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.     

On the identification of cerebral metabolites in localized 1H NMR spectra of human brain in vivo.

Localized 1H NMR spectra of human brain in vivo are affected by signal overlap, strong spin-spin coupling, and complex J modulation, and therefore differ considerably from those obtained at higher magnetic fields. This paper deals with the assignment of 1H NMR resonances of cerebral metabolites under the experimental conditions used for human investigations. Conventional 7.0-T FID spectra and 2.0 T localized, short echo time STEAM spectra (TE = 20 ms) of aqueous metabolite solutions are compared to in vivo brain spectra of human volunteers and patients. In addition to singlet resonances from N-acetyl aspartate (NAA), creatines, and cholines, short echo time STEAM spectra exhibit multiplets due to the NAA aspartyl group, glutamate, taurine, and myo-inositol. Enhanced levels of cerebral glutamine are detected in patients with liver cirrhosis. For the first time elevated levels of brain glucose are observed in patients with diabetes mellitus.     

Magnetization transfer attenuation of creatine resonances in localized proton MRS of human brain in vivo

To assess putative magnetization transfer effects on the proton resonances of cerebral metabolites in human brain, we performed quantitative proton magnetic resonance spectroscopy (2.0 T, STEAM, TR/TE/TM = 6000/40/10 ms, LCModel data evaluation) of white matter (7.68 mL, 10 healthy young subjects) in the absence and presence of fast repetitive off-resonance irradiation (2.1 kHz from the water resonance) using a train of 100 Gaussian-shaped RF pulses (12.8 ms duration, 120 Hz nominal bandwidth, 40 ms repetition period, 1080 degrees nominal flip angle). A comparison of pertinent metabolite concentrations revealed a magnetization transfer attenuation factor of the methyl and methylene resonances of creatine and phosphocreatine of 0.87 +/- 0.05 (p < 0.01). No attenuation was observed for the resonances of N-acetylaspartate and N-acetylaspartylglutamate, glutamate and glutamine, choline-containing compounds, and myo-inositol. The finding for total creatine is in excellent agreement with data reported for rat brain. The results are consistent with the hypothesis of a chemical exchange of mobile creatine or phosphocreatine molecules with a small immobilized or 'bound' pool.     

多体素1H磁共振频谱绝对定量脑内代谢物的方法

磁共振频谱(MRS)是一种利用磁共振原理和化学位移作用对一系列特定原子核及其化合物进行分析的方法.目前MRS的应用以1H谱最为广泛,其频谱技术已由单体素发展为三维多体素(3DCSI)扫描,为临床研究提供了许多重要的信息.就应用多体素磁共振频谱技术定量检测脑代谢物绝对浓度的方法进行综述.     

Localized proton NMR spectroscopy of experimental gliomas in rat brain in vivo.

Experimental brain tumors produced in rats (n = 10) by stereotactic implantation of cells from the F98 anaplastic glioma clone into the right caudate nucleus were studied in vivo using localized proton NMR and in vitro using high-resolution proton NMR, bioluminescent imaging of lactate, ATP and glucose distributions, and fluorescent imaging of regional pH. In vivo spectra from normal brain contralateral to the tumor regions showed resonances assignable to N-acetyl aspartate (NAA), creatines, choline-containing compounds, myo-inositol, glutamate and glucose in a pattern similar to those obtained from normal anaesthetized rats. In vivo tumor spectra were characterized by the almost complete absence of NAA, a substantial reduction of total creatine and glucose, and an increase of cholines. Based on the in vitro spectra the increase of the myo-inositol signal observed in vivo was mainly attributed to glycine. Histological examination as well as bioluminescent and fluorescent imaging indicated two stages of tumor development, i.e., solid vital tumors and tumors with necrosis. However, there was no consistent relationship between proton NMR observations and tumor development.     

