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Background and ObjectivesD-2-hydroxyglutarate (2HG) characterizesIDH-mutant gliomas and can be detected and quantified with edited MRS (MEGA-PRESS). In this study, we investigated the clinical, radiologic, and molecular parameters affecting 2HG levels.MethodsMEGA-PRESS data were acquired in 71 patients with glioma (24 untreated, 47 treated) on a 3 T system. Eighteen patients were followed during cytotoxic (n = 12) or targeted (n = 6) therapy. 2HG was measured in tumor samples using gas chromatography coupled to mass spectrometry (GCMS).ResultsMEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (>27 cm3;p= 0.02), voxel coverage (>75%;p= 0.002), and expansive presentation (defined by equal size of T1and FLAIR abnormalities,p= 0.04). 2HG levels were positively correlated withIDH-mutant allelic fraction (p= 0.03) and total choline levels (p< 0.001) and were higher inIDH2-mutant compared withIDH1R132H-mutant and non–R132HIDH1-mutant patients (p= 0.002). In patients receiving IDH inhibitors, 2HG levels decreased within a few days, demonstrating the on-target effect of the drug, but 2HG level decrease did not predict tumor response. Patients receiving cytotoxic treatments showed a slower decrease in 2HG levels, consistent with tumor response and occurring before any tumor volume change on conventional MRI. At progression, 1p/19q codeleted gliomas, but not the non-codeleted, showed detectable in vivo 2HG levels, pointing out to different modes of progression characterizing these 2 entities.DiscussionMEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy ofIDHinhibition and suggests different patterns of tumor progression in astrocytomas compared with oligodendrogliomas.

To evaluate the ability of the PRESS sequence (TTwenty-three subjects with a glioma were retrospectively included based on the availability of both MEGA-PRESS and PRESS acquisitions at 3T, and the presence of the cystathionine signal in the edited MR spectrum. In eight subjects, the PRESS acquisition was performed also in normal tissue. Metabolite quantification was performed using LCModel and simulated basis sets. The LCModel analysis for the PRESS data was performed with and without cystathionine.All subjects with glioma had detectable cystathionine levels1 mM with Cramér-Rao lower bounds (CRLB)15%. The mean cystathionine concentrations were 3.49 ± 1.17 mM for MEGA-PRESS and 2.20 ± 0.80 mM for PRESS data. Cystathionine concentrations showed a significant correlation between the two MRS methods (r = 0.58, p = .004), and it was not detectable in normal tissue. Using PRESS, 19 metabolites were quantified with CRLB50% for more than half of the subjects. The metabolites that were significantly (p .0028) and mostly affected by the omission of cystathionine were aspartate, betaine, citrate, γ-aminobutyric acid (GABA), and serine.Cystathionine was detectable by PRESS in all the selected gliomas, while it was not detectable in normal tissue. The omission from the spectral analysis of cystathionine led to severe biases in the quantification of other neurochemicals that may play key roles in cancer metabolism.

PURPOSE: Advanced MRS protocols improve data quality and reproducibility relative to vendor-provided protocols, however are challenging to incorporate into the clinical workflow and require local MRS expertise for successful implementation. Here, we developed an automated advanced MRS acquisition protocol at 3T to facilitate acquisition of high-quality spectroscopic data without local MRS expertise. METHODS: First, a B(0) shimming protocol was selected for automation by comparing three widely used B(0) algorithms (two vendor protocols and FAST(EST)MAP). Next, voxel-based B(0) and B(1) calibrations were incorporated into the consensus-recommended semi-LASER sequence and combined with AutoVOI, a recently developed method for automated voxel prescription. The efficiency of collecting single-voxel data from a clinical cohort (N=40) with the automated protocol (calibration time and fraction of usable datasets) was compared with the non-automated semi-LASER protocol (N=35) whereby all prescan calibrations were executed manually in the academic hospital setting with rotating MR technologists in the neuroradiology unit. RESULTS: A multi-iteration FAST(EST)MAP protocol resulted in narrower water linewidths than vendor’s B(0) shim protocols for data acquired from six brain locations (P

The increased spectral dispersion achieved at ultra-high field permits quantification of γ-aminobutyric acid (GABA) concentrations at ultra-short-TE without editing. This work investigated the influence of spectral quality and different LCModel fitting approaches on quantification of GABA. Additionally, the sensitivity with which cross-sectional and longitudinal variations in GABA concentrations can be observed was characterized.In - vivo spectra were acquired in the posterior cingulate cortex of 10 volunteers at 7 T using a STEAM sequence. Synthetically altered spectra with different levels of GABA signals were used to investigate the reliability of GABA quantification with different LCModel fitting approaches and different realizations of SNR. The synthetically altered spectra were also used to characterize the sensitivity of GABA quantification.The best LCModel fitting approach used stiff spline baseline, no soft constraints, and measured macromolecules in the basis set. With lower SNR, coefficients of variation increased dramatically. Longitudinal and cross-sectional variations in GABA of 10% could be detected with 79 and 48 participants per group, respectively. However, the small cohort may bias the calculation of the coefficients of variation and of the sample size that would be needed to detect variations in GABA.Reliable quantification of normal and abnormal GABA concentrations was achieved for high quality 7 T spectra using LCModel fitting.

Equilibrium between excitation and inhibition (E/I balance) is key to healthy brain function. Conversely, disruption of normal E/I balance has been implicated in a range of central neurological pathologies. Magnetic resonance spectroscopy (MRS) provides a non-invasive means of quantifying in vivo concentrations of excitatory and inhibitory neurotransmitters, which could be used as diagnostic biomarkers. Using the ratio of excitatory and inhibitory neurotransmitters as an index of E/I balance is common practice in MRS work, but recent studies have shown inconsistent evidence for the validity of this proxy. This is underscored by the fact that different measures are often used in calculating E/I balance such as glutamate and Glx (glutamate and glutamine). Here we used a large MRS dataset obtained at ultra-high field (7 T) measured from 193 healthy young adults and focused on two brain regions - prefrontal and occipital cortex - to resolve this inconsistency. We find evidence that there is an inter-individual common ratio between GABA+ (γ-aminobutyric acid and macromolecules) and Glx in the occipital, but not prefrontal cortex. We further replicate the prefrontal result in a legacy dataset (n = 78) measured at high-field (3 T) strength. By contrast, with ultra-high field MRS data, we find extreme evidence that there is a common ratio between GABA+ and glutamate in both prefrontal and occipital cortices, which cannot be explained by participant demographics, signal quality, fractional tissue volume, or other metabolite concentrations. These results are consistent with previous electrophysiological and theoretical work supporting E/I balance. Our findings indicate that MRS-detected GABA+ and glutamate (but not Glx), are a reliable measure of E/I balance .

