Localized Correlation Spectroscopy Research Articles

Diurnal variability of cerebral metabolites in healthy human brain with 2D localized correlation spectroscopy (2D L-COSY).

Two-dimensional localized correlation spectroscopy (2D L-COSY) is a research tool that has been applied to evaluate in vivo metabolic activity in many neurological and oncological disorders. Circadian mediators such as brain temperature, hydration, and osmotic regulation have been claimed to change metabolic profiles. To evaluate the diurnal variability of neuro-metabolites with 2D L-COSY in healthy subjects using a 3 T scanner. Crossover. Ten healthy subjects and magnetic resonance spectroscopy-high definition (MRS-HD) sphere or "Braino." Field Strength/Sequence: 3 T/2D L-COSY MRS. In vivo 2D L-COSY measurements were performed on ten healthy subjects (5 M/5F, mean age 36.1 ± 7.7 years) repeatedly at three timepoints (0700, 1200, and 1700) on the same day. in vitro evaluations were performed in a similar fashion as in vivo on Braino containing selected brain metabolites at physiological concentrations and pH. 2D L-COSY was acquired from a 27 cm3 voxel located in the posterior cingulate cortex. A total of 75 resonances were included in the analysis and spectral peak volumes were normalized to creatine. One-way repeated measured analysis of variance with Bonferroni post-hoc adjustment using SPSS software. In vitro data showed no statistically significant differences between different scans (P > 0.12). in vivo results showed statistically significant diurnal variations (P ≤ 0.05, F > 3.88) for 22 resonances. Bonferroni post-hoc testing showed there was statistically significant increases in metabolite ratios between 0700 and 1700 and these include different moieties of N-acetylaspartate, creatine, choline, myo-inositol, lipids, fucose, glutathione, and homocarnosine. 2D L-COSY can detect diurnal physiological variability in neuro-metabolite levels. Thus, time of the day should be considered when planning MRS studies to avoid confounding results. 1 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2019;50:592-601.

2D in-vivo L-COSY spectroscopy identifies neurometabolite alterations in treated multiple sclerosis.

Background:We have applied in vivo two-dimensional (2D) localized correlation spectroscopy (2D L-COSY), in treated relapsing relapsing-remitting multiple sclerosis (RRMS) to identify novel biomarkers in normal-appearing brain parenchyma.Methods:2D L-COSY magnetic resonance spectroscopy (MRS) spectra were prospectively acquired from the posterior cingulate cortex (PCC) in 45 stable RRMS patients undergoing treatment with Fingolimod, and 40 age and sex-matched healthy control (HC) participants. Average metabolite ratios and clinical symptoms including, disability, cognition, fatigue, and mental health parameters were measured, and compared using parametric and nonparametric tests. Whole brain volume and MRS voxel morphometry were evaluated using SIENAX and the SPM LST toolbox.Results:Despite the mean whole brain lesion volume being low in this RRMS group (6.8 ml) a significant reduction in PCC metabolite to tCr ratios were identified for multiple N-acetylaspartate (NAA) signatures, gamma-aminobutyric acid (GABA), glutamine and glutamate (Glx), threonine, and isoleucine/lipid. Of the clinical symptoms measured, visuospatial function, attention, and memory were correlated with NAA signatures, Glx, and isoleucine/lipid in the brain.Conclusions:2D L-COSY has the potential to detect metabolic alterations in the normal-appearing MS brain. Despite examining only a localised region, we could detect metabolic variability associated with symptoms.

Reliability of neurometabolite detection with two-dimensional localized correlation spectroscopy at 3T.

Two-dimensional localized correlational spectroscopy (2D L-COSY) has been applied in vivo to investigate metabolic profiles in many disorders due to its ability to detect several metabolites simultaneously. Successful application of this technique depends on the reliability of the detection and understanding of the variability result from test-retest measurements. To evaluate the test-retest repeatability/reliability of 2D L-COSY in detecting brain metabolites in a phantom and healthy subjects in a 3T scanner. Test-retest. Six healthy subjects and magnetic resonance spectroscopy-high definition (MRS-HD) sphere or "Braino". 3T/2D L-COSY MRS. Healthy subjects underwent eight weekly experiments over a period of 3 months with an intersession delay of 1 month after the first four measurements. Twenty-nine neurometabolite resonances (8 diagonal, 14 cross, and 7 composite resonances) were studied using a 27 cm3 voxel from the posterior cingulate cortex. In vitro evaluations were performed in a similar manner as in vivo on a Braino phantom containing brain metabolites at physiological concentrations and pH. Intra- and intersubject variability were measured. Test-retest repeatability was calculated using coefficient of variation (CV), and reliability was assessed with standard error measurement (SEM) and intraclass correlation coefficient (ICC), using SPSS software. The intra/inter CV for in vitro and in vivo data ranged from 0.01-0.23%/0.02-0.29% and 0.03-0.23%/0.04-0.39%, respectively. The major diagonal peaks showed ICC ranging from 0.31 to 0.93, while the ICC for cross peaks were 0.09-0.87. The SEM for in vivo data ranged from 0.0016 to 0.08. The interweek interval may have a positive effect on metabolite ratios (P = 0.08; F = 1.78). The low variability in metabolite concentration in this study shows a high level of reliability of 2D L-COSY in the human brain. 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;48:1559-1569.

