Validation of molecular neuroimaging biomarkers in Huntington's disease in view of therapeutic trials targeting the Krebs cycle – HDeNERGY
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<br />compensatory mechanisms to maintain homeostasis. However, one main limitation of in vivo methods to look at energy<br />metabolism is related to the fact that currently available biomarkers (direct or indirect) are “static” concentrations of<br />metabolites (NAA, Creatine, ATP, PhosphoCreatine). The detection of “dynamic” metabolic changes linked to the<br />alteration of the rate of metabolic reactions would constitute a real breakthrough to better understand the nature of the<br />metabolic changes in HD and identify novel brain biomarkers. In addition, these biomarkers will be directly useful in HD<br />carriers to assess the efficacy of therapeutic strategies targeting the Krebs cycle and for which a proof of concept has<br />already been obtained.«<br />
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.
(ongoing)
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.
(ongoing)
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.
Project coordination
Emmanuel Brouillet (Laboratoire des Maladies Neurodégénératives, MIRCen, CEA, Fontenay-aux-roses, France)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partner
CEA MIRCEN Laboratoire des Maladies Neurodégénératives, MIRCen, CEA, Fontenay-aux-roses, France
APHP Assistance Publique -Hôpitaux de Paris
APHP Assistance Publique-Hôpitaux de Paris
Help of the ANR 302,824 euros
Beginning and duration of the scientific project:
December 2014
- 45 Months