Friedreich ataxia is the most common hereditary ataxia. Atrophy of the spinal cord is one of the hallmarks of the disease. MRI and magnetic resonance spectroscopy are powerful and non-invasive tools to investigate pathological changes in the spinal cord. A handful of studies have reported cross-sectional alterations in Friedreich ataxia using MRI and diffusion MRI. However, to our knowledge no longitudinal MRI, diffusion MRI or MRS results have been reported in the spinal cord. Here, we investigated early-stage cross-sectional alterations and longitudinal changes in the cervical spinal cord in Friedreich ataxia, using a multimodal magnetic resonance protocol comprising morphometric (anatomical MRI), microstructural (diffusion MRI), and neurochemical (1H-MRS) assessments.We enrolled 28 early-stage individuals with Friedreich ataxia and 20 age- and gender-matched controls (cross-sectional study). Disease duration at baseline was 5.5 ± 4.0 years and Friedreich Ataxia Rating Scale total neurological score at baseline was 42.7 ± 13.6. Twenty-one Friedreich ataxia participants returned for 1-year follow-up, and 19 of those for 2-year follow-up (cohort study). Each visit consisted in clinical assessments and magnetic resonance scans. Controls were scanned at baseline only. At baseline, individuals with Friedreich ataxia had significantly lower spinal cord cross-sectional area (−31%, P = 8 × 10−17), higher eccentricity (+10%, P = 5 × 10−7), lower total N-acetyl-aspartate (tNAA) (−36%, P = 6 × 10−9) and higher myo-inositol (mIns) (+37%, P = 2 × 10−6) corresponding to a lower ratio tNAA/mIns (−52%, P = 2 × 10−13), lower fractional anisotropy (−24%, P = 10−9), as well as higher radial diffusivity (+56%, P = 2 × 10−9), mean diffusivity (+35%, P = 10−8) and axial diffusivity (+17%, P = 4 × 10−5) relative to controls. Longitudinally, spinal cord cross-sectional area decreased by 2.4% per year relative to baseline (P = 4 × 10−4), the ratio tNAA/mIns decreased by 5.8% per year (P = 0.03), and fractional anisotropy showed a trend to decrease (−3.2% per year, P = 0.08). Spinal cord cross-sectional area correlated strongly with clinical measures, with the strongest correlation coefficients found between cross-sectional area and Scale for the Assessment and Rating of Ataxia (R = −0.55, P = 7 × 10−6) and between cross-sectional area and Friedreich ataxia Rating Scale total neurological score (R = −0.60, P = 4 × 10−7). Less strong but still significant correlations were found for fractional anisotropy and tNAA/mIns. We report here the first quantitative longitudinal magnetic resonance results in the spinal cord in Friedreich ataxia. The largest longitudinal effect size was found for spinal cord cross-sectional area, followed by tNAA/mIns and fractional anisotropy. Our results provide direct evidence that abnormalities in the spinal cord result not solely from hypoplasia, but also from neurodegeneration, and show that disease progression can be monitored non-invasively in the spinal cord.

BackgroundFriedreich Ataxia (FRDA) is the most common hereditary ataxia. Atrophy of the spinal cord is one of the hallmarks of the disease. Magnetic resonance imaging (MRI) and spectroscopy (MRS) are powerful and non-invasive tools to investigate pathological changes in the spinal cord. A handful of studies have reported cross-sectional alterations in FRDA using MRI and diffusion MRI (dMRI) in FRDA. However, to our knowledge no longitudinal MRI, dMRI or MRS results have been reported in the spinal cord in FRDA.ObjectiveTo investigate early-stage cross-sectional alterations and longitudinal changes in the cervical spinal cord in FRDA, using a multimodal magnetic resonance (MR) protocol comprising morphometric (anatomical MRI), microstructural (dMRI), and neurochemical (1H MRS) assessments.DesignWe enrolled 28 early-stage individuals with FRDA and 20 age- and gender-matched controls (cross-sectional study). Disease duration at baseline was 5.5±4.0 years and Friedreich Ataxia Rating Scale (FARS) total neurological score at baseline was 42.7±13.6. Twenty-one FRDA participants returned for 1-year follow-up, and 19 of those for 2-year follow-up (cohort study). Each visit consisted in clinical assessments and MR scans. Controls were scanned at baseline only.ResultsAt baseline, individuals with FRDA had significantly lower spinal cord cross-sectional area (−31%, p=4.10−17), higher eccentricity (+10%, p=5.10−7), lower total N-acetyl-aspartate (−36%, p=6.10−9) and higher myo-inositol (+37%, p=2.10−6) corresponding to a lower ratio tNAA/mIns (−52%, p=2.10−13), lower fractional anisotropy (−24%, p=10−9) as well as higher radial diffusivity (+56%, p=2.10−9), mean diffusivity (+35%, p=10−8) and axial diffusivity (+17%, p=4.10−5) relative to controls.Longitudinally, spinal cord cross-sectional area decreased by 2.4% per year relative to baseline (p=4.10−4), the ratio tNAA/mIns decreased by 5.8% per year (p=0.03), and fractional anisotropy showed a trend to decrease (−3.2% per year, p=0.08).Spinal cord cross-sectional area correlated strongly with clinical measures, with the strongest correlation coefficients found between cross-sectional area and Scale for the Assessment and Rating of Ataxia (SARA) (R=-0.55, p=7.10−6) and between cross-sectional area and FARS total neurological score (R=-0.60, p=4.10−7). Less strong but still significant correlations were found for fractional anisotropy and tNAA/mIns.ConclusionWe report here the first quantitative longitudinal MR results in the spinal cord in FRDA. The largest longitudinal effect size was found for spinal cord cross-sectional area, followed by tNAA/mIns and fractional anisotropy. Our results provide direct evidence that abnormalities in the spinal cord result not solely from hypoplasia, but also from neurodegeneration, and show that disease progression can be monitored non-invasively in the spinal cord.

Proton magnetic resonance spectroscopy ((1)H MRS) may provide information on pathophysiological changes associated with tau deposition in cognitively unimpaired older adults. In this study, the associations of posterior cingulate gyrus tau and amyloid beta (Aβ) deposition on PET with proton magnetic resonance spectroscopy ((1)H MRS) metabolite ratios acquired from bilateral posterior cingulate gyri were investigated in cognitively unimpaired older adults. Participants (n = 40) from the Mayo Clinic Study of Aging underwent single-voxel sLASER (1)H MRS from the posterior cingulate gyrus at 3 Tesla, (18)F-flortaucipir and (11)C-Pittsburgh Compound B (PiB) PET. An increase in posterior cingulate gyrus tau deposition, but not elevated Aβ, was associated with lower N-acetylaspartate/total creatine (tCr) and glutamate (Glu)/tCr ratios, and a sex by tau interaction was observed in association with Glu/tCr. Higher tau levels in cognitively unimpaired older adults are associated with biomarkers of neural and synaptic injury even in the absence of cognitive impairment and these relationships appear to be stronger in women than in men.

PURPOSE: The aim of the study is to optimize the performance of localized (1)H MRS sequences at 3 T, using the entire spin system of N-Acetyl Aspartate (NAA) as an example of the large chemical shift spread of all the metabolites routinely detected in vivo, including the amide region. We specifically focus on the design of the suitable broadband excitation RF pulses to minimize chemical shift artifacts. METHODS: The performance of the excitation and refocusing pulse shapes is evaluated with respect to NAA localization. Two new excitation RF pulses are developed to achieve optimized performance in the brain using single-voxel (1)H MRS at 3 T. Numerical simulations and in vivo experiments are carried out to demonstrate the performance of the RF pulses. RESULTS: New excitation RF pulses with the same B(1) requirements but larger excitation bandwidth (up to a factor of 2) are shown to significantly reduce localization artifacts. The large frequency spread of the entire NAA spin system necessitates the use of broadband excitation and refocusing pulses for MRS at 3 T. CONCLUSION: To minimize chemical shift artifacts of metabolic compounds with spins in the amide area (> 5 ppm) at 3 T it is important to use broadband excitation and refocusing pulses.

D-2-hydroxyglutarate (2HG) characterizesMEGA-PRESS data were acquired in 71 patients with glioma (24 untreated, 47 treated) on a 3 T system. Eighteen patients were followed during cytotoxic (n = 12) or targeted (n = 6) therapy. 2HG was measured in tumor samples using gas chromatography coupled to mass spectrometry (GCMS).MEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (27 cmMEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy of

Neuroimaging with ultra-high field magnets (≥7T) provides superior signal-to-noise, spatial resolution and tissue contrast; but also greater safety concerns, longer scanning times, and increased distortion and field inhomogeneity. Brain and spinal cord anatomic microstructure and function imaged in greater detail offers improved lesion detection, delineation, and characterization. The ongoing development of novel imaging contrasts and translation of cutting-edge sequences will aid more accurate, sensitive, and precise diagnosis, interventional planning, and follow-up for a variety of pathologic conditions.