Non-invasive detection of 2-hydroxyglutarate in IDH-mutated gliomas using two-dimensional localized correlation spectroscopy (2D L-COSY) at 7 Tesla

BackgroundMutations in the isocitrate dehydrogenase enzyme are present in a majority of lower-grade gliomas and secondary glioblastomas. This mis-sense mutation results in the neomorphic reduction of isocitrate dehydrogenase resulting in an accumulation of the “oncometabolite” 2-hydroxyglutarate (2HG). Detection of 2HG can thus serve as a surrogate biomarker for these mutations, with significant translational implications including improved prognostication. Two dimensional localized correlated spectroscopy (2D L-COSY) at 7T is a highly-sensitive non-invasive technique for assessing brain metabolism. This study aims to assess tumor metabolism using 2D L-COSY at 7T for the detection of 2HG in IDH-mutant gliomas.MethodsNine treatment-naïve patients with suspected intracranial neoplasms were scanned at 7T MRI/MRS scanner using the 2D L-COSY technique. 2D-spectral processing and analyses were performed using a MATLAB-based reconstruction algorithm. Cross and diagonal peak volumes were quantified in the 2D L-COSY spectra and normalized with respect to the creatine peak at 3.0 ppm and quantified data were compared with previously-published data from six normal subjects. Detection of 2HG was validated using findings from immunohistochemical (IHC) staining in patients who subsequently underwent surgical resection.Results2HG was detected in both of the IDH-mutated gliomas (grade III Anaplastic Astrocytoma and grade II Diffuse Astrocytoma) and was absent in IDH wild-type gliomas and in a patient with breast cancer metastases. 2D L-COSY was also able to resolve complex and overlapping resonances including phosphocholine (PC) from glycerophosphocholine (GPC), lactate (Lac) from lipids and glutamate (Glu) from glutamine (Gln).ConclusionsThis study demonstrates the ability of 2D L-COSY to unambiguously detect 2HG in addition to other neuro metabolites. These findings may aid in establishing 2HG as a biomarker of malignant progression as well as for disease monitoring in IDH-mutated gliomas.

Localized 2D COSY sequences: Method and experimental evaluation for a whole metabolite quantification approach

Two-dimensional spectroscopy offers the possibility to unambiguously distinguish metabolites by spreading out the multiplet structure of J-coupled spin systems into a second dimension. Quantification methods that perform parametric fitting of the 2D MRS signal have recently been proposed for resolved PRESS (JPRESS) but not explicitly for Localized Correlation Spectroscopy (LCOSY). Here, through a whole metabolite quantification approach, correlation spectroscopy quantification performances are studied. The ability to quantify metabolite relaxation constant times is studied for three localized 2D MRS sequences (LCOSY, LCTCOSY and the JPRESS) in vitro on preclinical MR systems. The issues encountered during implementation and quantification strategies are discussed with the help of the Fisher matrix formalism. The described parameterized models enable the computation of the lower bound for error variance – generally known as the Cramér Rao bounds (CRBs), a standard of precision – on the parameters estimated from these 2D MRS signal fittings. LCOSY has a theoretical net signal loss of two per unit of acquisition time compared to JPRESS. A rapid analysis could point that the relative CRBs of LCOSY compared to JPRESS (expressed as a percentage of the concentration values) should be doubled but we show that this is not necessarily true. Finally, the LCOSY quantification procedure has been applied on data acquired in vivo on a mouse brain.