In vivo single-voxel proton MR spectroscopy in brain lesions with ring-like enhancement

It is often difficult to make a correct diagnosis of ring-like enhanced lesions on Gd-enhanced MR brain images. To differentiate these lesions using proton MR spectroscopy (1H-MRS), we retrospectively evaluated the correlation between the 1H-MR spectra and histopathological findings. We evaluated proton MR spectra obtained from the lesions in 45 patients, including metastasis (n = 19), glioblastoma (n = 10), radiation necrosis (n = 7), brain abscess (n = 5), and cerebral infarction (n = 4). The rate of misdiagnosis was found to be lowest at the threshold level of 2.48 for the (choline containing compounds)/(creatine and phosphocreatine) ratio (Cho/Cr) obtained from the whole lesions, which include the enhanced rim and the non-enhanced inner region. That is, the positively predictive values of a Cho/Cr greater than 2.48 for diagnosing metastasis or glioblastoma was 88.9 and 60.0%, respectively, and the positively predictive value of a Cho/Cr less than 2.48 for diagnosing radiation necrosis or cerebral infarction was 71.4 and 100%, respectively. For further differentiating between metastasis and glioblastoma, information about the presence and absence of an N-acetyl-aspartate (NAA) peak and lipid- or lactate-dominant peak was found to be useful. In 73.7% of metastasis cases a lipid-dominant peak was observed in the whole lesion without an NAA peak in the inner region, whereas the same pattern was observed in only 10% of the glioblastoma cases. Correlation with the histopathological findings showed that a high Cho signal is suggestive of neoplasm. Lipid signal in the non-enhanced central region was correlated to necrosis. Lactate signals were often observed in glioblastoma, abscess and sometimes metastasis, presumably reflecting the anaerobic glycolysis by the living cells in the ring-like enhanced rim. Single-voxel proton MR spectroscopy may serve as a potential tool to provide useful information of differentiation of ring-like enhanced lesions that cannot be diagnosed correctly using enhanced MR images alone.     

Quantification of glutamate, glutamine, and other metabolites in in vivo proton NMR spectroscopy.

A reliable quantification of in vivo 1H MRS spectra is hampered by extensive line overlap, by intensity distortions due to the water suppressing pulse sequence and complex modulation patterns of J-coupled spins, and by deviations between the experimental and model lineshapes in computer fitting programs. By correcting the experimental lineshape, using a suitable pulse sequence, and incorporating prior knowledge about the spin systems and the intensity distortions, a sufficient quantification is possible. If reliable T2 values are available absolute concentrations can be determined.     

Localized in vivo proton spectroscopy of renal cell carcinoma in human kidney.

In order to obtain proton magnetic resonance spectra from the renal tumor in human kidney we performed localized magnetic resonance spectroscopy using a saddle-type flexible surface coil. Five patients biopsy-proven as renal cell carcinoma at different stages were put in supine/lateral position to minimize motion artifacts while acquiring the spectrum. Water-suppressed 1H spectra were obtained with localized stimulated echo acquisition mode (STEAM) (20/13.7/2200; TE/TM/TR) and point resolved spectroscopy (PRESS) (288/2200; TE/TR) sequences. The principal resonances in the tumor STEAM spectrum were sorbitol (3.85 ppm), trimethylamines (TMA) (3.25 ppm), two unidentified signals (2.8 and 2.2 ppm), and lipid (0.9-1.8 ppm). In the PRESS spectrum using a long echo time (288 ms), two well localized signals, TMA at 3.25 ppm and lactate at 1.35 ppm were observed from a patient with a tumor at advanced stage. Interestingly only TMA at 3.25 ppm was observed from the patient with a low grade tumor. The spectral patterns of the tumor patients were different from those of normal kidney.     

A precise and user-independent quantification technique for regional comparison of single volume proton MR spectroscopy of the human brain

The aim of this work was to study and correct the influence of varying coil load and local B(1) field in single volume MR spectroscopy. A simple, precise, and user-independent way to adjust the transmitter gain has been developed and validated. It is based on a fit of the localized signal to flip angle variation around 90 degrees. This method proved to be robust against B(1) gradients and suitable for in vivo applications. Local B(1) correction was combined with an external reference and decomposition of the volume into CSF and tissue to obtain a comprehensive absolute quantification of tissue water content and metabolite concentrations in human brain. STEAM localized spectra of parietal and insular gray matter and subparietal white matter (n = 11, TE = 30 ms) were analyzed using a linear combination of model spectra (LCModel). Coefficients of variation (CV) between 1.5% and 4% were obtained for the tissue water content (1-2% in a single subject). The CVs of major metabolite concentrations (4-21%) were dominated by the errors of the spectral analysis. The largest B(1) variation in the in vivo experiments (range 30%) was due to changes in coil load. Differences in regional sensitivity due to B(1) inhomogeneity (parietal: 8% and 9%; insular: 16%) were found to be the second largest source of variation. Correction for local B(1) improved standard deviations and intra-subject reproducibility. On average, sensitivity was 9% less in insular than in parietal gray matter. If ignored, significant differences were introduced for water and N-acetyl-aspartate or were obscured for creatine and cholines. Hence, local sensitivity correction proved to be necessary for regional comparison of absolute metabolite concentrations.     

