Clinical trial NCT03647137: Amyloidopathy, Cholinopathy, Dopamine Responsiveness and Freezing of Gait in PD
Official title: Amyloidopathy, Cholinopathy, Dopamine Responsiveness and Freezing of Gait in PD
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Parkinson's Disease
Keywords: freezing of gait
amyloid
cholinergic
mobility
PET
imaging
MRI
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: University of Michigan
First posted: 2018-08-27
Enrollment: 53
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
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

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: L-DOPA Insensitivity
timeFrame: through study completion, an average of 6 months
measure: Striatal FEOVB PET Binding
timeFrame: through study completion, an average of 6 months
measure: Striatal DTBZ PET Binding
timeFrame: through study completion, an average of 6 months
measure: Striatal PIB PET Binding
timeFrame: through study completion, an average of 6 months
Secondary outcomes:
measure: Serotonergic Innervation of Striatum and Freezing
timeFrame: through study completion, an average of 6 months
Other outcomes:
Locations:
city: Ann Arbor
country: United States
facility: VA Ann Arbor Healthcare System, Ann Arbor, MI
state: Michigan
Study officials:
affiliation: VA Ann Arbor Healthcare System, Ann Arbor, MI
name: Nicolaas I Bohnen, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: