Two-dimensional spectroscopy of γ-aminobutyric acid on a clinical MRI scanner

Measurement of the cerebral metabolite y-aminobutyric acid (GABA) has been performed on clinical MRI scanners using a variety of magnetic resonance spectroscopy (MRS) techniques. MRS studies of GABA are difficult, especially at 1.5T due to low in-vivo concentrations and overlapping of higher concentration metabolites. Unlike spectral editing methods, two-dimensional (2D) MRS allows the simultaneous measurement of GABA and other, more traditional metabolites. This work evaluates three implementations of 2D MRS for both in-vitro and in-vivo GABA measurement on a clinical MRI scanner.Existing spectroscopy sequences were used to develop a protocol for performing 2D Jresolved MRS without a dedicated sequence. GABA was measured in-vitro at concentrations approaching normal physiological levels and volunteer results allowed assignment of the 3.01ppm GABA resonance at its J-coupling frequency (7.4Hz). However, the prolonged scan time of over two hours prevented practical application of this approach.A far more efficient method of acquiring 2D J-resolved spectra is achieved with a dedicated 2D J-resolved sequence. An optimised set of acquisition parameters was produced to allow GABA measurement with maximum SNR, and without macromolecule contamination, in 35 minutes. Since the reproducibility of the sequence must be sufficient to detect physiological changes, a formal reproducibility study was performed acquiring three measures of reproducibility at six concentrations of GABA, using a standard volume head coil, 3"- and 5"- surface coils. To our knowledge, this is the first such reproducibility study dedicated to 2D J-resolved GABA measurement, and as such, could have significant implications on the interpretation of in-vivo results. In-vivo 2D J-resolved spectra were acquired and compared well to the published results, allowing assignment of the 3.0Ippm GABA (plus macromolecule) peak (J = 7.4Hz). In the first reported 2D J-resolved spectra specifically designed to reduce the macromolecule contribution by optimising the echo time range, assignment of the in-vivo 3.01 ppm GABA peak was less convincing.As an alternative to 2D J-resolved spectroscopy, preliminary testing of 2D correlation spectroscopy (COSY) showed that it was not as sensitive or robust for either in-vitro or invivo GABA measurement. Although provisional assignment of the 3.01 ppm GABA peak was made, in their current form, neither technique is suitable for pure GABA measurement at 1.5T

Correlation chemical shift imaging with low-power adiabatic pulses and constant-density spiral trajectories

In this work we introduce the concept of correlation chemical shift imaging (CCSI). Novel CCSI pulse sequences are demonstrated on clinical scanners for two-dimensional Correlation Spectroscopy (COSY) and Total Correlation Spectroscopy (TOCSY) imaging experiments. To date there has been limited progress reported towards a feasible and robust multivoxel 2D COSY. Localized 2D TOCSY imaging is shown for the first time in this work. Excitation with adiabatic GOIA-W(16,4) pulses (Gradient Offset Independent Adiabaticity Wurst modulation) provides minimal chemical shift displacement error, reduced lipid contamination from subcutaneous fat, uniform optimal flip angles, and efficient mixing for coupled spins, while enabling short repetition times due to low power requirements. Constant-density spiral readout trajectories are used to acquire simultaneously two spatial dimensions and f2 frequency dimension in (kx,ky,t2) space in order to speed up data collection, while f1 frequency dimension is encoded by consecutive time increments of t1 in (kx,ky,t1,t2) space. The efficient spiral sampling of the k-space enables the acquisition of a single-slice 2D COSY dataset with an 8 × 8 matrix in 8:32 min on 3 T clinical scanners, which makes it feasible for in vivo studies on human subjects. Here we present the first results obtained on phantoms, human volunteers and patients with brain tumors. The patient data obtained by us represent the first clinical demonstration of a feasible and robust multivoxel 2D COSY. Compared to the 2D J-resolved method, 2D COSY and TOCSY provide increased spectral dispersion which scales up with increasing main magnetic field strength and may have improved ability to unambiguously identify overlapping metabolites. It is expected that the new developments presented in this work will facilitate in vivo application of 2D chemical shift correlation MRS in basic science and clinical studies.National Institutes of Health (U.S.) (NIH grant R01 1200-206456)National Institutes of Health (U.S.) (NIH grant R01 EB007942)Siemens Aktiengesellschaft (Siemens-MIT Alliance

