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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

Movement disorders 38(1), 45-56 (2023). doi:10.1002/mds.29261, Published by Wiley, New York, NY

ObjectiveSpinal cord damage is a hallmark of Friedreich ataxia (FRDA), but its progression and clinical correlates remain unclear. Here we performed a characterization of cervical spinal cord structural abnormalities in a large multisite FRDA cohort.MethodsWe performed a cross-sectional analysis of cervical spinal cord (C1 to C4) cross-sectional area (CSA) and eccentricity using MRI data from eight sites within the ENIGMA-Ataxia initiative, including 256 individuals with FRDA and 223 age- and sex-matched controls. Correlations and subgroup analyses within the FRDA cohort were undertaken based on disease duration, ataxia severity, and onset age.ResultsIndividuals with FRDA, relative to controls, had significantly reduced CSA at all examined levels, with large effect sizes (d>2.1) and significant correlations with disease severity (rd>1.2), but without significant clinical correlations. Subgroup analyses showed that CSA and eccentricity are abnormal at all disease stages. However, while CSA appears to decrease progressively, eccentricity remains stable over time.InterpretationPrevious research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage or both. Hence, our data support the hypothesis that damage to DC and CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, whereas CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression.

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.

Neurology : official journal of the American Academy of Neurology / Genetics 8(6), e200034 (2022). doi:10.1212/NXG.0000000000200034, Published by [Verlag nicht ermittelbar], Minneapolis, Minn.

Modern data often take the form of a multiway array. However, most classification methods are designed for vectors, i.e., 1-way arrays. Distance weighted discrimination (DWD) is a popular high-dimensional classification method that has been extended to the multiway context, with dramatic improvements in performance when data have multiway structure. However, the previous implementation of multiway DWD was restricted to classification of matrices, and did not account for sparsity. In this paper, we develop a general framework for multiway classification which is applicable to any number of dimensions and any degree of sparsity. We conducted extensive simulation studies, showing that our model is robust to the degree of sparsity and improves classification accuracy when the data have multiway structure. For our motivating application, magnetic resonance spectroscopy (MRS) was used to measure the abundance of several metabolites across multiple neurological regions and across multiple time points in a mouse model of Friedreich's ataxia, yielding a four-way data array. Our method reveals a robust and interpretable multi-region metabolomic signal that discriminates the groups of interest. We also successfully apply our method to gene expression time course data for multiple sclerosis treatment. An R implementation is available in the package MultiwayClassification at http://github.com/lockEF/MultiwayClassification ., 46 pages, 8 figures

In vivo MRS is a non-invasive measurement technique used not only in humans, but also in animal models using high-field magnets. MRS enables the measurement of metabolite concentrations as well as metabolic rates and their modifications in healthy animals and disease models. Such data open the way to a deeper understanding of the underlying biochemistry, related disturbances and mechanisms taking place during or prior to symptoms and tissue changes. In this work, we focus on the main preclinical (1)H, (31)P and (13)C MRS approaches to study brain metabolism in rodent models, with the aim of providing general experts’ consensus recommendations (animal models, anesthesia, data acquisition protocols). An overview of the main practical differences in preclinical compared with clinical MRS studies is presented, as well as the additional biochemical information that can be obtained in animal models in terms of metabolite concentrations and metabolic flux measurements. The properties of high-field preclinical MRS and the technical limitations are also described.

In a companion paper by Cohen-Adad et al. we introduce the spine generic quantitative MRI protocol that provides valuable metrics for assessing spinal cord macrostructural and microstructural integrity. This protocol was used to acquire a single subject dataset across 19 centers and a multi-subject dataset across 42 centers (for a total of 260 participants), spanning the three main MRI manufacturers: GE, Philips and Siemens. Both datasets are publicly available via git-annex. Data were analysed using the Spinal Cord Toolbox to produce normative values as well as inter/intra-site and inter/intra-manufacturer statistics. Reproducibility for the spine generic protocol was high across sites and manufacturers, with an average inter-site coefficient of variation of less than 5% for all the metrics. Full documentation and results can be found at https://spine-generic.rtfd.io/. The datasets and analysis pipeline will help pave the way towards accessible and reproducible quantitative MRI in the spinal cord., Measurement(s)spinal cordTechnology Type(s)magnetic resonance imagingFactor Type(s)manufacturer • siteSample Characteristic - OrganismHomo sapiensSample Characteristic - LocationCanada • Switzerland • Australia • United States of America • United Kingdom • Germany • French Republic • Czech Republic • Italy • Japan • Kingdom of Spain • China Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.14052269

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.

