Localized proton MRS of cerebral metabolite profiles in different mouse strains.

Localized proton MR spectroscopy (MRS) was used to quantify cerebral metabolite concentrations in NMRI (n = 8), BALB/c (n = 7), and C57BL/6 (n = 8) mice in vivo and 1 hr after global irreversible ischemia (2.35 T, STEAM, TR/TE/TM = 6000/20/10 ms, 4 x 3 x 4 mm(3) volume, corrections for cerebrospinal fluid). Anatomical MRI and proton MRS revealed significant differences of the C57BL/6 strain in comparison with both BALB/c and NMRI mice. While MRI volumetry yielded larger ventricular spaces of the C57BL/6 strain, proton MRS resulted in elevated concentrations of N-acetylaspartate (tNAA), creatine and phosphocreatine (tCr), choline-containing compounds (Cho), glucose (Glc), and lactate (Lac) relative to BALB/c mice and elevated Glc relative to NMRI mice. Apart from the expected decrease of Glc and increase of Lac 1 hr post mortem, C57BL/6 mice presented with significant reductions of tNAA, tCr, and Cho, whereas these metabolites remained unchanged in BALB/c and NMRI mice. The results support the hypothesis that the more pronounced vulnerability of C57BL/6 mice to brain ischemia is linked to strain-dependent differences of the cerebral energy metabolism.     

Regional metabolite concentrations in human brain as determined by quantitative localized proton MRS

The regional distribution of brain metabolites was studied in several cortical white and gray matter areas, cerebellum, and thalamus of young adults with use of quantitative single-voxel proton MRS at 2.0 T. Whereas the neuronal compound N-acetylaspartate is distributed homogeneously throughout the brain, N-acetylaspartylglutamate increases caudally and exhibits higher concentrations in white matter than in gray matter. Creatine, myo-inositol, glutamate, and glutamine are less concentrated in cortical white matter than in gray matter. The highest creatine levels are found in cerebellum, parallel to the distribution of creatine kinase and energy-requiring processes in the brain. Also myo-inositol has highest concentrations in the cerebellum. Choline-containing compounds exhibit a marked regional variability with again highest concentrations in cerebellum and lowest levels and a strong caudally decreasing gradient in gray matter. The present findings neither support a metabolic gender difference (except for a 1.3-fold higher myo-inositol level in parietal white matter of female subjects) nor a metabolic hemispheric asymmetry.     

Localized in vivo human 1H MRS at very short echo times.

A new point-resolved spectroscopy (PRESS) sequence was developed that allows localized human proton MR spectra to be acquired at echo times (TEs) of 10 ms or less. The method was implemented on a 4 Tesla Varian research console and a clinical 3 Tesla Siemens Trio scanner. Human brain spectra acquired in vivo from the prefrontal cortex at TE=8 ms showed improved signals from coupled resonances (such as glutamate, glutamine, and myo-inositol) compared to spectra acquired at TE=30 ms. These improvements should result in more accurate quantitation of these metabolites.     

Localized proton NMR spectroscopy in different regions of the human brain in vivo. Relaxation times and concentrations of cerebral metabolites

High-resolution proton NMR spectra of normal human brain in vivo have been obtained from selected 27- and 64-ml volumes-of-interest (VOI) localized in the insular area, the occipital area, the thalamus, and the cerebellum of normal volunteers. Localization was achieved by stimulated echo (STEAM) sequences using a conventional 1.5-T whole-body MRI system (Siemens Magnetom). The proton NMR spectra show resonances from lipids, lactate, acetate, N-acetylaspartate (NAA), gamma-aminobutyrate, glutamine, glutamate, aspartate, creatine and phosphocreatine, choline-containing compounds, taurine, and inositols. While T1 relaxation times of most of these metabolites were about 1100-1700 ms without significant regional differences, their T2 relaxation times varied between 100 and 500 ms. The longest T2 values of about (500 +/- 50) ms were observed for the methyl protons of NAA in the white matter of the occipital lobe compared to (320 +/- 30) ms in the other parts of the brain. No significant regional T2 differences were found for choline and creatine methyl resonances. The relative concentrations of NAA in gray and white matter were found to be 35% higher than those in the thalamus and cerebellum. Assuming a concentration of 10 mM for total creatine the resulting NAA concentrations of 13-18 mM are by a factor of 2-3 higher than previously reported using analytical techniques. Cerebral lactate reached a maximum concentration of about 1.0 mM.     

