The in vivo J‐difference editing MEGA‐PRESS technique for the detection of n‐3 fatty acids

In this study, we present a method for the detection of n‐3 fatty acid (n‐3 FA) signals using MRS in adipose tissue in vivo. This method (called oMEGA‐PRESS) is based on the selective detection of the CH₃ signal of n‐3 FA using the MEGA‐PRESS (MEshcher–GArwood Point‐RESolved Spectroscopy) J‐difference editing technique. We optimized the envelope shape and frequency of spectral editing pulses to minimize the spurious co‐editing and incomplete subtraction of the CH₃ signal of other FAs, which normally obscure the n‐3 FA CH₃ signal in MR spectra acquired using standard PRESS techniques. The post‐processing of the individual data scans with the phase and frequency correction before data subtraction and averaging was implemented to further improve the quality of in vivo spectra. The technique was optimized in vitro on lipid phantoms using various concentrations of n‐3 FA and examined in vivo at 3 T on 15 healthy volunteers. The proportion of n‐3 FA estimated by the oMEGA‐PRESS method in phantoms showed a highly significant linear correlation with the n‐3 FA content determined by gas chromatography. The signal attributed to n‐3 FA was observed in all subjects. Comparisons with the standard PRESS technique revealed an enhanced identification of the n‐3 FA signal using oMEGA‐PRESS. The presented method may be useful for the non‐invasive quantification of n‐3 FA in adipose tissue, and could aid in obtaining a better understanding of various aspects of n‐3 FA metabolism. Copyright © 2014 John Wiley & Sons, Ltd.     

Improved detection of lactate and β‐hydroxybutyrate using MEGA‐sLASER at 3 T

Lactate and β‐hydroxybutyrate are important MRS‐visible biomarkers for the energy metabolism of the human brain. A major obstacle for their unambiguous detection and quantification in vivo is their inherently low concentration and spectral overlap with resonances from lipids and macromolecules. In this work, we demonstrate the improved detectability of lactate and β‐hydroxybutyrate with MEGA‐sLASER compared to MEGA‐PRESS at the clinical field strength of 3 T. The method is validated by numerical simulations, in vitro measurements and in vivo experiments on healthy subjects. It is demonstrated that MEGA‐sLASER offers an SNR increase of approximately 70% for lactate and β‐hydroxybutyrate detection compared to MEGA‐PRESS in various brain regions. This increased SNR translates into reduced Cramér‐Rao lower bounds for quantification and enables a more robust detection of subtle changes in the (brain) energy metabolism. The sensitivity of the method for detection of β‐hydroxybutyrate concentration changes is demonstrated through measurements before and during a ketogenic diet while the sensitivity for detection of lactate concentration changes is shown by measurements before and after an intensive anaerobic exercise.     

In vivo detection and automatic analysis of GABA in the mouse brain with MEGA‐PRESS at 9.4 T

The goals of this study were to develop an acquisition protocol and the analysis tools for Meshcher–Garwood point‐resolved spectroscopy (MEGA‐PRESS) in mouse brain at 9.4 T, to allow the in vivo detection of γ‐aminobutyric acid (GABA) and to examine whether isoflurane alters GABA levels in the thalamus during anesthesia. We implemented the MEGA‐PRESS sequence on a Bruker 94/20 system with ParaVision 6.0.1, and magnetic resonance spectra were acquired from nine male wild‐type C57BL/6 J mice at the thalamus. Four individual scans were obtained for each mouse in a 2‐h time course whilst the mouse was anesthetized with isoflurane. We developed an automated analysis program with improved correction for frequency and phase drift compared with the standard creatine (Cr) fitting‐based method and provided automatic quantification. During MEGA‐PRESS acquisition, a single voxel with a size of 5 × 3 × 3 mm³ was placed at the thalamus to evaluate GABA to Cr (GABA/Cr) ratios during anesthesia. Detection and quantitative analysis of thalamic GABA levels were successfully achieved. We noticed a significant decrease in GABA/Cr during the 2‐h anesthesia (by linear regression analysis: slope < 0, p < 0.0001). In summary, our findings demonstrate that MEGA‐PRESS is a feasible technique to measure in vivo GABA levels in the mouse brain at 9.4 T.     

