Cerebellar Volumetry in Ataxias: Relation to Ataxia Severity and Duration.

Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Our results (i) confirmed SCA6 being considered as a pure cerebellar grey matter disease, (ii) emphasise the involvement of cerebellar white matter in the neuropathology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.

Stage-Dependent Biomarker Changes in Spinocerebellar Ataxia Type 3.

Spinocerebellar ataxia type 3/Machado-Joseph disease is the most common autosomal dominant ataxia. In view of the development of targeted therapies, knowledge of early biomarker changes is needed. We analyzed cross-sectional data of 292 spinocerebellar ataxia type 3/Machado-Joseph disease mutation carriers. Blood concentrations of mutant ATXN3 were high before and after ataxia onset, whereas neurofilament light deviated from normal 13.3 years before onset. Pons and cerebellar white matter volumes decreased and deviated from normal 2.2 years and 0.6 years before ataxia onset. We propose a staging model of spinocerebellar ataxia type 3/Machado-Joseph disease that includes a biomarker stage characterized by objective indicators of neurodegeneration before ataxia onset. ANN NEUROL 2024;95:400-406.

Cerebellar volumetry in ataxias: Relation to ataxia severity and duration.

Background: Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Methods: Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Results: Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Conclusion: Our results (i) confirmed SCA6 being considered as a pure cerebellar gray matter disease, (ii) emphasise the involvement of cerebellar white matter in the neurophatology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.

X-linked creatine transporter (SLC6A8) deficiency in females: Difficult to recognize, but a potentially treatable disease.

Creatine transporter deficiency (CTD), caused by pathogenic variants in SLC6A8, is the second most common cause of X-linked intellectual disability. Symptoms include intellectual disability, epilepsy, and behavioral disorders and are caused by reduced cerebral creatine levels. Targeted treatment with oral supplementation is available, however the treatment efficacy is still being investigated. There are clinical and theoretical indications that heterozygous females with CTD respond better to supplementation treatment than hemizygous males. Unfortunately, heterozygous females with CTD often have more subtle and uncharacteristic clinical and biochemical phenotypes, rendering diagnosis more difficult. We report a new female case who presented with learning disabilities and seizures. After determining the diagnosis with molecular genetic testing confirmed by proton magnetic resonance spectroscopy (1H-MRS), the patient was treated with supplementation treatment including creatine, arginine, and glycine. After 28 months of treatment, the patient showed prominent clinical improvement and increased creatine levels in the brain. Furthermore, we provide a review of the 32 female cases reported in the current literature including a description of phenotypes, genotypes, diagnostic approaches, and effects of supplementation treatment. Based on this, we find that supplementation treatment should be tested in heterozygous female patients with CTD, and a prospective treatment underlines the importance of diagnosing these patients. The diagnosis should be suspected in a broad clinical spectrum of female patients and can only be made by molecular genetic testing. 1H-MRS of cerebral creatine levels is essential for establishing the diagnosis in females, and especially valuable when assessing variants of unknown significance.

Stage-dependent biomarker changes in spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3) is the most common autosomal dominant ataxia. In view of the development of targeted therapies for SCA3, precise knowledge of stage-dependent fluid and MRI biomarker changes is needed. We analyzed cross-sectional data of 292 SCA3 mutation carriers including 57 pre-ataxic individuals, and 108 healthy controls from the European Spinocerebellar ataxia type 3/Machado-Joseph Disease Initiative (ESMI) cohort. Blood concentrations of mutant ATXN3 and neurofilament light (NfL) were determined, and volumes of pons, cerebellar white matter (CWM) and cerebellar grey matter (CGM) were measured on MRI. Mutant ATXN3 concentrations were high before and after ataxia onset, while NfL continuously increased and deviated from normal 11.9 years before onset. Pons and CWM volumes decreased, but the deviation from normal was only 2.0 years (pons) and 0.3 years (CWM) before ataxia onset. We propose a staging model of SCA3 that includes an initial asymptomatic carrier stage followed by the biomarker stage defined by absence of ataxia, but a significant rise of NfL. The biomarker stage leads into the ataxia stage, defined by manifest ataxia. The present analysis provides a robust framework for further studies aiming at elaboration and differentiation of the staging model of SCA3.

Downfield proton MRSI with whole-brain coverage at 3T.

