Exploration of Differences in Metabolite Concentrations by 7Teslas NMR Spectroscopy in Striatum and Subthalamic Nuclei in de Novo Parkinsonian Patients and Control Subjects

Overview

Initially, the exploration of brain metabolism by Nuclear Magnetic Resonance Spectroscopy (MRS) of the high magnetic field proton (1H) (11.7T) applied to acute and chronic animal models of Parkinson's disease (PD) showed glutamatergic hyperactivity within the striatum, one of the components of the basal ganglia. Interestingly, acute administration of L-dopa and acute, subchronic and chronic deep brain stimulation of the subthalamic nucleus (STN) normalizes these neurochemical profiles. Investigators also show an increase in glutamate levels in the STN ipsilateral to the substantia nigra pars compacta (SNpc) damaged by the neurotoxin, expected phenomenon, but also and surprisingly in the STN controlateral to the lesion. A degeneration of dopaminergic neurons is also observed in the controlateral SNpc at the lesion suggesting that the hyperglutamatergy of the controlateral STN to the lesion could promote neuronal death in the SNpc and thus participate in the progression and lateralization of the PD. Using 3T MRS in PD patients, as in other studies in humans, investigators do not see changes in glutamate and glutamine levels in the putamen of Parkinsonian patients. This difference between animal and human studies can be explained: 1. by the different rate of progression between PD in humans and animal models with plasticity phenomena limiting glutamatergic hyperactivity, 2. by the effect of treatment in PD masking changes in glutamate metabolism, 3. by limiting sensitivity in the detection of metabolites (Glutamate, glutamine, GABA) at 3T. The 7T 1H MRS improves the dispersion of chemical shifts of the metabolites studied, increases the sensitivity of the measurement, makes it possible to select regions of interest of smaller volumes (1 cm3) and thus limits the magnetic susceptibility effects that degrade the quality of the measured signal. This makes it possible to reliably separate glutamate and glutamine peaks. In this context, investigators propose to study the metabolic changes in a homogeneous group of de novo Parkinsonian patients, naive to any treatment intended to replace the missing dopamine. The gain in spatial resolution, contrast and signal will allow better characterization of localized anomalies in small-volume structures such as basal ganglia, putamen and STN.

Detailed description

The project presented is an open and controlled exploratory prospective study, assessing metabolic concentrations in putamen and NST left and right of treatment-naïve de novo Parkinsonian patients compared to healthy subjects. Patients will be included consecutively following the screening. Since this study is cross-sectional, a single visit will be made. De novo PD patients will be pre-selected in the departments of Neurology of the CHU of Clermont-Ferrand and Poitiers.

The inclusion visit will be carried out during a consultation during their usual follow-up in the departments of Neurology of the CHU of Clermont-Ferrand and Poitiers.

The following data will be noted: age, sex, level of study, duration of disease progression, ongoing treatments, medical history.

Patients verifying the inclusion and exclusion criteria will be definitively included and their consents will be collected.

De novo PD patients will undergo their NMR examination in the department of radiology, 7T MRI at the Poitiers hospital.

Patients will report to MRI and the following measurements will be performed:

* measurement of motor disorders by the UPDRS scale, the Hoehn and Yahr and Schwab and England score; * acquisition of NMR images and spectra. The experimental time will be 30 minutes for the UPDRS scale and 30 minutes for the NMR exam.

Recruitment of the subjects in the control group will be carried out in the patients' family and in that of the staff of the departments of neurology and radiology.

They will be matched to de novo PD patients according to age, sex and level of education. In practice, after pre-screening the control subjects, they will be informed about the protocol, their consent will be collected. The following data will also be noted: age, sex, duration and level of study.

After verification of the inclusion and exclusion criteria, the witnesses will take the NMR examination in the Radiological Department, 7T MRI at the Poitiers University Hospital Hospital.