Objective: Friedreich ataxia (FRDA) is an inherited neurological disease defined by progressive movement incoordination. We undertook a comprehensive characterization of the spatial profile and progressive evolution of structural brain abnormalities in people with FRDA. Methods: A coordinated international analysis of regional brain volume using magnetic resonance imaging data charted the whole-brain profile, interindividual variability, and temporal staging of structural brain differences in 248 individuals with FRDA and 262 healthy controls. Results: The brainstem, dentate nucleus region, and superior and inferior cerebellar peduncles showed the greatest reductions in volume relative to controls (Cohen d= 1.5–2.6). Cerebellar gray matter alterations were most pronounced in lobules I–VI (d= 0.8), whereas cerebral differences occurred most prominently in precentral gyri (d= 0.6) and corticospinal tracts (d= 1.4). Earlier onset age predicted less volume in the motor cerebellum (rmax= 0.35) and peduncles (rmax= 0.36). Disease duration and severity correlated with volume deficits in the dentate nucleus region, brainstem, and superior/inferior cerebellar peduncles (rmax= −0.49); subgrouping showed these to be robust and early features of FRDA, and strong candidates for further biomarker validation. Cerebral white matter abnormalities, particularly in corticospinal pathways, emerge as intermediate disease features. Cerebellar and cerebral gray matter loss, principally targeting motor and sensory systems, preferentially manifests later in the disease course. Interpretation: FRDA is defined by an evolving spatial profile of neuroanatomical changes beyond primary pathology in the cerebellum and spinal cord, in line with its progressive clinical course. The design, interpretation, and generalization of research studies and clinical trials must consider neuroanatomical staging and associated interindividual variability in brain measures. ANN NEUROL 2021;90:570–583.

In a companion paper by Cohen-Adad et al. we introduce the spine generic quantitative MRI protocol that provides valuable metrics for assessing spinal cord macrostructural and microstructural integrity. This protocol was used to acquire a single subject dataset across 19 centers and a multi-subject dataset across 42 centers (for a total of 260 participants), spanning the three main MRI manufacturers: GE, Philips and Siemens. Both datasets are publicly available via git-annex. Data were analysed using the Spinal Cord Toolbox to produce normative values as well as inter/intra-site and inter/intra-manufacturer statistics. Reproducibility for the spine generic protocol was high across sites and manufacturers, with an average inter-site coefficient of variation of less than 5% for all the metrics. Full documentation and results can be found at https://spine-generic.rtfd.io/ . The datasets and analysis pipeline will help pave the way towards accessible and reproducible quantitative MRI in the spinal cord.

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.

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

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.

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.

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

Objective: Based on our previous work in Huntington disease (HD) showing improved energy metabolism in muscle by providing substrates to the Krebs cycle, we wished to obtain a proof-of-concept of the therapeutic benefit of triheptanoin using a functional biomarker of brain energy metabolism validated in HD. Methods: We performed an open-label study using 31 P brain magnetic resonance spectroscopy (MRS) to measure the levels of phosphocreatine (PCr) and inorganic phosphate (Pi) before (rest), during (activation), and after (recovery) a visual stimulus. We performed 31 P brain MRS in 10 patients at an early stage of HD and 13 controls. Patients with HD were then treated for 1 month with triheptanoin after which they returned for follow-up including 31 P brain MRS scan. Results: At baseline, we confirmed an increase in Pi/PCr ratio during brain activation in controls—reflecting increased adenosine triphosphate synthesis—followed by a return to baseline levels during recovery ( p = 0.013). In patients with HD, we validated the existence of an abnormal brain energy profile as previously reported. After 1 month, this profile remained abnormal in patients with HD who did not receive treatment. Conversely, the MRS profile was improved in patients with HD treated with triheptanoin for 1 month with the restoration of an increased Pi/PCr ratio during visual stimulation ( p = 0.005). Conclusion: This study suggests that triheptanoin is able to correct the bioenergetic profile in the brain of patients with HD at an early stage of the disease. Classification of evidence: This study provides Class III evidence that, for patients with HD, treatment with triheptanoin for 1 month restores an increased MRS Pi/PCr ratio during visual stimulation.