Absolute quantification of carnosine in human calf muscle by proton magnetic resonance spectroscopy

Carnosine has been shown to be present in the skeletal muscle and in the brain of a variety of animals and humans. Despite the various physiological functions assigned to this metabolite, its exact role remains unclear. It has been suggested that carnosine plays a role in buffering in the intracellular physiological pHi range in skeletal muscle as a result of accepting hydrogen ions released in the development of fatigue during intensive exercise. It is thus postulated that the concentration of carnosine is an indicator for the extent of the buffering capacity. However, the determination of the concentration of this metabolite has only been performed by means of muscle biopsy, which is an invasive procedure. In this paper, we utilized proton magnetic resonance spectroscopy (1H MRS) in order to perform absolute quantification of carnosine in vivo non-invasively. The method was verified by phantom experiments and in vivo measurements in the calf muscles of athletes and untrained volunteers. The measured mean concentrations in the soleus and the gastrocnemius muscles were found to be 2.81 +/- 0.57/4.8 +/- 1.59 mM (mean +/- SD) for athletes and 2.58 +/- 0.65/3.3 +/- 0.32 mM for untrained volunteers, respectively. These values are in agreement with previously reported biopsy-based results. Our results suggest that 1H MRS can provide an alternative method for non-invasively determining carnosine concentration in human calf muscle in vivo.     

Metabolic changes after revascularization in a patient with innominate artery occlusion by localized in vivo proton magnetic resonance spectroscopy

Localized in vivo proton magnetic resonance spectroscopy ((1)H-MRS) has been used to measure the metabolic status of the human brain in a non-invasive manner; thus, it is often called "a non-invasive biochemical assay". MRS is more sensitive than magnetic resonance imaging (MRI) in detecting ischemic damage by measuring the metabolic changes that occur prior to the anatomic changes. We report a patient who presented with innominate artery occlusion and symptoms of posterior circulation insufficiency and showed favorable metabolic changes by (1)H-MRS after revascularization. He showed no visible lesion in brain MRI, but in (1)H-MRS, decreased N-acetylaspartate (NAA) signal was noted in a resting state.After revascularization, both symptomatic improvement and recovery of NAA signal were observed. (1)H-MRS may provide valuable clinical information in diagnosis and management of cerebral hypoperfusion at a much earlier stage prior to the anatomic changes.     

Volume-selective water-suppressed proton spectra of human brain and muscle in vivo

Volume-selective water-suppressed proton spectra were recorded from live human brain and muscle at 1.5T by combining a stimulated echo acquisition mode pulse sequence for localization and two saturation pulses for water suppression (Frahm et al., SMRM Abstracts, 1987). Metabolite signals were observed in voxels of size 4-64 cm3. Signals from -CH3 and beta-CH2 of N-acetylaspartate, =N-CH3 and =N-CH2 of phosphocreatine/creatine, -N(CH3)3 of choline and inositol protons were visible in the brain spectra from normal subjects. Differences in metabolite levels were observed between gray and white matters of brain from their water-suppressed spectra. Peaks from =N-CH3 of phosphocreatine/creatine and -N(CH3)3 of choline and carnitine were present in normal muscle spectra along with several resonances from fatty acyl chains.     

Non-invasive in vivo localized 1H spectroscopy of human astrocytoma implanted in rat brain: regional differences followed in time

Human astrocytoma cells were cultured and inoculated into the rat brain. From the pre-clinical to the terminal state, tumour growth was monitored by in vivo MR imaging and by localized water-suppressed 1H spectroscopy (0.12-0.15 cm3 volumes) and spectroscopic imaging (0.01 cm3 voxels) employing the ACE localization technique. The MR experiments were conducted completely non-invasively, leaving the scalp intact. Brain spectra were obtained, showing distinct resonances for more than five different brain metabolites; they were not contaminated with lipid signals because of the adequate localization. Tumour progression, monitored in a selected volume of interest, was reflected in the corresponding spectra by decreasing intensities for resonances of N-acetyl aspartate and (phospho)creatine and increasing intensities for resonances of choline compounds and lactate. From spectroscopic imaging experiments metabolic heterogeneity could be deduced within the tumorous region. At particular times during tumour development spectra were obtained greatly resembling localized 1H MR spectra obtained from patients with astrocytomas by the use of similar localization methods. This emphasizes the relevance of animal model study for the evaluation of MR spectroscopic investigations in human brain tumour diagnosis and therapy evaluation.     