Proton MRS in Kennedy disease: absolute metabolite and macromolecular concentrations

PURPOSE: To investigate whether glutamine and glutamate (Glx) were elevated in Kennedy Disease (KD), and whether pathological proteins were spectroscopically visible as altered macromolecular (MM) resonances. MATERIALS AND METHODS: Ten patients with KD and twelve healthy volunteers were investigated using a stimulated echo acquisition mode (STEAM) spectroscopy sequence with metabolite-nulling. RESULTS: The concentrations of Glx remained unchanged in KD. An increased myo-inositol (Ins), and elevated MM at 0.9 ppm were found within the motor area. The N-acetyl-aspartate (NAA)/creatine (Cr) ratio was negatively correlated to the number of cytosine adenosine guanine (CAG) repeats in the motor area. CONCLUSION: The elevated MM at 0.9 ppm may be attributed to a pathologically altered protein in KD. Additionally, the changes of Ins point to a clinically unexpected involvement of the motor cortex. The correlation of NAA/Cr with the number of CAG repeats indicates a link between metabolites and genetic failure.     

Magnetic field dependence of proton spin-lattice relaxation times.

The magnetic field dependence of the water-proton spin-lattice relaxation rate (1/T(1)) in tissues results from magnetic coupling to the protons of the rotationally immobilized components of the tissue. As a consequence, the magnetic field dependence of the water-proton (1/T(1)) is a scaled report of the field dependence of the (1/T(1)) rate of the solid components of the tissue. The proton spin-lattice relaxation rate may be represented generally as a power law: 1/T(1)omega = A omega(-b), where b is usually found to be in the range of 0.5-0.8. We have shown that this power law may arise naturally from localized structural fluctuations along the backbone in biopolymers that modulate the proton dipole-dipole couplings. The protons in a protein form a spin communication network described by a fractal dimension that is less than the Euclidean dimension. The model proposed accounts quantitatively for the proton spin-lattice relaxation rates measured in immobilized protein systems at different water contents, and provides a fundamental basis for understanding the parametric dependence of proton spin-lattice relaxation rates in dynamically heterogeneous systems, such as tissues.     

Biexponential transverse relaxation (T(2)) of the proton MRS creatine resonance in human brain.

Differences in proton MRS T(2) values for phosphocreatine (PCr) and creatine (Cr) methyl groups (3.0 ppm) were investigated in studies of phantoms and human brain. Results from phantom studies revealed that T(2) of PCr in solution is significantly shorter than T(2) of Cr. Curve-fitting results indicated that the amplitude-TE curves of the total Cr resonance at 3.0 ppm in human brain (N = 26) fit a biexponential decay model significantly better than a monoexponential decay model (P < 0.006), yielding mean T(2) values of 117 +/- 21 ms and 309 +/- 21 ms. Using a localized, long-TE (272 ms) point-resolved spectroscopy (PRESS) proton MRS during 2 min of photic stimulation (PS), an increase of 12.1% +/- 3.5% in the mean intensity of the total Cr resonance in primary visual cortex (VI) was observed at the end of stimulation (P < 0.021). This increase is consistent with the conversion of 26% of PCr in VI to Cr, which is concordant with (31)P MRS findings reported by other investigators. These results suggest a significantly shorter T(2) for PCr than for Cr in vivo. This difference possibly could be exploited to quantify regional activation in functional spectroscopy studies, and could also lead to inaccuracies in some circumstances when the Cr resonance is used as an internal standard for (1)H MRS studies in vivo.     