Context Upregulated brain glucose transport in response to recurrent hypoglycemia may contribute to the development of hypoglycemia-associated autonomic failure (HAAF) and impaired awareness of hypoglycemia. Whether recurrent hypoglycemia alters glucose transport in the hypothalamus is unknown. Objective To test the hypothesis that hypothalamic glucose transport will increase in healthy volunteers preconditioned with recurrent hypoglycemia to induce HAAF. Setting University medical center. Design and Participants Thirteen healthy subjects underwent paired euglycemic and hypoglycemic preconditioning studies separated by at least 1 month. Following preconditioning, hypothalamic glucose transport was measured by magnetic resonance spectroscopy (MRS) in the afternoon on day 2 of each preconditioning protocol. Outcome Measure The ratio of maximal transport rate to cerebral metabolic rate of glucose (Tmax/CMRglc), obtained from MRS-measured glucose in the hypothalamus as a function of plasma glucose. Results HAAF was successfully induced based on lower epinephrine, glucagon, and cortisol during the third vs first hypoglycemic preconditioning clamp (P ≤ 0.01). Hypothalamic glucose transport was not different following recurrent euglycemia vs hypoglycemia (Tmax/CMRglc 1.62 ± 0.09 after euglycemia preconditioning and 1.75 ± 0.14 after hypoglycemia preconditioning; P was not significant). Hypothalamic glucose concentrations measured by MRS were not different following the two preconditioning protocols. Conclusions Glucose transport kinetics in the hypothalamus of healthy humans with experimentally induced HAAF were not different from those measured without HAAF. Future studies of patients with diabetes and impaired awareness of hypoglycemia will be necessary to determine if the existence of the diabetes state is required for this adaptation to hypoglycemia to occur.

Purpose To determine whether neurochemical concentrations obtained at two MRI sites using clinical 3T scanners can be pooled when a highly optimized, nonvendor short-echo, single-voxel proton MRS pulse sequence is used 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 3T 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 body mass index. 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 with 3–5 metabolites in prior multisite magnetic resonance spectroscopy trials using vendor-provided sequences. The neurochemical profiles were nearly identical at the two sites and showed the feasibility to detect interindividual differences in the healthy brain. Conclusion Highly reproducible neurochemical profiles can be obtained on different clinical 3T scanners at different sites, provided that the same, optimized acquisition and analysis techniques are used. This will allow pooling of multisite data in clinical studies, which is particularly critical for rare neurological diseases. Magn Reson Med 73:1718–1725, 2015. © 2014 Wiley Periodicals, Inc.

Purpose To investigate the effect of Carr-Purcell (CP) pulse trains on transverse relaxation times, T2, of tissue water and metabolites (both noncoupled and J-coupled spins) in the rat brain at 9.4 Tesla (T) using LASER, CP-LASER, and T2ρ-LASER sequences. Methods Proton NMR spectra were measured in rat brain in vivo at 9.4T. Spectra were acquired at multiple echo times ranging from 18 to 402 ms. All spectra were analyzed using LCModel with simulated basis sets. Signals of metabolites as a function of echo time were fitted using a mono-exponential function to determine their T2 relaxation times. Results Measured T2s for tissue water and all metabolites were significantly longer with CP-LASER and T2ρ-LASER compared with LASER. The T2 increased by a factor of ∼1.3 for noncoupled and weakly coupled spins (e.g., N-acetylaspartate and total creatine) and by a factor of ∼2 (e.g., glutamine and taurine) to ∼4 (e.g., glutamate and myo-inositol) for strongly coupled spins. Conclusion Application of a CP pulse train results in a larger increase in T2 relaxation times for strongly coupled spins than for noncoupled (singlet) and weakly coupled spins. This needs to be taken into account when correcting for T2 relaxation in CP-like sequences such as LASER. Magn Reson Med 73:13–20, 2015. © 2014 Wiley Periodicals, Inc.

Purpose The gain in quantification precision that can be expected in human brain 1H MRS at very high field remains a matter of debate. Here, we investigate this issue using Monte-Carlo simulations. Methods Simulated human brain-like 1H spectra were fitted repeatedly with different noise realizations using LCModel at B0 ranging from 1.5T to 11.7T, assuming a linear increase in signal-to-noise ratio with B0 in the time domain, and assuming a linear increase in linewidth with B0 based on experimental measurements. Average quantification precision (Cramer–Rao lower bound) was then determined for each metabolite as a function of B0. Results For singlets, Cramer–Rao lower bounds improved (decreased) by a factor of ∼ as B0 increased, as predicted by theory. For most J-coupled metabolites, Cramer–Rao lower bounds decreased by a factor ranging from to B0 as B0 increased, reflecting additional gains in quantification precision compared to singlets owing to simplification of spectral pattern and reduced overlap. Conclusions Quantification precision of 1H magnetic resonance spectroscopy in human brain continues to improve with B0 up to 11.7T although peak signal-to-noise ratio in the frequency domain levels off above 3T. In most cases, the gain in quantification precision is higher for J-coupled metabolites than for singlets. Magn Reson Med 72:20–25, 2014. © 2013 Wiley Periodicals, Inc.