PURPOSE: To develop a 3D downfield (DF) MRSI protocol with whole brain coverage and post-processing pipeline for creation of metabolite maps. METHODS: A 3D, circularly phase-encoded version of the previously developed 2D DF MRSI sequence with 1 3 ‾ 3 1 ‾ $$ 1\overline{3}3\overline{1} $$ spectral-spatial excitation and frequency selective refocusing was implemented and tested in five healthy volunteers at 3T. The DF metabolite maps with a nominal spatial resolution of 0.7 cm3 were recorded in eight slices at 3T in a scan time of 22 m 40 s. An MRSI post-processing pipeline was developed to create DF metabolite maps. Metabolite concentrations and uncertainty estimates were compared between region differences for nine DF peaks. RESULTS: LCModel analysis showed Cramer Rao lower bounds average values of 3%-4% for protein amide resonances in the three selected regions (anterior cingulate, dorsolateral prefrontal cortex, and centrum semiovale); Cramer Rao lower bounds were somewhat higher for individual peaks but for the most part were less than 20%. While DF concentration maps were visually quite homogeneous throughout the brain, general linear regression analysis corrected for multiple comparisons found significant differences between centrum semiovale and dorsolateral prefrontal cortex for peaks at 7.09 ppm (p = 0.014), 7.90 ppm (p = 0.009), 8.18 ppm (p = 0.009), combined amides (p = 0.009), and between anterior cingulate and dorsolateral prefrontal cortex for the 7.30 ppm peak (p = 0.020). Cramer Rao lower bounds values were not significantly different between brain regions for any of the DF peaks. CONCLUSION: The 3D DF MRSI of the human brain at 3T with wide spatial coverage for the mapping of exchangeable amide and other resonances is feasible at a nominal spatial resolution of 0.7 cm3 .

A Phase 1 Study of Oral Vitamin D3 in Boys and Young Men With X-Linked Adrenoleukodystrophy.

Background and Objectives: There are no therapies for preventing cerebral demyelination in X-linked adrenoleukodystrophy (ALD). Higher plasma vitamin D levels have been linked to lower risk of inflammatory brain lesions. We assessed the safety and pharmacokinetics of oral vitamin D dosing regimens in boys and young men with ALD. Methods: In this open-label, multicenter, phase 1 study, we recruited boys and young men with ALD without brain lesions to a 12-month study of daily oral vitamin D3 supplementation. Our primary outcome was attainment of plasma 25-hydroxyvitamin D levels in target range (40-80 ng/mL) at 6 and 12 months. Secondary outcomes included safety and glutathione levels in the brain, measured with magnetic resonance spectroscopy, and blood, measured via mass spectrometry. Participants were initially assigned to a fixed dosing regimen starting at 2,000 IU daily, regardless of weight. After a midstudy safety assessment, we modified the dosing regimen, so all subsequent participants were assigned to a weight-stratified dosing regimen starting as low as 1,000 IU daily. Results: Between October 2016 and June 2019, we enrolled 21 participants (n = 12, fixed-dose regimen; n = 9, weight-stratified regimen) with a median age of 6.7 years (range: 1.9-22 years) and median weight of 20 kg (range: 11.7-85.5 kg). The number of participants achieving target vitamin D levels was similar in both groups at 6 months (fixed dose: 92%; weight stratified: 78%) and 12 months (fixed dose: 67%; weight stratified: 67%). Among the 12 participants in the fixed-dose regimen, half had asymptomatic elevations in either urine calcium:creatinine or plasma 25-hydroxyvitamin D; no laboratory deviations occurred with the weight-stratified regimen. Glutathione levels in the brain, but not the blood, increased significantly between baseline and 12 months. Discussion: Our vitamin D dosing regimens were well tolerated and achieved target 25-hydroxyvitamin D levels in most participants. Brain glutathione levels warrant further study as a biomarker for vitamin D and ALD. Classification of Evidence: This study provides Class IV evidence that fixed or weight-stratified vitamin D supplementation achieved target levels of 25-hydroxyvitamin D in boys and young men with X-ALD without brain lesions.

Downfield Proton MRSI with whole-brain coverage at 3T.

Purpose: To develop a 3D downfield magnetic resonance spectroscopic imaging (DF-MRSI) protocol with whole brain coverage and post-processing pipeline for creation of metabolite maps. Methods: A 3D, circularly phase-encoded version of the previously developed 2D DF-MRSI sequence with spectral-spatial excitation and frequency selective refocusing was implemented and tested in 5 healthy volunteers at 3T. Downfield metabolite maps with a nominal spatial resolution of 0.7 cm 3 were recorded in 8 slices at 3T in a scan time of 22m 40s. An MRSI post-processing pipeline was developed to create DF metabolite maps. Metabolite concentrations and uncertainty estimates were compared between region differences for nine downfield peaks. Results: LCModel analysis showed CRLB average values of 3-4% for protein amide resonances in the three selected regions (anterior cingulate (ACC), dorsolateral prefrontal cortex (DLPFC), and centrum semiovale (CSO)); CRLBs were somewhat higher for individual peaks but for the most part were less than 20%. While DF concentration maps were visually quite homogeneous throughout the brain, general linear regression analysis corrected for multiple comparisons found significant differences between CSO and DLPFC for peaks at 7.09 ppm (p= 0.014), 7.90 ppm (p=0.009), 8.18 ppm (p=0.009), combined amides (p=0.009), and between ACC and DLPFC for the 7.30 ppm peak (p=0.020). CRLB values were not significantly different between brain regions for any of the DF peaks. Conclusion: 3D DF-MRSI of the human brain at 3T with wide spatial coverage for the mapping of exchangeable amide and other resonances is feasible at a nominal spatial resolution of 0.7 cm 3 .