Quantification of GABA,glutamate and glutamine in a single measurement at 3 T using GABA‐edited MEGA‐PRESS

γ‐Aminobutyric acid (GABA) and glutamate (Glu), major neurotransmitters in the brain, are recycled through glutamine (Gln). All three metabolites can be measured by magnetic resonance spectroscopy in vivo, although GABA measurement at 3 T requires an extra editing acquisition, such as Mescher–Garwood point‐resolved spectroscopy (MEGA‐PRESS). In a GABA‐edited MEGA‐PRESS spectrum, Glu and Gln co‐edit with GABA, providing the possibility to measure all three in one acquisition. In this study, we investigated the reliability of the composite Glu + Gln (Glx) peak estimation and the possibility of Glu and Gln separation in GABA‐edited MEGA‐PRESS spectra. The data acquired in vivo were used to develop a quality assessment framework which identified MEGA‐PRESS spectra in which Glu and Gln could be estimated reliably. Phantoms containing Glu, Gln, GABA and N‐acetylaspartate (NAA) at different concentrations were scanned using GABA‐edited MEGA‐PRESS at 3 T. Fifty‐six sets of spectra in five brain regions were acquired from 36 healthy volunteers. Based on the Glu/Gln ratio, data were classified as either within or outside the physiological range. A peak‐by‐peak quality assessment was performed on all data to investigate whether quality metrics can discriminate between these two classes of spectra. The quality metrics were as follows: the GABA signal‐to‐noise ratio, the NAA linewidth and the Glx Cramer–Rao lower bound (CRLB). The Glu and Gln concentrations were estimated with precision across all phantoms with a linear relationship between the measured and true concentrations: R¹ = 0.95 for Glu and R¹ = 0.91 for Gln. A quality assessment framework was set based on the criteria necessary for a good GABA‐edited MEGA‐PRESS spectrum. Simultaneous criteria of NAA linewidth <8 Hz and Glx CRLB <16% were defined as optimum features for reliable Glu and Gln quantification. Glu and Gln can be reliably quantified from GABA‐edited MEGA‐PRESS acquisitions. However, this reliability should be controlled using the quality assessment methods suggested in this work.     

Optimized MEGA‐SPECIAL for in vivo glutamine detection in the rat brain at 14.1 T

Glutamine has multiple roles in brain metabolism and its concentration can be altered in various pathological conditions. An accurate knowledge of its concentration is therefore highly desirable to monitor and study several brain disorders in vivo. However, in recent years, several MRS studies have reported conflicting glutamine concentrations in the human brain. A recent hypothesis for explaining these discrepancies is that a short T₂ component of the glutamine signal may impact on its quantification at long echo times. The present study therefore aimed to investigate the impact of acquisition parameters on the quantified glutamine concentration using two different acquisition techniques, SPECIAL at ultra‐short echo time and MEGA‐SPECIAL at moderate echo time. For this purpose, MEGA‐SPECIAL was optimized for the first time for glutamine detection. Based on the very good agreement of the glutamine concentration obtained between the two measurements, it was concluded that no impact of a short T₂ component of the glutamine signal was detected. Copyright © 2014 John Wiley & Sons, Ltd.     