Two variants of a widely used two-compartment model were prepared for fitting the time course of [1,6-13C2]glucose metabolism in rat brain. Features common to most models were included, but in one model the enrichment of the substrates entering the glia and neuronal citric acid cycles was allowed to differ. Furthermore, the models included the capacity to analyze multiplets arising from 13C spin-spin coupling, known to improve parameter estimates in heart. Data analyzed were from a literature report providing time courses of [1,6-13C2]glucose metabolism. Four analyses were used, two comparing the effect of different pyruvate enrichment in glia and neurons, and two for determining the effect of multiplets present in the data. When fit independently, the enrichment in glial pyruvate was less than in neurons. In the absence of multiplets, fit quality and parameter values were typical of those in the literature, whereas the multiplet curves were not modeled well. This prompted the use of robust statistical analysis (the Kolmogorov-Smirnov test of goodness of fit) to determine whether individual curves were modeled appropriately. At least 50% of the curves in each experiment were considered poorly fit. It was concluded that the model does not include all metabolic features required to analyze the data.

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.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 TSpectral quality allowed quantification of [Glc+Tau] (sum reported due to high negative correlation between these metabolites) with CRLB25% in 35/36 timepoints during hyperglycemia. Increased [Glc+Tau] was observed with hyperglycemia in all subjects, but most reliably in those with plasma glucose targets ≥300 mg/dl. For these subjects, [Glc+Tau]It is feasible to measure glucose concentration changes in the human hypothalamus using a standard 3T scanner and a short-echo semi-LASER sequence by utilizing retrospective motion tracking, CSF correction, predetermined quality acceptance criteria, and hyperglycemic blood glucose levels ≥300 mg/dl.2 J. Magn. Reson. Imaging 2017;45:681-691.

Ataxia refers to deficits in coordination of movement and balance. This chapter focuses on recessively and dominantly inherited as well as sporadic degenerative ataxias. These diseases are characterized by neurodegeneration in the cerebellar system, including the cerebellum and its afferent and efferent connections, and frequently also in other brain regions such as the pontine nuclei. They display great pathological diversity, as well as phenotypic variability; thus there is a great need for imaging biomarkers that reflect the underlying pathology and that can be used for diagnostic, prognostic, and treatment monitoring purposes. Despite technical challenges of magnetic resonance spectroscopy (MRS) in the cerebellum and brainstem, MRS has been shown to be sensitive to neurochemical alterations in various degenerative ataxias. Namely, early neurochemical abnormalities have been detected by MRS in ataxias prior to the structural atrophy detectable by conventional MRI and prior to symptoms. Correlations with clinical status and pathological severity were demonstrated in clinical and animal model studies, respectively. MRS was also shown to distinguish different ataxia subtypes, with potential utility in differential diagnosis, especially valuable for sporadic ataxias in the absence of genetic testing. Finally, a few studies have utilized MRS for treatment monitoring in clinical trials of recessive ataxias, and a great need exists in this area for all degenerative ataxias. More longitudinal investigations and standardization of advanced MRS methodology for multi-site trials will be critical in this respect.

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease with complete penetrance. Although the understanding of the cellular mechanisms that drive neurodegeneration in HD and account for the characteristic pattern of neuronal vulnerability is incomplete, defects in energy metabolism, particularly mitochondrial function, represent a common thread in studies of HD pathogenesis in animal models and humans. Here we review the metabolic dysfunction captured by in vivo proton and phosphorus magnetic resonance spectroscopy (MRS) in animal models of HD and human carriers of the mutated huntingtin protein. Having access to a presymptomatic population of individuals gives a unique possibility of approaching early pathophysiological changes in HD. Although longitudinal studies are needed to determine more precisely the time course of these metabolic changes in humans, MRS tools are already used in clinical trials to obtain proof of concepts of the ability of disease-modifying drugs to impact on disease progression in HD.

Recently, hyperpolarized substrates generated through dynamic nuclear polarization have been introduced to study in vivo metabolism. Injection of hyperpolarized [1-13C] pyruvate, the most widely used substrate, allows detection of time courses of [1-13C] pyruvate and its metabolic products, such as [1-13C] lactate and 13C-bicarbonate, in various organs. However, quantitative metabolic modeling of in vivo data to measure specific metabolic rates remains challenging without measuring the input function. In this study, we demonstrate that the input function of [1-13C] pyruvate can be measured in vivo in the rat carotid artery using an implantable coil.

