Compensation Mechanisms in Parkinson's Disease

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

Interventions

GENETIC

Identification of COMT HH, COMT HL or COMT LL genes

COMT HH, COMT HL or COMT LL genes identification

OTHER

Brain MRI with resting state scan

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

OTHER

Brain MPET

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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris

  lead OTHER

Principal Investigators

• David Grabli, MD-PhD · Assistance Publique - Hôpitaux de Paris

Study Design

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2016-09-30

Primary Completion

2021-07-01

Completion

2021-07-01

Countries

• France

Study Locations