High-field proton MRS of human brain

Proton magnetic resonance spectroscopy (1H-MRS) of the brain reveals specific biochemical information about cerebral metabolites, which may support clinical diagnoses and enhance the understanding of neurological disorders. The advantages of performing 1H-MRS at higher field strengths include better signal to noise ratio (SNR) and increased spectral, spatial and temporal resolution, allowing the acquisition of high quality, easily quantifiable spectra in acceptable imaging times. In addition to improved measurement precision of N-acetylaspartate, choline, creatine and myo-inositol, high-field systems allow the high-resolution measurement of other metabolites, such as glutamate, glutamine, gamma-aminobutyric acid, scyllo-inositol, aspartate, taurine, N-acetylaspartylglutamate, glucose and branched amino acids, thus extending the range of metabolic information. However, these advantages may be hampered by intrinsic field-dependent technical difficulties, such as decreased T2 signal, chemical shift dispersion errors, J-modulation anomalies, increased magnetic susceptibility, eddy current artifacts, limitations in the design of homogeneous and sensitive radiofrequency (RF) coils, magnetic field instability and safety issues. Several studies demonstrated that these limitations could be overcome, suggesting that the appropriate optimization of high-field 1H-MRS would expand the application in the fields of clinical research and diagnostic routine.     

Comparison of longitudinal metabolite relaxation times in different regions of the human brain at 1.5 and 3 Tesla.

In vivo longitudinal relaxation times of N-acetyl compounds (NA), choline-containing substances (Cho), creatine (Cr), myo-inositol (mI), and tissue water were measured at 1.5 and 3 T using a point-resolved spectroscopy (PRESS) sequence with short echo time (TE). T(1) values were determined in six different brain regions: the occipital gray matter (GM), occipital white matter (WM), motor cortex, frontoparietal WM, thalamus, and cerebellum. The T(1) relaxation times of water protons were 26-38% longer at 3 T than at 1.5 T. Significantly longer metabolite T(1) values at 3 T (11-36%) were found for NA, Cho, and Cr in the motor cortex, frontoparietal WM, and thalamus. The amounts of GM, WM, and cerebrospinal fluid (CSF) within the voxel were determined by segmentation of a 3D image data set. No influence of tissue composition on metabolite T(1) values was found, while the longitudinal relaxation times of water protons were strongly correlated with the relative GM content.     

Localized in vivo proton spectroscopy of the human kidney.

In vivo 1H spectroscopy using the STEAM sequence for localization has been applied to the human kidney in normal volunteers and subjects with successful renal transplants. We show that, within the resolution of our measurements, trimethylamines are present in the spectra from some of the subjects and absent from others. The prominent peak seen at 5.8 ppm in the spectrum is identified as that from urea and not lipid, as previously suggested.     

Comparison of methods for the determination of absolute metabolite concentrations in human muscles by 31P MRS

In order to determine metabolite concentrations in human skeletal muscles by in vivo ³¹P MRS, different quantification methods were analyzed with regard to the accuracy and reproducibility of results and the simplicity of handling. Each quantification method comprised a calibration strategy and a localization technique. Extensive in vivo and in vitro tests showed that homonuclear phantom-based calibration strategies yielded significantly more accurate (lower systematic errors) and more reproducible (lower statistical errors) concentration estimates than heteronuclear strategies using internal water as a concentration standard. Additionally, the former strategies are easier to handle than the latter. Localization with the volume-selective sequence lSlS yielded slightly more reproducible results than localization by surface coil. We conclude that phosphorus metabolite concentrations are determined most accurately with phantom-based calibration strategies in combination with lSlS localization (measurement errors ≈ 5–7%).     

Single-voxel proton MRS of the human brain at 1.5T and 3.0T.

Single-voxel proton spectra of the human brain were recorded in five subjects at both 1.5T and 3.0T using the STEAM pulse sequence. Data acquisition parameters were closely matched between the two field strengths. Spectra were recorded in the white matter of the centrum semiovale and in phantoms. Spectra were compared in terms of resolution and signal-to-noise ratio (SNR), and transverse relaxation times (T(2)) were estimated at both field strengths. Spectra at 3T demonstrated a 20% improvement in sensitivity compared to 1.5T at short echo times (TE = 20 msec), which was lower than the theoretical 100% improvement. Spectra at long echo times (TE = 272 msec) exhibited similar SNR at both field strengths. T(2) relaxation times were almost twofold shorter at the higher field strength. Spectra in phantoms demonstrated significantly improved resolution at 3T compared to 1.5T, but resolution improvements in in vivo spectra were almost completely offset by increased linewidths at higher field.     

