Cholinergic Mechanisms of Gait Dysfunction in Parkinson's Disease Experiments 1 & 2 - Proj #3
Condition: Parkinson's Disease
MeSH terms: Parkinson Disease
Intervention: Varenicline
Intervention description: Participants take varenicline for 10 days. Each participant will be on one dosage throughout the 10 days, but not all participants receive the same dosage. The dosages that were utilized for both Parkinson's disease participants and healthy volunteers were 0.25mg once a day, 0.25mg twice a day, and 0.5mg twice a day. A fourth dosing group of 1 mg varenicline twice a day was studied in Parkinson's disease participants, but not in healthy volunteers.
Intervention MeSH terms: Varenicline
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: All participants (Parkinson's disease patients and healthy controls) will receive the study drug varenicline.
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 25.0
Sex: All
Minimum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      Varying oral doses of Varenicline (VCN), starting with very low doses, will be administered
      to participants with Parkinson's Disease (PD) or healthy controls without PD for several
      days. Positron emission tomography (PET) scans after administration of VCN will be used to
      determine the lowest oral dose of VCN producing an adequate brain level of VCN. These
      experiments (1 & 2) will be used to determine an appropriate oral dose of VCN to administer
      to PD participants for experiment 3 of the study (see NCT04403399).
    

Eligibility criteria:

        Inclusion Criteria:

          1. PD diagnosis will be based on the United Kingdom Parkinson's Disease Society Brain
             Bank Research Center (UKPDSBRC) clinical diagnostic criteria. The investigators will
             enrich the cohort by recruiting subjects at modified Hoehn and Yahr stages 2 or
             higher, duration of motor disease 5 years or longer, age >65 years, or the Postural
             Instability and Gait Disorder (PIGD) phenotype. Duration of motor disease will be
             defined as the time between onset of motor symptoms and time of entry into the study.
             The PIGD phenotype is defined as described previously. PD subjects with defined
             cholinergic deficits will be recruited as described in Project II. PD subjects will
             have cortical cholinergic deficits based on 5th percentile cutoff of the normal
             controls as defined previously.

          2. Stable dopaminergic replacement therapy for 3 months prior to enrollment and expected
             to maintain stable dopaminergic therapy for duration of study participation.

        Exclusion Criteria:

          1. Other disorders which may resemble PD with or without dementia, such as vascular
             dementia, normal pressure hydrocephalus, progressive supranuclear palsy, multiple
             system atrophy, corticobasal ganglionic degeneration, or toxic causes of parkinsonism.
             Prototypical cases have distinctive clinical profiles, like vertical supranuclear gaze
             palsy, early and severe dysautonomia or appendicular apraxia, which may differentiate
             them from idiopathic PD. The use of the UKPDSBRC clinical diagnostic criteria for PD
             will mitigate the inclusion of subjects with atypical parkinsonism and all
             participants will undergo [11-Carbon]dihydrotetrabenazine PET to confirm striatal
             dopaminergic denervation.

          2. Subjects on neuroleptic, anticholinergic (trihexphenidyl, benztropine), or
             cholinesterase inhibitor drugs.

          3. Current or previous (within last 6 months) use of any product or medication containing
             nicotinic agents,including use of tobacco products such as cigarettes, cigars, pipes,
             chewing tobacco, etc., electronic cigarettes, over-the-counter nicotine patches,
             chewing gum containing nicotine, or varenicline.

          4. Evidence of a stroke or mass lesion on structural brain imaging (MRI).

          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 participation in research procedures involving ionizing radiation.

          8. Pregnancy (test within 48 hours of each PET session) or breastfeeding.

          9. Significant risk of cardiovascular event.

         10. Active, significant mood disorder.