Doubly selective multiple quantum chemical shift imaging and T1 relaxation time measurement of glutathione (GSH) in the human brain in vivo

Mapping of a major antioxidant, glutathione (GSH), was achieved in the human brain in vivo using a doubly‐selective multiple quantum filtering based chemical shift imaging (CSI) of GSH at 3 T. Both in vivo and phantom tests in CSI and single voxel measurements were consistent with excellent suppression of overlapping signals from creatine, γ‐Amino butyric acid (GABA) and macromolecules. GSH concentration in the fronto‐parietal region was 1.20 ± 0.16 µmol/g (mean ± SD, n = 7). The longitudinal relaxation time (T₁) of GSH in the human brain was 397 ± 44 ms (mean ± SD, n = 5), which was substantially shorter than that of other metabolites. This GSH‐CSI method permits us to address regional differences of GSH in the human brain under conditions where oxidative stress has been implicated, including multiple sclerosis, aging and neurodegenerative diseases. Copyright © 2012 John Wiley & Sons, Ltd.     

Functional analysis of human parotid gland in vivo using the (1)H MRS MT effect

Magnetization transfer (MT) was measured in the parotid gland in vivo by (1)H MR spectroscopy in 10 adult volunteers. A comparison was made of stimulated (excess saliva) and resting parotid gland (SPG and RPG, respectively). Following irradiation at an MT pulse of 150 Hz downfield from the water proton signal, signal reductions in SPG and RPG were 83.8 +/- 4.7 and 91.4 +/- 5.7%, respectively. The larger reduction for SPG indicates that an increase in the amount of water in gland cells for the production of more parotid saliva may lead to greater affinity between the protons adjacent to macromolecules and free water which contributes to the MT effect. Activity in the parotid gland correlates with the effect. This method is useful for diagnosing disorders of parotid gland secretion.     

1H and 13C HR-MAS spectroscopy of intact biopsy samples ex vivo and in vivo 1H MRS study of human high grade gliomas

High-resolution magic angle spinning (HR-MAS) one- and two-dimensional 1H and 13C nuclear magnetic resonance (NMR) spectroscopy has been used to study intact glioblastoma (GBM) brain tumour tissue. The results were compared with in vitro chemical extract and in vivo spectra. The resolution of 1H one-dimensional, 1H TOCSY and 13C HSQC HR-MAS spectra is comparable to that obtained on perchloric extracts. 13C HSQC HR-MAS spectra have been particularly useful for the identification of 37 different metabolites in intact biopsy tumours, excluding water and DSS components. To our knowledge, this is the most detailed assignment of biochemical compounds obtained in intact human tissue, in particular in brain tumour tissue. Tissue degradation during the recording of the NMR experiment was avoided by keeping the sample at a temperature of 4 degrees C. Detailed metabolical compositions of 10 GBM (six primary, two secondary and two unclassified) were obtained. A good correlation between ex vivo and in vivo MRS has been found.     

Diffusion-weighted in vivo localized proton MR spectroscopy of human cerebral ischemia and tumor

The apparent diffusion coefficients (ADCs) of water and brain metabolites were determined by proton MR spectroscopy on a clinical MR scanner for healthy volunteers and for pathological changes in cases of acute cerebral infarction and brain tumor. The ADCs of N-acetyl aspartate (NAA) and creatines in tissue involved in acute infarction were decreased compared to normal control values, while in tumors they showed increased values. Since NAA is a neuronal marker, these findings suggest that neuronal cell viscosity changes according to the pathological status of the tissue. The lactate ADC was significantly larger than the values for other major metabolites in cases of ischemia and tumor, suggesting that lactate is present in a different compartment. These results indicate that metabolite diffusion data can be used to reveal changes in the intracellular environment depending on the pathological status.     