Metabolic modeling of dynamic 13C labeling curves during infusion of 13C-labeled substrates allows quantitative measurements of metabolic rates in vivo. However metabolic modeling studies performed in the brain to date have only modeled time courses of total isotopic enrichment at individual carbon positions (positional enrichments), not taking advantage of the additional dynamic 13C isotopomer information available from fine-structure multiplets in 13C spectra. Here we introduce a new 13C metabolic modeling approach using the concept of bonded cumulative isotopomers, or bonded cumomers. The direct relationship between bonded cumomers and 13C multiplets enables fitting of the dynamic multiplet data. The potential of this new approach is demonstrated using Monte-Carlo simulations with a brain two-compartment neuronal-glial model. The precision of positional and cumomer approaches are compared for two different metabolic models (with and without glutamine dilution) and for different infusion protocols ([1,6-13C2]glucose, [1,2-13C2]acetate, and double infusion [1,6-13C2]glucose + [1,2-13C2]acetate). In all cases, the bonded cumomer approach gives better precision than the positional approach. In addition, of the three different infusion protocols considered here, the double infusion protocol combined with dynamic bonded cumomer modeling appears the most robust for precise determination of all fluxes in the model. The concepts and simulations introduced in the present study set the foundation for taking full advantage of the available dynamic 13C multiplet data in metabolic modeling.

Background: We wished to identify noninvasive in vivo biomarkers of brain energy deficit in Huntington disease. Methods: We studied 15 early affected patients (mean motor United Huntington Disease Rating Scale, 18 ± 9) and 15 age- and sex-matched controls. We coupled 31phosphorus nuclear magnetic resonance spectroscopy with activation of the occipital cortex in order to measure the relative concentrations of adenosine triphosphate, phosphocreatine, and inorganic phosphate before, during, and after visual stimulation. Results: In controls, we observed an 11% increase in the inorganic phosphate/phosphocreatine ratio (P = .024) and a 13% increase in the inorganic phosphate/adenosine triphosphate ratio (P = .016) during brain activation, reflecting increased adenosine diphosphate concentrations. Subsequently, controls had a return to baseline levels during recovery (P = .012 and .022, respectively). In contrast, both ratios were unchanged in patients during and after visual stimulation. Conclusions: 31Phosphorus nuclear magnetic resonance spectroscopy could provide functional biomarkers of brain energy deficit to monitor therapeutic efficacy in Huntington disease. © 2012 Movement Disorder Society

A network model for the determination of tumor metabolic fluxes from 13C NMR kinetic isotopomer data has been developed and validated with perfused human DB-1 melanoma cells carrying the BRAF V600E mutation, which promotes oxidative metabolism. The model generated in the bonded cumomer formalism describes key pathways of tumor intermediary metabolism and yields dynamic curves for positional isotopic enrichment and spin-spin multiplets. Cells attached to microcarrier beads were perfused with 26 mm [1,6-13C2]glucose under normoxic conditions at 37 °C and monitored by 13C NMR spectroscopy. Excellent agreement between model-predicted and experimentally measured values of the rates of oxygen and glucose consumption, lactate production, and glutamate pool size validated the model. ATP production by glycolytic and oxidative metabolism were compared under hyperglycemic normoxic conditions; 51% of the energy came from oxidative phosphorylation and 49% came from glycolysis. Even though the rate of glutamine uptake was ∼50% of the tricarboxylic acid cycle flux, the rate of ATP production from glutamine was essentially zero (no glutaminolysis). De novo fatty acid production was ∼6% of the tricarboxylic acid cycle flux. The oxidative pentose phosphate pathway flux was 3.6% of glycolysis, and three non-oxidative pentose phosphate pathway exchange fluxes were calculated. Mass spectrometry was then used to compare fluxes through various pathways under hyperglycemic (26 mm) and euglycemic (5 mm) conditions. Under euglycemic conditions glutamine uptake doubled, but ATP production from glutamine did not significantly change. A new parameter measuring the Warburg effect (the ratio of lactate production flux to pyruvate influx through the mitochondrial pyruvate carrier) was calculated to be 21, close to upper limit of oxidative metabolism.

Diffusion weighted spectroscopy can provide microstructural information that is specific to compartmental geometry. So far, in human brain, apparent diffusion coefficients (ADCs) of only the metabolites N-acetyl aspartate, creatine (tCr) and choline (tCho) have been assessed. High field MR at 7 T allows the collection and analysis of diffusion weighted spectroscopy data of additional metabolites of interest such as glutamate (Glu), N-acetyl aspartyl glutamate, and glutamine (Gln), which are of interest due to their different compartmentalization and role in brain physiology. In this study, we performed 1H diffusion weighted spectroscopy at 7 T using a diffusion-weighted PRESS sequence in parietal white matter (n = 6) and occipital grey matter (n = 7). Data were analyzed using the LCmodel. ADCs could reliably be obtained of N-acetyl aspartate, tCr, tCho, Glu, Gln in grey and white matter, and N-acetyl aspartyl glutamate in white matter. Significant differences in ADC values were observed between grey and white matter for all metabolites. ADCs in grey matter were consistently lower than in white matter. These differences can probably be attributed to different compartmentalization as well as to the differential impact of diffusion time on ADC of different molecules under conditions of restricted diffusion. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc.

