Proton MRS (1H MRS) provides noninvasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Although most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges toward obtaining reliable good‐quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the PRESS localization sequence was found to be unacceptably high at 3 T, and use of the semi‐adiabatic localization by adiabatic selective refocusing sequence is a recommended solution. Incorporation of simulated metabolite basis sets into analysis routines is recommended for reliably capturing the full spectral detail available from short TE acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B0) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. Implementation of these recommendations should strengthen current clinical applications and advance progress toward developing and validating new MRS biomarkers for clinical use.

Once an MRS dataset has been acquired, several important steps must be taken to obtain the desired metabolite concentration measures. First, the data must be preprocessed to prepare them for analysis. Next, the intensity of the metabolite signal(s) of interest must be estimated. Finally, the measured metabolite signal intensities must be converted into scaled concentration units employing a quantitative reference signal to allow meaningful interpretation. In this paper, we review these three main steps in the post-acquisition workflow of a single-voxel MRS experiment (preprocessing, analysis and quantification) and provide recommendations for best practices at each step. Abbreviations: 1 H, proton; 13 C, carbon-13; B 0 , main magnetic field; B 1 , RF field; Cr, creatine; CRMVB, Cramér-Rao minimum variance bound; CSF, cerebrospinal fluid; d GM , water density of grey matter; d WM , water density of white matter; ERETIC, Electric Reference to Access in vivo Concentrations; f CSF , volume fraction of cerebrospinal fluid inside the MRS voxel; fCSF H2O , water mole fraction in cerebrospinal fluid; fGM, volume fraction of gray matter inside the MRS voxel; fGM H2O , water mole fraction in gray matter; FFT, fast Fourier transform; FID, free induction decay; FQN, fit quality number; FWHM, full width at half maximum; f WM , volume fraction of white matter inside the MRS voxel; fWM H2O , water mole fraction in white matter; GM, grey matter; GPC, glycerophosphocholine; [H 2 O] molal , water concentration in moles of water per kilogram of tissue water = 55.49 moles/kg; [H 2 O] molar , water concentration in moles of water per liter of tissue water; HERMES, Hadamard encoding and reconstruction of MEGA-edited spectroscopy; MEGA-PRESS, Mescher-Garwood point resolved spectroscopy; [M] GM /[M] WM , assumed ratio of grey matter to white matter metabolite concentrations; MM, macromolecules; [M]molal, metabolite concentration in moles of metabolite per kilogram of tissue water; [M]molar, metabolite concentration in moles of metabolite per liter of tissue water; MRSI, magnetic resonance spectroscopic imaging; NAA, N-acetylaspartate; NAAG, N-acetylaspartylglutamate; N M , number of protons contributing to metabolite signal; N P , number of points in FID/spectrum; N pc , number of phase encoding steps in one phase cycle; N RF , number of RF channels; N tra , number of transients;PCh, phosphocholine; PCr, phosphocreatine; RH2O CSF , relaxation scaling factor for water in cerebrospinal fluid; RH2O GM , relaxation scaling factor for water in grey matter; RH2O WM , relaxation scaling factor for water in white matter; RM, relaxation scaling factor for tissue metabolite signal; RM GM , relaxation scaling factor for metabolite in grey matter; RM WM , relaxation scaling factor for metabolite in white matter; S H2O , water signal intensity; SH2O obs , observed water signal intensity in the presence of relaxation; S M , metabolite signal intensity; SM obs , observed metabolite signal intensity in the presence of relaxation; SNR, signal-to-noise r...