The primary excitatory and inhibitory neurotransmitters glutamate (Glu) and gamma-aminobutyric acid (GABA) are thought to be involved in the response of the brain to changes in glycemia. Therefore, their reliable measurement is critical for understanding the dynamics of these responses. The concentrations of Glu and GABA, as well as glucose (Glc) in brain tissue, can be measured in vivo using proton (1H) magnetic resonance spectroscopy (MRS). Advanced MRS methodology at ultrahigh field allows reliable monitoring of these metabolites under changing metabolic states. However, the long acquisition times needed for these experiments while maintaining blood Glc levels at predetermined targets present many challenges. We present an advanced MRS acquisition protocol that combines commercial 7T hardware (Siemens Scanner and Nova Medical head coil), BaTiO3 dielectric padding, optical motion tracking, and dynamic frequency and B0 shim updates to ensure the acquisition of reproducibly high-quality data. Data were acquired with a semi-LASER sequence [repetition time/echo time (TR/TE) = 5,000/26 ms] from volumes of interest (VOIs) in the prefrontal cortex (PFC) and hypothalamus (HTL). Five healthy volunteers were scanned to evaluate the effect of the BaTiO3 pads on B1+ distribution. Use of BaTiO3 padding resulted in a 60% gain in signal-to-noise ratio in the PFC VOI over the acquisition without the pad. The protocol was tested in six patients with type 1 diabetes during a clamp study where euglycemic (~100 mg/dL) and hypoglycemic (~50 mg/dL) blood Glc levels were maintained in the scanner. The new protocol allowed retention of all HTL data compared with our prior experience of having to exclude approximately half of the HTL data in similar clamp experiments in the 7T scanner due to subject motion. The advanced MRS protocol showed excellent data quality (reliable quantification of 11–12 metabolites) and stability (p > 0.05 for both signal-to-noise ratio and water linewidths) between euglycemia and hypoglycemia. Decreased brain Glc levels under hypoglycemia were reliably detected in both VOIs. In addition, mean Glu level trended lower at hypoglycemia than euglycemia for both VOIs, consistent with prior observations in the occipital cortex. This protocol will allow robust mechanistic investigations of the primary neurotransmitters, Glu and GABA, under changing glycemic conditions.

PURPOSE: The goal of this study was to propose a novel localized proton magnetic resonance spectroscopy (MRS) sequence that reduces signal loss due to J-modulation in the rat brain in vivo. METHODS: Sprague-Dawley rats were studied at 9.4 T. A semi-LASER sequence with evenly distributed echo-time (T(E)) was used, and a 90° J-refocusing pulse was inserted at T(E)/2. Proton spectra were acquired at two T(E)s (30 and 68 ms), with and without the J-refocused pulse. Data were processed in MATLAB and quantified with LCModel. RESULTS: The J-refocused spectrum acquired at T(E) = 30 ms did not show any signal losses due to J-modulation and had comparable spectral pattern to the one acquired with semi-LASER using the minimum achievable T(E). Higher signal amplitudes for glutamine, γ-aminobutyric acid and glutathione led to more reliable quantification precision for these metabolites. The refocused signal intensities at T(E) = 68 ms were also unaffected by J-modulation but were smaller than the signals at T(E) = 30 ms mainly due to transverse T(2) relaxation of metabolites. CONCLUSION: The proposed localized MRS sequence will be beneficial in both animal and human MRS studies when using ultra-short T(E) is not possible while also providing more reliable quantification precision for J-coupled metabolites.

Purpose To demonstrate feasibility and performance of prospective motion and B0 shim correction for MRS in human brain at 7T. Methods Prospective motion correction using an optical camera and linear B0 shim correction using FASTMAP-like navigators were implemented into a semi-LASER sequence. The effect of motion on spectral quality was assessed without and with prospective correction in prefrontal cortex in 11 subjects. Results Without prospective motion and shim correction, motion resulted in considerable degradation of MR spectra (broader linewidth, lower signal-to-noise ratio, degraded water suppression). With prospective motion and shim correction, spectral quality remained excellent despite motion. Prospective motion correction alone was not sufficient to prevent degradation of spectral quality. Conclusion Prospective motion and B0 shim correction is feasible at 7T and should help improve the robustness of MRS, particularly in motion-prone populations.

Purpose To report the technical aspects of noninvasive detection of cystathionine in human brain glioma with edited MRS, and to investigate possible further acquisition improvements for robust quantification of this metabolite. Methods In vivo 1 H MR spectra were acquired at 3 T in 15 participants with an isocitrate dehydrogenase-mutated glioma using a MEGA-PRESS (MEscher GArwood point resolved spectroscopy) sequence previously employed for 2-hydroxyglutarate detection (TR = 2 s, TE = 68 ms). The editing pulse was applied at 1.9 ppm for the edit-on condition and at 7.5 ppm for the edit-off condition. To evaluate the editing efficiency, spectra were acquired in 1 participant by placing the editing pulse for the edit-on condition at 1.9, 2.03, and 2.16 ppm. Cystathionine concentration was quantified using LCModel and a simulated basis set. To confirm chemical shifts and J-coupling values of cystathionine, the 1 H NMR cystathionine spectrum was measured using a high-resolution 500 MHz spectrometer. Results In 12 gliomas, cystathionine was observed in the in vivo edited MR spectra at 2.72 and 3.85 ppm and quantified. The signal intensity of the cystathionine resonance at 2.72 ppm increased 1.7 and 2.13 times when the editing pulse was moved to 2.03 and 2.16 ppm, respectively. Cystathionine was not detectable in normal brain tissue. Conclusion Cystathionine can be detected in vivo by edited MRS using the same protocol as for 2-hydroxyglutarate detection. This finding may enable a more accurate, noninvasive investigation of cellular metabolism in glioma.

Background Codeletion of chromosome arms 1p and 19q (1p/19q codeletion) highly benefits diagnosis and prognosis in gliomas. In this study, we investigated the effect of 1p/19q codeletion on cancer cell metabolism and evaluated possible metabolic targets for tailored therapies. Methods We combined in vivo 1H (proton) magnetic resonance spectroscopy (MRS) measurements in human gliomas with the analysis of a series of standard amino acids by liquid chromatography-mass spectroscopy (LC-MS) in human glioma biopsies. Sixty-five subjects with low-grade glioma were included in the study: 31 underwent the MRI/MRS examination, 47 brain tumor tissue samples were analyzed with LC-MS, and 33 samples were analyzed for gene expression with quantitative PCR. Additionally, we performed metabolic tracer experiments in cell models with 1p deletion. Results We report the first in vivo detection of cystathionine by MRS in 1p/19q codeleted gliomas. Selective accumulation of cystathionine was observed in codeleted gliomas in vivo, in brain tissue samples, as well as in cells harboring heterozygous deletions for serine- and cystathionine-pathway genes located on 1p: phosphoglycerate dehydrogenase (PHGDH) and cystathionine gamma-lyase (CTH). Quantitative PCR analyses showed 40-50% lower expression of both PHGDH and CTH in 1p/19q codeleted gliomas compared with their non-codeleted counterparts. Conclusions Our results provide strong evidence of a selective vulnerability of codeleted gliomas to serine and glutathione depletion and point to cystathionine as a possible noninvasive marker of treatment response.

