.	through study completion, an average of 6 months

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: University of Michigan
• Investigators: Principal Investigator: Nicolaas I Bohnen, MD PhD, VA Ann Arbor Healthcare System, Ann Arbor, MI

Study record dates

Study Major Dates

• Study Start (Actual): June 7, 2016
• Primary Completion (Actual): May 26, 2021
• Study Completion (Actual): May 26, 2021

Study Registration Dates

• First Submitted: August 23, 2018
• First Submitted That Met QC Criteria: August 23, 2018
• First Posted (Actual): August 27, 2018

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: March 29, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: MRI; imaging; amyloid; PET; mobility; freezing of gait; cholinergic
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease
• Other Study ID 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