Mutations of the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are commonly found in primary brain cancers. We previously reported that a novel enzymatic activity of these mutations results in the production of the putative oncometabolite, R(–)-2-hydroxyglutarate (2-HG). Here we investigated the ability of magnetic resonance spectroscopy (MRS) to detect 2-HG production in order to non-invasively identify patients with IDH1 mutant brain tumors. Patients with intrinsic glial brain tumors (n = 27) underwent structural and spectroscopic magnetic resonance imaging prior to surgery. 2-HG levels from MRS data were quantified using LC-Model software, based upon a simulated spectrum obtained from a GAMMA library added to the existing prior knowledge database. The resected tumors were then analyzed for IDH1 mutational status by genomic DNA sequencing, Ki-67 proliferation index by immunohistochemistry, and concentrations of 2-HG and other metabolites by liquid chromatography–mass spectrometry (LC–MS). MRS detected elevated 2-HG levels in gliomas with IDH1 mutations compared to those with wild-type IDH1 (P = 0.003). The 2-HG levels measured in vivo with MRS were significantly correlated with those measured ex vivo from the corresponding tumor samples using LC–MS (r2 = 0.56; P = 0.0001). Compared with wild-type tumors, those with IDH1 mutations had elevated choline (P = 0.01) and decreased glutathione (P = 0.03) on MRS. Among the IDH1 mutated gliomas, quantitative 2-HG values were correlated with the Ki-67 proliferation index of the tumors (r2 = 0.59; P = 0.026). In conclusion, water-suppressed proton (1H) MRS provides a non-invasive measure of 2-HG in gliomas, and may serve as a potential biomarker for patients with IDH1 mutant brain tumors. In addition to 2-HG, alterations in several other metabolites measured by MRS correlate with IDH1 mutation status.

CD19-directed immunotherapies are clinically effective for treating B-cell malignancies but also cause a high incidence of neurotoxicity. A subset of patients treated with chimeric antigen receptor (CAR) T cells or bispecific T-cell engager (BiTE) antibodies display severe neurotoxicity, including fatal cerebral edema associated with T cell infiltration into the brain. Here we report that mural cells, which surround the endothelium and are critical for blood-brain-barrier integrity, express CD19. We identify CD19 expression in brain mural cells using single-cell RNA-seq data and confirm perivascular staining at the protein level. CD19 expression in the brain begins early in development alongside the emergence of mural cell lineages and persists throughout adulthood across brain regions. Mouse mural cells demonstrate lower levels of Cd19 expression, suggesting limitations in preclinical animal models of neurotoxicity. These data suggest an on-target mechanism for neurotoxicity in CD19-directed therapies and highlight the utility of human singlecell atlases for designing immunotherapies.

The quantitative mapping of the in vivo dynamics of cellular metabolism via non-invasive imaging contributes to the understanding of the initiation and progression of diseases associated with dysregulated metabolic processes. Current methods for imaging cellular metabolism are limited by low sensitivities, by costs, or by the use of specialized hardware. Here, we introduce a method that captures the turnover of cellular metabolites by quantifying signal reductions in proton magnetic resonance spectroscopy (MRS) resulting from the replacement of 1 H with 2 H. The method, which we termed quantitative exchanged-label turnover MRS, only requires deuterium-labelled glucose and standard MRI scanners, and with a single acquisition provides steady-state information and metabolic rates for several metabolites. We used the method to monitor glutamate, glutamine, γaminobutyric acid and lactate in the brains of normal and glioma-bearing rats following the administration of 2 H 2-labelled glucose and 2 H 3-labelled acetate. Quantitative exchanged-label turnover MRS should broaden the applications of routine 1 H MRS. Cellular metabolism is maintained by a network of biochemical reactions essential for normal tissue function 1. These reactions form larger metabolic pathways which exist under tight regulatory control to help balance metabolic fluctuations experienced by the cell. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

An alternative to the standard echo-planar spectroscopic imaging technique is presented, spectroscopic imaging using concentrically circular echo-planar trajectories (SI-CONCEPT). In contrast to the conventional chemical shift imaging data, the sampled data from each set of concentric rings were regridded into Cartesian space. Usage of concentric k-space trajectories has the advantage of requiring significantly reduced slew rates than echo-planar spectroscopic imaging, allowing for the collection of higher spectral bandwidths and opening the door for high-bandwidth echo-planar styled spectroscopic imaging at higher magnetic fields. Before two-dimensional spatial and one-dimensional spectral encoding, the volume of interest was localized using the standard point-resolved spectroscopy sequence. The feasibility of using concentric k-space trajectories is demonstrated, and the spatial profiles and representative spectra are compared with the standard echo-planar spectroscopic imaging technique in a gray matter phantom containing metabolites at physiological concentrations and healthy human brain in vivo. The symmetric nature of the concentric circles also reduces the number of required excitations for a given resolution by a factor of two. Possible artifacts and limitations are discussed. Magn Reson Med 67:1515-1522, 2012.

