Magnetic Resonance Spectroscopic Imaging Sequence Research Articles

Deuterium MRS of early treatment-induced changes in tumour lactate in vitro.

Elevated production of lactate is a key characteristic of aberrant tumour cell metabolism and can be non-invasively measured as an early marker of tumour response using deuterium (2 H) MRS. Following treatment, changes in the 2 H-labelled lactate signal could identify tumour cell death or impaired metabolic function, which precede morphological changes conventionally used to assess tumour response. In this work, the association between apoptotic cell death, extracellular lactate concentration, and early treatment-induced changes in the 2 H-labelled lactate signal was established in an in vitro tumour model. Experiments were conducted at 7 T on acute myeloid leukaemia (AML) cells, which had been treated with 10 μg/mL of the chemotherapeutic agent cisplatin. At 24 and 48 h after cisplatin treatment the cells were supplied with 20 mM of [6,6'-2 H2 ]glucose and scanned over 2 h using a two-dimensional 2 H MR spectroscopic imaging sequence. The resulting signals from 2 H-labelled glucose, lactate, and water were quantified using a spectral fitting algorithm implemented on the Oxford Spectroscopy Analysis MATLAB toolbox. After scanning, the cells were processed for histological stains (terminal deoxynucleotidyl transferase UTP nick end labelling and haematoxylin and eosin) to assess apoptotic area fraction and cell morphology respectively, while a colorimetric assay was used to measure extracellular lactate concentrations in the supernatant. Significantly lower levels of 2 H-labelled lactate were observed in the 48 h treated cells compared with the untreated and 24 h treated cells, and these changes were significantly correlated with an increase in apoptotic fraction and a decrease in extracellular lactate. By establishing the biological processes associated with treatment-induced changes in the 2 H-labelled lactate signal, these findings suggest that 2 H MRS of lactate may be valuable in evaluating early tumour response.

Achieving high-resolution 1H-MRSI of the human brain with compressed-sensing and low-rank reconstruction at 7 Tesla

Low sensitivity MR techniques such as magnetic resonance spectroscopic imaging (MRSI) greatly benefit from the gain in signal-to-noise provided by ultra-high field MR. High-resolution and whole-slab brain MRSI remains however very challenging due to lengthy acquisition, low signal, lipid contamination and field inhomogeneity. In this study, we propose an acquisition-reconstruction scheme that combines 1H free-induction-decay (FID)-MRSI sequence, short TR acquisition, compressed sensing acceleration and low-rank modeling with total-generalized-variation constraint to achieve metabolite imaging in two and three dimensions at 7 Tesla. The resulting images and volumes reveal highly detailed distributions that are specific to each metabolite and follow the underlying brain anatomy. The MRSI method was validated in a high-resolution phantom containing fine metabolite structures, and in five healthy volunteers. This new application of compressed sensing acceleration paves the way for high-resolution MRSI in clinical setting with acquisition times of 5 min for 2D MRSI at 2.5 mm and of 20 min for 3D MRSI at 3.3 mm isotropic.

A large fixed bed reactor for MRI operando experiments at elevated temperature and pressure.

Recently, in situ studies using nuclear magnetic resonance (NMR) have shown the possibility to monitor local transport phenomena of gas-phase reactions inside opaque structures. Their application to heterogeneously catalyzed reactions remains challenging due to inherent temperature and pressure constraints. In this work, an NMR-compatible reactor was designed, manufactured, and tested, which can endure high temperatures and increased pressure. In temperature and pressure tests, the reactor withstood pressures up to 28 bars at room temperature and temperatures over 400 °C and exhibited only little magnetic shielding. Its applicability was demonstrated by performing the CO2 methanation reaction, which was measured operando for the first time by using a 3D magnetic resonance spectroscopic imaging sequence. The reactor design is described in detail, allowing its easy adaptation for different chemical reactions and other NMR measurements under challenging conditions.

Imaging Neurochemistry and Brain Structure Tracks Clinical Decline and Mechanisms of ALS in Patients.

