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. 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