To improve the ability to move from preclinical trials in mouse models of Huntington's disease (HD) to clinical trials in humans, biomarkers are needed that can track similar aspects of disease progression across species. Brain metabolites, detectable by magnetic resonance spectroscopy (MRS), have been suggested as potential biomarkers in HD. In this study, the R6/2 transgenic mouse model of HD was used to investigate the relative sensitivity of the metabolite profiling and the brain volumetry to anticipate the disease progression. Magnetic resonance imaging (MRI) and 1H MRS data were acquired at 9.4 T from the R6/2 mice and wild-type littermates at 4, 8, 12, and 15 weeks. Brain shrinkage was detectable in striatum, cortex, thalamus, and hypothalamus by 12 weeks. Metabolite changes in cortex paralleled and sometimes preceded those in striatum. The entire set of metabolite changes was compressed into principal components (PCs) using Partial Least Squares-Discriminant Analysis (PLS-DA) to increase the sensitivity for monitoring disease progression. In comparing the efficacy of volume and metabolite measurements, the cortical PC1 emerged as the most sensitive single biomarker, distinguishing R6/2 mice from littermates at all time points. Thus, neurochemical changes precede volume shrinkage and become potential biomarkers for HD mouse models.

Glucose is the primary fuel for brain function, and determining the kinetics of cerebral glucose transport and utilization is critical for quantifying cerebral energy metabolism. The kinetic parameters of cerebral glucose transport, KMtand Vmaxt, in humans have so far been obtained by measuring steady-state brain glucose levels by proton (1H) NMR as a function of plasma glucose levels and fitting steady-state models to these data. Extraction of the kinetic parameters for cerebral glucose transport necessitated assuming a constant cerebral metabolic rate of glucose ( CMRglc) obtained from other tracer studies, such as13C NMR. Here we present new methodology to simultaneously obtain kinetic parameters for glucose transport and utilization in the human brain by fitting both dynamic and steady-state1H NMR data with a reversible, non-steady-state Michaelis-Menten model. Dynamic data were obtained by measuring brain and plasma glucose time courses during glucose infusions to raise and maintain plasma concentration at ∼17 mmol/l for ∼2 h in five healthy volunteers. Steady-state brain vs. plasma glucose concentrations were taken from literature and the steady-state portions of data from the five volunteers. In addition to providing simultaneous measurements of glucose transport and utilization and obviating assumptions for constant CMRglc, this methodology does not necessitate infusions of expensive or radioactive tracers. Using this new methodology, we found that the maximum transport capacity for glucose through the blood-brain barrier was nearly twofold higher than maximum cerebral glucose utilization. The glucose transport and utilization parameters were consistent with previously published values for human brain.

Accurate quantification of 1H NMR spectra often requires knowledge of the relaxation times to correct for signal losses due to relaxation and saturation. In human brain, T2 values for singlets such as N-acetylaspartate, creatine, and choline have been reported, but few T2 values are available for J-coupled spin systems. The purpose of this study was to measure the T2 relaxation times of J-coupled metabolites in the human occipital lobe using the LASER sequence. Spectra were acquired at multiple echo times and were analyzed with an LCModel using basis sets simulated at each echo time. Separate basis spectra were used for resonances of protons belonging to the same molecule but having very different T2 values (e.g., two separate basis spectra were used for the singlet and multiplet signal in N-acetylaspartate). The T2 values for the N-acetylaspartate multiplet (149 ± 12 ms), glutamate (125 ± 10 ms), myo-inositol (139 ± 20 ms), and taurine (196 ± 28 ms) were successfully measured in the human visual cortex at 4 T. These measured T2 relaxation times have enabled the accurate and absolute quantification of cerebral metabolites at longer echo times. Magn Reson Med, 2011. © 2011 Wiley-Liss, Inc.

Determination of oxidative metabolism in the brain using in vivo ¹³C NMR spectroscopy (¹³C MRS) typically requires repeated blood sampling throughout the study to measure blood glucose concentration and fractional enrichment (input function). However, drawing blood from small animals, such as young rats, placed deep inside the magnet is technically difficult due to their small total blood volume. In the present study, a custom-built animal holder enabled temporary removal of the animal from the magnet for blood collection, followed by accurate repositioning in the exact presampling position without degradation of B₀ shimming. ¹³C label incorporation into glutamate C4 and C3 positions during a 120 min [1,6-¹³C₂] glucose infusion was determined in 28-day-old rats (n = 4) under α-chloralose sedation using localized, direct-detected in vivo ¹³C MRS at 9.4T. The tricarboxylic acid cycle activity rate (V(TCA)) determined using a one-compartment metabolic modeling was 0.67 ± 0.13 μmol/g/min, a value comparable to previous ex vivo studies. This methodology opens the avenue for in vivo measurements of brain metabolic rates using ¹³C MRS in small animals.

