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AbstractAbstract
[en] The measurement of cerebral metabolic flows, in particular of those taking part in the energy metabolism, is of major interest as much fundamental point of view, for the comprehension of the biochemical reactions and of their coupling, that from a clinical point of view, for the update biomarkers of evolution of neurodegenerative pathologies and the determination of the defective mechanisms under unclaimed. Thus, during last decades, of the atraumatic and noninvasive techniques of neuroimagery allowing the measurement of cerebral metabolic flows, among which the tomography by emission of positrons (Mtoe) and the spectroscopy by nuclear magnetic resonance (SRM), experienced a considerable development. More particularly, the SRM of the 31P shows the characteristic and favours to allow the direct measurement of the cerebral flow of synthesis of ATP, and this without injection of marked precursor. However, this approach appears a methodological challenge still to date and complementary studies of validation remain necessary in order to show the relevance of the SRM of the 31P for the measurement of the cerebral energy synthesis. In this context, a study of multimode neuroimagery, based on the use of new techniques of neuroimagery, was undertaken in order to allow, in the same time, to obtain an integrated vision of the cerebral energy metabolism and to validate the method of transfer of saturation by SRM of the 31P like a method of robust and quantitative measurement of the synthesis of cerebral ATP. More precisely, the regional consumption of CMRglc glucose, the speed of the cycle of Krebs (VTCA) and the speed of synthesis of ATP (VATP) were measured in the brain of healthy primate respectively by FART 18F-FDG, SRM of the 13C and transfer of saturation by SRM of the 31P. These three complementary measurements, carried out in a definite cerebral zone in the same animals in identical physiological conditions, led to the following results: CMRglc= 0.27 ± 0.07 μmol/g/min, VTCA = 0.63 ± 0.12 μmol/g/min and VATP = 7.8 ± 2.3 μmol/g/min. The coherence of these three flows with the values reported in the literature, but especially their coherence one compared to the other, made it possible to validate the method of transfer of saturation by SMR of the 31P for the direct measurement of the synthesis of cerebral ATP. This stage of validation having been led, the interest of the technique of transfer of saturation has, in the second time, summer evaluated in private clinic on a population of patients reached of the disease of Huntington (MH). An exploratory attitude was adopted, in which the concentrations in metabolites phosphoryls, the cerebral pH and the speed of synthesis of ATP were evaluated. This study initially made it possible to highlight a maintenance of metabolic homeostasis among patients Huntington (HD), in particular in ATP, pi and PCr, and this in spite of an important cerebral atrophy. A reduction the speed of synthesis of cerebral ATP was also observed among these patients. However, within sight of the low sensitivity of the method of transfer of saturation by SRM of the 31P, the significancy of this reduction could not be established. Lastly, a significant increase in the cerebral pH was measured among patients HD relative with controls. This cerebral alkalisation, for the first time measured in the MH, presented moreover one correlation with the driving clinical scores evaluated among patients HD, showing the potential interest of the measurement of cerebral pH for the follow-up of pathology. Within sight of this result, a study aiming at evaluating the precocity of the variations of pH associated with laMH was carried out on a rodent model during a chronic intoxication with the acid 3-nitro-propionic (3NP), mitochondrial neurotoxin. This study made it possible to highlight a significant increase in the cerebral pH preceding the appearance of striatal lesions , showing the potentiality of the cerebral pH as early biomarker of the MH. At the biochemical level, it was shown that variations of pH and percentages of inhibition of succinate dehydrogenase (SDH), specific target of the 3NP, presented the same temporal evolution during the protocol of intoxication. Assumptions on the biochemical mechanisms under unclaimed were then proposed in order to try to explain the variations of cerebral pH measured in this study. (author)
[fr]