Background: Oxidative stress and protein aggregation are key mechanisms in amyotrophic lateral sclerosis (ALS) disease. Reduced glutathione (GSH) is the most important intracellular antioxidant that protects neurons from reactive oxygen species. We hypothesized that levels of GSH measured by MR spectroscopic imaging (MRSI) in the motor cortex and corticospinal tract are linked to clinical trajectory of ALS patients.Objectives: Investigate the value of GSH imaging to probe clinical decline of ALS patients in combination with other neurochemical and structural parameters.Methods: Twenty-four ALS patients were imaged at 3 T with an advanced MR protocol. Mapping GSH levels in the brain is challenging, and for this purpose, we used an optimized spectral-edited 3D MRSI sequence with real-time motion and field correction to image glutathione and other brain metabolites. In addition, our imaging protocol included (i) an adiabatic T1ρ sequence to image macromolecular fraction of brain parenchyma, (ii) diffusion tensor imaging (DTI) for white matter tractography, and (iii) high-resolution anatomical imaging.Results: We found GSH in motor cortex (r = −0.431, p = 0.04) and corticospinal tract (r = −0.497, p = 0.016) inversely correlated with time between diagnosis and imaging. N-Acetyl-aspartate (NAA) in motor cortex inversely correlated (r = −0.416, p = 0.049), while mean water diffusivity (r = 0.437, p = 0.033) and T1ρ (r = 0.482, p = 0.019) positively correlated with disease progression measured by imputed change in revised ALS Functional Rating Scale. There is more decrease in the motor cortex than in the white matter for GSH compared to NAA, glutamate, and glutamine.Conclusions: Our study suggests that a panel of biochemical and structural imaging biomarkers defines a brain endophenotype, which can be used to time biological events and clinical progression in ALS patients. Such a quantitative brain endophenotype may stratify ALS patients into more homogeneous groups for therapeutic interventions compared to clinical criteria.

Whole-Slab 3D MR Spectroscopic Imaging of the Human Brain With Spiral-Out-In Sampling at 7T.

Metabolic imaging using proton magnetic resonance spectroscopic imaging (MRSI) has increased the sensitivity and spectral resolution at field strengths of ≥7T. Compared to the conventional Cartesian-based spectroscopic imaging, spiral trajectories enable faster data collection, promising the clinical translation of whole-brain MRSI. Technical considerations at 7T, however, lead to a suboptimal sampling efficiency for the spiral-out (SO) acquisitions, as a significant portion of the trajectory consists of rewinders. To develop and implement a spiral-out-in (SOI) trajectory for sampling of whole-brain MRSI at 7T. We hypothesized that SOI will improve the signal-to-noise ratio (SNR) of metabolite maps due to a more efficient acquisition. Prospective. Five healthy volunteers (28-38 years, three females) and a phantom. Navigated adiabatic spin-echo spiral 3D MRSI at 7T. A 3D stack of SOI trajectories was incorporated into an adiabatic spin-echo MRSI sequence with real-time motion and shim correction. Metabolite spectral fitting, SNR, and Cramér-Rao lower bound (CRLB) were obtained. We compared the signal intensity and CRLB of three metabolites of tNAA, tCr, and tCho. Peak SNR (PSNR), structure similarity index (SSIM), and signal-to-artifact ratio were evaluated on water maps. The nonparametric Mann-Whitney U-test was used for statistical testing. Compared to SO, the SOI trajectory: 1) increased the k-space sampling efficiency by 23%; 2) is less demanding for the gradient hardware, requiring 36% lower Gmax and 26% lower Smax ; 3) increased PSNR of water maps by 4.94 dB (P = 0.0006); 4) resulted in a 29% higher SNR (P = 0.003) and lower CRLB by 26-35% (P = 0.02, tNAA), 35-55% (P = 0.03, tCr), and 22-23% (P = 0.04, tCho), which increased the number of well-fitted voxels (eg, for tCr by 11%, P = 0.03). SOI did not significantly change the signal-to-artifact ratio and SSIM (P = 0.65) compared to SO. SOI provided more efficient MRSI at 7T compared to SO, which improved the data quality and metabolite quantification. 1 TECHNICAL EFFICACY STAGE: 2.

Clinical High-Resolution 3D-MR Spectroscopic Imaging of the Human Brain at 7 T.

Available clinical magnetic resonance spectroscopic imaging (MRSI) sequences are hampered by long scan times, low spatial resolution, strong field inhomogeneities, limited volume coverage, and low signal-to-noise ratio. High-resolution, whole-brain mapping of more metabolites than just N-acetylaspartate, choline, and creatine within clinically attractive scan times is urgently needed for clinical applications. The aim is therefore to develop a free induction decay (FID) MRSI sequence with rapid concentric ring trajectory (CRT) encoding for 7 T and demonstrate its clinical feasibility for mapping the whole cerebrum of healthy volunteers and patients. Institutional review board approval and written informed consent were obtained. Time-efficient, 3-dimensional encoding of an ellipsoidal k-space by in-plane CRT and through-plane phase encoding was integrated into an FID-MRSI sequence. To reduce scan times further, repetition times were shortened, and variable temporal interleaves were applied. Measurements with different matrix sizes were performed to validate the CRT encoding in a resolution phantom. One multiple sclerosis patient, 1 glioma patient, and 6 healthy volunteers were prospectively measured. For the healthy volunteers, brain segmentation was performed to quantify median metabolic ratios, Cramér-Rao lower bounds (CRLBs), signal-to-noise ratios, linewidths, and brain coverage among all measured matrix sizes ranging from a 32 × 32 × 31 matrix with 6.9 × 6.9 × 4.2 mm nominal voxel size acquired in ~3 minutes to an 80 × 80 × 47 matrix with 2.7 × 2.7 × 2.7 mm nominal voxel size in ~15 minutes for different brain regions. Phantom structures with diameters down to 3 to 4 mm were visible. In vivo MRSI provided high spectral quality (median signal-to-noise ratios, >6.3 and linewidths, <0.082 ppm) and fitting quality. Cramér-Rao lower bounds were ranging from less than 22% for glutamine (highest CRLB in subcortical gray matter) to less than 9.5% for N-acetylaspartate for the 80 × 80 × 47 matrix (highest CRLB in the temporal lobe). This enabled reliable mapping of up to 8 metabolites (N-acetylaspartate, N-acetylaspartyl glutamate, total creatine, glutamine, glutamate, total choline, myo-inositol, glycine) and macromolecules for all resolutions. Coverage of the whole cerebrum allowed visualization of the full extent of diffuse and local multiple sclerosis-related neurochemical changes (eg, up to 100% increased myo-inositol). Three-dimensional brain tumor metabolic maps provided valuable information beyond that of single-slice MRSI, with up to 200% higher choline, up to 100% increased glutamine, and increased glycine in tumor tissue. Seven Tesla FID-MRSI with time-efficient CRT readouts offers clinically attractive acquisition protocols tailored either for speed or for the investigation of small pathologic details and low-abundant metabolites. This can complement clinical MR studies of various brain disorders. Significant metabolic anomalies were demonstrated in a multiple sclerosis and a glioma patient for myo-inositol, glutamine, total choline, glycine, and N-acetylaspartate concentrations.