Proton MR spectroscopy in neonates with perinatal cerebral hypoxic-ischemic injury: metabolite peak-area ratios, relaxation times, and absolute concentrations

BACKGROUND: Results from cerebral proton (1)H-MR spectroscopy studies of neonates with perinatal hypoxic-ischemic injury have generally been presented as metabolite peak-area ratios, which are T1- and T2-weighted, rather than absolute metabolite concentrations. We hypothesized that compared with (1)H-MR spectroscopy peak-area ratios, calculation of absolute metabolite concentrations and relaxation times measured within the first 4 days after birth (1) would improve prognostic accuracy and (2) enhance the understanding of underlying neurochemical changes in neonates with neonatal encephalopathy. METHODS: Seventeen term infants with neonatal encephalopathy and 10 healthy controls were studied at 2.4T at 1 (1-3) and 2 (2-4) (median [interquartile range]) days after birth, respectively. Infants with neonatal encephalopathy were classified into 2 outcome groups (normal/mild and severe/fatal), according to neurodevelopmental assessments at 1 year. The MR spectroscopy peak-area ratios, relaxation times, absolute concentrations, and concentration ratios of lactate (Lac), creatine plus phosphocreatine (Cr), N-acetylaspartate (NAA), and choline-containing compounds (Cho) from a voxel centered on the thalami were analyzed according to outcome group. RESULTS: Comparing the severe/fatal group with the controls (significance assumed with P < 0.05), we found that Lac/NAA, Lac/Cho, and Lac/Cr peak-area ratios increased and NAA/Cr and NAA/Cho decreased; Lac, NAA, and Cr T2s were increased; [Lac] was increased and [Cho], [Cr], and [NAA] decreased; and among the concentration ratios, only [Lac]/[NAA] was increased. Comparison of the normal/mild group with controls revealed no differences in peak-area ratios, relaxation times, or concentration ratios but decreased [NAA], [Cho], and [Cr] were observed in the infants with normal/mild outcome. Comparison of the normal/mild and severe/fatal groups showed increased Lac/NAA and Lac/Cho and decreased NAA/Cr and NAA/Cho peak-area ratios, reduced [NAA], and increased Lac T2 in the infants with the worse outcome. CONCLUSIONS: Metabolite concentrations, in particular [NAA], enhance the prognostic accuracy of cerebral (1)H-MR spectroscopy-[NAA] was the only measurable to discriminate among all (control, normal/mild, and severe/fatal outcome) groups. However, peak-area ratios are more useful prognostic indicators than concentration ratios because they depend on metabolite concentrations and T2s, both of which are pathologically modulated. Concentration ratios depend only on the concentrations of the constituent metabolites. Increased Cr T2 may provide an indirect marker of impaired cellular energetics, and similarly, NAA T2 may constitute an index of exclusively neuronal energy status. Our recommendation is to collect data that enable calculation of brain metabolite concentrations. However, if time constraints make this impossible, metabolite peak-area ratios provide the next best method of assigning early prognosis in neonatal encephalopathy.     

Assessment of absolute metabolite concentrations in human tissue by 31P MRS in vivo. Part II: Muscle,liver, kidney

