Dynamic Neuroimaging Biomarkers in Huntington's Disease

Compelling evidence indicate a key role of energy defects in neurodegenerative diseases (NDs). These defects would constitute extremely informative functional biomarkers of disease states and progression. Such functional biomarkers could be used as readouts for therapeutic efficacy in clinical trials, especially for drugs targeting brain energy metabolism. Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) are likely the most promising approaches to validate brain biomarkers linked to energy metabolism. However, existing methods allowing "static" measures of metabolites concentrations offer only a fragmented vision of brain energy metabolism in NDs. The validation of novel and "dynamic" methods is urgently needed. Our project addresses this challenge for Huntington disease (HD).

Our study is an observational study consisting of the transfer of methods from preclinical to clinical studies and their application in HD.

This study comprises two period:

• Period 1: transfer of 31P saturation transfer and CEST methods from preclinical to clinical MRS/MRI platforms and the validation of these methods in healthy individuals;
• Period 2: compare brain metabolic markers in early individuals affected by HD, presymptomatic individuals and controls, using 31P saturation transfer and CEST methods.

The primary objectives are:

Using 31P saturation transfer and CEST methods, the primary objective is to compare novel metabolic biomarkers between controls and HD carriers (patients and presymptomatic individuals).

Assessment criterion:

Comparison between controls, HD patients and HD presymptomatic individuals of the cerebral synthesis rate of creatine phosphate and of brain glutamate concentrations and pH values

The secondary objectives are:

• To develop/optimize 31P MRS/CEST methods to study the dynamics of brain energy metabolism in humans
• To improve the understanding and "modeling" the nature of energy deficits in HD
• To look for correlations between brain energy profiles and clinical scores.

Assessment criteria:

• Validation of the 31P MRS and CEST methods in healthy volunteers.
• Combination and integration of the 31P MRS and CEST data in order to obtain a model of energy deficits in HD.
• Correlations between creatine phosphate synthetic rate and clinical parameters (age, BMI, UHDRS); correlations between glutamate concentrations and clinical parameters; correlations between pH values and clinical parameters.

Ancillary studies:

The investigators wish to compare brain energy parameters (creatine phosphate synthetic rate, glutamate concentrations, pH values) with systemic metabolic markers (profiles of plasma metabolites obtained from metabolomic and lipidomic studies).

Inclusion criteria

Healthy Volunteers Period 1:

• At least 18 years of age
• Signature of the informed consent
• Covered by social security

Participants Period 2:

• At least 18 years of age
• Signature of the informed consent
• Covered by social security
• Presymptomatic individuals: Positive genetic test with CAG repeat length > 39 in HTT gene, UHDRS score < 5
• Early affected patients: Positive genetic test with CAG repeat length > 39 in HTT gene and UHDRS score between 5 and 40
• BMI between 18 and 30

Non-inclusion criteria

Healthy Volunteers Period 1:

• Contra-indications to MRI (claustrophobia, metallic or material implants)
• History of severe head injury
• Participation in another trial
• Pregnancy and breastfeeding
• Inability to understand information about the protocol
• Persons deprived of their liberty by judicial or administrative decision
• Adult subject under legal protection or unable to consent.
• Unwillingness to be informed in case of abnormal MRI

Participants Period 2:

• Contra-indications to MRI (claustrophobia, metallic or material implants)
• Additional psychiatric or neurological conditions / Additional major comorbidities
• History of severe head injury
• Participation in another trial
• Pregnancy and breastfeeding
• Inability to understand information about the protocol
• Persons deprived of their liberty by judicial or administrative decision
• Adult subject under legal protection or unable to consent.
• Unwillingness to be informed in case of abnormal MRI
• Treatment with tetrabenazine