In vivo imaging of brain glutamate defects in a knock-in mouse model of Huntington's disease.
Huntington's disease (HD) is an inherited neurodegenerative disease characterized by motor, cognitive and psychiatric symptoms. Atrophy of the striatum has been proposed for several years as a biomarker to assess disease progression in HD gene carriers. However, it does not provide any information about the biological mechanisms linked to HD pathogenesis. Changes in brain metabolites have been also consistently seen in HD patients and animal models using Magnetic Resonance Spectroscopy (MRS), but metabolite measurements are generally limited to a single voxel. In this study, we used Chemical Exchange Saturation Transfer imaging of glutamate (gluCEST) in order to map glutamate distribution in the brain of a knock-in mouse model (Ki140CAG) with a precise anatomical resolution. We demonstrated that both heterozygous and homozygous mice with pathological CAG repeat expansion in gene encoding huntingtin exhibited an atrophy of the striatum and a significant alteration of their metabolic profile in the striatum as compared to wild type littermate controls. The striatal decrease was then confirmed by gluCEST imaging. Surprisingly, CEST imaging also revealed that the corpus callosum was the most affected structure in both genotype groups, suggesting that this structure could be highly vulnerable in HD. We evaluated for the first time gluCEST imaging as a potential biomarker of HD and demonstrated its potential for characterizing metabolic defects in neurodegenerative diseases in specific regions.
Commissariat à l'Energie Atomique (CEA), Direction de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France; Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
Jérémy
J
Pépin
Commissariat à l'Energie Atomique (CEA), Direction de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France; Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
Laetitia
L
Francelle
Commissariat à l'Energie Atomique (CEA), Direction de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France; Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
Maria-Angeles
MA
Carrillo-de Sauvage
Commissariat à l'Energie Atomique (CEA), Direction de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France; Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
Lucie
L
de Longprez
Commissariat à l'Energie Atomique (CEA), Direction de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France; Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
Pauline
P
Gipchtein
Commissariat à l'Energie Atomique (CEA), Direction de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France; Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
Karine
K
Cambon
Commissariat à l'Energie Atomique (CEA), Direction de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France; Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
Julien
J
Valette
Commissariat à l'Energie Atomique (CEA), Direction de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France; Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
Emmanuel
E
Brouillet
Commissariat à l'Energie Atomique (CEA), Direction de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France; Institut national de la santé et de la recherche médicale (Inserm), UMS 27, F-92260 Fontenay-aux-Roses, France. Electronic address: julien.flament@cea.fr.
Julien
J
Flament
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D015536:Down-Regulation; D005260:Female; D055879:Gene Knock-In Techniques; D018698:Glutamic Acid / Q000378:metabolism*; D006816:Huntington Disease / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057054:Molecular Imaging / Q000379:methods*; D018377:Neurotransmitter Agents / Q000378:metabolism; D066244:Proton Magnetic Resonance Spectroscopy / Q000379:methods*
D018377:Neurotransmitter Agents; D018698:Glutamic Acid
Chemical exchange saturation transfer; GluCEST; Glutamate; Huntington's disease; Mouse model; Neurodegenerative disease