The application of compressed sensing is demonstrated in a recently implemented four-dimensional echo-planar based J-resolved spectroscopic imaging sequence combining two spatial and two spectral dimensions. The echo-planar readout simultaneously acquires one spectral and one spatial dimension. Therefore, the compressed sensing undersampling is performed along the indirectly acquired spatial and spectral dimensions, and the reconstruction is performed using the split Bregman algorithm, an efficient TV-minimization solver. The four-dimensional echo-planar-based J-resolved spectroscopic imaging data acquired in a prostate phantom containing metabolites at physiological concentrations are accurately reconstructed with as little as 20% of the original data. Experimental data acquired in six healthy prostates using the external body matrix "receive" coil on a 3T magnetic resonance imaging scanner are reconstructed with acquisitions using only 25% of the Nyquist-Shannon required amount of data, indicating the potential for a 4-fold acceleration factor in vivo, bringing the Magnetic resonance spectroscopy and magnetic resonance spectroscopic imaging have evolved as powerful research tools for their ability to study the underlying biochemistry of tissue (1) and can greatly complement standard magnetic resonance imaging (MRI). One of the major drawbacks of one-dimensional (1D) spectroscopy is the inherent overcrowding of spectra due to overlapping peaks. This limitation can be alleviated with the addition of more spectral dimensions by which resonances can be spread apart, increasing the spectral dispersion (2). Different twodimensional (2D) spectroscopic techniques have been successfully used in vivo such as J -resolved spectroscopy (3) and localized correlated spectroscopy (4). However, these were originally limited to single voxel acquisitions. To increase the spatial coverage, the localized correlated spectroscopy and J-resolved spectroscopy sequences were recently modified with an echo-planar spectroscopic imaging (EPSI) (5-7) readout to yield 2D spectra from multiple voxels in a single experiment, called echo-planar correlated spectroscopic imaging (8) and echo-planar J -resolved spectroscopic imaging (EP-JRESI) (9), respectively. Despite the rapid acquisition of EPSI, such four-dimensional (4D) scans still require a considerable amount of scan time (∼20 40 mins/average depending on the desired spatial/spectral resolution), severely limiting clinical applicability.In recent years, the field of compressed sensing (CS) has garnered much interest in the imaging community for its ability to reconstruct images from datasets whose sampling does not meet the Nyquist-Shannon criterion (10,11). CS operates under the assumption that the fully sampled data is sparse within some transform domain. The CS reconstruction attempts to enforce this assumption in that particular transform domain, while maintaining fidelity with the acquired measurements. Since the application of CS in MRI was demonstrated (12,13), there has been a tr...

No abstract

Purpose: To implement an accelerated five-dimensional (5D) echo-planar J-resolved spectroscopic imaging sequence combining 3 spatial and 2 spectral encoding dimensions and to apply the sequence in human brain. Methods: An echo planar readout was used to acquire a single spatial and a single spectral dimension during one readout. Nonuniform sampling was applied to the two phase-encoded spatial directions and the indirect spectral dimension. Nonlinear reconstruction was used to minimize the ' 1 -norm or the total variation and included a spectral mask to enhance sparsity. Retrospective reconstructions at multiple undersamplings were performed in phantom. Ten healthy volunteers were scanned with 8Â undersampling and compared to a fully sampled single slice scan. Results: Retrospective reconstruction of fully sampled phantom data showed excellent quality at 4Â, 8Â, 12Â, and 16Â undersampling using either reconstruction method. Reconstruction of prospectively acquired in vivo scans with 8Â undersampling showed excellent quality in the occipitoparietal lobes and good quality in the frontal lobe, consistent with the fully sampled single slice scan. Conclusion: By utilizing nonuniform sampling with nonlinear reconstruction, 2D J-resolved spectra can be acquired over a 3D spatial volume with a total scan time of 20 min, which is reasonable for in vivo studies. Magn Reson Med 000:000-000, 2015. V C 2015 Wiley Periodicals, Inc.

Purpose: Reliable monitoring of tissue nicotinamide adenine dinucleotide (NAD + ) concentration may provide insights on its roles in normal and pathological aging.In the present study, we report a 1 H MRS pulse sequence for the in vivo, localized 1 H MRS detection of NAD + from the human brain.Methods: Studies were carried out on a 7T Siemens MRI scanner using a 32-channel product volume coil. The pulse sequence consisted of a spectrally selective low bandwidth E-BURP-1 90° pulse. PRESS localization was achieved using optimized Shinnar-Le Roux 180° pulses and overlapping gradients were used to minimize the TE. The reproducibility of NAD + quantification was measured in 11 healthy volunteers. The association of cerebral NAD + with age was assessed in 16 healthy subjects 26-78 years old. Results: Spectra acquired from a voxel placed in subjects' occipital lobe consisted of downfield peaks from the H 2 , H 4 , and H 6 protons of the nicotinamide moiety of NAD + between 8.9-9.35 ppm. The mean ± SD within-session and between-session coefficients of variation were found to be 6.14 ± 2.03% and 6.09 ± 3.20%, respectively. In healthy volunteers, an age-dependent decline of the NAD + levels in the brain was also observed (β = −1.24 μM/y, SE = 0.21, P < 0.001). Conclusion:We demonstrated the feasibility and robustness of a newly developed 1 H MRS technique to measure localized cerebral NAD + at 7T MRI using a | 807 BAGGA et Al.