Evaluating early changes in cerebral metabolism in hydrocephalus can help in the decision making and the timing of surgical intervention. This study was aimed at examining the tricarboxylic acid (TCA) cycle rate and (13)C label incorporation into neurotransmitter amino acids and other compounds 2 weeks after rats were subjected to kaolin-induced progressive hydrocephalus. In vivo and ex vivo magnetic resonance spectroscopy (MRS), combined with the infusion of [1,6-(13)C]glucose, was used to monitor the time courses of (13)C label incorporation into the different carbon positions of glutamate in the forebrains of rats with hydrocephalus as well as in those of controls. Metabolic rates were determined by fitting the measured data into a one-compartment metabolic model. The TCA cycle rate was 1.3 ± 0.2 μmoles/gram/minute in the controls and 0.8 ± 0.4 μmoles/gram/minute in the acute hydrocephalus group, the exchange rate between α-ketoglutarate and glutamate was 4.1 ± 2.5 μmoles/gram/minute in the controls and 2.7 ± 2.6 μmoles/gram/minute in the hydrocephalus group calculated from in vivo MRS. There were no statistically significant differences between these rates. Hydrocephalus caused a decrease in the amounts of glutamate, alanine and taurine. In addition, the concentration of the neuronal marker N-acetyl aspartate was decreased. (13)C Labelling of most amino acids derived from [1,6-(13)C]glucose was unchanged 2 weeks after hydrocephalus induction. The only indication of astrocyte impairment was the decreased (13)C enrichment in glutamine C-2. This study shows that hydrocephalus causes subtle but significant alterations in neuronal metabolism already early in the course of the disease. These sub-lethal changes, however, if maintained and if ongoing might explain the delayed and programmed neuronal damage as seen in chronic hydrocephalus.

In this work, we investigated the frequency-offset dependence of the rotating frame longitudinal (R1ρ) and transverse (R2ρ) relaxation rate constants when using hyperbolic-secant adiabatic full passage pulses or continuous-wave spin-lock irradiation. Phantom and in vivo measurements were performed to validate theoretical predictions of the dominant relaxation mechanisms existing during adiabatic full passage pulses when using different settings of the frequency offset relative to the carrier. In addition, adiabatic R1ρ and R2ρ values of total creatine and N-acetylaspartate were measured in vivo from the human brain at 4 T. When the continuous-wave pulse power was limited to safe specific absorption rates for humans, simulations revealed a strong dependence of R1ρ and R2ρ values on the frequency offset for both dipolar interactions and anisochronous exchange mechanisms. By contrast, theoretical and experimental results showed adiabatic R1ρ and R2ρ values to be practically invariant within the large subregion of the bandwidth of the hyperbolic-secant pulse where complete inversion was achieved. However, adiabatic R1ρ and R2ρ values of the methyl protons of total creatine (at 3.03 ppm) were almost doubled when compared with those of the methyl protons of N-acetylaspartate (at 2.01 ppm) in spite of the fact that these resonances were in the flat region of the inversion band of the adiabatic full passage pulses. We conclude that differences in adiabatic R1ρ and R2ρ values of human brain metabolites are not a result of their chemical shifts, but instead reflect differences in dynamics.

OBJECTIVE To investigate the effect of acute insulin-induced hypoglycemia on cerebral glucose metabolism in healthy humans, measured by 13C magnetic resonance spectroscopy (MRS). RESEARCH DESIGN AND METHODS Hyperinsulinemic glucose clamps were performed at plasma glucose levels of 5 mmol/L (euglycemia) or 3 mmol/L (hypoglycemia) in random order in eight healthy subjects (four women) on two occasions, separated by at least 3 weeks. Enriched [1-13C]glucose 20% w/w was used for the clamps to maintain stable plasma glucose labeling. The levels of the 13C-labeled glucose metabolites glutamate C4 and C3 were measured over time in the occipital cortex during the clamp by continuous 13C MRS in a 3T magnetic resonance scanner. Time courses of glutamate C4 and C3 labeling were fitted using a one-compartment model to calculate metabolic rates in the brain. RESULTS Plasma glucose 13C isotopic enrichment was stable at 35.1 ± 1.8% during euglycemia and at 30.2 ± 5.5% during hypoglycemia. Hypoglycemia stimulated release of counterregulatory hormones (all P < 0.05) and tended to increase plasma lactate levels (P = 0.07). After correction for the ambient 13C enrichment values, label incorporation into glucose metabolites was virtually identical under both glycemic conditions. Calculated tricarboxylic acid cycle rates (VTCA) were 0.48 ± 0.03 μmol/g/min during euglycemia and 0.43 ± 0.08 μmol/g/min during hypoglycemia (P = 0.42). CONCLUSIONS These results indicate that acute moderate hypoglycemia does not affect fluxes through the main pathways of glucose metabolism in the brain of healthy nondiabetic subjects.

