Assessing Cholinergic Innervation in Parkinson's Disease Using the PET Imaging Marker [18F]Fluoroethoxybenzovesamicol

Although PD is considered predominantly as a motor disease caused by loss of dopaminergic neurons, multiple studies indicate that cholinergic dysfunction already starts in early PD and is crucial for the development of dementia in addition to motor symptoms.Because of its crucial role in CNS functioning and neurodegenerative disorders, including PD, it is of great importance to get a better understanding of the cholinergic functioning in the brain. Pathways of acetylcholine synthesis, transport and release provide possible targets for in vivo imaging of the cholinergic system. However,previous approaches are considered as indirect biomarkers of cholinergic terminal integrity because they measure both pre- and post-synaptic expressions. The novel vesicular acetylcholine transporter (VAChT) tracer [18F]Fluoroethoxy-Benzovesamicol ([18F]FEOBV) provides a more direct measurement of presynaptic cholinergic function. The use of [18F]FEOBV as a Positron Emission Tomography (PET) imaging marker of cholinergic innervations has, however, only been studied in healthy human volunteers and no data is available on patients.

With this study the differences in cholinergic function between PD patients and healthy aged-matched volunteers will be quantified. In addition the test-retest variability will be determined

Study Overview

• Status: Unknown
• Conditions: Parkinson's Disease
• Intervention / Treatment: Other: [18F] FEOBV PET scan

Detailed Description

Rationale:

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.

Objective:

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 the assessment of test-retest variability and confirming previous findings on [18F]FEOBV validation. Both secondary objectives are prerequisites for the main objective. In addition, an explorative analysis of the relationship between neuropsychological performance and cholinergic innervation will be performed.

Study design: 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).
• 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.

Study population:

In total, 10 PD patients and 10 age matched control subjects will be included in the study, all between the ages of 45-65 years. Of the 10 control subjects, 3 will undergo full dynamic scanning, all other subjects included will undergo simple static scanning. A total of 10 subjects, 5 from each group, will undergo a second static scan. The patient group includes patients with Parkinson's disease with a disease duration of at least 3 years and maximum 10 years. All subjects will undergo a neuropsychological assessment.

Main study parameters/endpoints:

The main endpoint of this study is the difference in VAChT brain binding on a [18F]FEOBV PET-scan between PD patients and healthy control subjects.

Secondary endpoints are test-retest variability in both patients and healthy control subjects, and neuropsychological performance in both groups.

• Study Type: Observational
• Enrollment (Anticipated): 20

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands, 9713 RB
    • Recruiting
    • University Medical Center Groningen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Two groups of subjects will be included in the study:

• Patients with Parkinson's disease
• Age-matched healthy control subjects A total of 20 subjects will be included in the study, with 10 subjects in each group.

Description

Inclusion Criteria:

• Diagnosis Parkinson's disease (for patient group only)
• Disease duration between 3 and 10 years. (for patient group only)
• Age between 45 - 65 years
• Willingness to cooperate and sign written informed consent
• Able and fit enough to participate in this study

Exclusion Criteria:

• The refusal to be informed about an unforeseen clinical finding
• Pregnant women, breast feeding
• Participation in scientific research using radioactivity in the past 12 months , exceeding the maximum annual radiation dose
• Anticoagulant medication, antiplatelet agents used in the 5d before the imaging visit
• Contra-indication for MRI-scanning (metal parts in the body, red pigments in the skin as used in some tattoos)
• Other neurological conditions, more specifically neurodegenerative disorders and brain lesions.
• Treatment with deep brain stimulation
• prior history of neurologic or psychiatric illness (healthy control group only)

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Parkinson's disease patients; patients with Parkinson's disease, between the ages of 45 and 65, with a disease duration of 3 - 10 years	Other: [18F] FEOBV PET scan; Cholinergic PET scan with the tracer [18F]Fluoroethoxybenzovesamicol
healthy control subjects; Healthy control subjects, between the ages of 45 and 65	Other: [18F] FEOBV PET scan; Cholinergic PET scan with the tracer [18F]Fluoroethoxybenzovesamicol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
[18F]FEOBV binding	the difference in VAChT brain binding on a [18F]FEOBV PET-scan between PD patients and healthy control subjects.	baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Test-retest reliability	The percentage change in mean Standardized Uptake Value (SUV) between test and retest to assess test-retest variability.	one week
Neuropsychological performance	short neuropsychological assessment	baseline

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Investigators: Principal Investigator: Teus van Laar, Prof. Dr., University Medical Center Groningen

Study record dates

Study Major Dates

• Study Start: September 1, 2016
• Primary Completion (Anticipated): February 1, 2017
• Study Completion: December 7, 2022

Study Registration Dates

• First Submitted: October 31, 2016
• First Submitted That Met QC Criteria: November 1, 2016
• First Posted (Estimate): November 2, 2016

Study Record Updates

• Last Update Posted (Estimate): November 29, 2016
• Last Update Submitted That Met QC Criteria: November 28, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: cognition; cholinergic system
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease
• Other Study ID Numbers: NL56173.042.15

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No