Simultaneous detection of glutathione and lactate using spectral editing at 3 T

Two spectral editing techniques for the simultaneous detection of glutathione (GSH) and lactate (Lac) in the human brain at 3 T are described and evaluated. These methods, ‘sMEGA’ (sinc‐MEscher and GArwood) and ‘DEW’ (Double Editing With), were optimized to detect GSH and Lac simultaneously at 3 T using density‐matrix simulations and validation in phantoms. Simulations to test for co‐edited metabolites within the detected GSH region of the spectrum were also performed. In vivo data were acquired in the midline parietal region of seven subjects using both methods, and compared with conventional MEGA‐PRESS (MEscher and GArwood‐Point RESolved Spectroscopy) acquisitions of GSH and Lac. Simulations and phantom experiments showed that sMEGA and DEW had a high editing efficiency for both GSH and Lac. In the phantom, the editing efficiency of GSH was >88% relative to a conventional GSH MEGA‐PRESS acquisition, whereas, for Lac, the editing efficiency was >95% relative to a conventional Lac MEGA‐PRESS acquisition. Simulations also showed that the editing efficiency of both methods was comparable with separate MEGA‐PRESS acquisitions of the same metabolites. In addition, simulations and in vivo spectra showed that, at a TE of 140 ms, there was a partial overlap between creatine (Cr) and GSH peaks, and that N‐acetyl aspartate/N‐acetyl aspartyl glutamate (NAA/NAAG) were sufficiently resolved from GSH. In vivo measurements showed that both sMEGA and DEW edited GSH and Lac reliably with the same editing efficiency as conventional MEGA‐PRESS acquisitions of the same metabolites, with measured GSH integrals of 2.23 ± 0.51, 2.31 ± 0.38, 2.38 ± 0.53 and measured Lac integrals of 1.72 ± 0.67, 1.55 ± 0.35 and 1.53 ± 0.54 for MEGA‐PRESS, DEW and sMEGA, respectively. Simultaneous detection of GSH and Lac using sMEGA and DEW is possible at 3 T with high editing efficiency.     

In silico GABA+ MEGA‐PRESS: Effects of signal‐to‐noise ratio and linewidth on modeling the 3 ppm GABA+ resonance

To investigate the GABA+ modeling accuracy of MEGA‐PRESS GABA+‐edited MRS data with various spectral quality scenarios, the influence of varying signal‐to‐noise ratio (SNR) and linewidth on the model estimates was quantified. MEGA‐PRESS data from 46 volunteers were averaged to generate a template MEGA‐PRESS spectrum, which was modeled and quantified to generate a GABA+ level ground truth. This spectrum was then manipulated by adding 427 combinations of varying artificial noise levels and line broadening, mimicking variations in GABA+ SNR and B₀ homogeneity. GABA+ modeling and quantification was performed with 100 simulated spectra per condition using automated routines in both Gannet 3.0 and Tarquin. The GABA+ estimation error was calculated as the relative deviation to the quantified GABA+ ground truth levels to assess the accuracy of GABA+ modeling. Finally, the accordance between the simulations and different in vivo scenarios was assessed. The GABA+ estimation error was smaller than 5% for all GABA+ SNR values with creatine linewidths lower than 9.7 Hz in Gannet 3.0 or unequal 10.6 Hz in Tarquin. The standard deviation of the GABA+ amplitude over 100 spectra per condition varied between 3.1 and 17% (Gannet 3.0) and between 1 and 11% (Tarquin) over the in vivo relevant GABA+ SNR range between 2.6 and 3.5. GABA+ edited studies might be realized for voxels with low GABA+ SNR at the cost of higher group‐level variance. The accuracy of GABA+ modeling had no relation to commonly used quality metrics. The Tarquin algorithm was found to be more robust against linewidth changes than the fitting algorithm in Gannet.     

Spatial variability and reproducibility of GABA‐edited MEGA‐LASER 3D‐MRSI in the brain at 3 T

The reproducibility of gamma‐aminobutyric acid (GABA) quantification results, obtained with MRSI, was determined on a 3 T MR scanner in healthy adults. In this study, a spiral‐encoded, GABA‐edited, MEGA‐LASER MRSI sequence with real‐time motion–scanner‐instability corrections was applied for robust 3D mapping of neurotransmitters in the brain. In particular, the GABA⁺ (i.e. GABA plus macromolecule contamination) and Glx (i.e. glutamate plus glutamine contamination) signal was measured. This sequence enables 3D‐MRSI with about 3 cm³ nominal resolution in about 20 min. Since reliable quantification of GABA is challenging, the spatial distribution of the inter‐subject and intra‐subject variability of GABA⁺ and Glx levels was studied via test–retest assessment in 14 healthy volunteers (seven men–seven women). For both inter‐subject and intra‐subject repeated measurement sessions a low coefficient of variation (CV) and a high intraclass correlation coefficient (ICC) were found for GABA⁺ and Glx ratios across all evaluated voxels (intra?/inter‐subject: GABA⁺ ratios, CV ~ 8%–ICC > 0.75; Glx ratios, CV ~ 6%–ICC > 0.70). The same was found in selected brain regions for Glx ratios versus GABA⁺ ratios (CV varied from about 5% versus about 8% in occipital and parietal regions, to about 8% versus about 10% in the frontal area, thalamus, and basal ganglia). These results provide evidence that 3D mapping of GABA⁺ and Glx using the described methodology provides high reproducibility for application in clinical and neuroscientific studies.     

