Hongxia Lei - Academia.edu (original) (raw)
Papers by Hongxia Lei
Magnetic resonance (MR) imaging (MRI) and spectroscopy (MRS) are ideally investigating tools suit... more Magnetic resonance (MR) imaging (MRI) and spectroscopy (MRS) are ideally investigating tools suited to study ischemia evolution events. Studying mouse is an attractive approach to help understand the pathogenesis but remains challenging due to its organ size, especially in MRS. High magnetic fields increase sensitivities and thus using a recently installed 14.1 T/26cm MR system, we sought to determine the feasibility of studying lesion developing and neurochemical changes following 30 min of endoluminal middle cerebral artery occlusion in four iCR-CD1 mice (~25g) using filament techniques. Absolute rCBF dropped to 21±6% of control during ischemia and recovered back to 70±24% shortly after. 8 and 24h after the insult, T 2 -weighted images presented lesion developing and localized spectra were obtained with 0.035ppm linewidths in the stroke region after adjusting magnetic field inhomogeneities. The resulting signal-noise-ratio at 13 could allow reliably analyzing 18 metabolites from an in vivo spectrum using a linear combination of model spectra of metabolites. T 2 -weighted images readily depicted the extent of the stroke at 8hr and more modest at 24hr. Prominent changes at 8hr include a transient doubling of brain Gln to 6.9±1.3mM, postulated to reflect Glu excitotoxicity, and decreases in several compounds such as NAA(3.6±1.2mM), Glu(5.0±1.0mM), Tau(5.0±1.0mM) , as well as increases in acetate 0.4±0.2mM, attributed to NAA breakdown) and lactate(10.0±2.3mM). Ischemia results in profound changes in the neurochemical profile with a complex evolution pattern, such as the Gln/Glu ratio, from 1.4 at 8hr to 0.4 at 24hr. Even at 8hr, the significant abnormality in the neurochemical profile was observed consistently when T 2 -weighted images presented minor lesion. We conclude that both MRI and MRS are feasible in ischemic mouse brain at 14.1T. Additionally, the capabilities of measuring the neurochemical profile permit the detection of early biochemical response to ischemia.
Journal of Molecular and Cellular Cardiology, 2015
The heart relies on continuous energy production and imbalances herein impair cardiac function di... more The heart relies on continuous energy production and imbalances herein impair cardiac function directly. The tricarboxylic acid (TCA) cycle is the primary means of energy generation in the healthy myocardium, but direct noninvasive quantification of metabolic fluxes is challenging due to the low concentration of most metabolites. Hyperpolarized (13)C magnetic resonance spectroscopy (MRS) provides the opportunity to measure cellular metabolism in real time in vivo. The aim of this work was to noninvasively measure myocardial TCA cycle flux (VTCA) in vivo within a single minute. Hyperpolarized [1-(13)C]acetate was administered at different concentrations in healthy rats. (13)C incorporation into [1-(13)C]acetylcarnitine and the TCA cycle intermediate [5-(13)C]citrate was dynamically detected in vivo with a time resolution of 3s. Different kinetic models were established and evaluated to determine the metabolic fluxes by simultaneously fitting the evolution of the (13)C labeling in acetate, acetylcarnitine, and citrate. VTCA was estimated to be 6.7±1.7μmol·g(-1)·min(-1) (dry weight), and was best estimated with a model using only the labeling in citrate and acetylcarnitine, independent of the precursor. The TCA cycle rate was not linear with the citrate-to-acetate metabolite ratio, and could thus not be quantified using a ratiometric approach. The (13)C signal evolution of citrate, i.e. citrate formation was independent of the amount of injected acetate, while the (13)C signal evolution of acetylcarnitine revealed a dose dependency with the injected acetate. The (13)C labeling of citrate did not correlate to that of acetylcarnitine, leading to the hypothesis that acetylcarnitine formation is not an indication of mitochondrial TCA cycle activity in the heart. Hyperpolarized [1-(13)C]acetate is a metabolic probe independent of pyruvate dehydrogenase (PDH) activity. It allows the direct estimation of VTCA in vivo, which was shown to be neither dependent on the administered acetate dose nor on the (13)C labeling of acetylcarnitine. Dynamic (13)C MRS coupled to the injection of hyperpolarized [1-(13)C]acetate can enable the measurement of metabolic changes during impaired heart function.