Proton MRS of early post-natal mouse brain modifications in vivo

NMR provides a non-invasive tool for the phenotypic characterisation of mouse models. The aim of the present study was to apply reliable in vivo MRS techniques for non-invasive investigations of brain development in normal and transgenic mice, by monitoring metabolite concentrations in different brain regions. The conditions of anaesthesia, immobilisation and respiratory monitoring were optimized to carry out in vivo MRS studies in young mice. All the experiments were performed in normal mice, at 9.4 T, applying a point-resolved spectroscopy (PRESS) sequence (TR = 2,000 ms; TE = 130 ms). We obtained reproducible in vivo (1)H NMR spectra of wild-type mouse brains as early as post-natal day 5, which allowed us to follow brain maturation variations from post-natal days 5 to 21. The survival rate of animals was between 66 and 90% at post-natal days 5 and 21, respectively. Developmental changes of metabolite concentrations were measured in three brain regions: the thalamus, a region rich in cell bodies, the olfactory bulb, rich in fibre tracts actively myelinated during brain maturation, and the cerebellum. The voxel size varied from 2 to 8 microL according to the size of the brain structure analysed. The absolute concentrations of the total creatine, taurine, total choline, N-acetylaspartate and of the glutamate/glutamine pool were determined from (1)H NMR spectra obtained in the different brain regions at post-natal day 5, 10, 15 and 21. Variations observed during brain development were in accordance with those previously reported in mice using ex vivo MRS studies, and also in rats and humans in vivo. Possibilities of longitudinal MRS analysis in maturing mice brains provide new perspectives to characterise better the tremendous number of transgenic mutant mice generated with the aim of decrypting the complexity of brain development and neurodegenerative diseases but also to follow the impact of environmental and therapeutic factors.     

Rapid multi‐echo measurement of brain metabolite T2 values at 7 T using a single‐shot spectroscopic Carr–Purcell–Meiboom–Gill sequence and prior information

We present a method for the robust and accurate estimation of brain metabolite transverse relaxation times (T₂) from multiple spin‐echo data acquired with a single‐shot Carr–Purcell–Meiboom–Gill (CPMG) spectroscopic sequence. Each acquired echo consists of a small number of complex time‐domain data points. The amplitudes of the spectral components in each echo are calculated by solving a set of linear equations in which previously estimated frequencies and linewidths serve as prior information. These priors are obtained from a short MRS experiment in which a large number of time‐domain data points are acquired, and are subsequently estimated using linear prediction with singular value decomposition (LPSVD) processing. We show that this process can be used to accurately and rapidly measure the T₂ values for the main singlet resonances in single‐volume MRS measurements in the brain. The proposed method can be generalized to any set of MRS experiments comprising repeated measurements of amplitude changes, e.g. as a function of an experimental parameter, such as TE, inversion time or diffusion weighting. Copyright © 2013 John Wiley & Sons, Ltd.     

Online 1H‐MRS measurements of time‐varying lactate production in an animal model of glioma during administration of an anti‐tumoral drug

The aims of this study were to implement a magnetic resonance spectroscopy (MRS) protocol for the online profiling of subnanomolar quantities of metabolites sampled from the extracellular fluid using implanted microdialysis and to apply this protocol in glioma‐bearing rats for the quantification of lactate concentration and the measurement of time‐varying lactate concentration during drug administration. MRS acquisitions on the brain microdialysate were performed using a home‐built, proton‐tuned, microsolenoid with an active volume of 2 μL. The microcoil was placed at the outlet of the microdialysis probe inside a preclinical magnetic resonance imaging (MRI) scanner. C6‐bearing rats were implanted with microdialysis probes perfused with artificial cerebrospinal fluid solution and the lactate dehydrogenase (LDH) inhibitor oxamate. Microcoil magnetic resonance spectra were continuously updated using a single‐pulse sequence. Localized in vivo spectra and high‐resolution spectra on the dialysate were also acquired. The limit of detection and limit of quantification per unit time of the lactate methyl peak were determined as 0.37 nmol/√min and 1.23 nmol/√min, respectively. Signal‐to‐noise ratios (SNRs) of the lactate methyl peak above 120 were obtained from brain tumor microdialysate in an acquisition time of 4 min. On average, the lactate methyl peak amplitude measured in vivo using the nuclear magnetic resonance (NMR) microcoil was 193 ± 46% higher in tumor dialysate relative to healthy brain dialysate. A similar ratio was obtained from high‐resolution NMR spectra performed on the collected dialysate. Following oxamate addition in the perfusate, a monotonic decrease in the lactate peaks was observed in all animals with an average time constant of 4.6 min. In the absence of overlapping NMR peaks, robust profiling of extracellular lactate can be obtained online using a dedicated sensitive NMR microcoil. MRS measurements of the dynamic changes in lactate production induced by anti‐tumoral drugs can be assessed accurately with temporal resolutions on the order of minutes. The MRS protocol can be readily transferred to the clinical environment with the use of suitable clinical microdialysis probes.     