Noninvasive quantification of ascorbate and glutathione concentration in the elderly human brain

In this study, ascorbate (Asc) and glutathione (GSH) concentrations were quantified noninvasively using double-edited (1)H MRS at 4 T in the occipital cortex of healthy young [age (mean ± standard deviation) = 20.4 ± 1.4 years] and elderly (age = 76.6 ± 6.1 years) human subjects. Elderly subjects had a lower GSH concentration than younger subjects (p < 0.05). The Asc concentration was not significantly associated with age. Furthermore, the lactate (Lac) concentration was higher in elderly than young subjects. Lower GSH and higher Lac concentrations are indications of defective protection against oxidative damage and impaired mitochondrial respiration. The extent to which the observed concentration differences could be associated with physiological differences and methodological artifacts is discussed. In conclusion, GSH and Asc concentrations were compared noninvasively for the first time in young vs elderly subjects.     

Detection of lactate in the striatum without contamination of macromolecules by J‐difference editing MRS at 7 T

Lactate levels are measurable by MRS and are related to neural activity. Therefore, it is of interest to accurately measure lactate levels in the basal ganglia networks. If sufficiently stable, lactate measurements may be used to investigate alterations in dopaminergic signalling in the striatum, facilitating the detection and diagnosis of metabolic deficits. The aim of this study is to provide a J‐difference editing MRS technique for the selective editing of lactate only, thus allowing the detection of lactate without contamination of overlapping macromolecules. As a validation procedure, macromolecule nulling was combined with J‐difference editing, and this was compared with J‐difference editing with a new highly selective editing pulse. The use of a high‐field (7T) MR scanner enables the application of editing pulses with very narrow bandwidth, which are selective for lactate. We show that, despite the sensitivity to B₀ offsets, the use of a highly selective editing pulse is more efficient for the detection of lactate than the combination of a broad‐band editing pulse with macromolecule nulling. Although the signal‐to‐noise ratio of uncontaminated lactate detection in healthy subjects is relatively low, this article describes the test–retest performance of lactate detection in the striatum when using highly selective J‐difference editing MRS at 7 T. The coefficient of variation, σ_w and intraclass correlation coefficients for within‐ and between‐subject differences of lactate were determined. Lactate levels in the left and right striatum were determined twice in 10 healthy volunteers. Despite the fact that the test–retest performance of lactate detection is moderate with a coefficient of variation of about 20% for lactate, these values can be used for the design of new studies comparing, for example, patient populations with healthy controls. Copyright © 2015 John Wiley & Sons, Ltd.     

Volumetric navigated MEGA‐SPECIAL for real‐time motion and shim corrected GABA editing

Mescher–Garwood (MEGA) editing with spin echo full intensity acquired localization (MEGA‐SPECIAL, MSpc) is a technique to acquire γ‐aminobutyric acid (GABA) without macromolecule (MM) contamination at a T_E of 68 ms. However, due to the requirement of multiple shot‐localization, it is often susceptible to subject motion and B₀ inhomogeneity. A method is presented for real‐time shim and motion correction (ShMoCo) using volumetric navigators to correct for motion and motion‐related B₀ inhomogeneity during MSpc acquisition. A phantom experiment demonstrates that ShMoCo restores the GABA peak and improves spectral quality in the presence of motion and zero‐ and first‐order shim changes. The ShMoCo scans were validated in three subjects who performed up–down and left–right head rotations. Qualitative assessment of these scans indicates effective reduction of subtraction artefacts and well edited GABA peaks, while quantitative analysis indicates superior fitting and spectral quality relative to scans with no correction. Copyright © 2015 John Wiley & Sons, Ltd.     