Introduction: Transgenic mouse models of Alzheimer's disease (AD) are useful for studying disease... more Introduction: Transgenic mouse models of Alzheimer's disease (AD) are useful for studying disease mechanism and for therapy testing. Mice expressing mutant amyloid precursor protein (APP) (1), those coexpressing mutant forms of human APP and presenilin 2 or 1 (PS2, PS1) proteins (2,3) and a triple transgenic model overexpressing APP, PS1 and tau protein genes (4) have been studied by in vivo proton MR spectroscopy. Interestingly, an increase of myo-inositol was observed only in the APP-PS1 model (3). The 5xFAD mouse model used in our study overexpresses APP genes with the Swedish (K670N, M671L), Florida (I716V), and London (V717I) familial Alzheimer's disease (FAD) mutations and PSEN1 gene harboring two FAD mutations, M146L and L286V. This AD model is aggressive and the mice start to develop amyloid plaques at the age of 2 months (5). In this study, development of the neurochemical profile of the 5xFAD mice with age was investigated by proton MRS. Furthermore, phosphorus spectroscopy was used for measuring relative concentrations of phosphorus-containing metabolites in brain, and the pseudo-first order forward rate constants k for of the creatine kinase reaction (PCr ↔ ATP) were obtained by localized phosphorus saturation transfer experiment. Experimental: Seven AD and seven wildtype mice anesthetized with 1-2 % isoflurane were measured at the age of about 36 weeks ( 31 P and 1 H), 40 and 44 weeks ( 1 H only). Experiments were done on a 14.1 T spectrometer (Varian/Magnex Scientific). Proton spectra were measured using a SPECIAL spectroscopy sequence (TR/TE = 4000/2.8 ms) (6). A home-built 14 mm diameter quadrature coil was used as a transceiver. VOIs of about 4 mm 3 were centered in dorsal hippocampus as well as near its temporal pole. 320 acquisitions were collected for each VOI. Using water signal as a reference, absolute metabolite concentrations were calculated using LCModel (7). 31 P spectra and saturation transfer data were measured by a dual coil consisting of a proton quadrature coil and a linearly polarized 10 mm diameter phosphorus coil using a protocol described in . The peak intensities were obtained by fitting to a Lorentzian function using AMARES (9) from the jMrui software (http://www.mrui.uab.es/mrui). The forward creatine kinase rate constants k for were obtained from a nonlinear regression of relative PCr signal intensities M(t ir )/M(0) versus γ-ATP saturation time t ir . A t-test was used to compare metabolite concentrations in the AD and wildtype mice. Results: Comparison of the neurochemical profiles in dorsal hippocampus of the AD and wildtype mice is shown in . At the age of 36 weeks, no statistically significant differences were found except a decrease of NAA in the AD mice (p < 0.003). However, at the age of 40 and 44 weeks, changes typical for the human form of the disease, i.e., a decrease of NAA (p < 0.004) and an increase of myo-inositol (p < 0.007) were observed
Background / Purpose: Despite improving imaging techniques it remains a challenge to predict the ... more Background / Purpose: Despite improving imaging techniques it remains a challenge to predict the early outcome after transient cerebral ischemia.The aim of this study was to identify early metabolic biomarkers for outcome prediction. We varied the duration of ischemia (middle cerebral artery occlusion in mice) in order to record reversible and irreversible ischemic damage. We then used high field magnetic resonance spectroscopy to correlate the early changes in the neurochemical profile of the ischemic striatum and histopathological alterations to find potential metabolic biomarkers for outcome prediction. Main conclusion: A significant increase in glutamine was measured between 3h and 8h after all ischemic events. This was followed by reperfusion independent of the outcome, suggesting it could be a potential indicator of recent transient ischemia. Conversely, a reduction of the score obtained by summing the concentrations of N-acetyl aspartate, glutamate and taurine seemed to be a ...
Manganese (Mn 2 + )-enhanced magnetic resonance imaging studies of the neuronal pathways of the h... more Manganese (Mn 2 + )-enhanced magnetic resonance imaging studies of the neuronal pathways of the hypothalamus showed that information about the regulation of food intake and energy balance circulate through specific hypothalamic nuclei. The dehydration-induced anorexia (DIA) model demonstrated to be appropriate for studying the hypothalamus with Mn 2 + -enhanced magnetic resonance imaging. Manganese is involved in the normal functioning of a variety of physiological processes and is associated with enzymes contributing to neurotransmitter synthesis and metabolism. It also induces psychiatric and motor disturbances. The molecular mechanisms by which Mn 2 + produces alterations of the hypothalamic physiological processes are not well understood. 1 H-magnetic resonance spectroscopy measurements of the rodent hypothalamus are challenging due to the distant location of the hypothalamus resulting in limited measurement sensitivity. The present study proposed to investigate the effects of Mn 2 + on the neurochemical profile of the hypothalamus in normal, DIA, and overnight fasted female rats at 14.1 T. Results provide evidence that c-aminobutyric acid has an essential role in the maintenance of energy homeostasis in the hypothalamus but is not condition specific. On the contrary, glutamine, glutamate, and taurine appear to respond more accurately to Mn 2 + exposure. An increase in glutamine levels could also be a characteristic response of the hypothalamus to DIA.
The mathematical model of compartmentalized cerebral metabolism was adapted from previous works 1... more The mathematical model of compartmentalized cerebral metabolism was adapted from previous works 1-3 where the reader can find an exhaustive description of the model. The metabolic pools and fluxes of the considered model are represented in figure 1. Metabolic steady-state was assumed for the metabolic fluxes (constant) and the metabolic pools. The in vivo measured mean glutamate and glutamine concentrations were 9.1 and 3.4 µmol/g, respectively, as measured with 1 H MRS.
