The François Jacob Institute of Biology brings together five departments and three services
The last two years in scientific news
Group leader : Julien Valette
Neurodegenerative diseases are largely associated with alterations of cellular metabolism and structure, which may precede neuron death. The magnetic resonance methodology team is developing original methods to non-invasively assess cellular metabolism and structure, in particular in animal models developed within the research unit UMR 9199, using the 7 T and 11.7 T MRI machines in MIRCen. We pursue two ultimate goals: to propose new biomarkers of neurodegenerative diseases, and to better understand physiopathological processes at stake in those diseases.
Beyond the sole determination of brain metabolite concentrations by proton spectroscopy (Figure 1), our group develops imaging methods based on CEST effect ("Chemical Exchange Saturation Transfer", Figure 2), in order to map with a good spatial resolution the distribution of some endogenous metabolite such as glutamate (which is involved in both energy metabolism and neurotransmission).
The team is strongly involved in the development of X-nuclei spectroscopy to measure of some important energy metabolism fluxes: carbon-13 (13C) spectroscopy to determine the TCA cycle (VTCA); oxygen-17 (17O) spectroscopy and imaging (Figure 3) to assess the rate of cellular respiration (CMRO2), which is itself coupled to TCA cycle; and phosphorus-31 (31P) spectroscopy to measure the ATP synthesis rate by oxidative phosphorylation (VATP).
In parallel, one of our current project deals with the use of CEST imaging of glucose to map cerebral metabolic rate of glucose (CMRglc). An originality of our team is that we combine these different techniques to get an integrated picture of energy metabolism (Figure 4).
We are also looking at the possibility of evaluating the organization of the intracellular medium in an indirect way, by measuring via original diffusion-weighted spectroscopy techniques how this organization constrains the displacement of metabolites. In particular, our group has explored the diffusion of brain metabolites over unprecedented time scales, making it possible to better characterize metabolite compartmentation and the parameters governing metabolite motion. We collaborate with the group of Itamar Ronen at the University of Leiden (the Netherlands) on this topic. We are also developing new diffusion modeling strategies (in collaboration with Marco Palombo at University College London) to extract quantitative information about the cellular structure from experimental diffusion data. Notably, we have shown that it was possible to differentiate neuronal from astrocytic structure, by studying diffusion of metabolites predominantly in neurons or in astrocytes (Figure 5). We are now investigating the possibility to use diffusion-weighted spectroscopy to assess cerebral lactate distribution between the different compartments (neurons, astrocytes, extracellular space…), which is related to the lactate shuttle. These thematics have been funded by two grants from the European Research Council ("INCELL" and "LactaDiff" projects).
ERC: LactaDiff project (2019-2024), INCELL project (2013-2018)
ANR: nrjCEST project (2018-2021); HDeNERGY project (2015-2019)
Can we detect the effect of spines and leaflets on the diffusion of brain intracellular metabolites?M.Palombo, C.Ligneul, E.Hernandez-Garzon, J.Valette.Neuroimage. 2017.
Subarachnoid Hemorrhage Severely Impairs Brain Parenchymal Cerebrospinal Fluid Circulation in Nonhuman PrimateGoulay R., Flament J., Gauberti M., Naveau M., Pasquet N., Gakuba C., Emery E., Hantraye P., Vivien D., Aron-Badin R., Gaberel T.Stroke 2017.
Primatologist: a modular segmentation pipeline for Macaque brain morphometryBalbastre Y., Rivière D., Souedet N., Fischer C., Hérard A-S., Williams S., Vandenberghe M. E., Flament J., Aron-Badin R., Hantraye P., Mangin J-F., Delzescaux T.NeuroImage 2017.
Using 31P-MRI of hydroxyapatite for bone attenuation correction in PET-MRI: proof of concept in the rodent brainV.Lebon, S.Jan, Y.Fontyn, B.Tiret, G.Pottier, E.Jaumain, J.Valette.EJNMMI Phys. 2017 Dec;4(1):16.
Probing metabolite diffusion at ultra-short time scales in the mouse brain using optimized oscillating gradients and "short" echo time diffusion-weighted MR spectroscopyC.Ligneul, J.Valette.NMR in Biomedicine 2017 Jan;30(1)
Modeling diffusion of intracellular metabolites in the mouse brain up to very high diffusion‐weighting: Diffusion in long fibers (almost) accounts for non‐monoexponential attenuationM.Palombo, C.Ligneul, J.Valette.Magnetic resonance in medicine 2016.
Imaging and spectroscopic approaches to probe brain energy metabolism dysregulation in neurodegenerative diseasesG.Bonvento, J.Valette, J.Flament, F.Mochel, E.Brouillet.J Cereb Blood Flow Metab. 2017 Jun;37(6)
Energy defects in Huntington's disease: Why "in vivo" evidence mattersG.Liot, J.Valette, J.Pépin, J.Flament, E.Brouillet.Biochem Biophys Res Commun. 2017 Feb 19;483(4) Review.