In vivo estimation of gamma‐aminobutyric acid levels in the neonatal brain

Gamma‐aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, and plays a key role in brain development. However, the in vivo levels of brain GABA in early life are unknown. Using edited MRS, in vivo GABA can be detected as GABA+ signal with contamination of macromolecule signals. GABA+ is evaluated as the peak ratio of GABA+/reference compound, for which creatine (Cr) or water is typically used. However, the concentrations and T₁ and T₂ relaxation times of these references change during development. Thus, the peak ratio comparison between neonates and children may be inaccurate. The aim of this study was to measure in vivo neonatal brain GABA+ levels, and to investigate the dependency of GABA levels on brain region and age. The basal ganglia and cerebellum of 38 neonates and 12 children were measured using GABA‐edited MRS. Two different approaches were used to obtain GABA+ levels: (i) multiplying the GABA/water ratio by the water concentration; and (ii) multiplying the GABA+/Cr by the Cr concentration. Neonates exhibited significantly lower GABA+ levels compared with children in both regions, regardless of the approach employed, consistent with previous ex vivo data. A similar finding of lower GABA+/water and GABA+/Cr in neonates compared with children was observed, except for GABA+/Cr in the cerebellum. This contrasting finding resulted from significantly lower Cr concentrations in the neonate cerebellum, which were approximately 52% of those of children. In conclusion, care should be taken to consider Cr concentrations when comparing GABA+/Cr levels between different‐aged subjects.     

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.     

Spatial Hadamard encoding of J‐edited spectroscopy using slice‐selective editing pulses

A new approach for simultaneous dual‐voxel J‐difference spectral editing is described, which uses spatially selective spectral‐editing pulses and Hadamard encoding. A theoretical framework for spatial Hadamard editing and reconstruction for parallel acquisition (SHERPA) was developed, applying gradient pulses during the frequency‐selective editing pulses. Spectral simulations were performed for either one (gamma‐aminobutyric acid, GABA) or two molecules (glutathione and lactate) simultaneously detected in two voxels. The method was tested in a two‐compartment GABA phantom, and finally applied to the left and right hemispheres of 10 normal control subjects, scanned at 3 T. SHERPA was successfully implemented at 3 T and gave results in close agreement with conventional MEGA‐PRESS scans in both the phantom and in vivo experiments. Simulations for GABA editing for (3 cm)³ voxels in the left and right hemispheres suggest that both editing efficiency losses and contamination between voxels are about 2%. Compared with conventional single‐voxel single‐metabolite J‐difference editing, two‐ or fourfold acceleration is possible without significant loss of SNR using the SHERPA method. Unlike some other dual‐voxel methods, the method can be used with single‐channel receiver coils, and there is no SNR loss due to unfavorable receive‐coil geometry factors.     

Validating a robust double‐quantum‐filtered 1H MRS lactate measurement method in high‐grade brain tumours

¹H MRS measurements of lactate are often confounded by overlapping lipid signals. Double‐quantum (DQ) filtering eliminates lipid signals and permits single‐shot measurements, which avoid subtraction artefacts in moving tissues. This study evaluated a single‐voxel‐localized DQ filtering method qualitatively and quantitatively for measuring lactate concentrations in the presence of lipid, using high‐grade brain tumours in which the results could be compared with standard acquisition as a reference. Paired standard acquisition and DQ‐filtered ¹H MR spectra were acquired at 3T from patients receiving treatment for glioblastoma, using fLASER (localization by adiabatic selective refocusing using frequency offset corrected inversion pulses) single‐voxel localization. Data were acquired from 2 × 2 × 2 cm³ voxels, with a repetition time of 1 s and 128 averages (standard acquisition) or 256 averages (DQ‐filtered acquisition), requiring 2.15 and 4.3 min respectively. Of 37 evaluated data pairs, 20 cases (54%) had measureable lactate (fitted Cramér–Rao lower bounds ≤ 20%) in either the DQ‐filtered or the standard acquisition spectra. The measured DQ‐filtered lactate signal was consistently downfield of lipid (1.33 ± 0.03 ppm vs 1.22 ± 0.08 ppm; p = 0.002), showing that it was not caused by lipid breakthrough, and that it matched the lactate signal seen in standard measurements (1.36 ± 0.02 ppm). In the absence of lipid, similar lactate concentrations were measured by the two methods (mean ratio DQ filtered/standard acquisition = 1.10 ± 0.21). In 7/20 cases with measurable lactate, signal was not measureable in the standard acquisition owing to lipid overlap but was quantified in the DQ‐filtered acquisition. Conversely, lactate was undetected in seven DQ‐filtered acquisitions but visible using the standard acquisition. In conclusion, the DQ filtering method has proven robust in eliminating lipid and permits uncontaminated measurement of lactate. This is important validation prior to use in tissues outside the brain, which contain large amounts of lipid and which are often susceptible to motion.     