In vivo monitoring of rat brain metabolites during vigabatrin treatment using localized 2D-COSY

A two-dimensional COSY-based localization sequence was designed to allow the in vivo monitoring of proton metabolites in rat brain [particularly gamma-aminobutyric acid (GABA), glutamine, taurine and myo-inositol]. The sequence incorporated OSIRIS signal localization, B1-insensitive water suppression and phase-sensitive COSY acquisition. The method was used to study the effects of the GABA-transaminase inhibitor vigabatrin on rat brain metabolite concentrations. Wistar rats were treated daily for 3 days with an oral dose of vigabatrin (200 mg/kg, n = 4). Localized COSY spectra were obtained during a 120 min acquisition from a 270 microl central brain voxel and compared with nine untreated control animals. Significant elevations were observed in GABA (267% of control, p < 0.005, Mann-Witney test), glutamine (130% of control, p < 0.005) and taurine (113% of control, p < 0.05). Changes in GABA and taurine were consistent with previous data on the action of Vigabatrin, and support a previously hypothesized link between these compounds. The increase in glutamine was more surprising and may reflect the balance between the level and/or site of GABA-transaminase inhibition and downregulation of GABA synthesis.     

Problems and expediencies in human 31P spectroscopy. The definition of localized volumes, dealing with saturation and the technique-dependence of quantification

Several technological problems in in vivo localized spectroscopy of metabolism are discussed in the context of comparing data obtained by different means. Deficiencies in spectroscopy localization methods can produce spectra that are dominated by artefactual signals derived from outside of selected volumes. Such artefacts are not usually correctly accounted for by representations of the profiles of the transverse magnetization alone. Selected sensitive volumes should be defined in terms of the size of tissue contributing the major fraction of signal to an observed spectrum, which is the integrated response from the sample including any phase cancellation effects. Phase cancellation in one-dimensional localization techniques employing excitation by an RF field with uniform phase distribution and surface coil detection such as depth resolved surface coil spectroscopy, chemical shift imaging (CSI) and rotating frame zeugmatography (RFZ) can significantly alter the effective radius of the sensitive volumes depending on the sample distribution and the extent of the homogeneous region of the magnet. Also, discrete spatial sampling in RFZ and CSI can radiate signal artefacts of around 25% into adjacent elements depending on the location and distribution of signal sources. Acquisition delays between excitation and detection and partial saturation are other major sources of systematic error. Saturation factors for metabolites are not easily obtainable on localized volumes during clinical exams on an individual basis, but may be expediently obtained as larger-volume tissue-averages. Better documentation of saturation effects, acquisition delays and localized volume sizes is needed to compare and validate clinical results and performance.     

Reproducibility of whole‐brain temperature mapping and metabolite quantification using proton magnetic resonance spectroscopy

Assessing brain temperature can provide important information about disease processes (e.g., stroke, trauma) and therapeutic effects (e.g., cerebral hypothermia treatment). Whole‐brain magnetic resonance spectroscopic imaging (WB‐MRSI) is increasingly used to quantify brain metabolites across the entire brain. However, its feasibility and reliability for estimating brain temperature needs further validation. Therefore, the present study evaluates the reproducibility of WB‐MRSI for temperature mapping as well as metabolite quantification across the whole brain in healthy volunteers. Ten healthy adults were scanned on three occasions 1 week apart. Brain temperature, along with four commonly assessed brain metabolites—total N‐acetyl‐aspartate (tNAA), total creatine (tCr), total choline (tCho) and myo‐inositol (mI)—were measured from WB‐MRSI data. Reproducibility was evaluated using the coefficient of variation (CV). The measured mean (range) of the intra‐subject CVs was 0.9% (0.6%‐1.6%) for brain temperature mapping, and 4.7% (2.5%‐15.7%), 6.4% (2.4%‐18.9%) and 14.2% (4.4%‐52.6%) for tNAA, tCho and mI, respectively, with reference to tCr. Consistently larger variability was found when using H₂O as the reference for metabolite quantifications: 7.8% (3.3%‐17.8%), 7.8% (3.1%‐18.0%), 9.8% (3.7%‐31.0%) and 17.0% (5.9%‐54.0%) for tNAA, tCr, tCho and mI, respectively. Further, the larger the brain region (indicated by a greater number of voxels within that region), the better the reproducibility for both temperature and metabolite estimates. Our results demonstrate good reproducibility of whole‐brain temperature and metabolite measurements using the WB‐MRSI technique.     