Experimental strategies for in vivo 13C NMR spectroscopyJ.Valette, B.Tiret, F.Boumezbeur.Analytical Biochemistry 2017 Jul 15;529:216-228
Evidence for a "metabolically inactive" inorganic phosphate pool in adenosine triphosphate synthase reaction using localized 31P saturation transfer magnetic resonance spectroscopy in the rat brain at 11.7 TB.Tiret, E.Brouillet, J.Valette.J Cereb Blood Flow Metab. 2016 Jun 28
In vivo imaging of brain glutamate defects in a knock-in mouse model of Huntington's diseaseJ.Pépin, L.Francelle, M.A.Carrillo-de Sauvage, L.de Longprez, P.Gipchtein, K.Cambon, J.Valette, E.Brouillet, J.Flament.Neuroimage. 2016 Jun 16;139:53-64.
New paradigm to assess brain cell morphology by diffusion-weighted MR spectroscopy in vivoM.Palombo, C.Ligneul, C.Najac, J.Le Douce, J.Flament, C.Escartin, P.Hantraye, E.Brouillet, G.Bonvento, J.Valette.Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):6671-6.
Metabolite diffusion up to very high b in the mouse brain in vivo: Revisiting the potential correlation between relaxation and diffusion propertiesC.Ligneul, M.Palombo, J.Valette.Magn Reson Med. 2016 Mar 28. doi: 10.1002/mrm.26217
Diffusion-weighted magnetic resonance spectroscopyI.Ronen, J.Valette.eMagRes 2015;4:733–750.
Metabolic Modeling of Dynamic (13)C NMR Isotopomer Data in the Brain In Vivo: Fast Screening of Metabolic Models Using Automated Generation of Differential EquationsB.Tiret B, A.A.Shestov, J.Valette, P.G.Henry.Neurochem Res. 2015 Dec;40(12):2482-92.
Brain intracellular metabolites are freely diffusing along cell fibers in grey and white matter, as measured by diffusion-weighted MR spectroscopy in the human brain at 7 TC.Najac, F. Branzoli, I. Ronen, J.Valette. Brain Struct Funct. 2014 (doi : 10.1007/s00429-014-0968-5).
Intracellular metabolites in the primate brain are primarily localized in long fibers rather than in cell bodies, as shown by diffusion weighted magnetic resonance spectroscopyC.Najac, C.Marchadour, M.Guillermier, D.Houitte, V.Slavov, E.Brouillet, P.Hantraye, V.Lebon, J.Valette. NeuroImage 2014 ; 90:374-380.
13C NMR spectroscopy applications to brain energy metabolismT.B.Rodrigues, J.Valette, A.-K.Bouzier-Sore. Front. Neuroenergetics 2013 Dec 9 ; 5:9. Review.
Anomalous diffusion of brain metabolites evidenced by diffusion-weighted magnetic resonance spectroscopy in vivoC.Marchadour, E.Brouillet, P.Hantraye, V.Lebon, J.Valette. J. Cereb. Blood Flow Metab. 2012 ; 32(12):2153-2160.
Metabolic modeling of brain 13C NMR multiplet data: concepts and simulations with a two-compartment neuronal-glial modelA.A.Shestov, J.Valette, D.K.Deelchand, K.Ugurbil, P.-G.Henry. Neurochem. Res. 2012 ; 37(11):2388-2401.
pH as a biomarker of neurodegeneration in Huntington's disease: a translational rodent-human MRS studyM.M.Chaumeil, J.Valette, C.Baligand, E.Brouillet, P.Hantraye, G.Bloch, V.Gaura, A.Rialland, P.Krystkowiak, C.Verny, P.Damier, P.Remy, A.-C.Bachoud-Levi, P.Carlier, V.Lebon. J Cereb Blood Flow Metab. 2012 ; 32(5):771-779.
A new sequence for single-shot diffusion-weighted NMR spectroscopy by the trace of the diffusion tensorJ.Valette, C.Giraudeau, C.Marchadour, B.Djemai, F.Geffroy, M.A.Ghaly, D.Le Bihan, P.Hantraye, V.Lebon, F.Lethimonnier. Magn Reson Med. 2012 ; 68(6):1705-1712
About the origins of NMR diffusion-weighting induced by frequency-swept pulsesJ.Valette, F.Lethimonnier, V.Lebon. Magn. Reson. 2010; 205(2):255-259.
Simplified 13C metabolic modeling for simplified measurements of cerebral TCA cycle rate in vivoJ.Valette, F.Boumezbeur, P.Hantraye, V.Lebon.Magn. Reson. Med. 2009 ; 62(6):1641-1645.
Multimodal neuroimaging provides a highly consistent picture of energy metabolism, validating 31P MRS for measuring brain ATP synthesisM.M.Chaumeil, J.Valette, M.Guillermier, E.Brouillet, F.Boumezbeur, A.S.Herard, G.Bloch, P.Hantraye, V.Lebon. Proc. Natl. Acad. Sci. USA 2009 ; 106(10):3988–3993.
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