In vivo quantification of the metabolites in normal brain and brain tumors by proton MR spectroscopy using water as an internal standard

Metabolite concentrations in normal adult brains and in gliomas were quantitatively analyzed by in vivo proton magnetic resonance spectroscopy (MRS) using the fully relaxed water signal as an internal standard. Between January 1998 and October 2001, 28 healthy volunteers and 18 patients with gliomas were examined by in vivo proton MRS. Single voxel spectra were acquired using the point-resolved spectroscopic pulse sequence with a 1.5-T scanner (TR/TE/Ave = 3000 ms/30 ms/64). The calculated concentrations of N-acetyl-aspartate (NAA), creatine (Cre), choline (Cho), and water (H2O) in the normal hemispheric white matter were 23.59 +/- 2.62 mM (mean +/- SD), 13.06 +/- 1.8 mM, 4.28 +/- 0.8 mM, and 47280.96 +/- 5414.85 mM, respectively. The metabolite concentrations were not necessarily uniform in different parts of the brain. The concentrations of NAA and Cre decreased in all gliomas (p < 0.001). The NAA/Cho and NAA/H2O ratios can distinguish the normal brain from gliomas, and low-grade astrocytoma from high-grade group (p < 0.001). The concentration of taurine (Tau) in medulloblastomas was 29.64 +/- 5.76 mM. This is the first quantitative analysis of Tau in medulloblastoma in vivo and confirms earlier in vitro findings.     

In vivo quantification of the metabolites in normal brain and brain tumors by proton MR spectroscopy using water as an internal standard

Metabolite concentrations in normal adult brains and in gliomas were quantitatively analyzed by in vivo proton magnetic resonance spectroscopy (MRS) using the fully relaxed water signal as an internal standard. Between January 1998 and October 2001, 28 healthy volunteers and 18 patients with gliomas were examined by in vivo proton MRS. Single-voxel spectra were acquired using the point-resolved spectroscopic (PRESS) pulse sequence with a 1.5 T scanner (TR/TE/Ave = 3000 ms/30 ms/64). The calculated concentrations of N-acetyl-aspartate (NAA), creatine (Cre), choline (Cho), and water(H(2)O) in the normal hemispheric white matter were 23.59 +/- 2.62 mM (mean +/- SD), 13.06 +/- 1.8 mM, 4.28 +/- 0.8 mM, and 47280.96 +/- 5414.85 mM, respectively. The metabolite concentrations were not necessarily uniform in different parts of the brain. The concentrations of NAA and Cre decreased in all gliomas (p < 0.001). The NAA/Cho and NAA/H(2)O ratios can distinguish the normal brain from gliomas and low-grade from high-grade astrocytoma (p < 0.001). The concentration of taurine (Tau) in medulloblastomas was 29.64 +/- 5.76 mM. This is the first quantitative analysis of Tau in medulloblastoma in vivo and confirms earlier in vitro findings.     

Proton spectroscopy of human stroke: Assessment of transverse relaxation times and partial volume effects in single volume STEAM MRS

Proton T₂ relaxation times were measured in 13 stroke patients and 13 aged-matched normal subjects at 2.1 T. Spectra were acquired from an 8-cc volume using the STEAM sequence with echo times (TE) of 30.4 ms and 270.0 ms and repetition time of 2.8 s. Transverse relaxation times were estimated using two-point calculations. Percentage volume of infarct in the STEAM voxel was measured on spin-echo MRI encompassing the infarct and correlated with the peak amplitude of N-acetylated compounds (NA). T₂ values of NA, creatine, and choline resonances showed no significant difference between patients and controls. T₂ for lactate in patients was 780 ± 257 ms, respectively (mean ± SE, n = 7). In stroke patients, high inverse correlation was found between the absolute NA signal and partial volume of normal brain contributing to each spectrum (p < .001, r = 0.97). Together with unchanged T₂, this suggests that NAA largely disappears from infarcted tissue within 24 hr postinfarct.     

