Localized Correlated Spectroscopy Research Articles

Deep learning can accelerate and quantify simulated localized correlated spectroscopy

Nuclear magnetic resonance spectroscopy (MRS) allows for the determination of atomic structures and concentrations of different chemicals in a biochemical sample of interest. MRS is used in vivo clinically to aid in the diagnosis of several pathologies that affect metabolic pathways in the body. Typically, this experiment produces a one dimensional (1D) 1H spectrum containing several peaks that are well associated with biochemicals, or metabolites. However, since many of these peaks overlap, distinguishing chemicals with similar atomic structures becomes much more challenging. One technique capable of overcoming this issue is the localized correlated spectroscopy (L-COSY) experiment, which acquires a second spectral dimension and spreads overlapping signal across this second dimension. Unfortunately, the acquisition of a two dimensional (2D) spectroscopy experiment is extremely time consuming. Furthermore, quantitation of a 2D spectrum is more complex. Recently, artificial intelligence has emerged in the field of medicine as a powerful force capable of diagnosing disease, aiding in treatment, and even predicting treatment outcome. In this study, we utilize deep learning to: (1) accelerate the L-COSY experiment and (2) quantify L-COSY spectra. All training and testing samples were produced using simulated metabolite spectra for chemicals found in the human body. We demonstrate that our deep learning model greatly outperforms compressed sensing based reconstruction of L-COSY spectra at higher acceleration factors. Specifically, at four-fold acceleration, our method has less than 5% normalized mean squared error, whereas compressed sensing yields 20% normalized mean squared error. We also show that at low SNR (25% noise compared to maximum signal), our deep learning model has less than 8% normalized mean squared error for quantitation of L-COSY spectra. These pilot simulation results appear promising and may help improve the efficiency and accuracy of L-COSY experiments in the future.

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.

Changes in the neurochemistry of athletes with repetitive brain trauma: preliminary results using localized correlated spectroscopy.

IntroductionThe goal was to identify which neurochemicals differ in professional athletes with repetitive brain trauma (RBT) when compared to healthy controls using a relatively new technology, in vivo Localized COrrelated SpectroscopY (L-COSY).MethodsTo achieve this, L-COSY was used to examine five former professional male athletes with 11 to 28 years of exposure to contact sports. Each athlete who had had multiple symptomatic concussions and repetitive sub concussive trauma during their career was assessed by an experienced neuropsychologist. All athletes had clinical symptoms including headaches, memory loss, confusion, impaired judgment, impulse control problems, aggression, and depression. Five healthy men, age and weight matched to the athlete cohort and with no history of brain trauma, were recruited as controls. Data were collected from the posterior cingulate gyrus using a 3 T clinical magnetic resonance scanner equipped with a 32 channel head coil.ResultsThe variation of the method was calculated by repeated examination of a healthy control and phantom and found to be 10% and 5%, respectively, or less. The L-COSY measured large and statistically significant differences (P ≤0.05), between healthy controls and those athletes with RBT. Men with RBT showed higher levels of glutamine/glutamate (31%), choline (65%), fucosylated molecules (60%) and phenylalanine (46%). The results were evaluated and the sample size of five found to achieve a significance level P = 0.05 and a power of 90%. Differences in N-acetyl aspartate and myo-inositol between RBT and controls were small and were not statistically significance.ConclusionsA study of a small cohort of professional athletes, with a history of RBT and symptoms of chronic traumatic encephalopathy when compared with healthy controls using 2D L-COSY, showed elevations in brain glutamate/glutamine and choline as recorded previously for early traumatic brain injury. For the first time increases in phenylalanine and fucose are recorded in the brains of athletes with RBT. Larger studies utilizing the L-COSY method may offer an in-life method of diagnosis and personalized approach for monitoring the acute effects of mild traumatic brain injury and the chronic effects of RBT.

Lipid and Metabolite Deregulation in the Breast Tissue of Women Carrying BRCA1 and BRCA2 Genetic Mutations.

