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

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.

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