Cholinergic Mechanisms of Gait Dysfunction in Parkinson's Disease

Balance and gait problems cause severe impairments for people with Parkinson's disease and
significantly affect their quality of life. Several changes occur in the brains of
Parkinson's disease patients. The hallmark change is a loss of a neurotransmitter ("chemical
messenger" between brain cells) called dopamine. To alleviate Parkinson's disease symptoms
doctors prescribe dopamine replacement therapy, for example Sinemet (levodopa). Although
effective for some of the symptoms, it typically does not sufficiently alleviate balance and
gait problems. This study focuses on other changes in the brain that occur in Parkinson's
disease that may contribute to balance and gait problems. In particular we will be looking at
another neurotransmitter called acetylcholine. In some Parkinson's disease patients we see a
loss of acetylcholine in the brain. In previous studies we have shown that this loss of
acetylcholine is related to impaired balance and gait function in Parkinson's disease. In
this study we will take a closer look at this finding.

Inclusion Criteria:

1. Age 50 and above (M/F).

2. PD diagnosis (with or without mild cognitive impairment; MCI) will follow the UK
Parkinson's Disease Society Brain Bank Research Center (UKPDSBRC) clinical diagnostic
criteria for PD (47), consistent with the typical nigrostriatal denervation pattern on
VMAT2. Absence of significant dementia confirmed by neuropsychological testing.
Modified Hoehn and Yahr stages 1-4 (48, 49).

3. PSP diagnosis will follow the NINDS-PSP clinical diagnostic criteria (50, 51).

4. All PD subjects will be required to have nigrostriatal dopaminergic denervation as
demonstrated by [11C]DTBZ PET imaging (52, 53). Subjects with Parkinsonism and absence
of this PD-typical pattern will be re-categorized .

Exclusion Criteria:

- 1. Presence of significant dementia. 2. Disorders which may resemble PD or PSP, such
as dementia with Lewy bodies, vascular dementia, normal pressure hydrocephalus,
multiple system atrophy, corticobasal ganglionic degeneration, or toxic causes of
parkinsonism. The use of the UKPDSBRC and NINDS-PSP clinical diagnostic criteria will
mitigate the inclusion of patients with atypical parkinsonism.

3. Subjects on neuroleptic (except for low dose quetiapine 25-50 mg/d),
anticholinergic (trihexyphenidyl, benztropine), cholinesterase inhibitors. Subjects
with prior exposure to disallowed medications may be eligible if there has been an
interval of > 2 months off these medications.

4. Evidence of a large vessel stroke in a clinically relevant area (cerebral cortex,
basal ganglia, thalamus) or mass lesion on structural brain imaging (MRI or CT).

5. Participants in whom magnetic resonance imaging (MRI) is contraindicated including,
but not limited to, those with a pacemaker, presence of metallic fragments near the
eyes or spinal cord, or cochlear implant.

6. Severe claustrophobia precluding MR or PET imaging. 7. Subjects limited by previous
participation in research procedures involving ionizing radiation.

8. Pregnancy (test within 48 hours of each PET session) or breastfeeding 9. History of
deep brain stimulation surgery.