Quantitative in vivo1H-spectroscopy of healthy and tumorous human brain tissue at 4 tesla

In 35 healthy volunteers 79 hydrogen spectra were measured from the parietal lobe, parieto-occipital lobe, frontal lobe, temporal lobe, thalamus and insular region. Voxels were selected with a double spin-echo sequence at TE 71, 135 and 270 ms. The spectra were quantitatively evaluated by fitting a Lorentzian model to the resonances of the creatine pool at 3.02 ppm and the choline pool at 3.22 ppm. No differences were found in the intensities of either metabolite in the 6 investigated regions. Creatine and choline were equally distributed in these regions. The interindividual reproducibility of the spectra decreases with longer echo delays. The coefficients of variation of the areas of creatine and choline corrected for the number of acquisitions and the voxel size are ±13% at TE 71 ms, ±23% at TE 135 ms, ±43% at TE 270 ms. This is caused by an interindividual variation in T₂ by ±15%, which affects all resonances of a spectrum. Signal variations from the fit, the Q-factor of the RF-coil loaded with different subjects and variations in the flip angle are less than 10% at each echo delay. The intraindividual variation without repositioning of the subject was better than 10%. Using creatine as an internal reference the ratios of the amplitudes of N-acetyl-aspartate (NAA) at 2.01 ppm and γ-methylene protons of glutamic acid at 2.34 ppm were not specific for special regions of the brain. Only in the temporal lobe the ratio of NAA and creatine was reduced. A mean concentration ratio of 1.7 for NAA and Cre was measured as an average over all subjects and the investigated brain regions with the exception of the temporal lobe. Initial applications of the method to 7 patients with brain tumors are described.     

H MR spectroscopy monitoring of changes in choline peak area and line shape after Gd-contrast administration

Fifteen percent loss in the peak area of choline containing compounds (Cho) was recently observed in ¹H MR spectra of contrast-enhancing tumor at 5–10 min after Gd-contrast administration [Magn. Reson. Med. 37:222–225, 1997]. In this study, chemical shift imaging (CSI, 1500/135 ms PRESS) was used to assess the spectral changes in 47 Gd-enhancing glial brain tumors and metastatic brain tumors measured at 0–5, 5–10, and/or 10–15 min after administration of Gd-contrast. Percent Cho peak area losses measured at these times, 3 ± 3, 12 ± 2, and 14 ± 3 SEM, respectively, coincided with trends of line narrowing and up-field shift of the Cho peak. Significant changes in creatine and N-acetyl acetate signals were not observed. It is concluded that the Gd-induced loss of tumor Cho signal measured after 5 min, typically required for post contrast-MRI and the positioning of the CSI volume on tumor, shows little further change with time, if any.     

Quantification of human brain metabolites from in vivo 1H NMR magnitude spectra using automated artificial neural network analysis

Long echo time (TE=270 ms) in vivo proton NMR spectra resembling human brain metabolite patterns were simulated for lineshape fitting (LF) and quantitative artificial neural network (ANN) analyses. A set of experimental in vivo 1H NMR spectra were first analyzed by the LF method to match the signal-to-noise ratios and linewidths of simulated spectra to those in the experimental data. The performance of constructed ANNs was compared for the peak area determinations of choline-containing compounds (Cho), total creatine (Cr), and N-acetyl aspartate (NAA) signals using both manually phase-corrected and magnitude spectra as inputs. The peak area data from ANN and LF analyses for simulated spectra yielded high correlation coefficients demonstrating that the peak areas quantified with ANN gave similar results as LF analysis. Thus, a fully automated ANN method based on magnitude spectra has demonstrated potential for quantification of in vivo metabolites from long echo time spectroscopic imaging.     

Short echo time in vivo prostate ¹H-MRSI

Visualization of short echo time (TE) metabolites in prostate magnetic resonance spectroscopic imaging is difficult due to lipid contamination and pulse timing constraints. In this work, we present a modified pulse sequence to permit short echo time (TE=40ms) acquisitions with reduced lipid contamination for the detection of short TE metabolites. The modified pulse sequence employs the conformal voxel MRS (CV-MRS) technique, which automatically optimizes the placement of spatial saturation planes to adapt the excitation volume to the shape of the prostate, thus reducing lipid contamination in prostate magnetic resonance spectroscopic imaging (MRSI). Metabolites were measured and assessed using a modified version of LCModel for analysis of in vivo prostate spectra. We demonstrate the feasibility of acquiring high quality spectra at short TEs, and show the measurement of short TE metabolites, myo-inositol, scyllo-inositol, taurine and glutamine/glutamate for both single and multi-voxel acquisitions. In single voxels experiments, the reduction in TE resulted in 57% improvement in the signal-to-noise ratio (SNR). Additional 3D MRSI experiments comparing short (TE=40 ms), and long (TE=130 ms) TE acquisitions revealed a 35% improvement in the number of adequately fitted metabolite peaks (775 voxels over all subjects). This resulted in a 42 ± 24% relative improvement in the number of voxels with detectable citrate that were well-fitted using LCmodel. In this study, we demonstrate that high quality prostate spectra can be obtained by reducing the TE to 40 ms to detect short T2 metabolites, while maintaining positive signal intensity of the spin-coupled citrate multiplet and managing lipid suppression.     