Two-dimensional semi-LASER correlation spectroscopy with well-maintained cross peaks

To demonstrate that the limited bandwidth of the second 90° radiofrequency (RF) pulse in two-dimensional (2D) localized correlation spectroscopy (L-COSY) induces spatially dependent magnetization transfer that results in attenuated cross-peaks, and to propose a new 2D semi-adiabatically localized COSY sequence to solve this problem. A semi-localization by adiabatic selective refocusing (semi-LASER or sLASER) method was incorporated into the COSY sequence with the slice-selective first 90° RF pulse and the non-slice-selective second 90° RF pulse to form a new 2D sLASER localized COSY sequence, named "sLASER-first-COSY," to solve the problem of spatially dependent magnetization transfer. Experiments were performed to verify the feasibility and advantages of sLASER-first-COSY sequence over a recently reported other sLASER COSY sequence with a slice-selective second 90° RF pulse, named "sLASER-last-COSY". Phantom, ex vivo, and in vivo human brain experiments demonstrated that sLASER-first-COSY yielded stronger cross peaks and higher ratios of cross peak volumes to diagonal peak volumes than sLASER-last-COSY. As COSY relies on the cross peaks to obtain larger dispersion of peaks for quantification, the new sLASER-first-COSY sequence yielding well-maintained cross peaks will facilitate more reliable and accurate quantification of metabolites with coupled spin systems.

L-COSY of breast cancer at 3T

Magnetic resonance techniques have been increasingly adopted in the clinic to aid diagnosis and monitor treatment. To this end, a variety of spectroscopic techniques have been developed. Mackinnon and colleagues [1] found out that choline (Cho) was present in fine-needle biopsy of breast carcinoma. Jagannathan and colleagues [2] noted that variation of water/fat ratio can be used to monitor breast patients receiving chemotherapy, while others [3] reported that Cho was detected in most breast carcinomas in vivo, which was later quantified using an external standard [4,5]. Few reviews have been recently published on breast MRS and the reader is referred to [6,7]. Two-dimensional (2D) localized correlation spectroscopy (L-COSY), a technique that spreads narrowly packed spectral information along a second dimension, was implemented by Thomas and colleagues on 1.5 T [8,9]. We aimed to evaluate the benefits of 2D L-COSY technique of the breast at 3T by inspecting ratios of all spectral features to prominent indigenous resonances.

Adiabatic localized correlation spectroscopy (AL‐COSY): Application in muscle and brain

To describe an enhanced version of a localized correlation spectroscopy (L-COSY) by introducing adiabatic radiofrequency (RF) pulses for localization in two dimensions. Adiabatic pulses will improve slice selection profile and reduce chemical shift artifacts. Optimized Mao and adiabatic hyperbolic secant pulses are tested in vivo. Region of interest is localized by a 90° nonselective adiabatic RF pulse followed by two pairs of adiabatic RF pulses and a terminal 90° RF sinc pulse. Slice profiles for both refocusing pulses and chemical shift artifacts are measured in a water-oil phantom for L-COSY and AL-COSY. In vivo results of both COSY sequences are shown from muscle and brain on a 3 Tesla (T) scanner. Chemical shift artifacts were reduced with AL-COSY compared with L-COSY. Slice profiles of adiabatic pulses were found to be sharper and more symmetrical than those of traditional Mao pulses. One-dimensional (1D) phantom studies showed longer T2 values using AL-COSY sequence. Comparison of 2D spectra obtained revealed spectroscopic peak volume improvements in AL-COSY and less residual water. In vivo 1D comparison showed more inphase and sharper peaks in AL-COSY spectrum. The AL-COSY sequence is an improved sequence due to sharper slice selection profiles, reduction of chemical shift artifacts, peak volume improvements in 2D techniques, and less J-modulation.

Use of in Vivo Two-dimensional MR Spectroscopy to Compare the Biochemistry of the Human Brain to That of Glioblastoma

To develop an in vivo two-dimensional localized correlation spectroscopy technique with which to monitor the biochemistry of the human brain and the pathologic characteristics of diseases in a clinically applicable time, including ascertainment of appropriate postprocessing parameters with which to allow diagnostic and prognostic molecules to be measured, and to investigate how much of the chemical information, known to be available from malignant cultured cells, could be recorded in vivo from human brain. The study was approved by the institutional review board and was compliant with HIPAA. With use of a 3.0-T clinical magnetic resonance (MR) unit and a 32-channel head coil, localized correlation spectroscopy was performed in six healthy control subjects and six patients with glioblastoma multiforme (GBM) with an acquisition time of 11 minutes. Two-dimensional spectra were processed and analyzed and peak volume ratios were tabulated. The data used were proved to be normally distributed by passing the Shapiro-Wilk normality test. The first row of the spectra was extracted to examine diagnostic features. The pathologic characteristics and grade of each GBM were determined after biopsy or surgery. Statistically significant differences were assessed by using a t test. The localized correlation spectroscopy method assigned biochemical species from the healthy human brain. The correlation spectra of GBM were of sufficiently high quality that many of the cross peaks, recorded previously from malignant cell models in vitro, were observed, demonstrating a statistically significant difference (P < .05) between the cross peak volumes measured for healthy subjects and those with GBM (which include lipid, alanine, N-acetylaspartate, γ-aminobutyric acid, glutamine and glutamate, glutathione, aspartate, lysine, threonine, total choline, glycerophosphorylcholine, myo-inositol, imidazole, uridine diphosphate glucose, isocitrate, lactate, and fucose). The first row of the spectra was found to contain diagnostic features. Localized correlation spectroscopy of the human brain at 3.0 T with use of a 32-channel head coil was performed in 11 minutes and provided information about neurotransmitters, metabolites, lipids, and macromolecules. The method was able to help differentiate healthy brain from the biochemical signature of GBM in vivo. This method may, in the future, reduce the need for biopsy and is now applicable for the study of selected neurologic diseases.