The neurochemical information provided by proton magnetic resonance spectroscopy (MRS) or MR spectroscopic imaging (MRSI) can be severely compromised if strong signals originating from brain water and extracranial lipids are not properly suppressed. The authors of this paper present an overview of advanced water/lipid-suppression techniques and describe their advantages and disadvantages. Moreover, they provide recommendations for choosing the most appropriate techniques for proper use. Methods of water signal handling are primarily focused on the VAPOR technique and on MRS without water suppression (metabolite cycling). The section on lipid-suppression methods in MRSI is divided into three parts. First, lipid-suppression techniques that can be implemented on most clinical MR scanners (volume preselection, outer-volume suppression, selective lipid suppression) are described. Second, lipid-suppression techniques utilizing the combination of k-space filtering, high spatial resolutions and lipid regularization are presented. Finally, three promising new lipid-suppression techniques, which require special hardware (a multi-channel transmit system for dynamic B1+ shimming, a dedicated second-order gradient system or an outer volume crusher coil) are introduced.

Spinocerebellar ataxia type 1 is a progressive neurodegenerative, movement disorder. With potential therapies on the horizon, it is critical to identify biomarkers that (i) differentiate between unaffected and spinocerebellar ataxia Type 1-affected individuals; (ii) track disease progression; and (iii) are directly related to clinical changes of the patient. Magnetic resonance imaging of volumetric changes in the brain may be a suitable source of biomarkers for spinocerebellar ataxia Type 1. In a previous report on a longitudinal study of patients with spinocerebellar ataxia Type 1, we evaluated the volume and magnetic resonance spectroscopy measures of the cerebellum and pons, showing pontine volume and pontine N-acetylaspartate-to-myo-inositol ratio were sensitive to change over time. As a follow-up, the current study conducts a whole brain exploration of volumetric MRI measures with the aim to identify biomarkers for spinocerebellar ataxia Type 1 progression. We adapted a joint label fusion approach using multiple, automatically generated, morphologically matched atlases to label brain regions including cerebellar sub-regions. We adjusted regional volumes by total intracranial volume allowing for linear and power-law relationships. We then utilized Bonferroni corrected linear mixed effects models to (i) determine group differences in regional brain volume and (ii) identify change within affected patients only. We then evaluated the rate of change within each brain region to identify areas that changed most rapidly. Lastly, we used a penalized, linear mixed effects model to determine the strongest brain predictors of motor outcomes. Decrease in pontine volume and accelerating decrease in putamen volume: (i) reliably differentiated spinocerebellar ataxia Type 1-affected and -unaffected individuals; (ii) were observable in affected individuals without referencing an unaffected comparison group; (iii) were detectable within ∼6–9 months; and (iv) were associated with increased disease burden. In conclusion, volumetric change in the pons and putamen may provide powerful biomarkers to track disease progression in spinocerebellar ataxia Type 1. The methods employed here are readily translatable to current clinical settings, providing a framework for study and usage of volumetric neuroimaging biomarkers for clinical trials., There is an urgent need for biomarkers that track neurodegenerative disease progression. Pontine and putamen volume decreases are specific to affected individuals, track disease progression within 6–9 months and are directly related to clinical changes in individuals affected by spinocerebellar ataxia Type 1, making them potential biomarkers for clinical trials., Graphical Abstract

Normal brain aging is associated with changes occurring at all levels. This study investigates age-related differences in the brain intracellular microenvironment by comparing the apparent diffusion coefficients (ADC) and apparent transverse relaxation time constants (T2) of 5 neurochemicals (i.e., total N-acetyl-aspartate, total creatine, total choline, glutamate, and myo-inositol) between young and older adults. Thirty-two young healthy adults (18–22 years) and 26 older healthy adults (70–83 years) were recruited. Three brain regions were studied at 3 T: prefrontal, posterior cingulate and occipital cortices. ADC and T2 were measured using stimulated echo acquisition mode and localization by adiabatic selective refocusing sequences, respectively. This study shows that the diffusivities of several neurochemicals are higher in older than in younger adults. In contrast, shorter apparent T2 values for several metabolites were measured in older adults. Age-related difference in ADC and apparent T2 of metabolites seem to be region-specific. Furthermore, this study shows that it is feasible to observe age-related differences in the cellular microenvironment of neurochemicals in the normal aging brain.

PURPOSE: To develop a fast and automated volume-of-interest (VOI) prescription pipeline (AutoVOI) for single-voxel MR spectroscopy (MRS) that removes the need for manual VOI placement, allows flexible VOI planning in any brain region, and enables high inter- and intra-subject consistency of VOI prescription. METHODS: AutoVOI was designed to transfer pre-defined VOIs from an atlas to the 3D anatomical data of the subject during the scan. The AutoVOI pipeline was optimized for consistency in VOI placement (precision), enhanced coverage of the targeted tissue (accuracy) and fast computation speed. The tool was evaluated against manual VOI placement using existing T(1)-weighted datasets and corresponding VOI prescriptions. Finally, it was implemented on two scanner platforms to acquire MRS data from clinically-relevant VOIs that span the cerebrum, cerebellum and the brainstem. RESULTS: The AutoVOI pipeline includes skull stripping, non-linear registration of the atlas to the subject’s brain, and computation of the VOI coordinates and angulations using a minimum oriented bounding box algorithm. When compared against manual prescription, AutoVOI showed higher intra- and inter-subject spatial consistency, as quantified by generalized Dice coefficients (GDC), lower intra- and inter-subject variability in tissue composition (gray matter, white matter and cerebrospinal fluid) and higher or equal accuracy, as quantified by GDC of prescribed VOI with targeted tissues. High quality spectra were obtained on Siemens and Philips 3T systems from 6 automatically prescribed VOIs by the tool. CONCLUSION: Robust automatic VOI prescription is feasible and can help facilitate clinical adoption of MRS by avoiding operator dependence of manual selection.

OBJECTIVE To investigate whether early neurochemical abnormalities are detectable by high-field magnetic resonance spectroscopy (MRS) in individuals with spinocerebellar ataxias (SCAs) 1, 2, 3, and 6, including patients without manifestation of ataxia. METHODS A cohort of 100 subjects (N = 18-21 in each SCA group, including premanifest mutation carriers; mean score on the Scale for the Assessment and Rating of Ataxia [SARA]

PURPOSE To measure the apparent diffusion coefficients (ADC) of five main metabolites in the human brain at 3T with PRESS and STEAM, avoiding measurement biases because of cross-terms. Cross-terms arise from interactions between slice-selection and spoiler gradients in the localized spectroscopy sequence and the diffusion gradients. METHODS Diffusion-weighted spectra were acquired from the prefrontal cortex in five healthy subjects using STEAM (echo time [TE]/mixing time [TM]/pulse repetition time [TR] = 21.22/105/3000 ms, b-values = 0 and 3172 s/mm2 ) and PRESS (TE/TR = 54.2/3000 ms, b-values = 0 and 2204 s/mm2 ). Diffusion weighting was applied using bipolar gradients in three orthogonal directions. Post-processed spectra were analyzed with LCModel, and the trace/3 ADC values were calculated. RESULTS Comparable trace/3 ADC values (0.14-0.18 µm2 /ms) were obtained for five main metabolites with both methods. These metabolites were quantified with Cramer-Rao lower bounds below 15%. CONCLUSION The ADC values of the five main metabolites were successfully measured in the human brain at 3T with eliminated directional dependence. Both STEAM and PRESS can be used to probe the diffusivity of metabolites in normal brain and various pathologies on the clinical scanner with slightly higher precision achieved with STEAM for glutamate and myo-inositol. Magn Reson Med 79:2896-2901, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Purpose The goal of this study was to measure and compare the apparent transverse relaxation time constants (T2 ) of five intracellular metabolites using localization by adiabatic selective refocusing (LASER) and point-resolved spectroscopy (PRESS) sequences in the human brain at 3 T. Methods Five healthy subjects were studied at 3 T. 1 H spectra from the prefrontal cortex were acquired at six different echo times using LASER and PRESS sequences. Postprocessed data were analyzed with LCModel, and the resulting amplitudes were fitted using a mono-exponential decay function to determine the T2 of metabolites. Results Twenty-one percent higher apparent T2 values for the singlet resonances of N-acetyl aspartate, total creatine, and total choline were measured with LASER as compared with PRESS, whereas comparable apparent T2 values were measured for strongly coupled metabolites, glutamate, and myo-inositol, with both sequences. Conclusions Reliable T2 measurements were obtained with both sequences for the five major intracellular metabolites. The LASER sequence appears to be more efficient in suppressing the diffusion component for singlets (having nonexchangeable protons) compared to J-coupled metabolites. Magn Reson Med 79:1260-1265, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