Interventions

• Other specific MRI Acquisition (NMR spectroscopy) at 7T
  The MRI protocol will be performed at 7T on a Siemens NMR imaging system (Magnetom Terra, Siemens Healthcare, Erlangen, Germany), the radio frequency emission and signal reception will be done through a head quadrature resonator (64-channel phase-array coil). To avoid motion-related artifacts, the patient will be seated in a supine position, with the arms along the body and the head immobilized using a suitable head restraint. The MR protocol will take place in two phases: * Acquisition of 3D m

Primary outcome measures

• Glutamate concentration (mmol.L-1) measured in the putamen [Time frame: day 90]

Secondary outcome measures (10)

• Glutamate concentration (mmol.L-1) measured in STN (right and left). [Time frame: day 90]
• NMR spectroscopy measurements of choline,in the central grey nuclei, striatum (right and left), and NST (right and left)(mmol.L-1). [Time frame: day 90]
• NMR spectroscopy measurements of myoinositol in the central grey nuclei, striatum (right and left), and NST (right and left)(mmol.L-1). [Time frame: day 90]
• NMR spectroscopy measurements of N-acetylaspartate in the central grey nuclei, striatum (right and left), and NST (right and left)(mmol.L-1). [Time frame: day 90]
• NMR spectroscopy measurements of creatine in the central grey nuclei, striatum (right and left), and NST (right and left)(mmol.L-1). [Time frame: day 90]
• NMR spectroscopy measurements of glutamine in the central grey nuclei, striatum (right and left), and NST (right and left)(mmol.L-1). [Time frame: day 90]
• NMR spectroscopy measurements of lactate in the central grey nuclei, striatum (right and left), and NST (right and left)(mmol.L-1). [Time frame: day 90]
• NMR spectroscopy measurements of taurine in the central grey nuclei, striatum (right and left), and NST (right and left)(mmol.L-1). [Time frame: day 90]
• NMR GABA in the central grey nuclei, striatum (right and left), and NST (right and left)(mmol.L-1). [Time frame: day 90]
• Severity of clinical conditions (UPDRS score) [Time frame: day 90]

Eligibility criteria

Inclusion criteria

Patients will be included:

• suffering from idiopathic Parkinson's disease according to UKPDSBB criteria (Gibb \& Lees, 1988; Hughes et al., 1992),
• the stage of the disease is I-II according to the Hoehn and Yahr scale,
• which do not receive dopaminergic treatment,
• duration of disease development 5 years,
• without major cognitive impairment (Moca > 24)
• men or women aged 18 to 75,
• having understood and signed the informed consent form,
• members of a social security scheme.

Controls:

• subjects male or female aged 18 -75 years
• subjects affiliated to a social security scheme.
• volunteers who have given their written consent.

Exclusion criteria

Patients will be excluded:

• having a severe tremor (> 3 for a trembling sub-item of UPDRS 3) making the MR examination impossible,
• patients with "contra-indications" to an MRI exam (without administration of a gadolinium chelate): presence of metal parts in the body (electronic devices such as a pacemaker, a neurostimulator, a cochlear implant, prostheses, etc.), claustrophobia,
• taking any treatment that may interact with brain concentrations of neurotransmitters, such as all psychotropic drugs and in particular antidepressants, neuroleptics, benzodiazepines, antiepileptics,
• pregnant women,
• treated by deep brain neurostimulation,
• patients under guardianship or guardianship or protection of justice,
• patients who are excluded from another study.

Controls:

• persons suffering from progressive neurological and psychiatric pathology,
• persons with "contra-indications" to an MRI examination (without administration of a gadolinium chelate): presence of metal parts in the body (electronic devices such as a pacemaker, a neurostimulator, a cochlear implant, prostheses, etc.), claustrophobia,
• taking any treatment that may interact with brain concentrations of neurotransmitters, such as: all psychotropic drugs and in particular antidepressants, neuroleptics, benzodiazepines, antiepileptics,
• pregnant women,
• persons under guardianship or trusteeship or protection of justice,
• people who are excluded from another study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Basic science

Study locations

France · 2 centers

• Chu Clermont Ferrand — Clermont-Ferrand
• CHU Poitiers — Poitiers

Identifiers

NCT: NCT04735172 · AOI 2020 DURIF (METABO-NGC-7T) · 2020-A03237-32

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