Over-discretized SENSE reconstruction and B0 correction for accelerated non-lipid-suppressed 1 H FID MRSI of the human brain at 9.4 T.

The aim of this work was to use post-processing methods to improve the data quality of metabolite maps acquired on the human brain at 9.4T with accelerated acquisition schemes. This was accomplished by combining an improved sensitivity encoding (SENSE) reconstruction with a B0 correction of spatially over-discretized magnetic resonance spectroscopic imaging (MRSI) data. Since MRSI scans suffer from long scan duration, investigating different acceleration techniques has recently been the focus of several studies. Due to strong B0 inhomogeneity and strict specific absorption rate (SAR) limitations at ultra-high fields, the use of a low-SAR sequence combined with an acceleration technique that is compatible with dynamic B0 shim updating is preferable. Hence, in this study, a non-lipid-suppressed ultra-short TE and TR1 H free induction decay MRSI sequence is combined with an in-plane SENSE acceleration technique to obtain high-resolution metabolite maps in a clinically feasible scan time. One of the major issues in applying parallel imaging techniques to non-lipid-suppressed MRSI is the presence of strong lipid aliasing artifacts, which if not thoroughly resolved will hinder the accurate quantification of the metabolites of interest. To achieve a more robust reconstruction, an over-discretized SENSE reconstruction (with direct control over the shape of the spatial response function) was combined with an over-discretized B0 correction. This method is compared with conventional SENSE reconstruction for seven acceleration schemes on four healthy volunteers. The over-discretized method consistently outperformed conventional SENSE, resulting in an average of 23±1.2% higher signal-to-noise ratio and 8±2.9% less error in the fitting of the N-acetylaspartate signal over a whole brain slice. The highest achievable acceleration factor with the proposed technique was determined to be 4. Finally, using the over-discretized method, high-resolution (97μL nominal voxel size) metabolite maps can be acquired in 3.75min at 9.4T. This enables the acquisition of high-resolution metabolite maps with more spatial coverage at ultra-high fields.

MultiNet PyGRAPPA: Multiple neural networks for reconstructing variable density GRAPPA (a 1H FID MRSI study)

Magnetic resonance spectroscopic imaging (MRSI) is a powerful tool for mapping metabolite levels across the brain, however, it generally suffers from long scan times. This severely hinders its application in clinical settings. Additionally, the presence of nuisance signals (e.g. the subcutaneous lipid signals close to the skull region in brain metabolite mapping) makes it challenging to apply conventional acceleration techniques to shorten the scan times. The goal of this work is, therefore, to increase the overall applicability of high resolution metabolite mapping using 1H MRSI by introducing a novel GRAPPA acceleration acquisition/reconstruction technique. An improved reconstruction method (MultiNet) is introduced that uses machine learning, specifically neural networks, to reconstruct accelerated data. The method is further modified to use more neural networks with nonlinear hidden layers and is then combined with a variable density undersampling scheme (MultiNet PyGRAPPA) to enable higher in-plane acceleration factors of R = 5.6 and R = 7 for a non-lipid suppressed ultra-short TR and TE 1H FID MRSI sequence. The proposed method is evaluated for high resolution metabolite mapping of the human brain at 9.4T. The results show that the proposed method is superior to conventional GRAPPA: there is no significant residual lipid aliasing artifact in the images when the proposed MultiNet method is used. Furthermore, the MultiNet PyGRAPPA acquisition/reconstruction method with R = 5.6 results in reproducible high resolution metabolite maps (with an in-plane matrix size of 64 × 64) that can be acquired in 2.8 min on 9.4T. In conclusion, using multiple neural networks to predict the missing points in GRAPPA reconstruction results in a more reliable data recovery while keeping the noise levels under control. Combining this high fidelity reconstruction with variable density undersampling (MultiNet PyGRAPPA) enables higher in-plane acceleration factors even for non-lipid suppressed 1H FID MRSI, without introducing any structured aliasing artifact in the image.