NMR in biomedicine, Jan 28, 2015
Alterations in the hepatic lipid content (HLC) and fatty acid composition are associated with dis... more Alterations in the hepatic lipid content (HLC) and fatty acid composition are associated with disruptions in whole body metabolism, both in humans and in rodent models, and can be non-invasively assessed by (1) H-MRS in vivo. We used (1) H-MRS to characterize the hepatic fatty-acyl chains of healthy mice and to follow changes caused by streptozotocin (STZ) injection. Using STEAM at 14.1 T with an ultra-short TE of 2.8 ms, confounding effects from T2 relaxation and J-coupling were avoided, allowing for accurate estimations of the contribution of unsaturated (UFA), saturated (SFA), mono-unsaturated (MUFA) and poly-unsaturated (PUFA) fatty-acyl chains, number of double bonds, PU bonds and mean chain length. Compared with in vivo (1) H-MRS, high resolution NMR performed in vitro in hepatic lipid extracts reported longer fatty-acyl chains (18 versus 15 carbons) with a lower contribution from UFA (61 ± 1% versus 80 ± 5%) but a higher number of PU bonds per UFA (1.39 ± 0.03 versus 0.58 ± 0...
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2014
The treatments for ischemic stroke can only be administered in a narrow time-window. However, the... more The treatments for ischemic stroke can only be administered in a narrow time-window. However, the ischemia onset time is unknown in ~30% of stroke patients (wake-up strokes). The objective of this study was to determine whether MR spectra of ischemic brains might allow the precise estimation of cerebral ischemia onset time. We modeled ischemic stroke in male ICR-CD1 mice using a permanent middle cerebral artery filament occlusion model with laser Doppler control of the regional cerebral blood flow. Mice were then subjected to repeated MRS measurements of ipsilateral striatum at 14.1 T. A striking initial increase in γ-aminobutyric acid (GABA) and no increase in glutamine were observed. A steady decline was observed for taurine (Tau), N-acetyl-aspartate (NAA) and similarly for the sum of NAA+Tau+glutamate that mimicked an exponential function. The estimation of the time of onset of permanent ischemia within 6 hours in a blinded experiment with mice showed an accuracy of 33±10 minutes...
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2014
An essential feature of magnetic resonance (MR) probes for magnetic resonance imaging and spectro... more An essential feature of magnetic resonance (MR) probes for magnetic resonance imaging and spectroscopy is the ability to generate uniform B1(+) excitation in a volume of interest. When the magnetic field strength is increased, leading to an increase in resonance frequency, the constraints on the MR probes size, the sample size and the associated radiation losses caused by conductor elements are higher. In this study we simulate, test and construct two birdcage coils for imaging rodents operated at 14.1 T. Bench experiments and imaging tests show that at 14.1 T dielectric resonance effect is the dominant factor accounting for B1(+) field inhomogeneity but remained achievable for imaging rodent brains.
Among numerous magnetic resonance imaging (MRI) techniques, perfusion MRI provides insight into t... more Among numerous magnetic resonance imaging (MRI) techniques, perfusion MRI provides insight into the passage of blood through the brain's vascular network noninvasively. Studying disease models and transgenic mice would intrinsically help understanding the underlying brain functions, cerebrovascular disease and brain disorders. This study evaluates the feasibility of performing continuous arterial spin labeling (CASL) on all cranial arteries for mapping murine cerebral blood flow at 9.4T. We showed that with an active-detuned two-coil system, a labeling efficiency of 0.82±0.03 was achieved with minimal magnetization transfer residuals in brain. The resulting cerebral blood flow of healthy mouse was 99±26mL/100g/min, in excellent agreement with other techniques. In conclusion, high magnetic fields deliver high sensitivity and allowing not only CASL but also other MR techniques, i.e. 1 H MRS and diffusion MRI etc, in studying murine brains.
Frontiers in Neuroenergetics, 2009
![Research paper thumbnail of Assessment of metabolic fluxes in the mouse brain in vivo using (1)H-[(13)C] NMR spectroscopy at 14.1 Tesla](https://attachments.academia-assets.com/43676960/thumbnails/1.jpg)
](Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, Jan 21, 2015
3,5 13 C magnetic resonance spectroscopy (MRS) combined with the administration of 13 C labeled s... more 3,5 13 C magnetic resonance spectroscopy (MRS) combined with the administration of 13 C labeled substrates uniquely allows to measure metabolic fluxes in vivo in the brain of humans and rats. The extension to mouse models may provide exclusive prospect for the investigation of models of human diseases. In the present study, the short-echo-time (TE) full-sensitivity 1 H-[ 13 C] MRS sequence combined with high magnetic field (14.1 T) and infusion of [U-13 C 6 ] glucose was used to enhance the experimental sensitivity in vivo in the mouse brain and the 13 C turnover curves of glutamate C4, glutamine C4, glutamate+glutamine C3, aspartate C2, lactate C3, alanine C3, γ-aminobutyric acid C2, C3 and C4 were obtained. A one-compartment model was used to fit 13 C turnover curves and resulted in values of metabolic fluxes including the tricarboxylic acid (TCA) cycle flux V TCA (1.05 ± 0.04 μmol/g per minute), the exchange flux between 2-oxoglutarate and glutamate V x (0.48 ± 0.02 μmol/g per minute), the glutamate-glutamine exchange rate V gln (0.20 ± 0.02 μmol/g per minute), the pyruvate dilution factor K dil (0.82 ± 0.01), and the ratio for the lactate conversion rate and the alanine conversion rate V Lac /V Ala (10 ± 2). This study opens the prospect of studying transgenic mouse models of brain pathologies.