BACKGROUND AND PURPOSE Glutamate levels may be informative about the declining neuronal health in the central nervous system. We used an advanced proton MR spectroscopy (1H-MRS) protocol composed of semi-localization by adiabatic selective refocusing (sLASER) localization and FAST(EST)MAP shimming for detection of alterations in brain glutamate concentrations in patients with amnestic mild cognitive impairment. METHODS Participants with amnestic mild cognitive impairment (n = 14; median age = 80) and age- and sex-matched clinically normal controls (n = 32; median age = 79) from the population-based Mayo Clinic Study of Aging were recruited prospectively to the 3T single-voxel 1H-MRS study that examined metabolite changes in the posterior cingulate gyri. To be included, controls had to have low β-amyloid load on [11C] Pittsburgh Compound B (PiB)-PET (standard uptake value ratio; SUVr < 1.42) and patients with amnestic mild cognitive impairment had to have high β-amyloid load (SUVr ≥ 1.42). RESULTS Glutamate concentration and the glutamate/myo-inositol ratio were lower in patients with amnestic mild cognitive impairment than clinically normal controls (P < .05). Higher global cortical PiB-PET SUVr correlated with lower glutamate/myo-inositol (r = –.3, P = .04). CONCLUSIONS The advanced sLASER with FAST(EST)MAP shimming is a promising protocol for identifying glutamate alterations. Advanced 1H-MRS protocols may add to the understanding of early Alzheimer's disease pathophysiology through detection of glutamate concentration in posterior cingulate gyri of individuals with amnestic mild cognitive impairment.

Purpose To investigate the utility of an advanced magnetic resonance spectroscopy (MRS) protocol in the clinical setting, and to compare the localization accuracy, spectral quality, and quantification repeatability between this advanced and the conventional vendor-provided MRS protocol on a clinical 3T platform. Methods Proton spectra were measured from the posterior cingulate cortices in 30 healthy elderly subjects by clinical MR technologists using a vendor-provided (point resolved spectroscopy with advanced 3D gradient-echo B0 shimming) and an advanced (semi-LASER with FAST(EST)MAP shimming) protocol, in random order. Spectra were quantified with LCModel using standard pipelines for the clinical and research settings, respectively. Results The advanced protocol outperformed the vendor-provided protocol in localization accuracy (chemical-shift-displacement error: 2.0%/ppm, semi-LASER versus 11.6%/ppm, point resolved spectroscopy), spectral quality (water linewidth: 6.1 ± 1.8 Hz, FAST(EST)MAP versus 10.5 ± 3.7 Hz, 3D gradient echo; P

The concentrations of fourteen neurochemicals associated with metabolism, neurotransmission, antioxidant capacity, and cellular structure were measured noninvasively from two distinct brain regions using 1H magnetic resonance spectroscopy. Seventeen young adults (age 19 – 22 years) and sixteen cognitively normal older adults (age 70 – 88 years) were scanned. To increase sensitivity and specificity, 1H magnetic resonance spectra were obtained at the ultra-high field of 7 T and at ultra-short echo time. The concentrations of neurochemicals were determined using water as an internal reference and accounting for gray matter, white matter, and cerebrospinal fluid content of the volume of interest. In the posterior cingulate cortex (PCC), the concentrations of neurochemicals associated with energy (i.e., creatine plus phosphocreatine), membrane turnover (i.e., choline containing compounds), and gliosis (i.e., myo-inositol) were higher in the older adults while the concentrations of N-acetylaspartylglutamate (NAAG) and phosphorylethanolamine (PE) were lower. In the occipital cortex (OCC), the concentration of N-acetylaspartate (NAA), a marker of neuronal viability, concentrations of the neurotransmitters Glu and NAAG, antioxidant ascorbate (Asc), and PE were lower in the older adults while the concentration of choline containing compounds was higher. Altogether, these findings shed light on how the human brain ages differently depending on region.

A major hurdle in the development of effective treatments for amyotrophic lateral sclerosis (ALS) has been the lack of robust biomarkers for use as clinical trial endpoints. Neurochemical profiles obtained in vivo by high field proton magnetic resonance spectroscopy (1H-MRS) can potentially provide biomarkers of cerebral pathology in ALS. However, previous 1H-MRS studies in ALS have produced conflicting findings regarding alterations in the levels of neurochemical markers such as glutamate (Glu) and myo-inositol (mIns). Furthermore, very few studies have investigated the neurochemical abnormalities associated with ALS early in its course. In this study, we measured neurochemical profiles using single-voxel 1H-MRS at 7 T (T) and glutathione (GSH) levels using edited MRS at 3 T in 19 subjects with ALS who had relatively high functional status [ALS Functional Rating Scale-Revised (ALSFRS-R) mean ± SD = 39.8 ± 5.6] and 17 healthy controls. We observed significantly lower total N-acetylaspartate over mIns (tNAA/mIns) ratio in the motor cortex and pons of subjects with ALS versus healthy controls. No group differences were detected in GSH at 3 and 7 T. In subjects with ALS, the levels of tNAA, mIns, and Glu in the motor cortex were dependent on the extent of disease represented by El Escorial diagnostic subcategories. Specifically, combined probable/definite ALS had lower tNAA than possible ALS and controls (both p = 0.03), higher mIns than controls (p

In the present study, we aimed at determining the metabolic responses of the human visual cortex during the presentation of chromatic and achromatic stimuli, known to preferentially activate two separate clusters of neuronal populations (called “blobs” and “interblobs”) with distinct sensitivity to color or luminance features. Since blobs and interblobs have different cytochrome-oxidase (COX) content and micro-vascularization level (i.e., different capacities for glucose oxidation), different functional metabolic responses during chromatic vs. achromatic stimuli may be expected. The stimuli were optimized to evoke a similar load of neuronal activation as measured by the bold oxygenation level dependent (BOLD) contrast. Metabolic responses were assessed using functional 1H MRS at 7 T in 12 subjects. During both chromatic and achromatic stimuli, we observed the typical increases in glutamate and lactate concentration, and decreases in aspartate and glucose concentration, that are indicative of increased glucose oxidation. However, within the detection sensitivity limits, we did not observe any difference between metabolic responses elicited by chromatic and achromatic stimuli. We conclude that the higher energy demands of activated blobs and interblobs are supported by similar increases in oxidative metabolism despite the different capacities of these neuronal populations.

γ-aminobutyric acid (GABA) was the first molecule that was edited with MEGA-PRESS. GABA edited spectroscopy is challenged by limited selectivity of editing pulses. Coediting of resonances from macromolecules (MM) is the greatest single limitation of GABA edited spectroscopy. In this contribution, relative signal contributions from GABA, MM and homocarnosine to the total MEGA-PRESS edited signal at ~3 ppm, i.e., GABA+, are simulated at 3 tesla using several acquisition schemes. The base scheme is modeled after those currently supplied by vendors: it uses typical pulse shapes and lengths, it minimizes the first echo time (TE), and the delay between the editing pulses is kept at TE/2. Edited spectra are simulated for imperfect acquisition parameters such as incorrect frequency, larger chemical shift displacement, incorrect transmit B(1)-field calibration for localization and editing pulses, and longer TE. An alternative timing scheme and longer editing pulses are also considered. Additional simulations are performed for symmetric editing around the MM frequency to suppress the MM signal. The relative influences of these acquisition parameters on the constituents of GABA+ are examined from the perspective of modern experimental designs for investigating brain GABA concentration differences in healthy and diseased humans. Other factors that influence signal contributions, such as T(1) and T(2) relaxation times are also considered.

