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ANR funded project

Innovation biomédicale (DS0404)
Edition 2014


HDeNERGY


Validation of molecular neuroimaging biomarkers in Huntington's disease in view of therapeutic trials targeting the Krebs cycle

New NMR brain imaging methods for Huntington's disease
Deficits in brain energy metabolism play a key role in Huntington's disease pathogenesis. Developments of novel methods for the in vivo follow up of brain energy defects using Nuclear Magentic Resonance (NMR) would constitute real breakthroughs to accelerate the discovery of efficacious therapies. In particular, new NMR spectroscopy detection methods and CEST (Chemical Exchange Saturation Transfert) imaging would be particularly useful.

Detection of brain energy defects by NMR in Huntington's disease
«To date, results obtained in HD patients and HD models suggest early changes in brain energy metabolism and early
compensatory mechanisms to maintain homeostasis. However, one main limitation of in vivo methods to look at energy
metabolism is related to the fact that currently available biomarkers (direct or indirect) are “static” concentrations of
metabolites (NAA, Creatine, ATP, PhosphoCreatine). The detection of “dynamic” metabolic changes linked to the
alteration of the rate of metabolic reactions would constitute a real breakthrough to better understand the nature of the
metabolic changes in HD and identify novel brain biomarkers. In addition, these biomarkers will be directly useful in HD
carriers to assess the efficacy of therapeutic strategies targeting the Krebs cycle and for which a proof of concept has
already been obtained.«

Development of new NMR methods
Our translational project aims at measuring “dynamic” parameters of brainenergy metabolism in a transgenic rat model and in affected and presymptomatic HD carriers using MR spectroscopy (MRS). Methodological breakthroughs will include the determination of the synthesis rate of phosphocreatine using saturation transfer 31P MRS, the turnover of the Krebs cycle using 13C MRS, and the establishment of brain maps of pH and glutamate using Chemical Exchange Saturation Transfer (CEST). Likewise, Partners 1 and Partner 2 will assemble their unique MRS setups and well–recognized expertise in HD. Through the implementation of cutting-edge MR methods, we will gain critical insight on the mechanisms underlying brain energy defects in HD and identify functional biomarkers to be used in clinical trials such as those targeting the Krebs cycle.

Results

(ongoing)

Outlook

The scientists involved in the project attended the kick off meeting of HDeNERGY on January 13. The scientific presentations that were given showed the high potential of the project to rapidly provide novel NMR methods that could allow for the detection of brain energy defects in HD gene carriers, especially during clinical trials.

Scientific outputs and patents

(ongoing)

Partners

APHP Assistance Publique -Hôpitaux de Paris

APHP Assistance Publique-Hôpitaux de Paris

CEA MIRCEN Laboratoire des Maladies Neurodégénératives, MIRCen, CEA, Fontenay-aux-roses, France

ANR grant: 302 824 euros
Beginning and duration: janvier 2015 - 45 mois

Submission abstract

Energy defects in Huntington disease (HD) would constitute extremely informative imaging biomarkers of disease progression and readouts in clinical trials. Our translational project aims at measuring “dynamic” parameters of brain energy metabolism in a transgenic rat model and in affected and presymptomatic HD carriers using MR spectroscopy (MRS). Methodological breakthroughs will include the determination of the synthesis rate of phosphocreatine using saturation transfer 31P MRS, the turnover of the Krebs cycle using 13C MRS, and the establishment of brain maps of pH and glutamate using Chemical Exchange Saturation Transfer (CEST). Likewise, Partners 1 and Partner 2 will assemble their unique MRS setups and well–recognized expertise in HD. Through the implementation of cutting-edge MR methods, we will gain critical insight on the mechanisms underlying brain energy defects in HD and identify functional biomarkers to be used in clinical trials such as those targeting the Krebs cycle.

 

ANR Programme: Innovation biomédicale (DS0404) 2014

Project ID: ANR-14-CE15-0007

Project coordinator:
Monsieur Emmanuel Brouillet (Laboratoire des Maladies Neurodégénératives, MIRCen, CEA, Fontenay-aux-roses, France)

 

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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.