Brain metabolite alterations demonstrated by proton magnetic resonance spectroscopy in diabetic patients with retinopathy

Due to the homology between retinal and cerebral microvasculatures, retinopathy is a putative indicator of cerebrovascular dysfunction. This study aimed to detect metabolite changes of brain tissue in type 2 diabetes mellitus (T2DM) patients with diabetic retinopathy (DR) using proton magnetic resonance spectroscopy (¹H-MRS). Twenty-nine T2DM patients with DR (DR group), thirty T2DM patients without DR (DM group) and thirty normal controls (NC group) were involved in this study. Single-voxel ¹H-MRS (TR: 2000 ms, TE: 30 ms) was performed at 3.0 T MRI/MRS imager in cerebral left frontal white matter, left lenticular nucleus, and left optic radiation. Our data showed that NAA/Cr ratios of the DR group were significantly lower than those of the DM group in the frontal white matter and optic radiation. In the lenticular nucleus, MI/Cr ratios were significantly higher in the DM group than those in the NC group, while MI/Cr ratios were significantly lower in the DR group than those in the DM group. In the frontal white matter, NAA/Cho ratios were found to be decreased in the DR group as compared to the NC group. Additionally, our finding indicated that NAA/Cr ratios were negatively associated with DR severity in both the frontal white matter and optic radiation. A decrease in NAA indicated neuronal loss and the likely explanation for a decrease in MI was glial loss. In conclusion, we inferred that cerebral neurons and glia cells were damaged in patients with DR. Our data support that DR is associated with brain tissue damage.     

Magnetic resonance spectroscopy study of proton metabolite level changes in sensorimotor cortex after upper limb replantation-revascularization

We aimed to investigate the changes in proton metabolite levels at the motor and somatosensory cortex by magnetic resonance spectroscopy (MRS) after upper extremity replantation or revascularization. Nine patients who referred to our clinic suffering from major total (two) and subtotal (seven) amputation of the upper extremity were enrolled in this study. Mean time value between the injury and operation was 5.1 h. Mean follow-up period or mean time between the injury and MRS analysis was 26.2 months (ranging from 7 to 41 months). Voxels (TR: 2000; TE: 136 ms) were placed onto locations in the bilateral precentral and postcentral cortex area of the cerebral hemispheres that represent the upper extremity. Contralateral sides of the brain hemisphere that represent the injured extremity were accounted as control groups. Metabolite ratios [NAA (N-acetyl aspartate)/Cr (creatine) and Cho (choline)/Cr] of the motor and somatosensory cortex were calculated. The NAA/Cr and Cho/Cr metabolite ratios between the two groups were found to be insignificant, and these results may indicate that there is no remarkable somatosensorial cortex disruption or demyelination in these patients. Fifty-six percent of patients were found as functional according to Chen's scale.     

Central pontine myelinolysis after liver transplantation: MR diffusion, spectroscopy and perfusion findings

Magnetic resonance spectroscopy (MRS) and perfusion of central pontine myelinolysis (CPM) have been rarely reported. One case of CPM that developed after liver transplantation was analyzed with serial diffusion-weighted imaging (DWI), MRS and MR perfusion. During the acute phase, a pontine lesion showed an obvious high-signal intensity on DWI with decreased apparent diffusion coefficient value, decreased N-acetylaspartate (NAA)/creatine (Cr) ratio, increased choline (Cho)/Cr ratio and increased perfusion on the cerebral blood volume map. In a later phase, the lesion showed isosignal intensity on DWI, further decreased NAA/Cr ratio, increased Cho/Cr ratio and decreased perfusion. The increase in lesion perfusion during the acute phase may reflect a higher metabolic activity due to an increase in cell number and activity.     