Longitudinal 1H MRS of rat forebrain from infancy to adulthood reveals adolescence as a distinctive phase of neurometabolite development

This study represents the first longitudinal, within‐subject ¹H MRS investigation of the developing rat brain spanning infancy, adolescence and early adulthood. We obtained neurometabolite profiles from a voxel located in a central location of the forebrain, centered on the striatum, with smaller contributions for the cortex, thalamus and hypothalamus, on postnatal days 7, 35 and 60. Water‐scaled metabolite signals were corrected for T₁ effects and quantified using the automated processing software LCModel, yielding molal concentrations. Our findings indicate age‐related concentration changes in N‐acetylaspartate + N‐acetylaspartylglutamate, myo‐inositol, glutamate + glutamine, taurine, creatine + phosphocreatine and glycerophosphocholine + phosphocholine. Using a repeated measures design and analysis, we identified significant neurodevelopment changes across all three developmental ages and identified adolescence as a distinctive phase in normative neurometabolic brain development. Between postnatal days 35 and 60, changes were observed in the concentrations of N‐acetylaspartate + N‐acetylaspartylglutamate, glutamate + glutamine and glycerophosphocholine + phosphocholine. Our data replicate past studies of early neurometabolite development and, for the first time, link maturational profiles in the same subjects across infancy, adolescence and adulthood. Copyright © 2013 John Wiley & Sons, Ltd.     

定量质子磁共振波谱对鉴别良性与恶性脑膜瘤的价值(英文)

本研究致力于探讨定量质子磁共振波谱(MRS)对鉴别良性与恶性脑膜瘤的价值。研究利用1.5T磁共振仪,对23例脑膜瘤(良性组(WHO I级)19例,恶性组(WHOⅡ～Ⅲ级)4例)进行单体素MRS检查(PRESS序列,TR/TE=2000ms/68,136,272ms),通过指数衰减模型估计组织水和胆碱(Choline,Cho)的T2弛豫时间,并以组织水为内参照计算Cho的绝对浓度,然后按MRS体素内坏死或囊变组织的比例对Cho浓度进行校正。研究发现,良、恶性脑膜瘤的组织水T2弛豫时间分别是(105±41)ms和(151±42)ms,差异有显著性(P=0.033)。良、恶性脑膜瘤的Cho T2弛豫时间分别是(242±73)ms和(316±102)ms,无显著差异(P=0.105)。良、恶性脑膜瘤的Cho浓度在校正前分别是(2.86±0.86)mmol/kg wet weight和(3.53±0.60)mmol/kg wet weight,在校正后分别是(2.98±0.93)mmol/kg wet weight和(4.58±1.22)mmol/kg wet weight,校正后差异具有显著性(P=0.019)。研究...     

Quantification of J‐resolved proton spectra in two‐dimensions with LCModel using GAMMA‐simulated basis sets at 4 Tesla

A two‐dimensional, J‐resolved magnetic resonance spectroscopic extraction approach was developed employing GAMMA‐simulated, LCModel basis‐sets. In this approach, a two‐dimensional J‐resolved (2D‐JPRESS) dataset was resolved into a series of one‐dimensional spectra where each spectrum was modeled and fitted with its theoretically customized LCModel template. Metabolite levels were derived from the total integral across the J‐series of spectra for each metabolite. Phantoms containing physiologic concentrations of the major brain chemicals were used for validation. Varying concentrations of glutamate and glutamine were evaluated at and around their accepted in vivo concentrations in order to compare the accuracy and precision of our method with 30 ms PRESS. We also assessed 2D‐JPRESS and 30 ms PRESS in vivo, in a single voxel within the parieto‐occipital cortex by scanning ten healthy volunteers once and a single healthy volunteer over nine repeated measures. Phantom studies demonstrated that serial fitting of 2D‐JPRESS spectra with simulated LCModel basis sets provided accurate concentration estimates for common metabolites including glutamate and glutamine. Our in vivo results using 2D‐JPRESS suggested superior reproducibility in measuring glutamine and glutamate relative to 30 ms PRESS. These novel methods have clear implications for clinical and research studies seeking to understand neurochemical dysfunction. Copyright © 2009 John Wiley & Sons, Ltd.     