A large body of published work shows that proton (hydrogen 1 [ 1 H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of 1 H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of 1 H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which 1 H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units.q RSNA, 2014 Online supplemental material is available for this article. G.O. (e-mail: gulin@cmrr.umn.edu). 2 The complete list of authors and affiliations is at the end of this article.q RSNA, 2014 Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at www.rsna.org/rsnarights. Radiology H MR Spectrum of the Brain: Metabolites and Their Biomarker PotentialMR spectroscopy provides a very different basic "readout" than MR imaging, namely a spectrum rather than an techniques were developed. These early localization techniques included pointresolved spectroscopy (PRESS) (1,2) and stimulated echo acquisition mode (STEAM) (3), methods that are now widely used in clinical MR spectroscopy applications.Preliminary studies revealed large differences in metabolite levels in acute stroke (4), chronic multiple sclerosis (5), and brain tumors compared with healthy brain (6). Although this work stimulated a surge of interest in 1 H MR spectroscopy for diagnosing and assessing CNS disorders during the early days of the "Decade of the Brain" (1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999), many suboptimal patient studies (7) and the lack of consistent guidelines have led to a situation where, 20 years later, MR spectroscopy is still considered an "investigational technique" by some medical professionals and health care organizations. However, the ability to make an early, noninvasive diagnosis or to increase confidence in a suspected diagnosis is highly valued by patients and clinicians alike. As a result, an increasing number of imaging centers are incorporating MR spectroscopy into their clinical protocols for brain...

Glial cells are thought to supply energy for neurotransmission by increasing nonoxidative glycolysis; however, oxidative metabolism in glia may also contribute to increased brain activity. To study glial contribution to cerebral energy metabolism in the unanesthetized state, we measured neuronal and glial metabolic fluxes in the awake rat brain by using a double isotopic-labeling technique and a twocompartment mathematical model of neurotransmitter metabolism. Rats (n ϭ 23) were infused simultaneously with ). The glial TCA cycle rate was ϳ30% of total TCA cycle activity. A high pyruvate carboxylase rate (V PC , ϳ0.14 -0.18 mol ⅐ gm Ϫ1 ⅐ min Ϫ1) contributed to the glial TCA cycle flux. This anaplerotic rate in the awake rat brain was severalfold higher than under deep pentobarbital anesthesia, measured previously in our laboratory using the same 13 C-labeling technique. We postulate that the high rate of anaplerosis in awake brain is linked to brain activity by maintaining glial glutamine concentrations during increased neurotransmission.

Purpose To determine the test-retest reproducibility of neurochemical concentrations obtained with a highly optimized, short-echo, single voxel proton MRS pulse sequence at 3T and 7T using state-of-the-art hardware. Methods A semi-LASER sequence (TE = 26–28ms) was used to acquire spectra from the posterior cingulate and cerebellum at 3T and 7T from 6 healthy volunteers who were scanned weekly 4 times on both scanners. Spectra were quantified with LCModel. Results More neurochemicals were quantified with mean Cramér-Rao lower bounds (CRLB) ≤ 20% at 7T than at 3T despite comparable frequency-domain SNR. While CRLB were lower at 7T (p < 0.05), between-session coefficients of variance (CVs) were comparable at the two fields with 64 transients. Five metabolites were quantified with between-session CVs ≤ 5% at both fields. Analysis of subspectra showed that a minimum achievable CV was reached with a lower number of transients at 7T for multiple metabolites and that between-session CVs were lower at 7T than at 3T with fewer than 64 transients. Conclusion State-of-the-art MRS methodology allows excellent reproducibility for many metabolites with 5 minute data averaging on clinical 3T hardware. Sensitivity and resolution advantages at 7T are important for weakly represented metabolites, short acquisitions and small volumes-of-interest.