Stroke, 2011
Background and Purpose-Despite the improving imaging techniques, it remains challenging to predic... more Background and Purpose-Despite the improving imaging techniques, it remains challenging to predict the outcome early after transient cerebral ischemia. The aim of this study was thus to identify early metabolic biomarkers for outcome prediction. Methods-We modeled transient ischemic attacks and strokes in mice. Using high-field MR spectroscopy, we correlated early changes in the neurochemical profile of the ischemic striatum with histopathologic alterations at a later time point. Results-A significant increase in glutamine was measured between 3 hours and 8 hours after all ischemic events followed by reperfusion independently of the outcome and can thus be considered as an indicator of recent transient ischemia.
PLoS ONE, 2013
C57BL/6 mice are the most widely used strain of laboratory mice. Using in vivo proton Magnetic Re... more C57BL/6 mice are the most widely used strain of laboratory mice. Using in vivo proton Magnetic Resonance Spectroscopy ( 1 H MRS), we have repeatedly observed an abnormal neurochemical profile in the brains of both wild-type and genetically modified mice derived from the C57BL/6J strain, consisting of a several fold increase in cerebral glutamine and two fold decrease in myo-inositol. This strikingly abnormal neurochemical ''phenotype'' resembles that observed in chronic liver disease or portosystemic shunting and appeared to be independent of transgene, origin or chow and was not associated with liver failure. As many as 25% of animals displayed the abnormal neurochemical profile, questioning the reliability of this model for neurobiology. We conducted an independent study to determine if this neurochemical profile was associated with portosystemic shunting. Our results showed that 100% of the mice with high brain glutamine displayed portosystemic shunting by concomitant portal angiography while all mice with normal brain glutamine did not. Since portosystemic shunting is known to cause alterations in gene expression in many organs including the brain, we conclude that portosystemic shunting may be the most significant problem associated with C57BL/6J inbreeding both for its effect on the central nervous system and for its systemic repercussions. Citation: Cudalbu C, McLin VA, Lei H, Duarte JMN, Rougemont A-L, et al. (2013) The C57BL/6J Mouse Exhibits Sporadic Congenital Portosystemic Shunts. PLoS ONE 8(7): e69782.
NMR in Biomedicine, 1990
We have obtained localized, water-suppressed proton magnetic resonance spectra from eleven astroc... more We have obtained localized, water-suppressed proton magnetic resonance spectra from eleven astrocytomas in vivo. Localized phosphorus spectra were also obtained from three of these tumors. All tumors were examined prior to surgery, radiotherapy or chemotherapy. Examinations were performed with a commercially available 1.5 Tesla combined imaging and spectroscopy system using a stimulated echo pulse sequence for protons and an ISIS pulse sequence for phosphorus. A relatively high lactate resonance intensity correlated with a more malignant histological tumor grade and more aggressive behaviour. The resonance intensity of N-acetylaspartate/creatine was decreased and choline/creatine was increased, but these did not reliably discriminate between tumor grades. Other unidentified resonances not present in spectra of normal brain were sometimes seen. Proton magnetic resonance spectroscopy provides a new method for determining the metabolic behaviour of astrocytomas that may be useful in the clinical assessment of patients with these tumors.
NMR in Biomedicine, 2010
The hypothalamus plays an essential role in the central nervous system of mammals by among others... more The hypothalamus plays an essential role in the central nervous system of mammals by among others regulating glucose homeostasis, food intake, temperature, and to some extent blood pressure. Assessments of hypothalamic metabolism using, e.g. 1 H MRS in mouse models can provide important insights into its function. To date, direct in vivo 1 H MRS measurements of hypothalamus have not been reported. Here, we report that in vivo single voxel measurements of mouse hypothalamus are feasible using 1 H MRS at 14.1T. Localized 1 H MR spectra from hypothalamus were obtained unilaterally (2-2.2 mL, VOI) and bilaterally (4-4.4 mL) with a quality comparable to that of hippocampus (3-3.5 mL). Using LCModel, a neurochemical profile consisting of 21 metabolites was quantified for both hypothalamus and hippocampus with most of the Cramé r-Rao lower bounds within 20%. Relative to the hippocampus, the hypothalamus was characterized by high g-aminobutryric acid and myo-inositol, and low taurine concentrations. When studying transgenic mice with no glucose transporter isoform 8 expressed, small metabolic changes were observed, yet glucose homeostasis was well maintained. We conclude that a specific neurochemical profile of mouse hypothalamus can be measured by 1 H MRS which will allow identifying and following metabolic alterations longitudinally in the hypothalamus of genetic modified models.