Compressed Sensing Accelerated Magnetic Resonance Spectroscopic Imaging

abstract: Magnetic resonance spectroscopic imaging (MRSI) is a valuable technique for assessing the in vivo spatial profiles of metabolites like N-acetylaspartate (NAA), creatine, choline, and lactate. Changes in metabolite concentrations can help identify tissue heterogeneity, providing prognostic and diagnostic information to the clinician. The increased uptake of glucose by solid tumors as compared to normal tissues and its conversion to lactate can be exploited for tumor diagnostics, anti-cancer therapy, and in the detection of metastasis. Lactate levels in cancer cells are suggestive of altered metabolism, tumor recurrence, and poor outcome. A dedicated technique like MRSI could contribute to an improved assessment of metabolic abnormalities in the clinical setting, and introduce the possibility of employing non-invasive lactate imaging as a powerful prognostic marker. However, the long acquisition time in MRSI is a deterrent to its inclusion in clinical protocols due to associated costs, patient discomfort (especially in pediatric patients under anesthesia), and higher susceptibility to motion artifacts. Acceleration strategies like compressed sensing (CS) permit faithful reconstructions even when the k-space is undersampled well below the Nyquist limit. CS is apt for MRSI as spectroscopic data are inherently sparse in multiple dimensions of space and frequency in an appropriate transform domain, for e.g. the wavelet domain. The objective of this research was three-fold: firstly on the preclinical front, to prospectively speed-up spectrally-edited MRSI using CS for rapid mapping of lactate and capture associated changes in response to therapy. Secondly, to retrospectively evaluate CS-MRSI in pediatric patients scanned for various brain-related concerns. Thirdly, to implement prospective CS-MRSI acquisitions on a clinical magnetic resonance imaging (MRI) scanner for fast spectroscopic imaging studies. Both phantom and in vivo results demonstrated a reduction in the scan time by up to 80%, with the accelerated CS-MRSI reconstructions maintaining high spectral fidelity and statistically insignificant errors as compared to the fully sampled reference dataset. Optimization of CS parameters involved identifying an optimal sampling mask for CS-MRSI at each acceleration factor. It is envisioned that time-efficient MRSI realized with optimized CS acceleration would facilitate the clinical acceptance of routine MRSI exams for a quantitative mapping of important biomarkers.Dissertation/ThesisDoctoral Dissertation Bioengineering 201

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

BACKGROUND: Mutations 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. METHODS: Nine 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. RESULTS: 2HG 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). CONCLUSIONS: This 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

Magnetic resonance spectroscopy in migraine: what have we learned so far?

Objective: To summarize and evaluate proton (H-1) and phosphorus (P-31) magnetic resonance spectroscopy (MRS) findings in migraine. Methods: A thorough review of H-1 and/or P-31-MRS studies in any form of migraine published up to September 2011. Results: Some findings were consistent in all studies, such as a lack of ictal/interictal brain pH change and a disturbed energy metabolism, the latter of which is reflected in a drop in phosphocreatine content, both in the resting brain and in muscle following exercise. In a recent interictal study ATP was found to be significantly decreased in the occipital lobe of migraine with aura patients, reinforcing the concept of a mitochondrial component to the migraine threshold, at least in a subgroup of patients. In several studies a correlation between the extent of the energy disturbance and the clinical phenotype severity was apparent. Less consistent but still congruent with a disturbed energy metabolism is an observed lactate increase in the occipital cortex of several migraine subtypes (MwA, migraine with prolonged aura). No increases in brain glutamate levels were found. Conclusion: The combined abnormalities found in MRS studies imply a mitochondrial component in migraine neurobiology. This could be due to a primary mitochondrial dysfunction or be secondary to, for example, alterations in brain excitability. The extent of variation in the data can be attributed to both the variable clinical inclusion criteria used and the variation in applied methodology. Therefore it is necessary to continue to optimize MRS methodology to gain further insights, especially concerning lactate and glutamate