The transverse relaxation times (T2) and concentrations of Ascorbate (Asc) and glutathione (GSH) were measured from a single dataset of double-edited spectra that were acquired at several TEs at 4 T in the human brain. Six TEs between 102 and 152 ms were utilized to calculate T2 for the group of 12 subjects scanned five times each. Spectra measured at all six TEs were summed to quantify the concentration in each individual scan. LCModel fitting was optimized for the quantification of the Asc and GSH double-edited spectra. When the fitted baseline was constrained to be flat, T2 was found to be 67 ms (95% confidence interval, 50–83 ms) for GSH and ≤115 ms for Asc using the sum of spectra measured over 60 scans. The Asc and GSH concentrations quantified in each of the 60 scans were 0.62 ± 0.08 and 0.81 ± 0.11 µmol/g [mean ± standard deviation (SD), n = 60], respectively, using 10 µmol/g N-acetylaspartate as an internal reference and assuming a constant influence of N-acetylaspartate and antioxidant T2 relaxation in the reference solution and in vivo. The T2 value of GSH was measured for the first time in the human brain. The data are consistent with short T2 for both antioxidants. These T2 values are essential for the absolute quantification of Asc and GSH concentrations measured at long TE, and provide a critical step towards addressing assumptions about T2, and therefore towards the quantification of concentrations without the possibility of systematic bias. Copyright © 2010 John Wiley & Sons, Ltd.

Recent studies with a conditional mouse model of spinocerebellar ataxia type 1 (SCA1) suggest that neuronal dysfunction is reversible and neurodegeneration preventable with early interventions. Success of such interventions will depend on early detection of neuronal and glial abnormalities before cell loss and availability of objective methods to monitor progressive neurodegeneration. Cerebellar concentrations ofN-acetylaspartate (NAA),myo-inositol, and glutamate as measured by magnetic resonance spectroscopy (MRS) correlate with ataxia scores of patients with SCA1, indicating their potential as reliable biomarkers of neurodegeneration. Here we investigated whether neurochemical levels are altered by early, presymptomatic disease and whether they gauge disease progression in a mouse model of SCA1. Cerebellar neurochemical profiles of transgenic mice that overexpress the mutant human ataxin-1 (theSCA1[82Q] line) were measured longitudinally up to 1 year by MRS at 9.4 T and compared to those of transgenic mice that overexpress the normal human ataxin-1 (theSCA1[30Q] line) and wild-type controls. Multiple neurochemicals distinguished theSCA1[82Q] mice from controls with no overlap at all ages. Six neurochemicals were significantly different inSCA1[82Q] mice at 6 weeks, before major pathological and neurological changes. Alterations in NAA,myo-inositol, and glutamate progressively worsened and were significantly correlated (p< 0.0001) with disease progression as assessed by histology (molecular layer thickness and an overall severity score). Therefore, the neurochemicals that correlate with clinical status in patients reflected progressive pathology in the mouse model. These data demonstrate that presymptomatic and progressive neurodegeneration in SCA1 can be noninvasively monitored using MRS.

International audience; The striatum is a well-known region affected in Huntington disease (HD). However, other regions, including the visual cortex, are implicated. We have identified previously an abnormal energy response in the visual cortex of patients at an early stage of HD using 31P magnetic resonance spectroscopy (31P MRS). We therefore sought to further characterize these metabolic alterations with 1H MRS using a well-validated semi-localized by adiabatic selective refocusing (semi-LASER) sequence that allows the measurement of an expanded number of neurometabolites. Ten early affected patients [Unified Huntington Disease Rating Scale (UHDRS), total motor score = 13.6 ± 10.8] and 10 healthy volunteers of similar age and body mass index (BMI) were recruited for the study. We performed 1H MRS in the striatum – the region that is primarily affected in HD – and the visual cortex. The protocol allowed a reliable quantification of 10 metabolites in the visual cortex and eight in the striatum, compared with three to five metabolites in previous 1H MRS studies performed in HD. We identified higher total creatine (p < 0.05) in the visual cortex and lower glutamate (p < 0.001) and total creatine (p < 0.05) in the striatum of patients with HD compared with controls. Less abundant neurometabolites [glutamine, γ-aminobutyric acid (GABA), glutathione, aspartate] showed similar concentrations in both groups. The protocol allowed the measurement of several additional metabolites compared with standard vendor protocols. Our study points to early changes in metabolites involved in energy metabolism in the visual cortex and striatum of patients with HD. Decreased striatal glutamate could reflect early neuronal dysfunction or impaired glutamatergic neurotransmission.