Magnetic resonance (MR) imaging (MRI) and spectroscopy (MRS) are ideally investigating tools suit... more Magnetic resonance (MR) imaging (MRI) and spectroscopy (MRS) are ideally investigating tools suited to study ischemia evolution events. Studying mouse is an attractive approach to help understand the pathogenesis but remains challenging due to its organ size, especially in MRS. High magnetic fields increase sensitivities and thus using a recently installed 14.1 T/26cm MR system, we sought to determine the feasibility of studying lesion developing and neurochemical changes following 30 min of endoluminal middle cerebral artery occlusion in four iCR-CD1 mice (~25g) using filament techniques. Absolute rCBF dropped to 21±6% of control during ischemia and recovered back to 70±24% shortly after. 8 and 24h after the insult, T 2 -weighted images presented lesion developing and localized spectra were obtained with 0.035ppm linewidths in the stroke region after adjusting magnetic field inhomogeneities. The resulting signal-noise-ratio at 13 could allow reliably analyzing 18 metabolites from an in vivo spectrum using a linear combination of model spectra of metabolites. T 2 -weighted images readily depicted the extent of the stroke at 8hr and more modest at 24hr. Prominent changes at 8hr include a transient doubling of brain Gln to 6.9±1.3mM, postulated to reflect Glu excitotoxicity, and decreases in several compounds such as NAA(3.6±1.2mM), Glu(5.0±1.0mM), Tau(5.0±1.0mM) , as well as increases in acetate 0.4±0.2mM, attributed to NAA breakdown) and lactate(10.0±2.3mM). Ischemia results in profound changes in the neurochemical profile with a complex evolution pattern, such as the Gln/Glu ratio, from 1.4 at 8hr to 0.4 at 24hr. Even at 8hr, the significant abnormality in the neurochemical profile was observed consistently when T 2 -weighted images presented minor lesion. We conclude that both MRI and MRS are feasible in ischemic mouse brain at 14.1T. Additionally, the capabilities of measuring the neurochemical profile permit the detection of early biochemical response to ischemia.
Journal of Molecular and Cellular Cardiology, 2015
The heart relies on continuous energy production and imbalances herein impair cardiac function di... more The heart relies on continuous energy production and imbalances herein impair cardiac function directly. The tricarboxylic acid (TCA) cycle is the primary means of energy generation in the healthy myocardium, but direct noninvasive quantification of metabolic fluxes is challenging due to the low concentration of most metabolites. Hyperpolarized (13)C magnetic resonance spectroscopy (MRS) provides the opportunity to measure cellular metabolism in real time in vivo. The aim of this work was to noninvasively measure myocardial TCA cycle flux (VTCA) in vivo within a single minute. Hyperpolarized [1-(13)C]acetate was administered at different concentrations in healthy rats. (13)C incorporation into [1-(13)C]acetylcarnitine and the TCA cycle intermediate [5-(13)C]citrate was dynamically detected in vivo with a time resolution of 3s. Different kinetic models were established and evaluated to determine the metabolic fluxes by simultaneously fitting the evolution of the (13)C labeling in acetate, acetylcarnitine, and citrate. VTCA was estimated to be 6.7±1.7μmol·g(-1)·min(-1) (dry weight), and was best estimated with a model using only the labeling in citrate and acetylcarnitine, independent of the precursor. The TCA cycle rate was not linear with the citrate-to-acetate metabolite ratio, and could thus not be quantified using a ratiometric approach. The (13)C signal evolution of citrate, i.e. citrate formation was independent of the amount of injected acetate, while the (13)C signal evolution of acetylcarnitine revealed a dose dependency with the injected acetate. The (13)C labeling of citrate did not correlate to that of acetylcarnitine, leading to the hypothesis that acetylcarnitine formation is not an indication of mitochondrial TCA cycle activity in the heart. Hyperpolarized [1-(13)C]acetate is a metabolic probe independent of pyruvate dehydrogenase (PDH) activity. It allows the direct estimation of VTCA in vivo, which was shown to be neither dependent on the administered acetate dose nor on the (13)C labeling of acetylcarnitine. Dynamic (13)C MRS coupled to the injection of hyperpolarized [1-(13)C]acetate can enable the measurement of metabolic changes during impaired heart function.