Noninvasive quantification of human brain ascorbate concentration using 1H NMR spectroscopy at 7 T

Ascorbate (Asc, vitamin C) was quantified in the human brain noninvasively using two different ¹H NMR spectroscopy methods: short‐echo time STEAM and MEGA‐PRESS homonuclear editing. Taking advantage of increased sensitivity and chemical shift dispersion at 7 T, Asc was quantified with increased reliability relative to our previous study accomplished at 4 T. Asc concentration quantified from short‐echo time spectra measured from the occipital lobe of eight healthy subjects ([Asc] = 1.1 ± 0.3 µmol/g, mean ± SD) was in excellent agreement with Asc concentration quantified from the same volume of interest using homonuclear editing ([Asc] = 1.2 ± 0.2 µmol/g). This agreement indicates that at 7 T, Asc can be reliably quantified in the human brain simultaneously with 15 other metabolites. Additional advantages of the short‐echo time approach were: shorter measurement time than homonuclear editing and minimal effect of T₂ relaxation on Asc quantification. High magnetic field was also beneficial for Asc quantification with MEGA‐PRESS because increased chemical shift dispersion enabled editing with full efficiency, which resulted in a supra‐linear gain in signal‐to‐noise ratio relative to 4 T. Copyright © 2009 John Wiley & Sons, Ltd.     

Measurement of brain lactate during visual stimulation using a long TE semi‐LASER sequence at 7 T

Estimation of metabolic changes during neuronal activation represents a challenge for in vivo MRS, especially for metabolites with low concentration and signal overlap, such as lactate. In this work, we aimed to evaluate the feasibility of detecting lactate during brain activation using a long (144 ms) semi‐LASER sequence at 7 T. spectra were acquired on healthy volunteers ( ) during a paradigm with 15 min of visual stimulation. Outer‐volume signals were further attenuated by the use of saturation slabs, and macromolecular signals in the vicinity of the inverted lactate peak were individually fitted with simulated Lorentzian peaks. All spectra were free of artefacts and highly reproducible across subjects. Lactate was accurately quantified with an average Cramér‐Rao lower bound of 8%. Statistically significant ( , one‐tailed ‐test) increases in lactate ( 10%) and glutamate ( 3%) levels during stimulation were detected in the visual cortex. Lactate and glutamate changes were consistent with previous measurements. We demonstrated that quantification of a clear and non‐contaminated lactate peak obtained with a long TE sequence has the potential of improving the accuracy of functional MRS studies targeting non‐oxidative reaction pathways.     

A comparative study of short‐ and long‐TE 1H MRS at 3 T for in vivo detection of 2‐hydroxyglutarate in brain tumors

2‐Hydroxyglutarate (2HG) is produced in gliomas with mutations of isocitrate dehydrogenase (IDH) 1 and 2. The ¹H resonances of the J‐coupled spins of 2HG are extensively overlapped with signals from other metabolites. Here, we report a comparative study at 3 T of the utility of the point‐resolved spectroscopy sequence with a standard short TE (35 ms) and a long TE (97 ms), which had been theoretically designed for the detection of the 2HG 2.25‐ppm resonance. The performance of the methods is evaluated using data from phantoms, seven healthy volunteers and 22 subjects with IDH‐mutated gliomas. The results indicate that TE = 97 ms provides higher detectability of 2HG than TE = 35 ms, and that this improved capability is gained when data are analyzed with basis spectra that include the effects of the volume localizing radiofrequency and gradient pulses. Copyright © 2013 John Wiley & Sons, Ltd.     