Serial Precision of Metabolite Peak Area Ratios and Water Referenced Metabolite Peak Areas in Proton MR Spectroscopy of the Human Brain

The precision of cerebral proton magnetic resonance spectroscopy (MRS) measurements is critical both in the clinical setting and for research purposes. Marshall et al. have recently concluded that “disappointing in vivo repeatability…is likely to limit” the ability of MRS to detect modest changes. We present here a comprehensive study of the precision of short- and long-term metabolite peak area ratios and water referenced metabolite peak areas for long echo time point resolved spectroscopy (PRESS) spectra (repetition time (TR) = 2000 ms, echo time (TE) = 136 ms) acquired from the occipital lobes of normal volunteers and a phantom using a conventional whole body 1.5 T MR system and conventional acquisition and analysis protocols. Short-term in vitro precision determined by five repeat scans on five occasions was excellent as measured by a mean coefficient of variation (NAA/Cho = 1.3%, NAA/Cr + PCr = 1.0%, Cho/Cr + PCr = 1.6%, NAA/H₂O = 0.5%, Cho/H₂O = 1.2%, Cr + PCr/H₂O = 0.8%). Long term in vitro precision using 100 spectra acquired over 2 years was also very good (NAA/Cho = 2.7%, NAA/Cr + PCr = 1.4%, Cho/Cr + PCr = 2.2%, NAA/H₂O = 1.5%, Cho/H₂O = 2.4%, Cr + PCr/H₂O = 1.5%). Short-term in vivo precision determined by five repeat scans in a single scanning session on eight subjects was also excellent (NAA/Cho = 5.2%, NAA/Cr + PCr = 3.0%, Cho/Cr + PCr = 6.6%, NAA/H₂O = 1.4%, Cho/H₂O = 4.9%, Cr + PCr/H₂O = 2.7%) and only worsened slightly for long-term in vivo precision determined by five repeat scans on eight subjects over 3 months (NAA/Cho = 5.2%, NAA/Cr + PCr = 4.8%, Cho/Cr + PCr = 7.7%, NAA/H₂O = 2.5%, Cho/H₂O = 6.4%, Cr + PCr/H₂O = 3.8%). We attribute the excellent precision reported here to the use of highly automated techniques for voxel shimming, water suppression and peak area measurements. These results allow us to repudiate Marshall’s assertion regarding disappointing repeatability of in vivo MRS.     

High-field localized 1H NMR spectroscopy in the anesthetized and in the awake monkey

Localized cerebral in vivo ¹H NMR spectroscopy (MRS) was performed in the anesthetized as well as the awake monkey using a novel vertical 7 T/60 cm MR system. The increased sensitivity and spectral dispersion gained at high field enabled the quantification of up to 16 metabolites in 0.1- to 1-ml volumes. Quantification was accomplished by using simulations of 18 metabolite spectra and a macromolecule (MM) background spectrum consisting of 12 components. Major cerebral metabolites (concentrations >3 mM) such as glutamate (Glu), N-acetylaspartate (NAA), creatine (Cr)/phosphocreatine (PCr) and myo-inositol (Ins) were identified with an error below 3%; most other metabolites were quantified with errors in the order of 10%. Metabolite ratios were 1.39:1 for total NAA, 1.38:1 for glutamate (Glu)/glutamine (Gln) and 0.09:1 for cholines (Cho) relative to total Cr. Taurine (Tau) was detectable at concentrations lower than 1 mM, while lactate (Lac) remained below the detection limit. The spectral dispersion was sufficient to separate metabolites of similar spectral patterns, such as Gln and Glu, N-acetylaspartylglutamate (NAAG) and NAA, and PCr–Cr. MRS in the awake monkey required the development and refinement of acquisition and correction strategies to minimize magnetic susceptibility artifacts induced by respiration and movement of the mouth or body. Periods with major motion artifacts were rejected, while a frequency/phase correction was performed on the remaining single spectra before averaging. In resting periods, both spectral amplitude and line width, that is, the voxel shim, were unaffected permitting reliable measurements. The corrected spectra obtained from the awake monkey afforded the reliable detection of 6–10 cerebral metabolites of 1-ml volumes.     

