Contribution of macromolecules to brain H-1 MR spectra: Experts' consensus recommendations

Proton MR spectra of the brain, especially those measured at short and intermediate echo times, contain signals from mobile macromolecules (MM). A description of the main MM is provided in this consensus paper. These broad peaks of MM underlie the narrower peaks of metabolites and often complicate their quantification but they also may have potential importance as biomarkers in specific diseases. Thus, separation of broad MM signals from low molecular weight metabolites enables accurate determination of metabolite concentrations and is of primary interest in many studies. Other studies attempt to understand the origin of the MM spectrum, to decompose it into individual spectral regions or peaks and to use the components of the MM spectrum as markers of various physiological or pathological conditions in biomedical research or clinical practice. The aim of this consensus paper is to provide an overview and some recommendations on how to handle the MM signals in different types of studies together with a list of open issues in the field, which are all summarized at the end of the paper.

In vivo macromolecule signals in rat brain 1 H‐MR spectra at 9.4T: Parametrization, spline baseline estimation, and T 2 relaxation times

Cristina Ramona Cudalbu, Bernard Lanz, Veronika Rackayová, Dunja Simicic, Lijing Xin

Purpose Reliable detection and fitting of macromolecules (MM) are crucial for accurate quantification of brain short-echo time (TE) 1H-MR spectra. An experimentally acquired single MM spectrum is commonly used. Higher spectral resolution at ultra-high field (UHF) led to increased interest in using a parametrized MM spectrum together with flexible spline baselines to address unpredicted spectroscopic components. Herein, we aimed to: (1) implement an advanced methodological approach for post-processing, fitting, and parametrization of 9.4T rat brain MM spectra; (2) assess the concomitant impact of the LCModel baseline and MM model (ie, single vs parametrized); and (3) estimate the apparent T2 relaxation times for seven MM components. Methods A single inversion recovery sequence combined with advanced AMARES prior knowledge was used to eliminate the metabolite residuals, fit, and parametrize 10 MM components directly from 9.4T rat brain in vivo 1H-MR spectra at different TEs. Monte Carlo simulations were also used to assess the concomitant influence of parametrized MM and DKNTMN parameter in LCModel. Results A very stiff baseline (DKNTMN ≥ 1 ppm) in combination with a single MM spectrum led to deviations in metabolite concentrations. For some metabolites the parametrized MM showed deviations from the ground truth for all DKNTMN values. Adding prior knowledge on parametrized MM improved MM and metabolite quantification. The apparent T2 ranged between 12 and 24 ms for seven MM peaks. Conclusion Moderate flexibility in the spline baseline was required for reliable quantification of real/experimental spectra based on in vivo and Monte Carlo data. Prior knowledge on parametrized MM improved MM and metabolite quantification.

2021

Improved ¹H-[¹³C] and ¹H NMR methods for in vivo measurement of cerebral metabolism

