Brain Neuroimaging Biomarkers in Huntington Disease Clinical Trial
Official title:
Validation of Molecular Neuroimaging Biomarkers in Huntington's Disease in View of Therapeutic Trials Targeting the Krebs Cycle
There is no curative treatment available today in Huntington disease (HD) despite the
identification of the mutated gene 20 years ago. Nonetheless, safe and promising therapeutic
strategies targeting brain energy metabolism are now becoming available.
In view of the small effect sizes of any clinical parameter in HD, robust neuroimaging
biomarkers reflecting brain energy metabolism are therefore urgently needed to better assess
the potential of therapeutics targeting the mitochondria, and especially the Krebs cycle.
Identifying such biomarkers at the presymptomatic phase in HD also provides a unique window
for therapeutic intervention, which can be used as a proof-of-concept for the real challenge
of tomorrow's medicine: the prevention of neurodegeneration HDeNERGY is an observational
study consisting of the transfer of methods from preclinical to clinical studies and their
application in HD. HDeNERGY aim at optimizing MRI/MRS methods to study the dynamics of brain
energy metabolism. At the CENIR (Centre de neuro-imagerie et de recherche, Paris) the
determination of creatine kinase rate will be first validated in healthy volunteers (n=20)
and then applied to the selected cohort of early affected HD patients (n=20), presymptomatic
individuals (n=20) and controls (n=20) together with the methods previously validated in HD
patients (Mochel et al., 2012b) to determine the ratio of inorganic phosphate (Pi)/
phosphocreatine (PCr) during visual stimulation in presymptomatic individuals. The Chemical
Exchange Saturation Transfer (CEST) method on the 3T clinical scanner of CENIR will be first
validated in healthy volunteers (n=20) and then applied to the selected cohort of early
affected HD patients (n=20), presymptomatic individuals (n=20) and controls (n=20).
The cerebral synthesis rate of creatine phosphate and of brain glutamate concentrations and
pH values will be compared between controls, HD patients and HD presymptomatic individuals,
and correlated with clinical parameters (age, BMI, UHDRS).
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).
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