Non-water-suppressed 1 H FID-MRSI at 3T and 9.4T.

This study investigates metabolite concentrations using metabolite-cycled 1 H free induction decay (FID) magnetic resonance spectroscopic imaging (MRSI) at ultra-high fields. A non-lipid-suppressed and slice-selective ultra-short echo time (TE) 1 H FID MRSI sequence was combined with a low-specific absorption rate (SAR) asymmetric inversion adiabatic pulse to enable non-water-suppressed metabolite mapping using metabolite-cycling at 9.4T. The results were compared to a water-suppressed FID MRSI sequence, and the same study was performed at 3T for comparison. The scan times for performing single-slice metabolite mapping with a nominal voxel size of 0.4 mL were 14 and 17.5 min on 3T and 9.4T, respectively. The low-SAR asymmetric inversion adiabatic pulse enabled reliable non-water-suppressed metabolite mapping using metabolite cycling at both 3T and 9.4T. The spectra and maps showed good agreement with the water-suppressed FID MRSI ones at both field strengths. A quantitative analysis of metabolite ratios with respect to N-acetyl aspartate (NAA) was performed. The difference in Cre/NAA was statistically significant, ∼0.1 higher for the non-water-suppressed case than for water suppression (from 0.73 to 0.64 at 3T and from 0.69 to 0.59 at 9.4T). The difference is likely because of chemical exchange effects of the water suppression pulses. Small differences in mI/NAA were also statistically significant, however, are they are less reliable because the metabolite peaks are close to the water peak that may be affected by the water suppression pulses or metabolite-cycling inversion pulse. We showed the first implementation of non-water-suppressed metabolite-cycled 1 H FID MRSI at ultra-high fields. An increase in Cre/NAA was seen for the metabolite-cycled case. The same methodology was further applied at 3T and similar results were observed. Magn Reson Med 80:442-451, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Volumetric relationship between 2-hydroxyglutarate and FLAIR hyperintensity has potential implications for radiotherapy planning of mutant IDH glioma patients.

Gliomas with mutant isocitrate dehydrogenase (IDH) produce high levels of 2-hydroxyglutarate (2HG) that can be quantitatively measured by 3D magnetic resonance spectroscopic imaging (MRSI). Current glioma MRI primarily relies upon fluid-attenuated inversion recovery (FLAIR) hyperintensity for treatment planning, although this lacks specificity for tumor cells. Here, we investigated the relationship between 2HG and FLAIR in mutant IDH glioma patients to determine whether 2HG mapping is valuable for radiotherapy planning. Seventeen patients with mutant IDH1 gliomas were imaged by 3 T MRI. A 3D MRSI sequence was employed to specifically image 2HG. FLAIR imaging was performed using standard clinical protocol. Regions of interest (ROIs) were determined for FLAIR and optimally thresholded 2HG hyperintensities. The overlap, displacement, and volumes of 2HG and FLAIR ROIs were calculated. In 8 of 17 (47%) patients, the 2HG volume was larger than FLAIR volume. Across the entire cohort, the mean volume of 2HG was 35.3 cc (range, 5.3-92.7 cc), while the mean volume of FLAIR was 35.8 cc (range, 6.3-140.8 cc). FLAIR and 2HG ROIs had mean overlap of 0.28 (Dice coefficients range, 0.03-0.57) and mean displacement of 12.2 mm (range, 3.2-23.5 mm) between their centers of mass. Our results indicate that for a substantial number of patients, the 2HG volumetric assessment of tumor burden is more extensive than FLAIR volume. In addition, there is only partial overlap and asymmetric displacement between the centers of FLAIR and 2HG ROIs. These results may have important implications for radiotherapy planning of IDH mutant glioma.