Introduction: Transgenic mouse models of Alzheimer's disease (AD) are useful for studying disease... more Introduction: Transgenic mouse models of Alzheimer's disease (AD) are useful for studying disease mechanism and for therapy testing. Mice expressing mutant amyloid precursor protein (APP) (1), those coexpressing mutant forms of human APP and presenilin 2 or 1 (PS2, PS1) proteins (2,3) and a triple transgenic model overexpressing APP, PS1 and tau protein genes (4) have been studied by in vivo proton MR spectroscopy. Interestingly, an increase of myo-inositol was observed only in the APP-PS1 model (3). The 5xFAD mouse model used in our study overexpresses APP genes with the Swedish (K670N, M671L), Florida (I716V), and London (V717I) familial Alzheimer's disease (FAD) mutations and PSEN1 gene harboring two FAD mutations, M146L and L286V. This AD model is aggressive and the mice start to develop amyloid plaques at the age of 2 months (5). In this study, development of the neurochemical profile of the 5xFAD mice with age was investigated by proton MRS. Furthermore, phosphorus spectroscopy was used for measuring relative concentrations of phosphorus-containing metabolites in brain, and the pseudo-first order forward rate constants k for of the creatine kinase reaction (PCr ↔ ATP) were obtained by localized phosphorus saturation transfer experiment. Experimental: Seven AD and seven wildtype mice anesthetized with 1-2 % isoflurane were measured at the age of about 36 weeks ( 31 P and 1 H), 40 and 44 weeks ( 1 H only). Experiments were done on a 14.1 T spectrometer (Varian/Magnex Scientific). Proton spectra were measured using a SPECIAL spectroscopy sequence (TR/TE = 4000/2.8 ms) (6). A home-built 14 mm diameter quadrature coil was used as a transceiver. VOIs of about 4 mm 3 were centered in dorsal hippocampus as well as near its temporal pole. 320 acquisitions were collected for each VOI. Using water signal as a reference, absolute metabolite concentrations were calculated using LCModel (7). 31 P spectra and saturation transfer data were measured by a dual coil consisting of a proton quadrature coil and a linearly polarized 10 mm diameter phosphorus coil using a protocol described in . The peak intensities were obtained by fitting to a Lorentzian function using AMARES (9) from the jMrui software (http://www.mrui.uab.es/mrui). The forward creatine kinase rate constants k for were obtained from a nonlinear regression of relative PCr signal intensities M(t ir )/M(0) versus γ-ATP saturation time t ir . A t-test was used to compare metabolite concentrations in the AD and wildtype mice. Results: Comparison of the neurochemical profiles in dorsal hippocampus of the AD and wildtype mice is shown in . At the age of 36 weeks, no statistically significant differences were found except a decrease of NAA in the AD mice (p < 0.003). However, at the age of 40 and 44 weeks, changes typical for the human form of the disease, i.e., a decrease of NAA (p < 0.004) and an increase of myo-inositol (p < 0.007) were observed
Background / Purpose: Despite improving imaging techniques it remains a challenge to predict the ... more Background / Purpose: Despite improving imaging techniques it remains a challenge to predict the early outcome after transient cerebral ischemia.The aim of this study was to identify early metabolic biomarkers for outcome prediction. We varied the duration of ischemia (middle cerebral artery occlusion in mice) in order to record reversible and irreversible ischemic damage. We then used high field magnetic resonance spectroscopy to correlate the early changes in the neurochemical profile of the ischemic striatum and histopathological alterations to find potential metabolic biomarkers for outcome prediction. Main conclusion: A significant increase in glutamine was measured between 3h and 8h after all ischemic events. This was followed by reperfusion independent of the outcome, suggesting it could be a potential indicator of recent transient ischemia. Conversely, a reduction of the score obtained by summing the concentrations of N-acetyl aspartate, glutamate and taurine seemed to be a ...
Manganese (Mn 2 + )-enhanced magnetic resonance imaging studies of the neuronal pathways of the h... more Manganese (Mn 2 + )-enhanced magnetic resonance imaging studies of the neuronal pathways of the hypothalamus showed that information about the regulation of food intake and energy balance circulate through specific hypothalamic nuclei. The dehydration-induced anorexia (DIA) model demonstrated to be appropriate for studying the hypothalamus with Mn 2 + -enhanced magnetic resonance imaging. Manganese is involved in the normal functioning of a variety of physiological processes and is associated with enzymes contributing to neurotransmitter synthesis and metabolism. It also induces psychiatric and motor disturbances. The molecular mechanisms by which Mn 2 + produces alterations of the hypothalamic physiological processes are not well understood. 1 H-magnetic resonance spectroscopy measurements of the rodent hypothalamus are challenging due to the distant location of the hypothalamus resulting in limited measurement sensitivity. The present study proposed to investigate the effects of Mn 2 + on the neurochemical profile of the hypothalamus in normal, DIA, and overnight fasted female rats at 14.1 T. Results provide evidence that c-aminobutyric acid has an essential role in the maintenance of energy homeostasis in the hypothalamus but is not condition specific. On the contrary, glutamine, glutamate, and taurine appear to respond more accurately to Mn 2 + exposure. An increase in glutamine levels could also be a characteristic response of the hypothalamus to DIA.
The mathematical model of compartmentalized cerebral metabolism was adapted from previous works 1... more The mathematical model of compartmentalized cerebral metabolism was adapted from previous works 1-3 where the reader can find an exhaustive description of the model. The metabolic pools and fluxes of the considered model are represented in figure 1. Metabolic steady-state was assumed for the metabolic fluxes (constant) and the metabolic pools. The in vivo measured mean glutamate and glutamine concentrations were 9.1 and 3.4 µmol/g, respectively, as measured with 1 H MRS.