Volume localized in vivo proton MR spectroscopy of breast carcinoma: variation of water-fat ratio in patients receiving chemotherapy

Results are reported on in vivo volume localized proton magnetic resonance spectroscopy (MRS) of patients (n = 44) suffering from carcinoma of the breast, using a bilateral breast surface coil. Localized proton MR spectra of the unaffected contralateral breast of these patients are dominated by resonances arising from fat and are similar to the breast tissue from normal volunteers (controls, n = 13), while in the malignant breast tissues the water resonance dominates. On the other hand, the water suppressed proton MR spectra of malignant breast tissue reveal several metabolites of low concentration including the choline peak around 3.2 ppm and other resonances attributable to purine and pyrimidine nucleotides, in the 8.5 ppm region. Elevated water- fat (W-F) ratios are measured in the malignant tissues, compared with the normal breast tissue of controls and from the contralateral unaffected breast tissue of the patients (n = 11). In the case of patients receiving chemotherapy resulting in the reduction of primary tumor size, the W-F ratio shows a statistically significant (P < 0.01) decrease compared with the pre-therapy value, thus providing a non-invasive indicator of favourable clinical outcome of neoadjuvant chemotherapy for locally advanced breast cancer. The method provides the potential for non-invasively monitoring and assessing the response of breast cancer to neoadjuvant chemotherapy.     

Depth selective quantification of phosphorus metabolites in human calf muscle.

We have used phase modulated rotating frame imaging, a depth selective NMR technique, in conjunction with two methods of calibration, in order to determine the feasibility of quantifying phosphorus compounds in selected regions of a biological sample. In one method, we related peak areas obtained from a sample to the peak area of an external reference located within the receiver coil, previously calibrated against a standard. In the second method we measured peak areas from a standard separately and related them directly to the area of the sample peak. We examined the calf muscles of male volunteers, positioning the coil to obtain signal mainly from the gastrocnemius in the shallow slices and soleus in the deep slices. The concentrations of Pi, phosphocreatine and ATP (in mmol/kg tissue) were 3.0 +/- 0.5, 18 +/- 2 and 4.8 +/- 0.2 at 2 cm depth (mean +/- SD; n = 5). These results are similar to published biopsy data. A comparison with published values obtained from other NMR quantification methods suggests that, while it is possible to obtain consistent results within one laboratory, it is not currently possible to obtain similar results between laboratories. This is evident from the fact that different laboratories report different phosphocreatine/ATP ratios, indicating that the techniques are limited by variations in the processes of data collection and peak area measurement.     

Combined proton MR spectroscopy and dynamic contrast enhanced MR imaging of human intracranial tumours in vivo

A study was undertaken to determine if the vascular characteristics measured by dynamic contrast-enhanced magnetic resonance imaging (primarily permeability surface area product and extracellular-extravascular tissue volume fraction) would be beneficial in explaining the inter-lesion metabolic heterogeneity displayed by human intracranial tumours. Magnetic resonance spectroscopy was carried out using a single-voxel STEAM sequence and dynamic imaging was carried out using a combination of pre-contrast proton density-weighted FSPGR images (to remove the influence of native tissue T1), bolus injection of Gd-DTPA and subsequent T1-weighted FSPGR dynamic imaging. A two-compartment pharmacokinetic model was employed to determine vascular characteristics. Results obtained from 12 meningiomas suggest a possible correlation between the level of lipids/macromolecules and permeability surface area product, although the confounding issue of extra-voxel contamination arising from lipids in the scalp and skull marrow cannot be ruled out in the more superficial lesions. Results obtained from 11 gliomas (four low and seven high grade) demonstrate that permeability surface area product is not specific for the range of vascular characteristics and metabolite profiles observed in gliomas and is therefore unable to explain metabolic heterogeneity in these lesions.