Compensation Mechanisms in Parkinson's Disease

NCT02869945 | Completed

• 1 other identifier: P130939
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Parkinson's disease onset is clinically defined as the appearance of motor symptoms including akinesia, tremor and hypertonia. Several studies have shown that motor symptoms occur when at least 50 % of dopaminergic neurons are lost. However, there are evidence suggesting that the level of dopaminergic denervation is not homogenous at the time of diagnosis. Some patients have a higher level of dopaminergic loss at disease onset indicating the existence of compensation mechanisms. The aim of this study is to decipher how the metabolism of dopamine is involved in this compensation with a focus on the polymorphism of the COMT gene. This gene is expressed according to two variant: (i) COMT H that encodes a form of the enzyme with a high level of activity and (ii) COMT L that encode a form of the enzyme with a low level of activity. Thus, there are 3 possible genotypes in the population: (i) COMT HH associated with an increased degradation of dopamine, (ii) COMT LL associated with a decreased degradation of dopamine and (iii) COMT HH (intermediary between COMT HH and COMT LL). The hypothesis is that this polymorphism of the COMT gene may participate to compensation mechanisms in early PD. Patients with COMT HH genotype may have an earlier motor symptoms onset than patients with COMT LL genotype. To test this hypothesis, we will recruit 51 patients with de novo PD will be recruited (17 patients for each genotype). Given the distribution of COMT polymorphism in the population, a maximum sample of 76 patients will be screened to recruit 17 patients for each genotype. Clinical evaluation will include MDS-UPDRS, Non Motor Symptoms Scale, segmental symptoms scale, Montreal Cognitive assessment, MMSE, Frontal assessment battery and Parkinson's disease behavioral assessment scale (ECMP). All the patients will have a monophotonic emission tomography with I-123-Ioflupane in order to assess the level of dopaminergic denervation and an MRI scan with resting state study. Cerebrospinal fluid sampling will be optional and will allow direct measurements of dopamine metabolites. The main outcome measure will be the level of dopaminergic denervation on I-123-Ioflupane scans according to COMT genotype, age, gender and severity of motor symptoms on the MDS-UPDRS part 3. If this hypothesis is confirmed, this will allow to test the efficacy of COMT inhibitors in order to delay dopaminergic drugs initiation for PD patients.

Conditions

Parkinson Disease

Keywords

de novo untreated Parkinson Disease; genetic; COMT Polymorphism; gene; brain MRI; brain MPET

Outcome Measures

Primary Outcomes (1)

• Comparison of the degree of presynaptic dopaminergic denervation across the 3 genotypes group (COMT HH, COMT HL and COMT LL) at the time of diagnostic of Parkinson disease

  The degree of presynaptic dopaminergic denervation estimated by the potential links of 123I-FP-CIT (radioligand dopamine transporter) on scintigraphy images of single photon emission

  Within 3 months after inclusion

Secondary Outcomes (4)

• Degree of presynaptic denervation in three groups: COMT HH, COMT LL, COMT HL with and without adjustment for age, sex and UPDRS III score

  Within 3 months after inclusion

• CSF dopamine metabolite levels at the time of diagnosis (CSF sampling will be optional) in the groups COMT HH, COMT HL and COMT LL

  Within 3 months after inclusion

• Functional connectivity resting MRI Index obtained by full integration and graph theory based on genotypes (COMT HH, COMT LL, COMT HL) and denervation degree (MPET).

  Within 3 months after inclusion

• MDS UPDRS-III motor score according to the genotypes (COMT HH, COMT LL, COMT HL) and denervation degree observed by MPET

  Within 3 months after inclusion

Study Arms (3)

COMT HH

OTHER

COMT HH gene

Genetic: Identification of COMT HH, COMT HL or COMT LL genes; Other: Brain MRI with resting state scan; Other: Brain MPET

COMT HL

OTHER

COMT HL gene

Genetic: Identification of COMT HH, COMT HL or COMT LL genes; Other: Brain MRI with resting state scan; Other: Brain MPET

COMT LL

OTHER

COMT LL gene

Genetic: Identification of COMT HH, COMT HL or COMT LL genes; Other: Brain MRI with resting state scan; Other: Brain MPET

Interventions

Identification of COMT HH, COMT HL or COMT LL genes GENETIC

COMT HH, COMT HL or COMT LL genes identification

COMT HH; COMT HL; COMT LL

Brain MRI with resting state scan OTHER

MRI scan with resting state study to be performed to assess the compensation mechanisms at the networks level.

COMT HH; COMT HL; COMT LL

Brain MPET OTHER

Monophotonic emission tomography with I-123-Ioflupane to assess the level of dopaminergic denervation.

COMT HH; COMT HL; COMT LL

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Man or woman ≥ 18 years old,
• Caucasian origin
• Parkinson's disease considered to be probable as defined by the criteria of UK Parkinson's disease Brain Bank (Hugues and coll 2002)
• Absence of anti-parkinsonian medication
• Patient affilied to a social security system
• Signed information consent form

You may not qualify if:

• Parkinsonian syndrome secondary to neuroleptics
• Atypical parkinsonian syndrome such a multisystem atrophy, progressive supranuclear paralysis, dementia with levy bodies.
• MRI contraindication (claustrophobia, not compatible mechanical heart valve MRI, pacemaker, cochlear implant, other body ferromagnetic objects, pregnancy) - MPET contraindication (pregnancy, feeding, hypersensitivity to ioflupane \[123\]
• Patient under guardianship or trusteeship
• Any other significant pathology that could prevent patient participation and achievement of planned examinations (except for lumbar puncture)
• Hypersensitivity to local anesthetics with amide link or to any of the excipients

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Groupe Hospitalier Pitié-Salpêtrière

Paris, 75013, France

Location

MeSH Terms

Conditions

Parkinson Disease

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Study Officials

• David Grabli, MD-PhD

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 4, 2016
• First Posted: August 17, 2016
• Study Start: September 1, 2016
• Primary Completion: July 1, 2021
• Study Completion: July 1, 2021
• Last Updated: February 18, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)