NMR in biomedicine, Jan 28, 2015
Alterations in the hepatic lipid content (HLC) and fatty acid composition are associated with dis... more Alterations in the hepatic lipid content (HLC) and fatty acid composition are associated with disruptions in whole body metabolism, both in humans and in rodent models, and can be non-invasively assessed by (1) H-MRS in vivo. We used (1) H-MRS to characterize the hepatic fatty-acyl chains of healthy mice and to follow changes caused by streptozotocin (STZ) injection. Using STEAM at 14.1 T with an ultra-short TE of 2.8 ms, confounding effects from T2 relaxation and J-coupling were avoided, allowing for accurate estimations of the contribution of unsaturated (UFA), saturated (SFA), mono-unsaturated (MUFA) and poly-unsaturated (PUFA) fatty-acyl chains, number of double bonds, PU bonds and mean chain length. Compared with in vivo (1) H-MRS, high resolution NMR performed in vitro in hepatic lipid extracts reported longer fatty-acyl chains (18 versus 15 carbons) with a lower contribution from UFA (61 ± 1% versus 80 ± 5%) but a higher number of PU bonds per UFA (1.39 ± 0.03 versus 0.58 ± 0...
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2014
The treatments for ischemic stroke can only be administered in a narrow time-window. However, the... more The treatments for ischemic stroke can only be administered in a narrow time-window. However, the ischemia onset time is unknown in ~30% of stroke patients (wake-up strokes). The objective of this study was to determine whether MR spectra of ischemic brains might allow the precise estimation of cerebral ischemia onset time. We modeled ischemic stroke in male ICR-CD1 mice using a permanent middle cerebral artery filament occlusion model with laser Doppler control of the regional cerebral blood flow. Mice were then subjected to repeated MRS measurements of ipsilateral striatum at 14.1 T. A striking initial increase in γ-aminobutyric acid (GABA) and no increase in glutamine were observed. A steady decline was observed for taurine (Tau), N-acetyl-aspartate (NAA) and similarly for the sum of NAA+Tau+glutamate that mimicked an exponential function. The estimation of the time of onset of permanent ischemia within 6 hours in a blinded experiment with mice showed an accuracy of 33±10 minutes...
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2014
An essential feature of magnetic resonance (MR) probes for magnetic resonance imaging and spectro... more An essential feature of magnetic resonance (MR) probes for magnetic resonance imaging and spectroscopy is the ability to generate uniform B1(+) excitation in a volume of interest. When the magnetic field strength is increased, leading to an increase in resonance frequency, the constraints on the MR probes size, the sample size and the associated radiation losses caused by conductor elements are higher. In this study we simulate, test and construct two birdcage coils for imaging rodents operated at 14.1 T. Bench experiments and imaging tests show that at 14.1 T dielectric resonance effect is the dominant factor accounting for B1(+) field inhomogeneity but remained achievable for imaging rodent brains.
Among numerous magnetic resonance imaging (MRI) techniques, perfusion MRI provides insight into t... more Among numerous magnetic resonance imaging (MRI) techniques, perfusion MRI provides insight into the passage of blood through the brain's vascular network noninvasively. Studying disease models and transgenic mice would intrinsically help understanding the underlying brain functions, cerebrovascular disease and brain disorders. This study evaluates the feasibility of performing continuous arterial spin labeling (CASL) on all cranial arteries for mapping murine cerebral blood flow at 9.4T. We showed that with an active-detuned two-coil system, a labeling efficiency of 0.82±0.03 was achieved with minimal magnetization transfer residuals in brain. The resulting cerebral blood flow of healthy mouse was 99±26mL/100g/min, in excellent agreement with other techniques. In conclusion, high magnetic fields deliver high sensitivity and allowing not only CASL but also other MR techniques, i.e. 1 H MRS and diffusion MRI etc, in studying murine brains.
Frontiers in Neuroenergetics, 2009
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, Jan 21, 2015
3,5 13 C magnetic resonance spectroscopy (MRS) combined with the administration of 13 C labeled s... more 3,5 13 C magnetic resonance spectroscopy (MRS) combined with the administration of 13 C labeled substrates uniquely allows to measure metabolic fluxes in vivo in the brain of humans and rats. The extension to mouse models may provide exclusive prospect for the investigation of models of human diseases. In the present study, the short-echo-time (TE) full-sensitivity 1 H-[ 13 C] MRS sequence combined with high magnetic field (14.1 T) and infusion of [U-13 C 6 ] glucose was used to enhance the experimental sensitivity in vivo in the mouse brain and the 13 C turnover curves of glutamate C4, glutamine C4, glutamate+glutamine C3, aspartate C2, lactate C3, alanine C3, γ-aminobutyric acid C2, C3 and C4 were obtained. A one-compartment model was used to fit 13 C turnover curves and resulted in values of metabolic fluxes including the tricarboxylic acid (TCA) cycle flux V TCA (1.05 ± 0.04 μmol/g per minute), the exchange flux between 2-oxoglutarate and glutamate V x (0.48 ± 0.02 μmol/g per minute), the glutamate-glutamine exchange rate V gln (0.20 ± 0.02 μmol/g per minute), the pyruvate dilution factor K dil (0.82 ± 0.01), and the ratio for the lactate conversion rate and the alanine conversion rate V Lac /V Ala (10 ± 2). This study opens the prospect of studying transgenic mouse models of brain pathologies.
