Modulation of GABA-A Receptors in Parkinson Disease-Flumazenil Arm
Modulation of GABA-A Receptors in Parkinson Disease-Flumazenil Arm
This arm is a positron emission tomography (PET) biomechanistic GABA-A receptor target
 engagement study that includes detailed clinical and motor assessments before and after the
 i.v. administration of 1 mg flumazenil or placebo in Parkinson disease subjects. Each subject
 will receive 1mg flumazenil or placebo at two visits.
This biomechanistic GABA-A receptor target engagement study includes clinical and motor
 assessments before and at various time points up to approximately 90 minutes after the i.v.
 administration of 1 mg flumazenil and placebo in Parkinson disease subjects. Thirty Parkinson
 disease subjects with disease severity (Hoehn and Yahr) stages 2-4 will be recruited.
 Baseline [11C]FMZ and vesicular monoamine transporter type 2 (VMAT2) [11C]DTBZ brain PET
 imaging will be performed prior to drug administration to assess for GABA-A receptor
 availability and the integrity of nigrostriatal dopaminergic nerve terminals, respectively.
Inclusion Criteria:

 1. Parkinson's disease (PD): PD diagnosis will follow the UK Parkinson's Disease Society
 Brain Bank Research Center (UKPDSBRC) clinical diagnostic criteria for PD.

 2. Hoehn and Yahr stages 2-4

 3. Absence of dementia confirmed by cognitive testing.

 4. Abnormal 11C-Dihydrotetrabenazine ([11C]-DTBZ) PET study to demonstrate nigrostriatal
 dopaminergic denervation.

 Exclusion Criteria:

 1. PD with Dementia (PDD) or dementia with Lewy bodies (DLB).

 2. Other disorders which may resemble PD, such as vascular dementia, normal pressure
 hydrocephalus, multiple system atrophy, corticobasal ganglionic degeneration, or toxic
 causes of parkinsonism. Prototypical cases have distinctive clinical profiles, like
 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.

 3. Subjects on benzodiazepine, GABA-ergic medications (baclofen, tizanidine),
 neuroleptic, anticholinergic (trihexyphenidyl, benztropine), or cholinesterase
 inhibitor drugs.

 4. Evidence of a mass lesion on structural brain imaging (MRI).

 5. 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, chest, or
 cochlear implant.

 6. Severe claustrophobia precluding MR or PET imaging.

 7. Subjects limited by participation in research procedures involving ionizing radiation.

 8. Pregnancy (urine or serum pregnancy test within 48 hours of each PET session) or
 breastfeeding.

 9. History of seizures

 10. Significant anxiety or history of panic disorder.

 11. History of recent suicide attempt or overdose of tricyclic antidepressants or other
 medications

 12. Any other medical history determined by investigators to preclude safe participation.

 13. Allergy to flumazenil

 14. Significant liver disease

 15. History of alcohol or other substance abuse within past two years.

 16. History of regular benzodiazepine use within past year