To use localized correlated spectroscopy (COSY) to assess for an altered biochemical state or states in breast tissue of women with BRCA gene mutations that potentially constitute preinvasive conditions. Institutional review board approval was obtained. Participants provided written informed consent. In vivo localized COSY images were recorded at 3 T in the breast tissue of women carrying BRCA1 (n = 9) or BRCA2 (n = 14) gene mutations and were compared with images in healthy control subjects with no family history of breast cancer (n = 10). All participants underwent contrast material-enhanced MR imaging and ultrasonography (US). Statistical significance was calculated with the Mann-Whitney two-sided nonparametric test. No abnormality was recorded with MR imaging or US. Metabolite levels in the BRCA1 cohort were reduced by 79% (P = .014) when compared with triglycerides level, and there was a 19% increase in lipid unsaturation and triglyceride levels (P = .027 and P = .086, respectively) when compared with cellular cholesterol level. Cholesterol level was reduced by 47% (P = .027) when compared with diallylic lipid level. Metabolite levels in the BRCA2 cohort showed increased unsaturation of 21% (P = .030) relative to triglycerides level. Comparison of the BRCA1 and BRCA2 cohorts showed a 47% (P = .002) increase in cholesterol level in the BRCA2 cohort when compared with diallylic lipid level and a 52% (P = .003) increase when compared with triglycerides level. Levels of diallylic lipid, unsaturated lipid, triglycerides, and terminal methyl on the acyl chain are reduced by 46% (P = .002), 57% (P = .003), 66% (P = .003), and 29% (P = .010), respectively, when compared with cholesterol level. Localized COSY recorded significant changes in women with BRCA1 and BRCA2 gene mutations when compared with control subjects. If these changes are ultimately proven to be a premalignant stage, this method may prove useful in screening.

Abstracts of the Hunter Cancer Research Alliance Annual Symposium 2014, November 21, 2014, New Lambton Heights, New South Wales, Australia.

Despite no evidence of any changes to breast tissue from current imaging modalities, in vivo two-dimensional localized correlated MR spectroscopy can be used to identify biochemical abnormalities that may represent preinvasive changes in the breast tissue of women carrying BRCA1 or BRCA2 gene mutations.

Implementation of two‐dimensional L‐COSY at 7 tesla: An investigation of reproducibility in human brain

To evaluate the utility of two-dimensional (2D) Localized Correlated Spectroscopy (L-COSY) in metabolic profiling of the human brain at 7 Tesla (T). The 2D L-COSY sequence was implemented at 7 T and its reliability was assessed by test-retest studies of a metabolite phantom and a healthy volunteer. L-COSY data were acquired from the occipital lobe of healthy subjects (n = 6; all male; age, 30-72 years) to assess intersubject variability. Additionally, two subjects underwent scans from the parieto-occipital region, basal ganglia, frontal lobe or dorsolateral prefrontal cortex to test the versatility of L-COSY in studying differing anatomy. Integral/volume measurements of L-COSY spectra were used to estimate normalized metabolite-to-creatine concentrations. Phantom test-retest studies revealed coefficients of variation (CVs) of 3-20% for most metabolites. Human 2D L-COSY spectra permitted detection of several metabolite resonances from multiple locations and inter-subject variation studies demonstrated CVs of 4-26%. Cross-peaks from gamma-aminobutyric acid (GABA), isoleucine (Ile), lysine (Lys) and Ethanolamine (Eth) were quantified, which are not readily resolvable with conventional one-dimensional (1D) MR spectroscopy. 2D L-COSY at 7 T demonstrated improved sensitivity in detecting additional metabolites with reliability comparable to established techniques at lower fields, which may aid in the metabolic assessment of diseased states.

Characterization of Intra-myocellular Lipids Using 2d Localized Correlated Spectroscopy and Abdominal Fat Using Mri in Type 2 Diabetes

A major goal of this pilot study was to quantify intramyocellular lipids (IMCL), extramyocellular lipids (EMCL), unsaturation index (UI) and metabolites such as creatine (Cr), choline (Ch) and carnosine (Car), in the soleus muscle using two-dimensional (2D) localized correlated spectroscopy (L-COSY). Ten subjects with type 2 diabetes (T2D), controlled by lifestyle management alone, and 9 healthy control subjects, were studied. In T2D patients only, the following measurements were obtained: body mass index (BMI); waist circumference (WC); abdominal visceral and subcutaneous fat quantified using breath-held magnetic resonance imaging (MRI); a fasting blood draw for assessment of glucose, insulin, and estimation of homeostasis model assessment of insulin resistance (HOMA-IR), HbA1c, and high-sensitivity c-reactive protein (hs-CRP). Analysis of the soleus muscle 2D L-COSY spectral data showed significantly elevated IMCL ratios with respect to Cr and decreased IMCL UI in T2D when compared to healthy subjects (P < 0.05). In T2D subjects, Pearson correlation analysis showed a positive correlation of IMCL/Cr with EMCL/Cr (0.679, P < 0.05) and HOMA-IR (0.633, P < 0.05), and a non-significant correlation of visceral and subcutaneous fat with magnetic resonance spectroscopy (MRS) and other metrics. Characterization of muscle IMCL and EMCL ratios, UI, and abdominal fat, may be useful for the noninvasive assessment of the role of altered lipid metabolism in the pathophysiology of T2D, and for assessment of the effects of future therapeutic interventions designed to alter metabolic dysfunction in T2D.