HR‐MAS MRS of the pancreas reveals reduced lipid and elevated lactate and taurine associated with early pancreatic cancer

The prognosis for patients with pancreatic cancer is extremely poor, as evidenced by the disease's five‐year survival rate of ~5%. New approaches are therefore urgently needed to improve detection, treatment, and monitoring of pancreatic cancer. MRS‐detectable metabolic changes provide useful biomarkers for tumor detection and response‐monitoring in other cancers. The goal of this study was to identify MRS‐detectable biomarkers of pancreatic cancer that could enhance currently available imaging approaches. We used ¹H high‐resolution magic angle spinning MRS to probe metabolite levels in pancreatic tissue samples from mouse models and patients. In mice, the levels of lipids dropped significantly in pancreata with lipopolysaccharide‐induced inflammation, in pancreata with pre‐cancerous metaplasia (4 week old p48‐Cre;LSL‐Kras^G12D mice), and in pancreata with pancreatic intraepithelial neoplasia, which precedes invasive pancreatic cancer (8 week old p48‐Cre LSL‐Kras^G12D mice), to 26 ± 19% (p = 0.03), 19 ± 16% (p = 0.04), and 26 ± 10% (p = 0.05) of controls, respectively. Lactate and taurine remained unchanged in inflammation and in pre‐cancerous metaplasia but increased significantly in pancreatic intraepithelial neoplasia to 266 ± 61% (p = 0.0001) and 999 ± 174% (p < 0.00001) of controls, respectively. Importantly, analysis of patient biopsies was consistent with the mouse findings. Lipids dropped in pancreatitis and in invasive cancer biopsies to 29 ± 15% (p = 0.01) and 26 ± 38% (p = 0.02) of normal tissue. In addition, lactate and taurine levels remained unchanged in inflammation but rose in tumor samples to 244 ± 155% (p = 0.02) and 188 ± 67% (p = 0.02), respectively, compared with normal tissue. Based on these findings, we propose that a drop in lipid levels could serve to inform on pancreatitis and cancer‐associated inflammation, whereas elevated lactate and taurine could serve to identify the presence of pancreatic intraepithelial neoplasia and invasive tumor. Our findings may help enhance current imaging methods to improve early pancreatic cancer detection and monitoring. Copyright © 2014 John Wiley & Sons, Ltd.     

Single‐shot single‐voxel lactate measurements using FOCI‐LASER and a multiple‐quantum filter

Measurement of tissue lactate using ¹H MRS is often confounded by overlap with intense lipid signals at 1.3 ppm. Single‐voxel localization using PRESS is also compromised by the large chemical shift displacement between voxels for the 4.1 ppm (–CH) resonance and the 1.3 ppm –CH₃ resonance, leading to subvoxels with signals of opposite phase and hence partial signal cancellation. To reduce the chemical shift displacement to negligible proportions, a modified semi‐LASER sequence was written (“FOCI‐LASER”, abbreviated as fLASER) using FOCI pulses to permit high RF bandwidth even with the limited RF amplitude characteristic of clinical MRI scanners. A further modification, MQF‐fLASER, includes a selective multiple‐quantum filter to detect lactate and reject lipid signals. The sequences were implemented on a Philips 3 T Achieva TX system. In a solution of brain metabolites fLASER lactate signals were 2.7 times those of PRESS. MQF‐fLASER lactate was 47% of fLASER (the theoretical maximum is 50%) but still larger than PRESS lactate. In oil, the main 1.3 ppm lipid peak was suppressed to less than 1%. Enhanced suppression was possible using increased gradient durations. The minimum detectable lactate concentration was approximately 0.5 mM. Coherence selection gradients needed to be at the magic angle to avoid large water signals derived from intermolecular multiple‐quantum coherences. In pilot patient measurements, lactate peaks were often observed in brain tumours, but not in cervix tumours; lipids were effectively suppressed. In summary, compared with PRESS, the fLASER sequence yields greatly superior sensitivity for direct detection of lactate (and equivalent sensitivity for other metabolites), while the single‐voxel single‐shot MQF‐fLASER sequence surpasses PRESS for lactate detection while eliminating substantial signals from lipids. This sequence will increase the potential for in vivo lactate measurement as a biomarker in targeted anti‐cancer treatments as well as in measurements of tissue hypoxia. Copyright © 2015 John Wiley & Sons, Ltd.