NIMG-02VOLUMETRIC RELATIONSHIP BETWEEN 2-HYDROXYGLUTARATE AND FLAIR HYPERINTENSITY IN PATIENTS WITH MUTANT IDH1 GLIOMA

BACKGROUND: The hallmark metabolic alteration of mutant IDH gliomas is the production of 2-hydroxyglutarate (2HG) [1], and high levels of this metabolite play a central role in downstream effects of gene mutation [2]. Hence, 2HG may be an ideal biomarker for both diagnosing IDH mutations and monitoring response to treatment. On the other hand tumor extension assessed by MRI FLAIR hyperintensity is the most used neuroimaging method for glioma treatment planning and monitoring. Here, we investigated the relationship between 2HG volume and FLAIR hyperintensity volume in a cohort of IDH mutant glioma patients. METHODS: Twenty-two patients with mutant IDH1 gliomas were imaged by MRI at 3T. A 3D MR spectroscopic imaging sequence [3] was employed to specifically image 2HG edited signal. FLAIR imaging was performed using standard clinical protocols. The overlap and displacement of 2HG and FLAIR volumes were calculated and compared. RESULTS: In 14 patients the 2HG volume was larger than the FLAIR volume. Across the entire cohort, the median volume of 2HG was 39.2 cc (95% CI = 11.7-83.1 cc) while the median volume of FLAIR was 25.7 cc (95% CI = 7.2-52.5 cc). The median displacement between the centers of mass of the 2HG and FLAIR volumes was 11.9 mm (95% CI = 6.2-22.2 mm). CONCLUSIONS: Our results indicate that for most patients the 2HG volumetric assessment of tumor burden is more extensive than the FLAIR volume. In addition, there is frequently an asymmetric displacement between the center of tumor volume probed by FLAIR and the center of 2HG volume. These results may have important implications for treatment planning and monitoring.

Polyphenon E, non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: Phase I single group and phase II randomized placebo-controlled studies

ObjectivesPhase I (PhI): assess the safety of Polyphenon E in people with multiple sclerosis (MS) and determine the futility of Polyphenon E as a neuroprotective agent. Correlate plasma levels of EGCG with neuroprotective effects.Phase II (PhII): Further assess safety and confirm the neuroprotective effects of Polyphenon E. DesignPhI: single group futility study. PhII: parallel group randomized double-blind placebo-controlled study. ParticipantsRecruitment area (both studies): LSU MS Center, New Orleans, LA and general public from surrounding areas.Inclusion criteria (both studies): 1) MS per 2005 McDonald criteria; 2) relapsing remitting or secondary progressive MS; 3) stable for six months prior to enrollment on either no therapy or glatiramer acetate (GA) for the PhI study and on either on GA or Interferon β for the PhII study.Exclusion criteria (both studies): 1) complete bone marrow ablation or alentuzumab use at any time; 2) mitoxantrone, cyclophosphamide, natalizumab or fingolimod use in the prior nine months; 3) liver problems or significant medical problems. InterventionsPhI: Polyphenon E, a green tea extract containing 50% of the antioxidant Epigallocatechin-gallate (EGCG), two capsules twice daily (200mg of EGCG per capsule; total daily dose 800mg) for six months.PhII: Polyphenon E or matching placebo capsules, same dose for one year. Only the research pharmacist knew treatment assignment and she randomized participants (one-to-one, stratified by GA or Interferon β, blocks of 4 or 6). Outcome evaluators did not discuss side effects with participants. Outcome measuresPhI: 1) adverse events (AE); 2) futility: decrease in N-acetyl aspartate (NAA) from baseline to six months of 10% or more; 3) association between EGCG plasma levels and change in NAA.PhII: 1) AEs; 2) difference in the rate of change of NAA-levels over twelve months.We measured NAA using a point resolved magnetic resonance spectroscopic imaging sequence (TE30/TR2000) on a 10cm×10cm×1cm volume of interest (VOI) located just superior to the lateral ventricles. The field of view was 16×16 resulting in 1cm3 voxels. We quantified NAA and creatine/phosphocreatine (Cr) levels using LCModel for post-processing. ResultsPhI: Ten participants enrolled and completed all assessments with no serious AEs. One discontinued therapy due to grade (G) I abnormal liver function tests (LFTs). We included all participants in the analysis. NAA adjusted for creatine increased by 10% [95% CI(3.4%,16.2%), p<0.01] rejecting the futility endpoint.PhII: Thirteen participants enrolled and twelve started treatment. The DSMB stopped the study because 5/7 participants on Polyphenon E had abnormal LFTs (G I, and 1G III). Median time to onset of abnormal LFTs was 20weeks [Inter-Quartile Range (IQR) (10,23)]. Only two participants completed the six-month visit, so we could not analyze the NAA levels.PhI participants took capsules from lot 189I1107 while 6/7 PhII participants took capsules from a new lot (L0206306). Both lots had similar levels of EGCG but differed in the levels of minor catechins. There were no significant differences between the lots on participants' median free EGCG plasma levels at either 3h or 8h as well as conjugated EGCG levels at 3h (all p>0.4, Wilcoxon exact test).Free EGCG levels at 8h correlated with changes in NAA adjusted by water content. A 1ng/ml higher EGCG plasma concentration correlated with a 0.9% increase in NAA[95% CI(0.5%,1.4%), visit*level interaction F=14.4, p<0.001]. However, EGCG plasma concentrations did not correlate with NAA adjusted by creatine (1ng/ml higher EGCG was associated with 0.02%,[95% CI(−0.27%,0.3%) change in NAA, p>0.5]). There was a trend towards an increase in creatine levels (referenced to water content) from baseline to exit (1 5% increase, [95% CI(−6%,17%), p=0.4]). The free EGCG levels at 8hours correlated significantly with change in creatine levels (1ng/ml higher EGCG level at 8h was associated with a 1.1% increase in creatine [95% CI(0.6%,1.6%)]). Thus it is possible that the discrepancy between the correlation of the EGCG 8h levels with NAA changes referenced to water and the 8h EGCG levels with NAA changes referenced to creatine was due to a change in creatine among the subjects with higher EGCG levels.Conjugated 3h and 8h levels and free 3h levels did not correlate with NAA changes (all p >0.5). Conclusions/classification of evidenceClass III evidence: Polyphenon E at a dose of 400mg of EGCG twice a day is not futile at increasing brain NAA levels. Class I evidence: some lots of Polyphenon E have a high risk of hepatotoxicity. FundingNational Center for Complementary and Alternative Medicine K23AT004433, National Multiple Sclerosis Society RG4816-A-1 and National Institute of General Medical Sciences 1 U54 GM104940. Mitsui Norin provided Polyphenon E and placebo and their representative reviewed the manuscript prior to publication. Mitsui Norin was not involved in other aspects of the study. The decision to submit the manuscript remained with the investigators. RegistrationNCT00836719 and NCT01451723NCT00836719NCT01451723.

