Brain Bioenergetics in Parkinson's Disease and Response to Repeated Oral UDCA Treatment
Brain Bioenergetics in Parkinson's Disease and Response to Repeated Oral UDCA Treatment
The objective of this study is to understand the bioenergetic impairments that underlie
 Parkinson's disease (PD) and evaluating treatments that may improve abnormal mitochondrial
 function that is present in PD. The hypothesis is that repeated oral dosing of UDCA will
 result in increased brain ATP levels in individuals with Parkinson's disease (PD). The
 specific aims are 1.) to measure plasma UDCA levels in individuals with PD at baseline and
 after four weeks of repeated high doses of oral UDCA (50mg/kg/day) and 2.) to measure
 cortical bioenergetic profile and ATPase activity (as ascertained through MRS) in those with
 PD at baseline and at four weeks after repeated high doses of oral UDCA (50mg/kg/day)
 simultaneously. Secondary aims are to characterize oral UDCA pharmacokinetics and develop a
 pharmacokinetic/pharmacodynamic model to characterize the relationship between peripheral
 measurements of UDCA (and associated conjugates) and peripheral measures and/or central
 (brain) bioenergetic measurements.
The objective of this study is to understand the bioenergetic impairments that underlie
 Parkinson's disease (PD) and evaluating treatments that may improve abnormal mitochondrial
 function that is present in PD. High field - 7 tesla (T) - magnetic resonance spectroscopy
 (MRS) is able to non-invasively assess for changes in brain energetics and will be used to
 evaluate the effects that repeated oral doses of the mitochondrial enhancer ursodeoxycholic
 acid (UDCA) has on brain bioenergetics derived from MRS measurements. This study will combine
 results obtained using MRS brain scans along with peripheral measurements of bile acids
 (e.g., total UDCA). This research will require at least 2 visits: baseline evaluation and at
 approximately 6 weeks after subjects are on a stable oral dose for 4 weeks. Participants will
 provide their medical history during the first visit, and undergo a physical examination and
 rating scale each visit (duration: ~1 hour) as well as a brain MRI scan (1-1.5 hours). Blood
 will be obtained at both visits to monitor for adverse effects as well as to assess for
 changes in bile acids from orally administered UDCA. If additional funding is obtained we may
 have another visit added between the first and second assessments to obtain additional blood
 measurements and MRS data.

 Since there is extensive animal and cell model data supporting the rationale for a
 therapeutic trial of UDCA in PD, and because MRS methods can non-invasively detect changes in
 brain chemistry we propose a study to evaluate the effects of a 4-6 weeks of high-dose oral
 UDCA on central (brain) and peripheral measures (through MRS and blood measurements,
 respectively) in individuals with PD and healthy controls. The hypothesis and specific aims
 are as follows:

 Hypothesis: Repeated oral dosing of UDCA will result in increased brain ATP levels in
 individuals with Parkinson's disease (PD).

 Specific Aims:

 1. Measure plasma UDCA levels in individuals with PD at baseline and after four weeks of
 repeated high doses of oral UDCA (50mg/kg/day).

 2. Measure cortical bioenergetic profile and ATPase activity (as ascertained through MRS)
 in those with PD at baseline and at four weeks after repeated high doses of oral UDCA
 (50mg/kg/day) simultaneously with Aim 1.

 Secondary Aims:

 1. Characterize oral UDCA pharmacokinetics

 2. Develop a pharmacokinetic/pharmacodynamic model to characterize the relationship between
 peripheral measurements of UDCA (and associated conjugates) and peripheral measures
 and/or central (brain) bioenergetic measurements.
Inclusion Criteria:

 1. All participants must be 18 years or older.

 2. All enrollees must understand and cooperate with requirements of the study and be able
 to provide written informed consent

 3. Individuals with medically stable mild to moderate Parkinson's disease or healthy
 controls (as determined by enrolling investigator)

 4. All participants must not have taken UDCA for 4 weeks prior to the study.

 5. Absence of dementia in all subjects, as determined by pre-scanning cognitive
 assessment.

 Exclusion Criteria:

 1. Inability to undergo MRI scanning without sedation and other MRI counterindications,
 such as metal in the body.

 2. Medically unstable conditions

 3. Pregnant or lactating or those women of child-bearing age that are not using
 acceptable forms of contraception

 4. Unable to adhere to study protocol as determined by the PI