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Proton Diffusion Spectroscopy and Modeling of Brain Metabolism at 14.1T

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Proton Diffusion Spectroscopy and Modeling of Brain Metabolism at 14.1T Proton diffusion spectroscopy and modeling of brain metabolism at 14.1T THÈSE NO 7275 (2016) PRÉSENTÉE LE 25 NOVEMBRE 2016 À LA FACULTÉ DES SCIENCES DE BASE LABORATOIRE LEENAARDS-JEANTET D'IMAGERIE FONCTIONNELLE ET MÉTABOLIQUE PROGRAMME DOCTORAL EN PHYSIQUE ÉCOLE POLYTECHNIQUE FÉDÉRALE DE LAUSANNE POUR L'OBTENTION DU GRADE DE DOCTEUR ÈS SCIENCES PAR Masoumeh DEHGHANI MOGHADAM acceptée sur proposition du jury: Prof. V. Savona, président du jury Prof. R. Gruetter, directeur de thèse Prof. S. Williams, rapporteur Dr J. Valette, rapporteur Dr G. Boero , rapporteur Suisse 2016 Abstract Nuclear magnetic resonance (NMR) spectroscopy is intrinsically interdisciplinary, embracing physics, mathematics, neuroscience and physical biochemistry. As a field at the CIBM, NMR spectroscopy can be applied non-invasively to explore the metabolic fate of energy fuel substrates, as well as the rate at which they are consumed, using 13C and 1H nuclei. The work of this thesis encompasses both nuclei, and focuses on (1) improving the quantification and modeling of glucose-derived metabolites; and (2) characterizing diffusion-related parameters of the purportedly glial-specific energy substrate, acetate. Both aim to quantitatively explore cerebral energy metabolism, at ultra-high magnetic field, in vivo, in the healthy rat. 13C NMR spectroscopy, as a tool, enables measuring the progressive incorporation of 13C-glucose into brain glucose and then NMR detectable amino acids (glutamate and glutamine); this relies on the infusion of the 13C-labeled energy substrate. The experimentally obtained 13C labelling curves are analyzed using suitable mathematical models to provide an estimation of cerebral metabolic rates. Here, a dynamic model of time-courses of 13C multiplets arising from isotopomers was considered. So beyond the two-compartment neuronal-glial model, we took into account additional data on the dynamics of 13C isotopomers, available from the fine structure multiplets in 13C spectra of glutamate and glutamine, measured under prolonged [1-6,13C] glucose infusion. We concluded that the dynamic analyses of 13C multiplet time courses of glutamate and glutamine resulted in a higher precision for estimating the absolute values of most cerebral metabolic rates. Acetate metabolism is challenging because dynamic metabolic modeling requires prior knowledge of the transport and uptake kinetics of infused acetate. We sought this information by determining the apparent concentration and distribution volume (ܸௗ) of cerebral acetate between the intracellular and the extracellular compartments. Experimentally, the diffusion characteristics of cerebral acetate were measured, relative to that of N-Acetylaspartate (NAA, known to be mainly intracellular) using diffusion-weighted 1H NMR spectroscopy at 14.1T, under prolonged acetate infusion. The detection of an acetate and NAA signal at large diffusion weighting provided direct experimental evidence of intracellular cerebral acetate and NAA, although a substantial fraction of acetate was extracellular. To estimate the apparent concentration of in vivo brain acetate, T1 and T2 relaxation times of acetate were measured. The longer T1 relaxation and shorter T2 relaxation times of acetate compared with NAA provided evidence of its small molecular size, and possibly different chemical environment. Our experimentally determined value of ܸௗled to cerebral metabolic rates of acetate (CMR acetate) of the same order reported for the glial Kreb’s cycle rate, an indication that estimates of CMR acetate are highly dependent on ܸௗ. Finally, in order to pursue metabolic mapping of cerebral acetate uptake in the rat, in vivo, at 14.1 T, the design and construction of a combined transmit-birdcage coil and receive-quadrature pair surface coil was considered. Its performance was compared to a single birdcage coil in the transmit/receive Abstract iv mode. So far, the preliminary results of the 2-coil configuration are promising: homogenous excitation and a gain in sensitivity up to a distance of 5 mm are achievable. Improvements are ongoing for NMR spectroscopic and imaging applications at 14.1 T. Keywords: Brain energy metabolism, 13C NMR spectra, diffusion weighted spectroscopy, physical distribution volume, cerebral metabolic rate, TCA cycle, T1 and T2 relaxations, kinetic of transport and uptake of acetate, surface coil, birdcage coil. Résumé La spectroscopie de résonance magnétique nucléaire (RMN) est intrinsèquement interdisciplinaire, englobant la physique, les mathématiques, la neuroscience et la biochimie physique. Comme champ d’étude au CIBM, la spectroscopie RMN peut être utilisée de façon non invasive pour explorer le devenir métabolique des substrats énergétiques tout autant