Improved volume selective (1) H MR spectroscopic imaging of the prostate with gradient offset independent adiabaticity pulses at 3 tesla.

Volume selection in (1) H MR spectroscopic imaging (MRSI) of the prostate is commonly performed with low-bandwidth refocusing pulses. However, their large chemical shift displacement error (CSDE) causes lipid signal contamination in the spectral range of interest. Application of high-bandwidth adiabatic pulses is limited by radiofrequency (RF) power deposition. In this study, we aimed to provide an MRSI sequence that overcomes these limitations. Measurements were performed at 3 T with an endorectal receive coil. A semi-LASER sequence was equipped with low RF power demanding gradient-modulated offset-independent adiabaticity (GOIA) refocusing pulses with WURST(16,4) modulation, with a 10 kHz bandwidth. Simulations and phantom studies verified that the GOIA pulses select slices with a flat top and sharp edges and minimal CSDE. The sequence timing was tuned to an optimal citrate signal shape at an echo time of 88 ms. Patient studies (n = 10) demonstrated that high quality spectra with reduced lipid artifacts can be obtained from the whole prostate. Compared with PRESS acquisition at 145 ms the signal-to-noise ratio (SNR) of citrate is increased up to 2.6 and choline up to 1.3. An MRSI sequence of the prostate is presented with minimized spectral lipid contamination and improved SNR, to facilitate routine clinical acquisition of metabolic data.

O8.02 * MONITORING OF TREATMENT RESPONSE IN IDH-MUTANT GLIOMAS WITH IN-VIVO 3D MAGNETIC RESONANCE SPECTROSCOPY

The hallmark metabolic alteration in mutant IDH gliomas is the production of R-2-hydroxyglutarate (2HG). 2HG can be measured in-vivo by magnetic resonance spectroscopy of patients, representing an ideal biomarker for IDH mutant gliomas. 3D mapping of 2HG and other metabolites is important to capture tumor heterogeneity and for longitudinal studies where changes in size and shape of tumors during treatment makes positioning of a single voxel or a single slice difficult to appropriately match over time. A 3D 2HG map provides selectivity and specificity for the spatial extent of tumor in all directions, and can thereby reduce variance in longitudinal MRS studies. Here we present results obtained with a 3D MR spectroscopic imaging (MRSI) that edits 2HG with high efficiency. Measurements were performed in 20 mutant IDH1 glioma patients who were consented under an IRB-approval. A robust and efficient 3D MRSI sequence for 2HG imaging was newly developed. Spectra were fitted with LCModel software and metabolic maps were obtained from the fitted signal. All experiments were performed on a whole-body 3T MR scanner (Tim Trio with VB17 software, Siemens, Erlangen), using body coil for transmit and a 32-channel head coil for receive. Prior to receiving adjuvant therapy, detectable levels of 2HG were measured in all patients that had not undergone gross total resection. 3D metabolic maps were obtained for 2HG and several important metabolites for assessing brain tumors, such as total choline (Cho), N-acetyl-aspartate (NAA), glutamate and glutamine (Glx), and lactate (Lac). All metabolites were measured simultaneously within a single acquisition, 2HG and Glx maps were obtained from the difference spectra, while the other metabolites were obtained from the off-resonance spectra. In 9 patients who have undergone both pre- and post-treatment scans, 4 demonstrated marked decrease in the level of 2HG at the first time point after completion of adjuvant therapy. The remainder demonstrated partial reduction of 2HG, with no patients demonstrating increased 2HG levels. We demonstrate 3D imaging of 2HG is clinically feasible in patients with IDH1 mutated gliomas. Further validation and development is underway for longitudinal quantification of 2HG levels during treatment of IDH mutant gliomas. Acknowledgements: Burroughs-Wellcome Career Award, NCI/NIH 1K22CA178269-01 and 1P50CA165962-01, Harvard-MIT Koch Institute Bridge Project.