In vivo quantitative 1H MRS of cerebellum and evaluation of quantitation reproducibility by simulation of different levels of noise and spectral resolution

A quantitative analysis of cerebellar metabolites in normal subjects has been performed by proton MR spectroscopy (MRS) with relaxation time correction. Quantitation was carried out in seven healthy human subjects with the well-established LCModel program. The prior knowledge utilized for quantitation was obtained from solutions containing the major brain metabolites and MRS investigated under the same experimental conditions. The tissue water signal was used as an internal standard for the in vivo studies. Both in vitro (for the prior knowledge template) and in vivo data were acquired separately at 1.5 T by PRESS sequence (TR, 1500 ms; TE, 30 ms). The absolute concentration of main cerebellar metabolites was corrected for relaxation time effects. Different noise and line broadening conditions were considered and simulated in the spectral processing in order to evaluate the effect of spectral quality on the concentration estimates.     

Short echo time proton spectroscopy of human brain using a gradient head coil.

Short echo time, single voxel localized proton spectroscopy was accomplished using a stimulated echo (STEAM) sequence running on a Siemens 1.5-T system with a head coil incorporating the Z and Y gradients. Spectra from the temporal lobe, the cerebellum and mid brain were acquired from a group of normal volunteers using the following parameters: voxel size = 8 ml, TE = 22 msec, 512 signal averages and TR = 1.7 sec. STEAM spectra acquired with the small diameter gradients showed significantly fewer artifacts at short TE, allowing the observation of glutamate/glutamine, GABA, taurine, and inositol in addition to the prominent resonance of choline, creatine/phosphocreatine and N-acetylaspartate (NAA). The levels of chlorine, creatine and NAA were found to be significantly different in the three regions of the brain examined.     

The effect of orientation on quantification of muscle creatine by 1H MR spectroscopy

Creatine is a central energy metabolite whose N-CH3 group can be detected with 1H MR spectroscopy (1H MRS) with relatively high sensitivity. Prior studies suggest that muscle fiber orientation can influence the appearance of other resonances attributed to total creatine (CR). Our purpose was to determine whether muscle fiber orientation affects muscle CR concentration quantification by 1H MRS with the commonly used N-CH3 resonance at 3.0 ppm. Skeletal muscle CR was quantified with water-referenced 1H MRS in normal subjects with different forearm muscle orientations relative to the static magnetic field at 1.5T. There were no significant differences in mean total [CR] in two different series of experiments separately including two orthogonal orientations and four orientations (0 degrees, 30 degrees, 60 degrees, 90 degrees) of the forearm relative to the static field using either short (TE = 15 ms) or long (TE = 100 ms) echo times for voxels containing or centered on the same tissues. Subtle differences in CR line-width and T2 correction factors were observed with orientation. These observations are consistent with the primary hypothesis that careful water-referenced [CR] quantification, accounting for T2 effects and using the N-CH3 peak at 3.0ppm, is not affected by muscle orientation.     

Respiratory motion-corrected proton magnetic resonance spectroscopy of the liver

Purpose

To develop a post-processing, respiratory-motion correction algorithm for magnetic resonance spectroscopy (MRS) of the liver and to determine the incidence and impact of respiratory motion in liver MRS.

Materials and Methods

One hundred thirty-two subjects (27 healthy, 31 with nonalcoholic fatty liver disease and 74 HIV-infected with or without hepatitis C) were scanned with free breathing MRS at 1.5 T. Two spectral time series were acquired on an 8-ml single voxel using TR/TE=2500 ms/30 ms and (1) water suppression, 128 acquisitions, and (2) no water suppression, 8 acquisitions. Individual spectra were phased and frequency aligned to correct for intrahepatic motion. Next, water peaks more than 50% different from the median water peak area were identified and removed, and remaining spectra averaged to correct for presumed extrahepatic motion. Total CH₂+CH₃ lipids to unsuppressed water ratios were compared before and after corrections.

Results

Intrahepatic-motion correction increased the signal to noise ratio (S/N) in all cases (median=11-fold). Presumed extrahepatic motion was present in 41% (54/132) of the subjects. Its correction altered the lipids/water magnitude (magnitude change: median=2.6%, maximum=290%, and was >5% in 25% of these subjects). The incidence and effect of respiratory motion on lipids/water magnitude were similar among the three groups.