The semi‐adiabatic localization by adiabatic selective refocusing (sLASER) sequence provides single-shot full intensity signal with clean localization and minimal chemical shift displacement error and was recommended by the international MRS Consensus Group as the preferred localization sequence at high- and ultra-high fields. Across-vendor standardization of the sLASER sequence at 3 tesla has been challenging due to the B(1) requirements of the adiabatic inversion pulses and maximum B(1) limitations on some platforms. The aims of this study were to design a short-echo sLASER sequence that can be executed within a B(1) limit of 15 μT by taking advantage of gradient-modulated RF pulses, to implement it on three major platforms and to evaluate the between-vendor reproducibility of its perfomance with phantoms and in vivo. In addition, voxel-based first and second order B(0) shimming and voxel-based B(1) adjustments of RF pulses were implemented on all platforms. Amongst the gradient-modulated pulses considered (GOIA, FOCI and BASSI), GOIA-WURST was identified as the optimal refocusing pulse that provides good voxel selection within a maximum B(1) of 15 μT based on localization efficiency, contamination error and ripple artifacts of the inversion profile. An sLASER sequence (30 ms echo time) that incorporates VAPOR water suppression and 3D outer volume suppression was implemented with identical parameters (RF pulse type and duration, spoiler gradients and inter-pulse delays) on GE, Philips and Siemens and generated identical spectra on the GE ‘Braino’ phantom between vendors. High-quality spectra were consistently obtained in multiple regions (cerebellar white matter, hippocampus, pons, posterior cingulate cortex and putamen) in the human brain across vendors (5 subjects scanned per vendor per region; mean signal-to-noise ratio > 33; mean water linewidth between 6.5 Hz to 11.4 Hz). The harmonized sLASER protocol is expected to produce high reproducibility of MRS across sites thereby allowing large multi-site studies with clinical cohorts.

BACKGROUND: Spinocerebellar ataxia type 1 (SCA1) causes progressive degeneration of the cerebellum and brainstem. Volumetric magnetic resonance imaging (MRI) was shown to be more sensitive to disease progression than the most sensitive clinical measure, the Scale for the Assessment and Rating of Ataxia (SARA), in longitudinal studies, and magnetic resonance spectroscopy (MRS) was shown to detect neurochemical abnormalities with high sensitivity cross‐sectionally in SCA1. OBJECTIVES: The objectives of this study were to compare the sensitivities to change of volumetric MRI, MRS, and SARA in a 3‐year longitudinal study in SCA1. METHODS: A total of 16 early‐to‐moderate stage patients with SCA1 (SARA 0‐14) and 21 matched healthy participants were scanned up to 3 times with 1.5‐year intervals. Ataxia severity was assessed with SARA. T(1)‐weighted images and magnetic resonance spectra from the cerebellar vermis, cerebellar white matter, and pons were acquired at 3T. RESULTS: The pontine total N‐acetylaspartate‐to‐myo‐inositol ratio was the most sensitive MRS measure to change (−3.9 ± 4.6%/yr in SCA1 vs. −0.3 ± 3.5%/yr in controls; P

The mechanisms of how recurrent hypoglycemia (HG) leads to impaired awareness of HG (IAH) remain elusive. Cortical glutamate (Glu) dynamics may be involved, as Glu levels were shown to decrease during HG in healthy controls and in patients with type 1 diabetes (T1D) and normal awareness of HG (T1D-NAH), but not in patients with IAH. While these data supported an association between blunted Glu response to HG and IAH, whether recurrent HG causes a blunting of the Glu response to HG remains unclear. We measured the neurochemical response to HG before and after induction of IAH in T1D-NAH patients undergoing four 2-hour HG clamps over 2 days. 1H-magnetic resonance spectroscopy at 7 tesla was used to measure Glu levels in the anterior cingulate cortex (ACC, 24x12x30 mm3) during the first (C1) and fourth clamps (C4), before and after induction of IAH, respectively. We focused on the ACC as differences in PET-measured glucose kinetics in ACC were associated with IAH. Epinephrine and symptom responses to HG during C1 and C4 confirmed induction of IAH. Glu levels significantly decreased in response to HG during C1, but not during C4. Glucose+Taurine (reported as sum due to cross-correlation) dropped by 40% with HG in C1, whereas it dropped by 32% in C4. We show that recurrent HG blunts the cortical Glu response to HG, which may be due to higher glucose or alternative fuel availability, eliminating the need to oxidize Glu. Disclosure Y. Park: None. D. Deelchand: None. A. Kumar: None. A. Moheet: None. Y. Zhang: None. L.E. Eberly: None. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company, Zucara Therapeutics Inc. Consultant; Self; 360 Consulting, MannKind Corporation. Research Support; Self; Eli Lilly and Company, JDRF, National Institutes of Health. Other Relationship; Self; American Diabetes Association, Sanofi, WebMD. G. Oz: None. Funding National Institutes of Health (R01NS035192, P41EB015894, P30NS076408)

Conventional proton MRS has been successfully utilized to non-invasively assess tissue biochemistry in conditions that result in large changes in metabolite levels. For more challenging applications, namely in conditions that result in subtle metabolite changes, the limitations of vendor-provided MRS protocols are increasingly recognized, especially when used at high fields (≥ 3 tesla) where chemical shift displacement errors, B(0) and B(1) inhomogeneities and limitations in transmit B(1) field become prominent. To overcome the limitations of conventional MRS protocols at 3T and 7T, use of advanced MRS methodology, including pulse sequences and adjustment procedures, is recommended. Specifically, the semi-LASER sequence is recommended when T(E) values of 25–30ms are acceptable, and the semi-adiabatic SPECIAL sequence is suggested as an alternative when shorter T(E) values are critical. The magnetic field B(0) homogeneity should be optimized and RF pulses should be calibrated for each voxel. Unsuppressed water signal should be acquired for eddy current correction and preferably also for metabolite quantification. Metabolite and water data should be saved in single shots to facilitate phase and frequency alignment and to exclude motion-corrupted shots. Final averaged spectra should be evaluated for SNR, linewidth, water suppression efficiency and presence of unwanted coherences. Spectra that do not fit predefined quality criteria should be excluded from further analysis. Commercially available tools to acquire all data in consistent anatomical locations are recommended for voxel prescriptions, in particular in longitudinal studies. To enable the larger MRS community to take advantage of these advanced methods, a list of resources for these advanced protocols on the major clinical platforms is provided. Finally, a set of recommendations are provided for vendors to enable development of advanced MRS on standard platforms, including implementation of advanced localization sequences, tools for quality assurance on the scanner, and tools for prospective volume tracking and dynamic linear shim corrections.