Sherry Apple Resident Travel Scholarship 194 Assessment of Treatment Response in Isocitrate Dehydrogenase-Mutant Gliomas by Quantification of 2-Hydroxyglutarate With In Vivo 3-Dimensional Magnetic Resonance Spectroscopy

INTRODUCTION: Mutations in isocitrate dehydrogenase (IDH)—present in a distinct subset of human gliomas characterized by younger age and improved prognosis- cause a marked elevation of the metabolite 2-hydroxyglutarate (2HG) [1,2]. This excess production of 2HG represents an ideal biomarker for these gliomas and can be measured with in-vivo magnetic resonance spectroscopy [3]. We previously demonstrated that 2HG can be detected reliably in IDH-mutant gliomas with 3-dimensional (3-D) spectral-edited magnetic resonance spectroscopic imaging (MRSI) [4]. Here, we aimed to show that 3-D metabolomic mapping of 2HG can be utilized to evaluate treatment response in IDH-mutant gliomas. METHODS: 3-D metabolomic maps were measured in 18 IDH-mutant glioma patients prior to adjuvant radiation or chemotherapy with a robust and efficient 3-D MRSI sequence. All measurements were performed with a whole-body 3T MR scanner (Siemens Tim Trio with VB17 software). Spectra were fitted with LCModel software. All patients with detectable levels of 2HG in the baseline scan were subjected to a post-treatment 3-D MRSI to measure changes of 2HG-levels after adjuvant therapy. RESULTS: Sixteen of 18 patients (88.9%) demonstrated detectable levels of 2HG on their baseline scan. Matched pre- and post-treatment 3-D metabolomic maps indicated varying response to treatment: 4 patients demonstrated significant reduction of 2HG intensities after radiation therapy (Fig 1), while the remaining patients demonstrated mixed response (partial reduction of 2HG) to adjuvant treatment. CONCLUSION: Assessment of treatment response is feasible with in-vivo 3-D MRSI of 2HG in IDH-mutant glioma patients. Significant reduction of 2HG-levels in patients after completion of radiotherapy is suggestive of positive response to treatment. Further validation and longitudinal quantification of 2HG in IDH-mutant gliomas with 3-D MRSI is needed to evaluate the ability of the presented approach to reliably determine treatment response. Nevertheless, this non-invasive method yields great potential for clinical applicability and could tremendously improve the management of IDH-mutant glioma patients.

Short-echo three-dimensional H-1 MR spectroscopic imaging of patients with glioma at 7 Tesla for characterization of differences in metabolite levels.

The purpose of this study was to evaluate the feasibility of using a short echo time, three-dimensional H-1 magnetic resonance spectroscopic imaging (MRSI) sequence at 7 Tesla (T) to assess the metabolic signature of lesions for patients with glioma. Twenty-nine patients with glioma were studied. MRSI data were obtained using CHESS water suppression, spectrally selective adiabatic inversion-recovery pulses and automatically prescribed outer-volume-suppression for lipid suppression, and spin echo slice selection (echo time = 30 ms). An interleaved flyback echo-planar trajectory was applied to shorten the total acquisition time (∼10 min). Relative metabolite ratios were estimated in tumor and in normal-appearing white and gray matter (NAWM, GM). Levels of glutamine, myo-inositol, glycine, and glutathione relative to total creatine (tCr) were significantly increased in the T2 lesions for all tumor grades compared with those in the NAWM (P < 0.05), while N-acetyl aspartate to tCr were significantly decreased (P < 0.05). In grade 2 gliomas, level of total choline-containing-compounds to tCr was significantly increased (P = 0.0137), while glutamate to tCr was significantly reduced (P = 0.0012). The improved sensitivity of MRSI and the increased number of metabolites that can be evaluated using 7T MR scanners is of interest for evaluating patients with glioma. This study has successfully demonstrated the application of a short-echo spin-echo MRSI sequence to detect characteristic differences in regions of tumor versus normal appearing brain.