que la vitesse à laquelle ils sont consommés, en utilisant les noyaux 13C and 1H. Le travail de cette thèse inclut les deux noyaux, et se focalise (1) sur l’amélioration de la quantification et de la modélisation des métabolites dérivés du glucose ; et (2) sur la caractérisation des paramètres liés à la diffusion de l’acétate, substrat énergétique supposé spécifique aux cellules gliales, dans le but d’explorer quantitativement le métabolisme énergétique cérébral, à très haut champ magnétique, in vivo, dans le rat sain. La spectroscopie RMN du carbone 13 permet de mesurer l’incorporation progressive de glucose-13C dans le glucose cérébral, puis dans les acides aminés détectables par NMR (glutamate et glutamine) ; ceci repose sur l’infusion de substrats énergétiques marqués au 13C. Les courbes expérimentales de marquage 13C sont analysées avec un modèle mathématique adapté pour estimer les taux métaboliques cérébraux. Un modèle dynamique temporel des multiplets 13C provenant des isotopomères a été considéré. En plus du modèle à deux compartiments neuronal-glial, des données additionnelles sur la dynamique des isotopomères, disponibles grâce aux multiplets de structure fine des spectres 13C du glutamate et glutamine mesurés lors d’une infusion prolongée de [1-6,13C] glucose, ont été prises en compte. Nous concluons que les analyses dynamiques des multiplets 13C du glutamate et glutamine permettent une plus haute précision dans l’estimation des valeurs absolues de la plupart des taux métaboliques cérébraux. Le métabolisme de l’acétate est complexe à étudier, car un modèle métabolique dynamique requiert des connaissances préalables sur la cinétique du transport et de l’absorption de l’acétate infusé. Cette information a été recherchée en déterminant la concentration apparente et le volume de distribution (Vd) de l’acétate cérébrale entre les compartiments intra et extracellulaires. Les caractéristiques de diffusion de l’acétate cérébral ont été mesurées expérimentalement, relativement à celles de l’acide N- acétylaspartique (NAA, connu pour être principalement intracellulaire) en utilisant la spectroscopie RMN 1H pondérée en diffusion à 14.1T, sous infusion prolongée d’acétate. La détection de signaux d’acétate et de NAA avec une pondération large en diffusion a apporté des preuves expérimentales évidentes d’acétate et de NAA intracellulaire, bien qu’une fraction substantielle d’acétate soit extracellulaire. Pour estimer la concentration apparente d’aspartate cérébral in vivo, les temps de relaxation T1 et T2 de l’acétate ont été mesurés. Un plus long T1 et un plus court T2 de l’acétate apportent des preuves de sa petite taille moléculaire, et d’un possible environnement chimique différent. Nos valeurs expérimentales de Vd mènent à des taux métaboliques cérébraux d’acétate (CMR acétate) du même ordre de grandeur que ceux rapportés pour le taux du cycle de Krebs glial, indiquant que le CMR acétate est hautement dépendant de Vd. Résumé vi Finalement, afin de poursuivre la cartographie métabolique de la consommation d’acétate cérébral dans le rat in vivo à 14.1T, la conception et la construction d’une antenne combinée birdcage en transmission et paire d’antenne de surface en quadrature en réception ont été considérées. Sa performance a été comparée à une antenne birdcage en transmission et réception. Les résultats préliminaires de la configuration à deux antennes sont prometteurs : une excitation homogène et un gain en sensitivité jusqu’à une distance de 5 mm sont atteints. Des améliorations sont en cours pour des applications de spectroscopie NMR et d’imagerie à 14.1T. Mots clés: Métabolisme énergétique cérébral, les spectres de RMN 13C, la spectroscopie pondérée en diffusion, le volume physique de distribution, le taux métabolique, le cycle de Krebs, les temps de relaxations T1 et T2, la cinétique du transport et de l’absorption de l’acétate, l’antenne de surface, birdcage antenne. Contents Abstract ............................................................................................................................ iii Résumé .............................................................................................................................. v Contents ........................................................................................................................... vii Outline of thesis ....................................................................................................................... xi Chapter 1. An introduction to nuclear magnetic resonance ................................................ 1 1.1. The Physics of NMR ................................................................................................................................................ 1 1.1.1. Nuclear spin ............................................................................................................................................................
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