Multi-dimensional MR spectroscopy: towards a better understanding of hepatic encephalopathy

Hepatic encephalopathy (HE) is normally diagnosed by neuropsychological (NP) tests. The goals of this study were to quantify cerebral metabolites, separate glutamate (Glu) from glutamine (Gln) in patients with minimal hepatic encephalopathy (MHE) as well as healthy subjects using the prior-knowledge fitting (ProFit) algorithm on data acquired by two-dimensional (2D) localized correlated spectroscopy (L-COSY) on two different MR scanners, and to correlate the metabolite changes with neuropsychological (NP) tests. We studied 14 MHE patients and 18 healthy controls using a GE 1.5T Signa MR scanner. Another group of 16 MHE patients and 18 healthy controls were studied using a Siemens 1.5T Avanto MR scanner. The following parameters were used for L-COSY: TR/TE = 2s/30ms, 3 × 3 × 3cm(3) voxel size, 96 Δt(1) increments with 8 averages per Δt(1). Using the ProFit algorithm, we were able to differentiate Gln from Glu on the GE 1.5T data in the medial frontal white/gray matter. The ratios of myo-inositol (mI), Glu, total choline, scyllo-inositol (sI), phosphoethanolamine (PE), and total N-acetyl aspartate (NAA) showed statistically significant decline in HE patients compared to healthy controls, while the ratio of Gln was significantly increased. Similar trend was seen in the ProFit quantified Siemens 1.5T data in the frontal and occipito-parietal white/gray regions. Among the NP domain scores, motor function, cognitive speed, executive function and the global scores showed significant differences. Excellent correlations between various NP domains and metabolite ratios were also observed. ProFit based cerebral metabolite quantitation enhances the understanding and basis of the current hypothesis of MHE.

Two‐dimensional MR spectroscopy of minimal hepatic encephalopathy and neuropsychological correlates in vivo

To evaluate regional cerebral metabolic and structural changes in patients with minimal hepatic encephalopathy (MHE) using two-dimensional (2D) MR spectroscopy (MRS) and T( (1) )-weighted MRI, to correlate the observed MR changes with neuropsychological (NP) test scores, and to compare the diagnostic accuracy of MRI, 2D MRS, and NP tests in discriminating between patients and healthy subjects. Thirty-three MHE patients and 30 healthy controls were investigated. The 2D localized correlated spectroscopy (L-COSY) was performed in the frontal and occipital brain on a 1.5 Tesla (T) MR scanner. The NP test battery included 15 tests, grouped into 6 cognitive domains. Globus pallidus signal intensities were calculated from T(1)-weighted images. The 2D MRS showed significant differences in ratios of the following metabolite(s) peaks with respect to creatine (Cr): decreased myo-inositol (mI), choline (Ch), mICh, and increased (glutamate plus glutamine) (Glx) in patients compared with healthy subjects in both occipital and frontal lobes. Frontal lobe taurine also showed a decline in patients. The NP test results revealed declines in cognitive speed, motor function, executive function, and global cognitive status. Significant correlations were found between the altered metabolites and NP tests. Alteration in the mICh/Cr ratio was noted as a powerful discriminant between healthy subjects and the patients. The study demonstrates that relative metabolite levels determined by 2D MRS, in particular mICh/Cr, provide the best diagnostic prediction for MHE. The results suggest that depletions of myo-inositol, choline and taurine with respect to creatine correlate with measures of neuropsychological impairment.

