Amyloidopathy, Cholinopathy, Dopamine Responsiveness and Freezing of Gait in PD

Completed

Conditions: Parkinson's Disease

Interventions: Other: Detailed motor testing, including FoG, in PD subjects

Registration Number: NCT03647137

Lead Sponsor: VA Office of Research and Development

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 53

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 & Design

Study Type: OBSERVATIONAL

Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Parkinson's disease without FoG	Detailed motor testing, including FoG, in PD subjects	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).
Parkinson's disease with FoG equivalent between on and off meds	Detailed motor testing, including FoG, in PD subjects	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).
Parkinson's disease with FoG only while off-meds	Detailed motor testing, including FoG, in PD subjects	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).
Parkinson's disease with FoG worse while off-meds	Detailed motor testing, including FoG, in PD subjects	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).

Primary Outcome Measures

Name	Time	Method
Striatal FEOVB PET Binding	through study completion, an average of 6 months	Parametric distribution volume ratio (DVR) of FEOVB, a cholinergic PET tracer, in the striatum.
Striatal DTBZ PET Binding	through study completion, an average of 6 months	Parametric distribution volume ratio (DVR) of DTBZ, a dopaminergic PET tracer, in the striatum.
L-DOPA Insensitivity	through study completion, an average of 6 months	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.
Striatal PIB PET Binding	through study completion, an average of 6 months	Parametric distribution volume ratio (DVR) of PIB, an amyloid PET tracer, in the striatum.

Secondary Outcome Measures

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