A comprehensive comparative study of metabolite quantification from the human brain was performed on the same 10 subjects at 4T and 7T using MR scanners with identical consoles, the same type of RF coils, and identical pulse sequences and data analysis. Signal-to-noise ratio (SNR) was increased by a factor of 2 at 7T relative to 4T in a volume of interest selected in the occipital cortex using half-volume quadrature radio frequency (RF) coils. Spectral linewidth was increased by 50% at 7T, which resulted in a 14% increase in spectral resolution at 7T relative to 4T. Seventeen brain metabolites were reliably quantified at both field strengths. Metabolite quantification at 7T was less sensitive to reduced SNR than at 4T. The precision of metabolite quantification and detectability of weakly represented metabolites were substantially increased at 7T relative to 4T. Because of the increased spectral resolution at 7T, only one-half of the SNR of a 4T spectrum was required to obtain the same quantification precision. The Cramé r-Rao lower bounds (CRLB), a measure of quantification precision, of several metabolites were lower at both field strengths than the intersubject variation in metabolite concentrations, which resulted in a strong correlation between metabolite concentrations of individual subjects measured at 4T and 7T. The potential of high-field in vivo 1 H NMR spectroscopy to provide extended neurochemical information based on increased sensitivity and spectral resolution was demonstrated approximately a decade ago (1,2). Since then, a number of comparison studies have investigated the improvement in signal-to-noise ratio (SNR), spectral resolution, and the precision of metabolite quantification with an increase in static magnetic field B 0 (3-10). However, reported gains in SNR and metabolite quantification have not been consistent, which might be explained by the complexity of the comparison of two different MR scanners operating at different B 0 values. A number of factors influence the SNR, spectral resolution, and ultimately the quantification precision, such as functionality of the transmit and receive channels, B 0 shimming efficiency, radio frequency (RF) coils, pulse sequence design, and data processing (11). Increases in SNR by 20% to 46% at 3T relative to 1.5T were reported in single-voxel (3,7) and chemical-shift imaging (CSI) studies (5,6) of the human brain. Modest increase (5), almost no improvement (3), or even decrease (7) in spectral resolution (ppm) at 3T relative to 1.5T have been observed. The diagnostic accuracy of 1 H NMR spectroscopy to distinguish patients with Alzheimer disease from cognitively normal subjects was not improved at 3T relative to 1.5T (7). On the other hand, precision and reproducibility of myo-inositol quantification were significantly increased in another comparative study at 3T vs. 1.5T (10). The SNR in human brain stimulatedecho acquisition mode (STEAM) spectra was increased by ϳ80% at 4T relative to 1.5T (4), while SNR of singlet resonances increased linearly with...

The spinocerebellar ataxias (SCAs) comprise more than 40 autosomal dominant neurodegenerative disorders that present principally with progressive ataxia. Within the past few years, studies of pathogenic mechanisms in the SCAs have led to the development of promising therapeutic strategies, especially for SCAs caused by polyglutamine-coding CAG repeats. Nucleotide-based gene-silencing approaches that target the first steps in the pathogenic cascade are one promising approach not only for polyglutamine SCAs but also for the many other SCAs caused by toxic mutant proteins or RNA. For these and other emerging therapeutic strategies, well-coordinated preparation is needed for fruitful clinical trials. To accomplish this goal, investigators from the United States and Europe are now collaborating to share data from their respective SCA cohorts. Increased knowledge of the natural history of SCAs, including of the premanifest and early symptomatic stages of disease, will improve the prospects for success in clinical trials of disease-modifying drugs. In addition, investigators are seeking validated clinical outcome measures that demonstrate responsiveness to changes in SCA populations. Findings suggest that MRI and magnetic resonance spectroscopy biomarkers will provide objective biological readouts of disease activity and progression, but more work is needed to establish disease-specific biomarkers that track target engagement in therapeutic trials. Together, these efforts suggest that the development of successful therapies for one or more SCAs is not far away.

Purpose To determine if neurochemical concentrations obtained at two MRI sites using clinical 3 T scanners can be pooled when a highly optimized, non-vendor short-echo, single voxel proton MRS pulse sequence is utilized in conjunction with identical calibration and quantification procedures. Methods A modified semi-LASER sequence (TE = 28 ms) was used to acquire spectra from two brain regions (cerebellar vermis and pons) on two Siemens 3 T scanners using the same B0 and B1 calibration protocols from two different cohorts of healthy volunteers (N=24–33 per site) matched for age and BMI. Spectra were quantified with LCModel using water scaling. Results The spectral quality was very consistent between the two sites and allowed reliable quantification of at least 13 metabolites in the vermis and pons compared to 3 – 5 metabolites in prior multi-site MRS trials using vendor-provided sequences. The neurochemical profiles were nearly identical at the two sites and showed the feasibility to detect inter-individual differences in the healthy brain. Conclusion Highly reproducible neurochemical profiles can be obtained on different clinical 3 T scanners at different sites, provided that the same, optimized acquisition and analysis techniques are utilized. This will allow pooling of multi-site data in clinical studies, which is particularly critical for rare neurological diseases.