Conclusion

Respiratory-motion correction of free breathing liver MRS greatly increased the S/N and, in a significant number of subjects, changed the lipids/water ratios, relevant for monitoring subjects.     

In vivo relaxation of N-acetyl-aspartate, creatine plus phosphocreatine, and choline containing compounds during the course of brain infarction: a proton MRS study.

Localized water suppressed proton spectroscopy has opened up a new field of pathophysiological studies of severe brain ischemia. The signals obtained with the pulse sequences used so far are both T₁ and T₂ weighted. In order to evaluate the extent to which changes in metabolite signals during the course of infarction can be explained by changes in T₁ and T₂ relaxation times, eight patients with acute stroke were studied. STEAM sequences with varying echo delay times and repetition times were used to measure T₁ and T₂ of N-acetyl-aspartate (NAA), creatine plus phosphocreatine (Cr+PCr) and choline containing compounds (CHO) in a 27-ml voxel located in the affected area of the brain. Ten healthy volunteers served as controls. We found no difference in T₁ or T₂ of the metabolites between the patients and the normal controls. The T₂ of CHO was longer than that of NAA and Cr+PCr. Our results indicate that spectra obtained in brain infarcts and normal tissue with the same acquisition parameters are directly comparable with respect to relative signal intensities as well as signals scaled with internal and external standards.     

Ex vivo proton MR spectroscopy (1H-MRS) for evaluation of human gastric carcinoma

The present study was performed to determine the characteristics of the biochemical metabolites related to gastric cancer using ex vivo (1)H magnetic resonance spectroscopy (MRS), and to assess the clinical usefulness. A total of 35 gastric specimens resected during surgery for gastric cancer were used to compare MR spectra. A 1.5-T (64-MHz) clinical MR imager equipped with facilities for spectroscopy was used to obtain MR spectra from 33 gastric specimens. High-resolution (1)H nuclear magnetic resonance (NMR) spectra of the remains of two specimens were also examined with a 9.4-T (400-MHz) NMR spectrometer. Localized spectroscopic measurements were performed in two layers of gastric tissue, the proper muscle layer and the composite mucosa/submucosa layer. T(2) FSE and 3D SPGR images were used to determine the voxel size and the location for MRS data collection. MR spectra were obtained using the single-voxel PRESS technique with parameters of TR/TE = 2000/30 ms, NA = 256, and voxel size = 3 x 3 x 3 mm(3) (27 microL). Cancerous and noncancerous gastric tissues in the voxel were determined by histopathological analysis. On 9.4-T ex vivo NMR spectroscopy, the following metabolite peaks were found: lipids at 0.9 ppm (CH(3)) and 1.3 ppm (CH(2)); alanine (beta-CH(3)) at 1.58 ppm; N-Acetyl neuraminic acid (NANA: sialic acid) at 2.03 ppm; and glutathione at 2.25 ppm in normal gastric tissue layers. In the 1.5-T MR system, broad and featureless spectral peaks of the various metabolites in normal human gastric tissue were observed at 0.9 ppm, 1.3 ppm, 2.0 ppm, and 2.2 ppm regardless of gastric tissue layer. In specimens (Borrmann type III) with tubular adenocarcinoma, resonance peaks were observed at 1.26 ppm, 1.36 ppm (doublet of lactate), and 3.22 ppm (choline). Cancer lesions showed decreased levels of lipid peaks, showing the significant lactate doublet peaks, and increased intensity of the choline peak as compared with noncancerous gastric tissue. We found that decreased levels of lipids and increases in lactate and choline peaks in gastric tissue were markers for malignancy in gastric lesions. Information provided by ex vivo (1)H MRS, together with the development of in vivo (1)H MRS with high field strength and high resolution, may be very useful for the diagnosis of gastric cancer in clinical situation.     

N-Acetylaspartate and epilepsy

Proton magnetic resonance spectra include signals from N-acetylaspartate, creatine + phosphocreatine, and choline-containing compounds. Abnormalities in these signals can be used in the assessment of patients with intractable epilepsy. In particular, they provide a means of identifying metabolic abnormalities within the temporal lobes, detecting bilateral and diffuse pathology, and aiding lateralization of the seizure focus. The pathology demonstrated on MRS can also be related to cognitive dysfunction.