31P magnetic resonance spectroscopy of the breast and the influence of the menstrual cycle

Phosphorus metabolite ratios are potential biomarkers in breast cancer diagnosis and treatment monitoring. Our purpose was to investigate the metabolite ratios phosphomonoester to phosphodiester, phosphoethanolamine (PE) to glycerophosphoethanolamine (GPE), and phosphocholine (PC) to glycerophosphocholine (GPC) in glandular breast tissue, and the potential effect of the menstrual cycle, using (31)P magnetic resonance spectroscopy (MRS) at 7T. Seven women with regular menstrual cycles each underwent four examinations using a 3D (31)P multi-echo magnetic resonance spectroscopic imaging sequence. Peak integrals were assessed using IDL and JMRUI software. First, T2 relaxation times were calculated using multi-echo data pooled across subjects and time points. Subsequent, metabolite ratios were calculated for each phase of the menstrual cycle using the calculated T2 values to account for when combining the free induction decay and all five echoes. The metabolite ratios were calculated both on group level and individually. T2 decay fits resulted in a T2 relaxation time for PE of 154 ms (95 % CI 144-164), for PC of 173 ms (95 % CI 148-205), for Pi of 188 ms (95 % CI 182-193), for GPE of 48 ms (95 % CI 44-53), and for GPC of 23 ms (95 % CI 21-26). The metabolite ratios analyzed on group level showed negligible variation throughout the menstrual cycle. Individual results did show an apparent intra-individual variation; however, not significant due to the measurements' uncertainty. To conclude, phospholipids in glandular tissue as measured with (31)P MRS at 7 T are not significantly affected by the menstrual cycle.

Real-time motion- and B0-correction for LASER-localized spiral-accelerated 3D-MRSI of the brain at 3 T

The full potential of magnetic resonance spectroscopic imaging (MRSI) is often limited by localization artifacts, motion-related artifacts, scanner instabilities, and long measurement times.Localized adiabatic selective refocusing (LASER) provides accurate B1-insensitive spatial excitation even at high magnetic fields. Spiral encoding accelerates MRSI acquisition, and thus, enables 3D-coverage without compromising spatial resolution. Real-time position- and shim/frequency-tracking using MR navigators correct motion- and scanner instability-related artifacts. Each of these three advanced MRI techniques provides superior MRSI data compared to commonly used methods.In this work, we integrated in a single pulse sequence these three promising approaches. Real-time correction of motion, shim, and frequency-drifts using volumetric dual-contrast echo planar imaging-based navigators were implemented in an MRSI sequence that uses low-power gradient modulated short-echo time LASER localization and time efficient spiral readouts, in order to provide fast and robust 3D-MRSI in the human brain at 3T.The proposed sequence was demonstrated to be insensitive to motion- and scanner drift-related degradations of MRSI data in both phantoms and volunteers. Motion and scanner drift artifacts were eliminated and excellent spectral quality was recovered in the presence of strong movement.Our results confirm the expected benefits of combining a spiral 3D-LASER-MRSI sequence with real-time correction. The new sequence provides accurate, fast, and robust 3D metabolic imaging of the human brain at 3T. This will further facilitate the use of 3D-MRSI for neuroscience and clinical applications.

Sparse spectral deconvolution algorithm for noncartesian MR spectroscopic imaging

To minimize line shape distortions and spectral leakage artifacts in MR spectroscopic imaging (MRSI). A spatially and spectrally regularized non-Cartesian MRSI algorithm that uses the line shape distortion priors, estimated from water reference data, to deconvolve the spectra is introduced. Sparse spectral regularization is used to minimize noise amplification associated with deconvolution. A spiral MRSI sequence that heavily oversamples the central k-space regions is used to acquire the MRSI data. The spatial regularization term uses the spatial supports of brain and extracranial fat regions to recover the metabolite spectra and nuisance signals at two different resolutions. Specifically, the nuisance signals are recovered at the maximum resolution to minimize spectral leakage, while the point spread functions of metabolites are controlled to obtain acceptable signal-to-noise ratio. The comparisons of the algorithm against Tikhonov regularized reconstructions demonstrates considerably reduced line-shape distortions and improved metabolite maps. The proposed sparsity constrained spectral deconvolution scheme is effective in minimizing the line-shape distortions. The dual resolution reconstruction scheme is capable of minimizing spectral leakage artifacts.

Phase-difference and spectroscopic imaging for monitoring of human brain temperature during cooling

Decrease of the human brain temperature was induced by intranasal cooling. The main purpose of this study was to compare the two magnetic resonance methods for monitoring brain temperature changes during cooling: phase-difference and magnetic resonance spectroscopic imaging (MRSI) with high spatial resolution. Ten healthy volunteers were measured. Selective brain cooling was performed through nasal cavities using saline-cooled balloon catheters. MRSI was based on a radiofrequency spoiled gradient echo sequence. The spectral information was encoded by incrementing the echo time of the subsequent eight image records. Reconstructed voxel size was 1×1×5 mm3. Relative brain temperature was computed from the positions of water spectral lines. Phase maps were obtained from the first image record of the MRSI sequence. Mild hypothermia was achieved in 15–20 min. Mean brain temperature reduction varied in the interval <−3.0; −0.6>°C and <−2.7; −0.7>°C as measured by the MRSI and phase-difference methods, respectively. Very good correlation was found in all locations between the temperatures measured by both techniques except in the frontal lobe. Measurements in the transversal slices were more robust to the movement artifacts than those in the sagittal planes. Good agreement was found between the MRSI and phase-difference techniques.