Stroke, 2011
Background and Purpose-Despite the improving imaging techniques, it remains challenging to predic... more Background and Purpose-Despite the improving imaging techniques, it remains challenging to predict the outcome early after transient cerebral ischemia. The aim of this study was thus to identify early metabolic biomarkers for outcome prediction. Methods-We modeled transient ischemic attacks and strokes in mice. Using high-field MR spectroscopy, we correlated early changes in the neurochemical profile of the ischemic striatum with histopathologic alterations at a later time point. Results-A significant increase in glutamine was measured between 3 hours and 8 hours after all ischemic events followed by reperfusion independently of the outcome and can thus be considered as an indicator of recent transient ischemia.
PLoS ONE, 2013
C57BL/6 mice are the most widely used strain of laboratory mice. Using in vivo proton Magnetic Re... more C57BL/6 mice are the most widely used strain of laboratory mice. Using in vivo proton Magnetic Resonance Spectroscopy ( 1 H MRS), we have repeatedly observed an abnormal neurochemical profile in the brains of both wild-type and genetically modified mice derived from the C57BL/6J strain, consisting of a several fold increase in cerebral glutamine and two fold decrease in myo-inositol. This strikingly abnormal neurochemical ''phenotype'' resembles that observed in chronic liver disease or portosystemic shunting and appeared to be independent of transgene, origin or chow and was not associated with liver failure. As many as 25% of animals displayed the abnormal neurochemical profile, questioning the reliability of this model for neurobiology. We conducted an independent study to determine if this neurochemical profile was associated with portosystemic shunting. Our results showed that 100% of the mice with high brain glutamine displayed portosystemic shunting by concomitant portal angiography while all mice with normal brain glutamine did not. Since portosystemic shunting is known to cause alterations in gene expression in many organs including the brain, we conclude that portosystemic shunting may be the most significant problem associated with C57BL/6J inbreeding both for its effect on the central nervous system and for its systemic repercussions. Citation: Cudalbu C, McLin VA, Lei H, Duarte JMN, Rougemont A-L, et al. (2013) The C57BL/6J Mouse Exhibits Sporadic Congenital Portosystemic Shunts. PLoS ONE 8(7): e69782.
NMR in Biomedicine, 1990
We have obtained localized, water-suppressed proton magnetic resonance spectra from eleven astroc... more We have obtained localized, water-suppressed proton magnetic resonance spectra from eleven astrocytomas in vivo. Localized phosphorus spectra were also obtained from three of these tumors. All tumors were examined prior to surgery, radiotherapy or chemotherapy. Examinations were performed with a commercially available 1.5 Tesla combined imaging and spectroscopy system using a stimulated echo pulse sequence for protons and an ISIS pulse sequence for phosphorus. A relatively high lactate resonance intensity correlated with a more malignant histological tumor grade and more aggressive behaviour. The resonance intensity of N-acetylaspartate/creatine was decreased and choline/creatine was increased, but these did not reliably discriminate between tumor grades. Other unidentified resonances not present in spectra of normal brain were sometimes seen. Proton magnetic resonance spectroscopy provides a new method for determining the metabolic behaviour of astrocytomas that may be useful in the clinical assessment of patients with these tumors.
NMR in Biomedicine, 2010
The hypothalamus plays an essential role in the central nervous system of mammals by among others... more The hypothalamus plays an essential role in the central nervous system of mammals by among others regulating glucose homeostasis, food intake, temperature, and to some extent blood pressure. Assessments of hypothalamic metabolism using, e.g. 1 H MRS in mouse models can provide important insights into its function. To date, direct in vivo 1 H MRS measurements of hypothalamus have not been reported. Here, we report that in vivo single voxel measurements of mouse hypothalamus are feasible using 1 H MRS at 14.1T. Localized 1 H MR spectra from hypothalamus were obtained unilaterally (2-2.2 mL, VOI) and bilaterally (4-4.4 mL) with a quality comparable to that of hippocampus (3-3.5 mL). Using LCModel, a neurochemical profile consisting of 21 metabolites was quantified for both hypothalamus and hippocampus with most of the Cramé r-Rao lower bounds within 20%. Relative to the hippocampus, the hypothalamus was characterized by high g-aminobutryric acid and myo-inositol, and low taurine concentrations. When studying transgenic mice with no glucose transporter isoform 8 expressed, small metabolic changes were observed, yet glucose homeostasis was well maintained. We conclude that a specific neurochemical profile of mouse hypothalamus can be measured by 1 H MRS which will allow identifying and following metabolic alterations longitudinally in the hypothalamus of genetic modified models.