La mesure de flux metaboliques cerebraux, en particulier de ceux participant au metabolisme energetique, presente un interet majeur autant d'un point de vue fondamental, pour la comprehension des reactions biochimiques et de leur couplage, que d'un point de vue clinique, pour la mise a jour de biomarqueurs d'evolution des pathologies neurodegeneratives et la determination des mecanismes deficients sous- jacents. Ainsi, au cours des dernieres decennies, des techniques de neuroimagerie atraumatiques et non invasives permettant la mesure de flux metaboliques cerebraux, parmi lesquelles la tomographie par emission de positrons (TEP) et la spectroscopie par resonance magnetique nucleaire (SRM), ont connu un developpement considerable. Plus particulierement, la SRM du 31P presente la caracteristique et l'avantage de permettre la mesure directe du flux cerebral de synthese d'ATP, et ce sans injection de precurseur marque. Cependant, cette approche apparait encore a ce jour un defi methodologique et des etudes de validation complementaires restent necessaires afin de demontrer la pertinence de la SRM du 31P pour la mesure de la synthese energetique cerebrale. Dans ce contexte, une etude de neuroimagerie multimodale, basee sur l'utilisation de nouvelles techniques de neuroimagerie, a ete menee afin de permettre, dans un meme temps, d'obtenir une vision integree du metabolisme energetique cerebral et de valider la methode de transfert de saturation par SRM du 31P comme une methode de mesure robuste et quantitative de la synthese d'ATP cerebrale. Plus precisement, la consommation regionale de glucose CMRglc, la vitesse du cycle de Krebs (VTCA) et la vitesse de synthese d'ATP (VATP) ont ete mesurees dans le cerveau de primate sain respectivement par PET 18F-FDG, SRM du 13C et transfert de saturation par SRM du 31P. Ces trois mesures complementaires, realisees dans une zone cerebrale definie chez les memes animaux en conditions physiologiques identiques, ont conduit aux resultats suivants: CMRglc= 0.27 ± 0.07 μmol/g/min, VTCA = 0.63 ± 0.12 μmol/g/min et VATP = 7.8 ± 2.3 μmol/g/min. La coherence de ces trois flux avec les valeurs rapportees dans la litterature, mais surtout leur coherence l'un par rapport a l'autre, a permis de valider la methode de transfert de saturation par SMR du 31P pour la mesure directe de la synthese d'ATP cerebrale. Cette etape de validation ayant ete conduite, l'interet de la technique de transfert de saturation a, dans un deuxieme temps, ete evalue en clinique sur une population de patients atteints de la maladie de Huntington (MH). Une attitude exploratoire a ete adoptee, dans laquelle les concentrations en metabolites phosphoryles, le pH cerebral et la vitesse de synthese d'ATP ont ete evalues. Cette etude a permis en premier lieu de mettre en evidence un maintien de l'homeostasie metabolique chez les patients Huntington (HD), en particulier en ATP, Pi et PCr, et ce malgre une atrophie cerebrale importante. Une diminution de la vitesse de synthese d'ATP cerebrale a egalement ete observee chez ces patients. Cependant, au vu de la faible sensibilite de la methode de transfert de saturation par SRM du 31P, la significativite de cette diminution n'a pu etre etablie. Enfin, une augmentation significative du pH cerebral a ete mesuree chez les patients HD relativement aux controles. Cette alcalinisation cerebrale, pour la premiere fois mesuree dans la MH, presentait de plus une correlation avec les scores cliniques moteurs evalues chez les patients HD, demontrant l'interet potentiel de la mesure de pH cerebral pour le suivi de la pathologie. Au vu de ce resultat, une etude visant a evaluer la precocite des variations de pH associees a la MH a ete realisee sur un modele rongeur au cours d'une intoxication chronique a l'acide 3-nitropropionique (3NP), neurotoxine mitochondriale. Cette etude a permis de mettre en evidence une augmentation significative du pH cerebral precedant l'apparition de lesions striatales, demontrant la potentialite du pH cerebral comme biomarqueur precoce de la MH. Au niveau biochimique, il a ete montre que variations de pH et pourcentages d'inhibition de la succinate deshydrogenase (SDH), cible specifique du 3NP, presentaient la meme evolution temporelle au cours du protocole d'intoxication. Des hypotheses sur les mecanismes biochimiques sous-jacents ont alors ete proposees afin de tenter d'expliquer les variations de pH cerebral mesurees dans cette etude. (auteur)Original Title
Mesure du metabolisme energetique cerebral par RMN du 31P in vivo: Validation methodologique multimodale et application a l'etude de la neurodegenerescence
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17 Sep 2008; 205 p; 210 refs.; Available from the INIS Liaison Officer for France, see the INIS website for current contact and E-mail addresses; These de doctorat, discipline: physique
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Miscellaneous
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ALDEHYDES, ANIMALS, ANTIGENS, BIOLOGICAL PATHWAYS, BODY, CARBOHYDRATES, CARBOXYLIC ACIDS, CENTRAL NERVOUS SYSTEM, CHEMICAL REACTIONS, DECOMPOSITION, DIAGNOSTIC TECHNIQUES, DISEASES, ENZYMES, HAZARDOUS MATERIALS, HEXOSES, MAMMALS, MATERIALS, METABOLISM, MONKEYS, MONOCARBOXYLIC ACIDS, MONOSACCHARIDES, NERVOUS SYSTEM, NUCLEOTIDES, ORGANIC ACIDS, ORGANIC COMPOUNDS, ORGANS, PATHOLOGICAL CHANGES, PRIMATES, PROCESSING, PROTEINS, RODENTS, SACCHARIDES, TOXIC MATERIALS, VERTEBRATES
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