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

Study Overview
=================
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-DTBZ, vesicular acetylcholine transporter 18F-FEOBV and -amyloid 11C-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 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.

Official Title
-----------------
Amyloidopathy, Cholinopathy, Dopamine Responsiveness and Freezing of Gait in PD

Conditions
-----------------
Parkinson's Disease

Intervention / Treatment
-----------------
* Other: Detailed motor testing, including FoG, in PD subjects


Participation Criteria
=================
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 MMSE > 23 Exclusion Criteria: Dementia Dementia with Lewy Bodies Other disorders which may resemble PD Subjects on neuroleptic, anticholinergic (trihexiphenidyl, 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

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Parkinson's disease with FoG<br>Subjects with Parkinson's disease that have freezing of gait (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<br>* 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.<br>|
| Parkinson's disease without FoG<br>Subjects with Parkinson's disease that do not have freezing of gait 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<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Freezing episodes during the FoG provocation protocol | Change in FOG episodes between on and off dopaminergic medications | through study completion, up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantitative correlation of freezing episodes to brain PET imaging | The individual and combined effects of dopaminergic 11-C-DBTZ, vesicular acetylcholine transporter 18-F-FEOBV, and B-amyloid 11C-PIB brain PET imaging on freezing episodes. | through study completion, up to 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PET, MRI, freezing of gait, amyloid, cholinergic, mobility, imaging