3D localized 1H-13C heteronuclear single-quantum coherence correlation spectroscopy in vivoThis work was presented in part at the 4th Annual Meeting of the International Society for Magnetic Resonance, New York, May, 1996

A method for spatially three-dimensional (3D) localized two-dimensional (2D) 1H-13C correlation spectroscopy, localized HSQC, is proposed. This method has the following special feature in the preparation period. The 180°(13C) and 180°(1H) pulses are separated in time, and the 180°(13C) pulse is applied at 1/(4 1JCH) before the 90°(1H) polarization transfer pulse. The preparation (echo) period 2τ can then be set substantially longer than 1/(2 1JCH), so that even in a whole-body system, slice-selective 90°(1H) pulses and gradient pulses can be applied in that period. The localization capabilities of this method were confirmed in a phantom experiment. The 3D localized 2D 1H-13C correlation spectra from a monkey brain in vivo were obtained after [1-13C]glucose injection, and amino acid metabolism was detected; that is, [4-13C]glutamate appeared immediately after the injection, followed by the appearance of [2-13C]glutamate, [3-13C]glutamate, and [4-13C]glutamine. Magn Reson Med 43:200–210, 2000. © 2000 Wiley-Liss, Inc.

Increased Sensitivity of COSY Spectra by Use of Constant-Time t1 Periods (CT COSY)

Two-dimensional spectroscopy offers the possibility to unambiguously distinguish metabolites by spreading out the multiplet structure of J-coupled spin systems into a second dimension. Quantification methods that perform parametric fitting of the 2D MRS signal have recently been proposed for resolved PRESS (JPRESS) but not explicitly for Localized Correlation Spectroscopy (LCOSY). Here, through a whole metabolite quantification approach, correlation spectroscopy quantification performances are studied. The ability to quantify metabolite relaxation constant times is studied for three localized 2D MRS sequences (LCOSY, LCTCOSY and the JPRESS) in vitro on preclinical MR systems. The issues encountered during implementation and quantification strategies are discussed with the help of the Fisher matrix formalism. The described parameterized models enable the computation of the lower bound for error variance – generally known as the Cramér Rao bounds (CRBs), a standard of precision – on the parameters estimated from these 2D MRS signal fittings. LCOSY has a theoretical net signal loss of two per unit of acquisition time compared to JPRESS. A rapid analysis could point that the relative CRBs of LCOSY compared to JPRESS (expressed as a percentage of the concentration values) should be doubled but we show that this is not necessarily true. Finally, the LCOSY quantification procedure has been applied on data acquired in vivo on a mouse brain.

Localized double-quantum filter and correlation spectroscopy experiments.

Problems with in vivo proton spectroscopy include strong water and lipid signals, and the very complicated structures of the spectra. Multiple-quantum experiments can be designed to overcome these difficulties. Using a volume selective refocusing technique, one can demonstrate how multiple-quantum experiments can be performed in a spatially localized manner. Rather than trying to integrate a localization procedure into a particular spectroscopy experiment itself, the approach here is to leave the basic experiment intact and to add a volume selective "block" to the end of the sequence. This "block" must, of course, preserve the integrity of the particular experiment. The volume selective refocusing method, presented here, does just this for a wide variety of proton NMR experiments. The advantage of this approach is that the analysis of the particular experiment is not changed. This is very important considering the complexity involved. Using this procedure, two very elementary multiple-quantum experiments have been performed on a 1.5-T whole-body scanner. These experiments are a localized double-quantum filter experiment (for water suppression) and a localized two-dimensional correlation spectroscopy experiment.