PURPOSE To evaluate the feasibility of using a clinical magnetic resonance (MR) system and MR spectroscopy (MRS) to measure glucose concentration changes in the human hypothalamus, a structure central to whole-body glucose regulation. SUBJECTS AND METHODS A time series of MR spectra (semi-LASER, TE = 28 msec), localized to the bilateral hypothalamus (∼1.6 ml) were obtained at 3T in six healthy subjects at baseline (euglycemia) and during a ∼65-70-minute-long hyperglycemic clamp in 11-minute blocks with interleaved T1 FLASH images to retrospectively assess head motion, and track changes in cerebrospinal fluid (CSF) partial volume. The LCModel was used to quantify the sum of glucose and taurine concentrations, [Glc+Tau], along with their associated Cramer-Rao lower bounds (CRLB). RESULTS Spectral quality allowed quantification of [Glc+Tau] (sum reported due to high negative correlation between these metabolites) with CRLB

Although the MR editing techniques that have traditionally been used for the measurement of glutathione (GSH) concentrations in vivo address the problem of spectral overlap, they suffer detriments associated with inherently long TEs. The purpose of this study was to characterize the sensitivity and specificity for the quantification of GSH concentrations without editing at short TE. The approach was to measure synthetically generated changes in GSH concentrations from in vivo stimulated echo acquisition mode (STEAM) spectra after in vitro GSH spectra had been added to or subtracted from them. Spectra from five test subjects were synthetically altered to mimic changes in the GSH signal. To account for different background noise between measurements, retest spectra (from the same individuals as used to generate the altered data) and spectra from five other individuals were compared with the synthetically altered spectra to investigate the reliability of the quantification of GSH concentration. Using STEAM spectroscopy at 7 T, GSH concentration differences on the order of 20% were detected between test and retest studies, as well as between differing populations in a small sample (n = 5) with high accuracy (R(2) > 0.99) and certainty (p ≤ 0.01). Both increases and decreases in GSH concentration were reliably quantified with small impact on the quantification of ascorbate and γ-aminobutyric acid. These results show the feasibility of using short-TE (1)H MRS to measure biologically relevant changes and differences in human brain GSH concentration. Although these outcomes are specific to the experimental approach used and the spectral quality achieved, this study serves as a template for the analogous scrutiny of quantification reliability for other compounds, methodologies and spectral qualities.

CONTEXT: Longstanding type 1 diabetes (T1D) may lead to alterations in hippocampal neurochemical profile. Upregulation of hippocampal glucose transport as a result of recurrent exposure to hypoglycemia may preserve cognitive function during future hypoglycemia in subjects with T1D and impaired awareness of hypoglycemia (IAH). The effect of T1D on hippocampal neurochemical profile and glucose transport is unknown. OBJECTIVE: To test the hypothesis that hippocampal neurochemical composition is altered in T1D and glucose transport is upregulated in T1D with IAH. DESIGN AND PARTICIPANTS: Hippocampal neurochemical profile was measured with single-voxel magnetic resonance spectroscopy at 3T during euglycemia in 18 healthy controls (HC), 10 T1D with IAH, and 12 T1D with normal awareness to hypoglycemia (NAH). Additionally, 12 HC, 8 T1D-IAH, and 6 T1D-NAH were scanned during hyperglycemia to assess hippocampal glucose transport with metabolic modeling. SETTING: University medical center. MAIN OUTCOME MEASURES: Concentrations of hippocampal neurochemicals measured during euglycemia and ratios of maximal transport rate to cerebral metabolic rate of glucose (T(max)/CMR(Glc)), derived from magnetic resonance spectroscopy–measured hippocampal glucose as a function of plasma glucose. RESULTS: Comparison of hippocampal neurochemical profile revealed no group differences (HC, T1D, T1D-IAH, and T1D-NAH). The ratio T(max)/CMR(Glc) was not significantly different between the groups, T1D-IAH (1.58 ± 0.09) and HC (1.65 ± 0.07, P = 0.54), between T1D-NAH (1.50 ± 0.09) and HC (P = 0.19), and between T1D-IAH and T1D-NAH (P = 0.53). CONCLUSIONS: Subjects with T1D with sufficient exposure to recurrent hypoglycemia to create IAH did not have alteration of T(max)/CMR(glc) or neurochemical profile compared with participants with T1D-NAH or HC.

ObjectiveTo determine whether proton magnetic resonance spectroscopy (1H-MRS) can detect neurochemical changes in amyotrophic lateral sclerosis (ALS) associated with heterogeneous functional decline.MethodsNineteen participants with early-stage ALS and 18 age-matched and sex ratio-matched controls underwent ultra-high field 1H-MRS scans of the upper limb motor cortex and pons, ALS Functional Rating Scale-Revised (ALSFRS-R total, upper limb and bulbar) and upper motor neuron burden assessments in a longitudinal observational study design with follow-up assessments at 6 and 12 months. Slopes of neurochemical levels over time were compared between patient subgroups classified by the rate of upper limb or bulbar functional decline. 1H-MRS and clinical ratings at baseline were assessed for ability to predict study withdrawal due to disease progression.ResultsMotor cortex total N-acetylaspartate to myo-inositol ratio (tNAA:mIns) significantly declined in patients who worsened in upper limb function over the follow-up period (n=9, p=0.002). Pons glutamate + glutamine significantly increased in patients who worsened in bulbar function (n=6, pConclusionNeurochemical changes in motor areas of the brain are associated with functional decline in corresponding body regions. 1H-MRS was a better predictor of study withdrawal due to ALS progression than ALSFRS-R.

IAH occurs commonly in patients with T1D but its pathogenesis remains uncertain. Previous investigation has suggested that recurrent hypoglycemia leads to an upregulation of brain glucose transport thereby assuring that the brain will have better fuel delivery during subsequent episodes of hypoglycemia. If so, subjects with T1D and IAH should have higher hypothalamic brain glucose concentrations than subjects with T1D without IHA when studied at the same level of glycemia. Here we used 1H-magnetic resonance spectroscopy at 7 T to measure (Glucose+Taurine)/ total Creatine in a 13x12x10 mm3 hypothalamic voxel in such patient groups while they were maintained at euglycemia and then hypoglycemia using a glucose clamp. Since taurine and creatine do not change with glycemia, this is a valid measure of brain glucose concentrations. IAH was defined using the Clarke questionnaire with subjects found indeterminate further classified using the Gold questionnaire. We found that hypothalamic (Glucose+Taurine)/ total Creatine was significantly higher in T1D with IAH at both euglycemia and hypoglycemia when compared to T1D without IAH. These data support the hypothesis that a change in glucose transport may contribute to the pathogenesis of IAH. T1D with IAH (n=9)T1D without IAH (n=9)Age (years)47.6 ± 1729.2 ± 8Hemoglobin A1c (%)7.3 ± 0.97.3 ± 0.7Glycemia at euglycemia (mg/dl)98 ± 495 ± 7Glycemia during hypoglycemia (mg/dl)48 ± 348 ± 5Epinephrine during hypoglycemia (pg/ml)250 ± 155711±442*Symptom score during hypoglycemia8 ± 936 ± 14**Hypothalamic glucose at euglycemia (Glucose+Taurine)/ total Creatine (mM)0.43 ± 0.110.27 ± 0.08**Hypothalamic glucose at hypoglycemia (Glucose+Taurine)/ total Creatine (mM)0.23 ± 0.040.15 ± 0.02***p=0.03, **p < 0.001. Disclosure A. Moheet: None. D. Deelchand: None. A. Kumar: None. G. Oz: Research Support; Self; Takeda Pharmaceuticals U.S.A., Inc. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company, Sanofi, Zucera, InfoMed, 360 consulting. Other Relationship; Self; Novo Nordisk Inc..

Carbon-13 NMR spectroscopy ((13)C MRS) offers the unique capability to measure brain metabolic rates in vivo. Hyperpolarized (13)C reduces the time required to assess brain metabolism from hours to minutes compared to conventional (13)C MRS. This study investigates metabolism of hyperpolarized [1-(13)C]pyruvate and [2-(13)C]pyruvate in the rat brain in vivo under various anesthetics: pentobarbital, isoflurane, α-chloralose, and morphine. The apparent metabolic rate from pyruvate to lactate modeled using time courses obtained after injection of hyperpolarized [1-(13)C]pyruvate was significantly greater for isoflurane than for all other anesthetic conditions, and significantly greater for morphine than for α-chloralose. The apparent metabolic rate from pyruvate to bicarbonate was significantly greater for morphine than for all other anesthetic conditions, and significantly lower for pentobarbital than for α-chloralose. Results show that relative TCA rates determined from hyperpolarized (13)C data are consistent with TCA cycle rates previously measured using conventional (13)C MRS under similar anesthetic conditions, and that using morphine for sedation greatly improves detection of downstream metabolic products compared to other anesthetics.

