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

High-resolution magic angle spinning magnetic resonance spectroscopy detects glycine as a biomarker in brain tumors

The non-essential amino acid neurotransmitter glycine (Gly) may serve as a biomarker for brain tumors. Using 36 biopsies from patients with brain tumors [12 glioblastoma multiforme (GBM); 10 low-grade (LG), including 7 schwannoma and 3 pylocytic astrocytoma; 7 meningioma (MN); 7 brain metastases (MT), including 3 adenocarcinoma and 4 breast cancer] and 9 control biopsies from patients undergoing surgery for epilepsy, we tested the hypothesis that the presence of glycine may distinguish among these brain tumor types. Using high-resolution magic angle spinning (HRMAS) 1H magnetic resonance spectroscopy (MRS), we determined a theoretically optimum echo time (TE) of 50 ms for distinguishing Gly signals from overlapping myo-inositol (Myo) signals and tested our methodology in phantom and biopsy specimens. Quantitative analysis revealed higher levels of Gly in tumor biopsies (all combined) relative to controls; Gly levels were significantly elevated in LG, MT and GBM biopsies (P≤0.05). Residual Myo levels were elevated in LG and MT and reduced in MN and GBM (P<0.05 vs. control levels). We observed higher levels of Gly in GBM as compared to LG tumors (P=0.05). Meanwhile, although Gly levels in GBM and MT did not differ significantly from each other, the Gly:Myo ratio did distinguish GBM from MT (P<0.003) and from all other groups, a distinction that has not been adequately made previously. We conclude from these findings that Gly can serve as a biomarker for brain tumors and that the Gly:Myo ratio may be a useful index for brain tumor classification

Molecular characterization and quantification using state of the art solid-state adiabatic TOBSY NMR in burn trauma

We describe a novel solid-state nuclear magnetic resonance (NMR) method that maximizes the advantages of high-resolution magic-angle-spinning (HRMAS), relative conventional liquid-state NMR approaches, when applied to intact biopsies of skeletal muscle specimens collected from burn trauma patients. This novel method, termed optimized adiabatic TOtal through Bond correlation SpectroscopY (TOBSY) solid-state NMR pulse sequence for two-dimensional (2D)1H-1H homonuclear scalar-coupling longitudinal isotropic mixing, was demonstrated to provide a 40–60% improvement in signal-to-noise ratio (SNR) relative to its liquid-state analogue TOCSY (TOtal Correlation SpectroscopY). Using 1-and 2-dimensional HRMAS NMR experiments, we identified several metabolites in burned tissues. Quantification of metabolites in burned tissues showed increased levels of lipid compounds, intracellular metabolites (e.g., taurine and phosphocreatine) and substantially decreased water-soluble metabolites (e.g., glutathione, carnosine, glucose, glutamine/glutamate and alanine). These findings demonstrate that HRMAS NMR Spectroscopy using TOBSY is a feasible technique that reveals new insights into the pathophysiology of burn trauma. Moreover, this method has applications that facilitate the development of novel therapeutic strategies

Festkörper-NMR von (Membran-) Proteinkomplexen: Neue Methoden und Anwendungen

Das Ziel dieser Arbeit war es, hochaufgelöste mehrdimensionale Experimente zu entwickeln, die im Rahmen einer allgemeinen Strategie zur 3D-Strukturbestimmung von uniform isotopenmarkierten Membranproteinen oder Fibrillen (d.h. Proteinkomplexen) durch Festkörper-MAS-NMR-Spektroskopie eingesetzt werden können. Insbesondere wurden molekulare Orientierung, Dynamik und Hydratisierung untersucht. Es wird gezeigt, daß die Orientierung von Membranproteinen (z.B. Gramicidin A, WALP23) in ausgerichteten Lipiddoppelschichten durch Wiedereinführung des CSA von N-15 bei hohen MAS-Raten bestimmt werden kann. Eine Kombination von auf skalarer und dipolarer Kopplung basierenden Experimenten (d.h. dynamikbasiertes spektrales Editieren) wird vorgestellt, um die Mobilität von Proteindomänen zu untersuchen; dies wird am die Herzfunktion modulierenden Protein Phospholamban gezeigt. Schließlich wird ein Modell für die gepaarten helikalen Filamente, die das Protein Tau in der Alzheimerschen Erkrankung bildet, aus Experimenten mit Magnetisierungstransfer von Wasser zu Protein (d.h. wassereditierte Experimente) entwickelt.The aim of this thesis was to develop multidimensional high-resolution experiments that can be incorporated in a general strategy for 3D structure determination of uniformly labeled membrane proteins or fibrils (i.e. protein complexes) by MAS solid-state NMR spectroscopy. In particular, molecule orientation, dynamics and hydration have been investigated. It is proved that orientation of membrane proteins (e.g. Gramicidin A, WALP23) in aligned lipid bilayers can be obtained by recoupling N-15 CSA at fast MAS rates. A combination of scalar-coupling and dipolar-coupling based experiments (i.e. dynamics-based spectral editing) is proposed to study mobility of protein domains as shown for the cardiac modulator Phospholamban. Finally, a model of the paired helical filaments formed by protein Tau in Alzheimer`s Disease is obtained from water-protein magnetization transfer (i.e. water-edited) experiments

Loss of ATRX and DAXX expression identifies poor prognosis for smooth muscle tumours of uncertain malignant potential and early stage uterine leiomyosarcoma