Brain GABA editing by localized in vivo (1)H magnetic resonance spectroscopy

Editing of GABA by (1)H MRS in a specific brain area is a unique tool for in vivo non-invasive investigation of neurotransmission disorders. Selective GABA detection is achieved using sequences based on double quantum coherence (DQC). Our pulse sequence makes accurate measurements without artefacts due to spatial localization. The sequence was tested on a phantom solution. The effect of vigabatrin, a specific inhibitor of GABA transaminase, was measured in rat brain and GABA detection was performed in vivo in monkey brain using this procedure. Rats were split into two groups. In the control group, the rats had access to water and, in the other group (vigabatrin, VGB, rats), animals were allowed free access to drinking water containing vigabatrin. After 3 weeks of treatment, rats were anesthetized for in vivo NMR spectroscopy investigation. At the end of the experiment, brains were quickly removed, freeze-clamped and extracted with 4% perchloric acid. One part of the acid extract was used for GABA concentrations assessment by ion exchange chromatography with ninhydrin detection. The second was used for high-resolution NMR analysis. By chromatography measurements, the GABA concentration was 1.23+/-0.06 micromol/g for controls, while for vigabatrin-treated rats the GABA concentration was 4.89+/-1.60 micromol/g. The NMR in vivo results were closely correlated with the NMR ex vivo (r=0.99, p<0.01) and chromatography results (r=0.98, p<0.01). The correlation between ex vivo results and chromatography results was also high (r=0.99, p<0.001). This pulse sequence performed GABA editing from a 376 microl voxel located on the right basal ganglia area in a non-human primate brain. This in vivo GABA editing scheme can thus be proposed for accurate measurement of brain GABA concentrations.     

In vivo analysis of the post-natal development of normal mouse brain by DTI

The water diffusion characteristics of wild-type mouse brains have been studied in vivo by DTI to follow developmental changes. Here, axial (lambda(//)) and radial (lambda(perpendicular)) diffusivities and fractional anisotropy were measured from the fifth day of life (P5) and at three other post-natal ages (P12, P19 and P54). Magnetic resonance images were collected from a single sagittal slice in the middle of the two hemispheres; ROI were chosen in nine different structures of both grey and white matter. Fractional anisotropy (FA) from P5 onwards distinguished structures of both white and grey matter, even though myelination had yet to occur. Between P5 and P54, a significant increase in FA was observed in the genu of the corpus callosum due to a significant decrease in lambda(perpendicular) whereas lambda(//) remained stable. Many other significant variations of lambda(//) and lambda(perpendicular) were measured in different structures. They were substantially correlated with axon and myelin maturation which are responsible for the main evolutions of the brain during its post-natal development. These quantitative data show that in vivo characterization of the anatomy and microstructure of the normal mouse brain during development is possible. The normative data will greatly improve the characterization of abnormal development in the transgenic mouse brain.     

Hyperpolarized singlet lifetimes of pyruvate in human blood and in the mouse

Hyperpolarized NMR is a promising technique for non‐invasive imaging of tissue metabolism in vivo. However, the pathways that can be studied are limited by the fast T₁ decay of the nuclear spin order. In metabolites containing pairs of coupled nuclear spins‐1/2, the spin order may be maintained by exploiting the non‐magnetic singlet (spin‐0) state of the pair. This may allow preservation of the hyperpolarization in vivo during transport to tissues of interest, such as tumors, or to detect slower metabolic reactions. We show here that in human blood and in a mouse in vivo at millitesla fields the ¹³C singlet lifetime of [1,2‐¹³C₂]pyruvate was significantly longer than the ¹³C T₁, although it was shorter than the T₁ at field strengths of several tesla. We also examine the singlet‐derived NMR spectrum observed for hyperpolarized [1,2‐¹³C₂]lactate, originating from the metabolism of [1,2‐¹³C₂]pyruvate. © 2013 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd.     

Evaluation of lactate detection using selective multiple quantum coherence in phantoms and brain tumours

Lactate is a product of glucose metabolism. In tumour tissues, which exhibit enhanced glycolytic metabolism, lactate signals may be elevated, making lactate a potential useful tumour biomarker. Methods of lactate quantitation are complicated because of overlap between the lactate methyl doublet CH₃ resonance and a lipid resonance at 1.3 ppm. This study presents the use of a selective homonuclear multiple quantum coherence transfer sequence (SelMQC‐CSI), at 1.5 T, to better quantify lactate in the presence of lipids. Work performed on phantoms showed good lactate detection (49%) and lipid suppression (98%) efficiencies. To evaluate the method in the brain, the sequence was tested on a group of 23 patients with treated brain tumours, either glioma (N = 20) or secondary metastases in the brain (N = 3). Here it was proved to be of use in determining lactate concentrations in vivo. Lactate was clearly seen in SelMQC spectra of glioma, even in the presence of lipids, with high grade glioma (7.3 ± 1.9 mM, mean ± standard deviation) having higher concentrations than low grade glioma (1.9 ± 1.5 mM, p = 0.048). Lactate was not seen in secondary metastases in the brain. SelMQC‐CSI is shown to be a useful technique for measuring lactate in tumours whose signals are otherwise contaminated by lipid. © 2015 The Authors NMR in Biomedicine Published by John Wiley & Sons Ltd.