Lijing Xin

Nuclear magnetic resonance (NMR) spectroscopy can be applied in vivo to measure static or dynamic biochemical information, e.g., concentrations of metabolites and metabolic fluxes, using various nuclei such as 1H, 13C, 31P and 15N. The work of this thesis involves both 1H and 13C nuclei and focuses on improving 1H NMR detection methods for measuring metabolites in vivo in rat brain. 13C NMR spectroscopy can be used to monitor the flow of 13C label from a 13C enriched substrate, such as glucose or acetate, into different NMR detectable metabolites, e.g., glutamate (Glu) and glutamine (Gln), for the quantitative study of cerebral metabolism in vivo. 1H-observed 13C-edited (1H-[13C]) NMR spectroscopy is an alternative to direct 13C NMR detection of 13C labeled metabolites, allowing a higher spatial and temporal resolution, albeit at a lower spectral resolution. In this context, a hybrid full signal intensity 1H-[13C] NMR sequence, combining a 13C editing block based on an inversion B1 insensitive spectral editing pulse (BISEP) with a spin-echo based localization (SPECIAL), was developed and implemented at ultra-high magnetic field (14.1 T) to benefit from increased sensitivity and spectral resolution at high B0. As a result, high quality 1H-[13C] NMR spectra were obtained, leading to an improved quantification of 13C labeled metabolites, which allowed the measurement of time courses of Glu C4, Gln C4, as well as, for the first time, of Glu C3 and of Gln C3, with high temporal resolution from a small acquisition volume. Although at high magnetic field spectral resolution and sensitivity are improved, spectral overlap is still present, e.g., the N-acetylaspartate (NAA) C6 is easily obscured by the intensive labeling of Glu C3 and Gln C3 (Glx C3), due to their complex coupling patterns. To improve the detection of unresolved 13C labeled metabolites, we developed an alternative 1H-[13C] NMR editing sequence termed RACED-STEAM (selective Resonances suppression by Adiabatic Carbon Editing and Decoupling single-voxel STimulated Echo Acquisition Mode), which can selectively suppress 1H resonances bound to a specific 13C to uncover resonances that are difficult to resolve in the 1H-[13C] NMR spectrum. Results showed the efficient suppression of Glx C3 and Glu C4, allowing the detection of NAA C6 and Gln C4 at 9.4 T. The application of this method to measure the time course of NAA C6 demonstrated that NAA C6 turnover can be measured at very low levels of isotopic enrichment in a small volume, within a time frame of a few hours. The proposed scheme could also be extended to lower magnetic fields provided that the 13C chemical shifts remain sufficiently resolved. Similarly, due to limited spectral resolution and sensitivity, editing techniques for the in vivo detection of metabolites using 1H NMR spectroscopy are still in development. Many in vivo 1H NMR editing sequences are usually performed at moderate to long echo times (TE). Furthermore, several 1H NMR spectroscopy studies are performed at long TE to avoid the confounding effect of macromolecular signals on metabolite quantification. In such cases, proton T2 relaxation times of metabolites have to be taken into account for proper quantification of metabolite concentrations. While T2 relaxation times of singlets have been characterized in several studies, due to the relative experimental simplicity, similar information is lacking from coupled spin resonances of cerebral metabolites. In this thesis, spectral simulations based on the density matrix formalism were initially performed to predict the response of spin systems to the pulse sequence used. T2 relaxation times of coupled spin resonances and singlet resonances of cerebral metabolites were then measured in rat brain in vivo at 9.4 T. Data analysis was performed using LCModel combined with simulated TE-specific spectra. The aforementioned spectral simulations were further used to optimize pulse sequence parameters for the detection of metabolites, such as glycine, whose resonance signal is overlapped with the more intense myo-inositol resonances. A favorable short TE (i.e., 20 ms) was sufficient to reduce the signal intensity of myo-inositol, allowing the detection of glycine in vivo in rat brain at 9.4 T. This work suggests that at high magnetic fields, glycine can be measured at a relatively short TE without additional editing efforts. Moreover, glycine is present at a particularly high concentration in the medulla oblongata (MO). Therefore, we further measured regional distribution of glycine in the hippocampus, cortex, striatum and MO of the rat brain, as well as the highly specific neurochemical profile of the MO. In conclusion, dedicated approaches for 1H NMR detection developed and validated in this thesis lead to improved dynamic measurement of 13C labeling time courses such as the time courses of 13C labeling of Glu C3 and Gln C3, as well as the spectral resolved NAA C6, the direct in vivo detection of glycine in rat brain at 9.4 T and the measurement of T2 relaxation times of numerous J-coupled metabolites for the first time.

EPFL2009

H-1 NMR spectroscopy of rat brain in vivo at 14.1 Tesla: Improvements in quantification of the neurochemical profile

Cristina Ramona Cudalbu, Rolf Gruetter, Lijing Xin

Ultra-short echo-time proton single voxel spectra of rat brain were obtained on a 14.1 T 26 cm horizontal bore system. At this field, the fitted linewidth in the brain tissue of adult rats was about 11 Hz. New, separated resonances ascribed to phosphocholine, glycerophosphocholine and N-acetylaspartate were detected for the first time in vivo in the spectral range of 4.2-4.4 ppm. Moreover, improved separation of the resonances of lactate, alanine, gamma-aminobutyrate, glutamate and glutathione was observed. Metabolite concentrations were estimated by fitting in vivo spectra to a linear combination of simulated spectra of individual metabolites and a measured spectrum of macromolecules (LCModel). The calculated concentrations of metabolites were generally in excellent agreement with those obtained at 9.4 T. These initial results further indicated that increasing magnetic field strength to 14.1 T enhanced spectral resolution in H-1 NMR spectroscopy. This implies that the quantification of the neurochemical profile in rodent brain can be achieved with improved accuracy and precision. (C) 2008 Elsevier Inc. All rights reserved.

2008

Improved ¹H-[¹³C] and ¹H NMR methods for in vivo measurement of cerebral metabolism

Lijing Xin

EPFL2009