Purpose To determine the test-retest reproducibility of neurochemical concentrations obtained with a highly optimized, short-echo, single-voxel proton MR spectroscopy (MRS) pulse sequence at 3T and 7T using state-of-the-art hardware. Methods A semi-LASER sequence (echo time = 26–28 ms) was used to acquire spectra from the posterior cingulate and cerebellum at 3T and 7T from six healthy volunteers who were scanned four times weekly on both scanners. Spectra were quantified with LCModel. Results More neurochemicals were quantified with mean Cramer-Rao lower bounds (CRLBs) ≤20% at 7T than at 3T despite comparable frequency-domain signal-to-noise ratio. Whereas CRLBs were lower at 7T (P

Hippocampal dysfunction is known to be associated with several neurological and neuropsychiatric disorders such as Alzheimer's disease, epilepsy, schizophrenia and depression; therefore, there has been significant clinical interest in studying hippocampal neurochemistry. However, the hippocampus is a challenging region to study using H-1 MRS, hence the use of MRS for clinical research in this region has been limited. Our goal was therefore to investigate the feasibility of obtaining high-quality hippocampal spectra that allow reliable quantification of a neurochemical profile and to establish inter-session reproducibility of hippocampal MRS, including reproducibility of voxel placement, spectral quality and neurochemical concentrations. Ten healthy volunteers were scanned in two consecutive sessions using a standard clinical 3T MR scanner. Neurochemical profiles were obtained with a short-echo (T-E=28ms) semi-LASER localization sequence from a relatively small (similar to 4mL) voxel that covered about 62% of the hippocampal volume as calculated from segmentation of T-1-weighted images. Voxel composition was highly reproducible between sessions, with test-retest coefficients of variation (CVs) of 3.5% and 7.5% for gray and white matter volume fraction, respectively. Excellent signal-to-noise ratio (similar to 54 based on the N-acetylaspartate (NAA) methyl peak in non-apodized spectra) and linewidths (similar to 9Hz for water) were achieved reproducibly in all subjects. The spectral quality allowed quantification of NAA, total choline, total creatine, myo-inositol and glutamate with high scan-rescan reproducibility (CV6%) and quantification precision (Cramer-Rao lower bound, CRLB

Quantification of (31)P NMR spectra is commonly performed using line-fitting techniques with prior knowledge. Currently available time- and frequency-domain analysis software includes AMARES (in jMRUI) and CFIT respectively. Another popular frequency-domain approach is LCModel, which has been successfully used to fit both (1)H and (13)C in vivo NMR spectra. To the best of our knowledge LCModel has not been used to fit (31)P spectra. This study demonstrates the feasibility of using LCModel to quantify in vivo (31)P MR spectra, provided that adequate prior knowledge and LCModel control parameters are used. Both single-voxel and MRSI data are presented, and similar results are obtained with LCModel and with AMARES. This provides a new method for automated, operator-independent analysis of (31)P NMR spectra.

Spinocerebellar ataxias (SCAs) belong to polyglutamine repeat disorders and are characterized by a predominant atrophy of the cerebellum and the pons. Proton magnetic resonance spectroscopy (1H MRS) using an optimized semiadiabatic localization by adiabatic selective refocusing (semi-LASER) protocol was performed at 3 T to determine metabolite concentrations in the cerebellar vermis and pons of a cohort of patients with SCA1 (n = 16), SCA2 (n = 12), SCA3 (n = 21), and SCA7 (n = 12) and healthy controls (n = 33). Compared with controls, patients displayed lower total N-acetylaspartate and, to a lesser extent, lower glutamate, reflecting neuronal loss/dysfunction, whereas the glial marker, myoinositol (myo-Ins), was elevated. Patients also showed higher total creatine as reported in Huntington's disease, another polyglutamine repeat disorder. A strong correlation was found between the Scale for the Assessment and Rating of Ataxia and the neurometabolites in both affected regions of patients. Principal component analyses confirmed that neuronal metabolites (total N-acetylaspartate and glutamate) were inversely correlated in the vermis and the pons to glial (myo-Ins) and energetic (total creatine) metabolites, as well as to disease severity (motor scales). Neurochemical plots with selected metabolites also allowed the separation of SCA2 and SCA3 from controls. The neurometabolic profiles detected in patients underlie cell-specific changes in neuronal and astrocytic compartments that cannot be assessed by other neuroimaging modalities. The inverse correlation between metabolites from these two compartments suggests a metabolic attempt to compensate for neuronal damage in SCAs. Because these biomarkers reflect dynamic aspects of cellular metabolism, they are good candidates for proof-of-concept therapeutic trials. © 2015 International Parkinson and Movement Disorder Society

Tourette's syndrome (TS) is a neurodevelopmental disorder characterized primarily by motor and vocal tics. Comorbidities such as attention deficit and hyperactivity disorder (ADHD) are observed in over 50% of TS patients. We applied aripiprazole in a juvenile rat model that displays motor tics and hyperactivity. We additionally assessed the amount of ultrasonic vocalizations (USVs) as an indicator for the presence of vocal tics and evaluated the changes in the striatal neurometabolism using in vivo proton magnetic resonance spectroscopy (1H-MRS) at 11.7T. Thirty-one juvenile spontaneously hypertensive rats (SHRs) underwent bicuculline striatal microinjection and treatment with either aripiprazole or vehicle. Control groups were sham operated and sham injected. Behavior, USVs, and striatal neurochemical profile were analyzed at early, middle, and late adolescence (postnatal days 35 to 50). Bicuculline microinjections in the dorsolateral striatum induced motor tics in SHR juvenile rats. Acute aripiprazole administration selectively reduced both tic frequency and latency, whereas stereotypies, USVs, and hyperactivity remained unaltered. The striatal neurochemical profile was only moderately altered after tic-induction and was not affected by systemic drug treatment. When applied to a young rat model that provides high degrees of construct, face, and predictive validity for TS and comorbid ADHD, aripiprazole selectively reduces motor tics, revealing that tics and stereotypies are distinct phenomena in line with clinical treatment of patients. Finally, our 1H-MRS results suggest a critical revision of the striatal role in the hypothesized cortico-striatal dysregulation in TS pathophysiology.

Background Mutations in the isocitrate dehydrogenase (IDH) enzyme affect 40% of gliomas and represent a major diagnostic and prognostic marker. The goals of this study were to evaluate the performance of noninvasive magnetic resonance spectroscopy (MRS) methods to determine the IDH status of patients with brain gliomas through detection of the oncometabolite 2-hydroxyglutarate (2HG) and to compare performance of these methods with DNA sequencing and tissue 2HG analysis. Methods Twenty-four subjects with suspected diagnosis of low-grade glioma were included prospectively in the study. For all subjects, MRS data were acquired at 3T using 2 MRS methods, edited MRS using Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence and a PRESS sequence optimized for 2HG detection, using a volume of interest larger than 6 mL. IDH mutational status was determined by a combination of automated immunohistochemical analysis and Sanger sequencing. Levels of 2HG in tissue samples measured by gas chromatography-mass spectrometry were compared with those estimated by MRS. Results Edited MRS provided 100% specificity and 100% sensitivity in the detection of 2HG. The 2HG levels estimated by this technique were in line with those derived from tissue samples. Optimized PRESS provided lower performance, in agreement with previous findings. Conclusions Our results suggest that edited MRS is one of the most reliable tools to predict IDH mutation noninvasively, showing high sensitivity and specificity for 2HG detection. Integrating edited MRS in clinical practice may be highly beneficial for noninvasive diagnosis of glioma, prognostic assessment, and treatment planning.