Absolute metabolite concentrations were assessed in the muscle, the liver, and the kidney of healthy human volunteers by ³¹P MRS. Fully relaxed in vivo spectra were acquired with a surface coil and were localized with an adiabatic lSlS pulse sequence. The spectra were quantified with a subsequent measurement of a calibration phantom and were processed iteratively in the time domain. The following mean metabolite concentrations (mmollliter) were measured in the resting male calf muscle (n = 9), in the fasting liver (n = 12), and in the orthiotopic kidney (n= 5): [PME] = 2.0 ± 0.6, 3.8 ± 0.7, and 2.6 ± 0.9, [Pi] = 2.9 ± 0.3, 1.8 ± 0.3, and 1.6 ± 0.4, [PDE] = 3.8 ± 0.8, 9.7 ± 1.5, and 4.9 ± 1.1, [PCr] = 22.0 ± 1.2, 0, and 0, [NTP] = 5.7 ± 0.4, 2.9 ± 0.4, and 2.0 ± 0.3, respectively. Several interesting findings are to be emphasized: The concentrations of Pi, PCr, and NTP were 20% lower in the muscle of women than of men. In addition, the pH, was significantly lower in female muscle (6.99 ± 0.03) than in male muscle (7.05 ± 0.03). The pH, in the liver (7.12 ± 0.09) and in the kidney (7.09 ± 0.08) were higher than in the muscle of both genders. The free magnesium concentration (mmollliter) was higher in the lliver (1.40 ± 0.64) than in the kidney (0.79 ± 0.39) and in the muscle (0.52 ± 0.10).     

In vivo proton spin-lattice relaxation times of normal and dystrophic muscles

In vivo spin-lattice relaxation times (T1) of water and lipid protons were measured in normal and dystrophic chicken pectoralis muscles at different ages. Values were obtained with a surface coil used as both a receiver and a transmitter. A 2 theta-T1-theta-Acquisition sequence was used for these measurements. Accuracy was verified with an inversion-recovery method using a slotted tube resonator as the transmitter and a surface coil as the receiver. It was observed that the T1 values of water protons in normal muscles decrease with age, the T1 values of water protons do not change with age in dystrophic muscles, and the T1 values of lipid protons increase with age in normal and dystrophic muscles. These results indicate a failure of the normal maturation of dystrophic muscles.     

Brain metabolite changes in alcoholism: Localized proton magnetic resonance spectroscopy study of the occipital lobe

Chronic alcoholism is associated with altered brain metabolism, morphology and cognitive abilities. Besides deficits in higher order cognitive functions, alcoholics also show a deficit in the processing of basic sensory information viz. visual stimulation. To assess the metabolic changes associated with this deficit, ¹H MRS was carried out in the occipital lobe of alcohol dependents. A significant increase in Cho/Cr ratio (p < 0.015) was observed in occipital lobe in the alcoholic group indicating altered cell membrane metabolism, which may probably be associated with the alterations in the cognitive abilities associated with vision.     

Age dependence of regional proton metabolites T2 relaxation times in the human brain at 3 T

Although recent studies indicate that use of a single global transverse relaxation time, T₂, per metabolite is sufficient for better than ±10% quantification precision at intermediate and short echo‐time spectroscopy in young adults, the age‐dependence of this finding is unknown. Consequently, the age effect on regional brain choline (Cho), creatine (Cr), and N‐acetylaspartate (NAA) T₂s was examined in four age groups using 3D (four slices, 80 voxels 1 cm³ each) proton MR spectroscopy in an optimized two‐point protocol. Metabolite T₂s were estimated in each voxel and in 10 gray and white matter (GM, WM) structures in 20 healthy subjects: four adolescents (13 ± 1 years old), eight young adults (26 ± 1); two middle‐aged (51 ± 6), and six elderly (74 ± 3). The results reveal that T₂s in GM (average ± standard error of the mean) of adolescents (NAA: 301 ± 30, Cr: 162 ± 7, Cho: 263 ± 7 ms), young adults (NAA: 269 ± 7, Cr: 156 ± 7, Cho: 226 ± 9 ms), and elderly (NAA: 259 ± 13, Cr: 154 ± 8, Cho: 229 ± 14 ms), were 30%, 16%, and 10% shorter than in WM, yielding mean global T₂s of NAA: 343, Cr: 172, and Cho: 248 ms. The elderly NAA, Cr, and Cho T₂s were 12%, 6%, and 10% shorter than the adolescents, a change of under 1 ms/year assuming a linear decline with age. Formulae for T₂ age‐correction for higher quantification precision are provided. Magn Reson Med 60:790–795, 2008. © 2008 Wiley‐Liss, Inc.