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Treatment Response Assessment in IDH-Mutant Glioma Patients by Noninvasive 3D Functional Spectroscopic Mapping of 2-Hydroxyglutarate

Purpose: Measurements of objective response rates are critical to evaluate new glioma therapies. The hallmark metabolic alteration in gliomas with mutant isocitrate dehydrogenase (IDH) is the overproduction of oncometabolite 2-hydroxyglutarate (2HG), which plays a key role in malignant transformation. 2HG represents an ideal biomarker to probe treatment response in IDH-mutant glioma patients, and we hypothesized a decrease in 2HG levels would be measureable by in vivo magnetic resonance spectroscopy (MRS) as a result of antitumor therapy. Experimental Design: We report a prospective longitudinal imaging study performed in 25 IDH-mutant glioma patients receiving adjuvant radiation and chemotherapy. A newly developed 3D MRS imaging was used to noninvasively image 2HG. Paired Student t test was used to compare pre- and posttreatment tumor 2HG values. Test-retest measurements were performed to determine the threshold for 2HG functional spectroscopic maps (fSM). Univariate and multivariate regression were performed to correlate 2HG changes with Karnofsky performance score (KPS). Results: We found that mean 2HG (2HG/Cre) levels decreased significantly (median=48.1%; 95% confidence interval=27.3%-56.5%; P=0.007) in the posttreatment scan. The volume of decreased 2HG correlates (R2=0.88, P=0.002) with clinical status evaluated by KPS. Conclusions: We demonstrate that dynamic measurements of 2HG are feasible by 3D fSM, and the decrease of 2HG levels can monitor treatment response in patients with IDH-mutant gliomas. Our results indicate that quantitative in vivo 2HG imaging maybe used for precision medicine and early response assessment in clinical trials of therapies targeting IDH-mutant gliomas

Dynamic 31P-MRSI using spiral spectroscopic imaging can map mitochondrial capacity in muscles of the human calf during plantar flexion exercise at 7T

Phosphorus MRSI (31P–MRSI) using a spiral‐trajectory readout at 7 T was developed for high temporal resolution mapping of the mitochondrial capacity of exercising human skeletal muscle. The sensitivity and localization accuracy of the method was investigated in phantoms.In vivoperformance was assessed in 12 volunteers, who performed a plantar flexion exercise inside a whole‐body 7 T MR scanner using an MR‐compatible ergometer and a surface coil. In five volunteers the knee was flexed (~60°) to shift the major workload from the gastrocnemii to the soleus muscle. Spiral‐encoded MRSI provided 16–25 times faster mapping with a better point spread function than elliptical phase‐encoded MRSI with the same matrix size. The inevitable trade‐off for the increased temporal resolution was a reduced signal‐to‐noise ratio, but this was acceptable. The phosphocreatine (PCr) depletion caused by exercise at 0° knee angulation was significantly higher in both gastrocnemii than in the soleus (i.e. 64.8 ± 19.6% and 65.9 ± 23.6% in gastrocnemius lateralis and medialis versus 15.3 ± 8.4% in the soleus). Spiral‐encoded 31P–MRSI is a powerful tool for dynamic mapping of exercising muscle oxidative metabolism, including localized assessment of PCr concentrations, pH and maximal oxidative flux with high temporal and spatial resolution

From genetics to epigenetics: new perpectives in Tourette Syndrome research

Gilles de la Tourette Syndrome (TS) is a neurodevelopmental disorder marked by the appearance of multiple involuntary motor and vocal tics. TS presents high comorbidity rates with other disorders such as attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). TS is highly heritable and has a complex polygenic background. However, environmental factors also play a role in the manifestation of symptoms. Different epigenetic mechanisms may represent the link between these two causalities. Epigenetic regulation has been shown to have an impact in the development of many neuropsychiatric disorders, however very little is known about its effects on Tourette Syndrome.This review provides a summary of the recent findings in the genetic background of TS, followed by an overview on different epigenetic mechanisms, such as DNA methylation, histone modifications and non-coding RNAs in the regulation of gene expression. Epigenetic studies in other neurological and psychiatric disorders are discussed along with the TS-related epigenetic findings available in the literature to date. Moreover, we are proposing that some general epigenetic mechanisms seen in other neuropsychiatric disorders may also play a role in the pathogenesis of TS

ECCENTRIC: a fast and unrestrained approach for high-resolution in vivo metabolic imaging at ultra-high field MR

A novel method for fast and high-resolution metabolic imaging, called ECcentric Circle ENcoding TRajectorIes for Compressed sensing (ECCENTRIC), has been developed and implemented on 7 Tesla human MRI. ECCENTRIC is a non-Cartesian spatial-spectral encoding method optimized for random undersampling of magnetic resonance spectroscopic imaging (MRSI) at ultra-high field. The approach provides flexible and random (k,t) sampling without temporal interleaving to improve spatial response function and spectral quality. ECCENTRIC needs low gradient amplitudes and slew-rates that reduces electrical, mechanical and thermal stress of the scanner hardware, and is robust to timing imperfection and eddy-current delays. Combined with a model-based low-rank reconstruction, this approach enables simultaneous imaging of up to 14 metabolites over the whole-brain at 2-3mm isotropic resolution in 4-10 minutes with high signal-to-noise ratio. In 20 healthy volunteers and 20 glioma patients ECCENTRIC demonstrated unprecedented mapping of fine structural details of metabolism in healthy brains and an extended metabolic fingerprinting of glioma tumors.Comment: 20 pages, 7 figures,2 tables, 10 pages supplementary materia