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 non-responsiveness of FoG. We have previously identified cholinergic denervation as a prominent factor related to both falls and gait slowing in PD. We 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, we presen preliminary data suggesting that FoG is associated with either cholinopathy, amyloidopathy or both in PD. We 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, we propose to perform 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 our subsequent observation of an intriguing inverse relationship between ?-amyloid plaque deposition and striatal serotoninergic terminal in PD, we 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 differnt 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 veterans with PD.
Costs of Parkinson disease (PD) are an increasing source of expense for the VA because of the disproportionately elderly population of Veterans. The major cause of disability in PD is impaired mobility, in particular freezing of gait. The management of dopamine resistant gait problems represents the most important unmet need in PD. The project proposes to investigate the build-up of ?-amyloid plaques and cholinergic denervation as novel determinants of freezing of gait in PD. The relevance of the project is that it tests a mechanistic hypothesis of dopamine non-responsiveness of freezing of gait based on the presence of amyloidopathy in PD. Positive findings in this study would open up a new avenue to explore anti-amyloid and targeted cholinergic therapies as novel approaches to treat and ultimately prevent this disabling motor complication.
| Rektor, Ivan; Bohnen, Nicolaas I; Korczyn, Amos D et al. (2018) An updated diagnostic approach to subtype definition of vascular parkinsonism - Recommendations from an expert working group. Parkinsonism Relat Disord 49:9-16 |
