Assessing cholinergic innervation in Parkinson*s disease using the PET imaging marker [18F]Fluoroethoxybenzovesamicol

Cholinergic neurons play an important role in neurotransmission within the
central nervous system (CNS). They are involved in complex functions like
memory, learning, recognition, attention, consciousness, regulation of
sleep-wake cycles and maintenance of posture and gait. Cholinergic neuron
degeneration in the neocortex and hippocampus of the CNS, is an important
neurochemical change observed in several neurodegenerative diseases, including
Parkinson*s disease (PD) and Alzheimer*s disease (AD). Therefore, assessment of
the vesicular acetylcholine transporter (VAChT) as an important molecular
target in the cholinergic circuit, has sparked interest in the development of
radiotracers for studying this target in vivo. Preclinical studies show the
VAChT tracer (-)-5- [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV) to be
potentially useful in detecting cholinergic lesions in vivo. A previous
[18F]FEOBV PET study confirms that the tracer binds to VAChT with the expected
in vivo human brain distribution. The use of [18F]FEOBV as a PET imaging marker
of cholinergic innervations has, however, only been studied in healthy human
volunteers and no data is available on patients.

The main objective of this study is to evaluate the differences in [18F]FEOBV
binding between PD patients and healthy control subjects, in order to evaluate
the clinical feasibility of [18F]FEOBV as a cholinergic imaging ligand in PD.

Secondary objectives are:
- Confirming previous findings on [18F]FEOBV validation, in order to establish
an optimal scan protocol for a static scan.
- The assessment of test-retest variability in both healthy control subjects
and PD patients.
- Explorative analysis of the relationship between neuropsychological
performance and cholinergic innervation

In order to establish the difference in [18F]FEOBV binding between PD patients
and healthy control subjects, the study will be conducted in three parts.
The first part of the study is to establish [18F]FEOBV as a PET tracer for
application in clinical research by confirming previous findings on [18F]FEOBV
validation. This will include dynamic scanning of 3 healthy control subjects in
3 imaging sessions (0-120, 150-180, 210-240 min after injection of [18F]FEOBV).
From this part of the study, the optimal short static scan period will be
determined by comparing relative uptake values with the results of kinetic
analysis.
Part 2 of the study is to evaluate differences in [18F]FEOBV in Parkinson*s
disease and healthy controls. For this, the three dynamic scans of part 1 will
be used and an additional 7 healthy control subjects and 10 PD patients will be
included for a simple static scan (period determined after part 1 of the
study).

All 20 subjects included in Part 1 and 2 of the study will undergo a
neuropsychological assessment. This assessment will take 30-45 minutes and will
be performed on the same day as the PET or the MRI scan.

In part 3, test-retest variability is evaluated in both groups. Of each group,
5 patients will undergo a short second static scan.
All subjects will be screened within 30 days before the PET scan for
demographic information and detailed clinical history.

Burden: Participating in the study will take 1 or 2 visits of the subjects to
University Medical Center Groningen (UMCG). Participants will undergo one brain
MRI, a neuropsychological assessment and one or two [18F]FEOBV PET-scan of the
brain.
Risks: The risks involved in this study is related to the PET imaging. The
[18F]FEOBV PET scan will result in a radiation dose of 4.6 mSv for one scan,
after administration of 200 MBq. For subjects undergoing two scans in order to
evaluate test-retest variability, radiation dose is 9.2 mSV (ICRP risk category
IIb).

Benefits: With this study we will quantify the differences in cholinergic
function between PD patients and healthy aged-matched volunteers. In addition
we will determine the test-retest variability. By combining this information we
will be able to perform power calculations for the assessment of longitudinal
changes. This is essential to follow the normal clinical development as well as
to investigate the effect of therapeutic approaches once they become available.
An additional benefit of [18F]FEOBV is that it provides a direct and specific
measurement of presynaptic cholinergic function only rather than both pre- and
post-synaptic expression. This gives a more specific measurement of cholinergic
functioning and can be helpful in determining underlying pathology of
neurodegenerative diseases.

Group relatedness: Cognitive impairment in Parkinson*s Disease is associated
with cholinergic and dopaminergic deficiencies in the brain. Although
dopaminergic neuronal degeneration is quite well established, the rate and
extent of the cholinergic neuronal degeneration in the course of PD is unknown.
It is also unclear how cholinergic degeneration contributes to cognitive
deficits found in early and more advanced PD. The use of [18F]FEOBV as a PET
imaging marker offers the opportunity to study cholinergic innervation in vivo
in Parkinson*s disease and other neurodegenerative disorders.