Combined DCE‐MRI and single‐voxel 2D MRS for differentiation between benign and malignant breast lesions

Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and proton (1H) magnetic resonance spectroscopy (MRS) provide structural and biochemical information, including vascular volume, vascular permeability and tissue metabolism. In this study, we performed analysis of the enhancement characteristic from DCE-MRI and the biochemical information provided by two-dimensional (2D) Localized Correlated Spectroscopy (L-COSY) MRS to determine the sensitivity and specificity of using DCE-MRI alone compared to the combination with 2D MRS. The metabolite ratios from the 2D MRS spectra were analyzed using multivariate statistical analyses to determine a method capable of automatic separation of the patient cohort into malignant and benign lesions. A total of 24 lesions were studied with 21 diagnosed accurately using the enhancement characteristics alone resulting in sensitivity and specificity of 100% and 73%, respectively. Analysis of the 2D MRS data demonstrated a significant difference (p < 0.05) in 12 of 18 metabolite ratios analyzed for malignant compared to benign lesions. Previous research focused on utilizing the choline signal to noise ratio (SNR) as a marker for malignancy has been verified using 2D MRS in this study. Using Fisher's linear discriminant test using water (WAT)/olefinic fat diagonal (UFD), choline (CHO)/fat (FAT), CHO/UFD, and FAT/methyl fat (FMETD) as predictors the sensitivity and specificity increased to 92% and 100%, respectively. Using the Classification and Regression Tree (CART) statistical analysis the resulting sensitivity and specificity were 100% and 91%, respectively, with the most accurate predictor for differentiating malignant and benign determined to be FAT/FMETD. The cases within the study that presented a indeterminate diagnosis using DCE-MRI alone were able to be accurately diagnosed when the metabolic information from 2D MRS was incorporated. The results suggest improved breast cancer detection through the combination of morphological and enhancement information from DCE-MRI and metabolic information from 2D MRS.

Detection of Amide and Aromatic Proton Resonances of Human Brain Metabolites Using Localized Correlated Spectroscopy Combined with Two Different Water Suppression Schemes.

The purpose of the study was to demonstrate the J-coupling connectivity network between the amide, aliphatic, and aromatic proton resonances of metabolites in human brain using two-dimensional (2D) localized correlated spectroscopy (L-COSY). Two different global water suppression techniques were combined with L-COSY, one before and another after localizing the volume of interest (VOI). Phantom solutions containing several cerebral metabolites at physiological concentrations were evaluated initially for sequence optimization. Nine healthy volunteers were scanned using a 3T whole body MRI scanner. The VOI for 2D L-COSY was placed in the right occipital white/gray matter region. The 2D cross and diagonal peak volumes were measured for several metabolites such as N-acetyl aspartate (NAA), creatine (Cr), free choline (Ch), glutamate/glutamine (Glx), aspartate (Asp), myo-inositol (mI), GABA, glutathione (GSH), phosphocholine (PCh), phosphoethanolamine (PE), tyrosine (Tyr), lactate (Lac), macromolecules (MM) and homocarnosine (Car). Using the pre-water suppression technique with L-COSY, the above mentioned metabolites were clearly identifiable and the relative ratios of metabolites were calculated. In addition to detecting multitude of aliphatic resonances in the high field region, we have demonstrated that the amide and aromatic resonances can also be detected using 2D L-COSY by pre water suppression more reliably than the post-water suppression.

Implementation and validation of localized constant‐time correlated spectroscopy (LCT‐COSY) on a clinical 3T MRI scanner for investigation of muscle metabolism

To implement and evaluate a novel single-volume two-dimensional localized constant-time-based correlated spectroscopy (2D LCT-COSY) sequence on a clinical 3T MR scanner. This sequence exhibits homonuclear decoupling along the F1 dimension, leading to improved spectral resolution compared to that of non-constant-time localized correlated spectroscopy (L-COSY). A GE 3T MR scanner equipped with a quadrature transmit and receive extremity coil was used in this study. The 2D LCT-COSY sequence was programmed using General Electric's EPIC compiler. Simulations for a two-spin 1/2 system were performed using GAMMA libraries to evaluate the theoretical performance of the sequences, and were also compared with corresponding phantom experiments using trans-cinnamic acid. Finally, spectra were acquired from the soleus muscle of healthy volunteers in order to evaluate performance in vivo. Simulations and experimental results confirmed the improved spectral resolution of LCT-COSY over L-COSY, as well as its homonuclear decoupling performance. The behavior of resonance amplitudes as a function of evolution time in the experiment also was appropriately reflected by the simulation. Corresponding results were obtained for the in vivo muscle spectra, in which separation of overlapping olefinic and allylic methylene protons from the intra- and extramyocellular lipids (IMCL and EMCL, respectively) was achieved. Simulations and experimental results in vitro and in vivo demonstrate the strengths of LCT-COSY. This technique can be implemented on systems of any field strength, and has the potential to separate overlapping metabolites in tissue when employed on high-field clinical MRI scanners equipped for proton spectroscopy.