Excitatory neurotransmitters in brain regions in interictal migraine patients

<p>Abstract</p> <p>Objective</p> <p>To examine biochemical differences in the anterior cingulate cortex (ACC) and insula during the interictal phase of migraine patients. We hypothesized that there may be differences in levels of excitatory amino acid neurotransmitters and/or their derivatives in migraine group based on their increased sensitivity to pain.</p> <p>Methods</p> <p>2D <it>J</it>-resolved proton magnetic resonance spectroscopy (¹H-MRS) data were acquired at 4.0 Tesla (T) from the ACC and insula in 10 migraine patients (7 women, 3 men, age 43 ± 11 years) and 8 age gender matched controls (7 women, 3 men, age 41 ± 9 years).</p> <p>Results</p> <p>Standard statistical analyses including analysis of variance (ANOVA) showed no significant metabolite differences between the two subject cohorts in the ACC nor the insula. However, linear discriminant analysis (LDA) introduced a clear separation between subject cohorts based on N-acetyl aspartylglutamate (NAAG) and glutamine (Gln) in the ACC and insula.</p> <p>Conclusion</p> <p>These results are consistent with glutamatergic abnormalities in the ACC and insula in migraine patients during their interictal period compared to healthy controls. An alteration in excitatory amino acid neurotransmitters and their derivatives may be a contributing factor for migraineurs for a decrease in sensitivity for migraine or a consequence of the chronic migraine state. Such findings, if extrapolated to other regions of the brain would offer new opportunities to modulate central system as interictal or preemptive medications in these patients.</p

Double diffusion encoding and applications for biomedical imaging

Diffusion Magnetic Resonance Imaging (dMRI) is one of the most important contemporary non-invasive modalities for probing tissue structure at the microscopic scale. The majority of dMRI techniques employ standard single diffusion encoding (SDE) measurements, covering different sequence parameter ranges depending on the complexity of the method. Although many signal representations and biophysical models have been proposed for SDE data, they are intrinsically limited by a lack of specificity. Advanced dMRI methods have been proposed to provide additional microstructural information beyond what can be inferred from SDE. These enhanced contrasts can play important roles in characterizing biological tissues, for instance upon diseases (e.g. neurodegenerative, cancer, stroke), aging, learning, and development. In this review we focus on double diffusion encoding (DDE), which stands out among other advanced acquisitions for its versatility, ability to probe more specific diffusion correlations, and feasibility for preclinical and clinical applications. Various DDE methodologies have been employed to probe compartment sizes (Section 3), decouple the effects of microscopic diffusion anisotropy from orientation dispersion (Section 4), probe displacement correlations, study exchange, or suppress fast diffusing compartments (Section 6). DDE measurements can also be used to improve the robustness of biophysical models (Section 5) and study intra-cellular diffusion via magnetic resonance spectroscopy of metabolites (Section 7). This review discusses all these topics as well as important practical aspects related to the implementation and contrast in preclinical and clinical settings (Section 9) and aims to provide the readers a guide for deciding on the right DDE acquisition for their specific application

Prognostic factor from MR spectroscopy in rat with astrocytic tumour during radiation therapy

Objective: To investigate the relationship between the tumour volume and metabolic rates of astrocytic tumours using MR spectroscopy (MRS) during radiation therapy (RT). Methods: 12 healthy male Sprague-Dawley® rats (Sprague–Dawley Animal Company, Madison, WI) were used, and a tumour model was created through injecting C6 tumour cells into the right caudate nuclei of the rats. Tumours grew for 18 days after the injection and before the imaging study and radiation treatment. MRS was performed with two-dimensional multivoxel point-resolved spectroscopy sequence using a GE Signa VH/i 3.0-T MR scanner (GE Healthcare, Milwaukee, WI) equipped with rat-special coil. RT was given on the 19th day with a dose of 4 Gy in one single fraction. The image examinations were performed before RT, and on the 4th, 10th, 14th and 20th days after treatment, respectively. GE FuncTool software package (GE Healthcare) was used for post-processing of spectrum. Results: Metabolic ratios of serial MRS decrease progressively with time after RT. Choline-containing components (Cho)/creatine and creatine phosphate (Cr) ratios immediately prior to RT differed significantly from those on the 10th, 14th and 20th days after RT; both Cho/N-acetyl aspartate (NAA) ratios and NAA/Cr ratios immediately prior to RT differed significantly from those on the 14th and 20th days after RT. A positive correlation between changes of tumour volume and changes of Cho/Cr, lipid and lactate/Cr and glutamate plus glutamine/Cr ratio was observed on the 4th day after RT. Conclusion: MRS provides potential in monitoring tumour response during RT, and the imaging biomarkers predict the response of astrocytic tumours to treatment. Advances in knowledge: MRS is combined with both tumour size and Ki-67 labelling index to access tumour response to radiation.ECU Open Access Publishing Support Fun