Clinically Meaningful Magnetic Resonance Endpoints Sensitive to Preataxic Spinocerebellar Ataxia Types 1 and 3.

OBJECTIVE: This study was undertaken to identify magnetic resonance (MR) metrics that are most sensitive to early changes in the brain in spinocerebellar ataxia type 1 (SCA1) and type 3 (SCA3) using an advanced multimodal MR imaging (MRI) protocol in the multisite trial setting. METHODS: SCA1 or SCA3 mutation carriers and controls (n = 107) underwent MR scanning in the US-European READISCA study to obtain structural, diffusion MRI, and MR spectroscopy data using an advanced protocol at 3T. Morphometric, microstructural, and neurochemical metrics were analyzed blinded to diagnosis and compared between preataxic SCA (n = 11 SCA1, n = 28 SCA3), ataxic SCA (n = 14 SCA1, n = 37 SCA3), and control (n = 17) groups using nonparametric testing accounting for multiple comparisons. MR metrics that were most sensitive to preataxic abnormalities were identified using receiver operating characteristic (ROC) analyses. RESULTS: Atrophy and microstructural damage in the brainstem and cerebellar peduncles and neurochemical abnormalities in the pons were prominent in both preataxic groups, when patients did not differ from controls clinically. MR metrics were strongly associated with ataxia symptoms, activities of daily living, and estimated ataxia duration. A neurochemical measure was the most sensitive metric to preataxic changes in SCA1 (ROC area under the curve [AUC] = 0.95), and a microstructural metric was the most sensitive metric to preataxic changes in SCA3 (AUC = 0.92). INTERPRETATION: Changes in cerebellar afferent and efferent pathways underlie the earliest symptoms of both SCAs. MR metrics collected with a harmonized advanced protocol in the multisite trial setting allow detection of disease effects in individuals before ataxia onset with potential clinical trial utility for subject stratification. ANN NEUROL 2022.

Magnetic resonance spectroscopic imaging of downfield proton resonances in the human brain at 3 T.

PURPOSE: To develop an MRSI technique capable of mapping downfield proton resonances in the human brain. METHODS: A spectral-spatial excitation and frequency-selective refocusing scheme, in combination with 2D phase encoding, was developed for mapping of downfield resonances without any perturbation of the water magnetization. An alternative scheme using spectral-spatial refocusing was also investigated for simultaneous detection of both downfield and upfield resonances. The method was tested in 5 healthy human volunteers. RESULTS: Downfield metabolite maps with a nominal spatial resolution of 1.5 cm3 were recorded at 3 T in a scan time of 12 minutes. Cramer-Rao lower bounds for nine different downfield peaks were 20% or less over a single supraventricular slice. Downfield spectral profiles were similar to those in the literature recorded previously using single-voxel localization methods. The same approach was also used for upfield MRSI, and simultaneous upfield and downfield acquisitions. CONCLUSION: The developed MRSI pulse sequence was shown to be an efficient way of rapidly mapping downfield resonances in the human brain at 3 T, maximizing sensitivity through the relaxation enhancement effect. Because the MRSI approach is efficient in terms of data collection and can be readily implemented at short TE, somewhat higher spatial resolution can be achieved than has been reported in previous single-voxel downfield MRS studies. With this approach, nine downfield resonances could be mapped in a single slice for the first time using MRSI at 3 T.

Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder.

Psilocybin has shown promise for the treatment of mood disorders, which are often accompanied by cognitive dysfunction including cognitive rigidity. Recent studies have proposed neuropsychoplastogenic effects as mechanisms underlying the enduring therapeutic effects of psilocybin. In an open-label study of 24 patients with major depressive disorder, we tested the enduring effects of psilocybin therapy on cognitive flexibility (perseverative errors on a set-shifting task), neural flexibility (dynamics of functional connectivity or dFC via functional magnetic resonance imaging), and neurometabolite concentrations (via magnetic resonance spectroscopy) in brain regions supporting cognitive flexibility and implicated in acute psilocybin effects (e.g., the anterior cingulate cortex, or ACC). Psilocybin therapy increased cognitive flexibility for at least 4 weeks post-treatment, though these improvements were not correlated with the previously reported antidepressant effects. One week after psilocybin therapy, glutamate and N-acetylaspartate concentrations were decreased in the ACC, and dFC was increased between the ACC and the posterior cingulate cortex (PCC). Surprisingly, greater increases in dFC between the ACC and PCC were associated with less improvement in cognitive flexibility after psilocybin therapy. Connectome-based predictive modeling demonstrated that baseline dFC emanating from the ACC predicted improvements in cognitive flexibility. In these models, greater baseline dFC was associated with better baseline cognitive flexibility but less improvement in cognitive flexibility. These findings suggest a nuanced relationship between cognitive and neural flexibility. Whereas some enduring increases in neural dynamics may allow for shifting out of a maladaptively rigid state, larger persisting increases in neural dynamics may be of less benefit to psilocybin therapy.

Estimation and removal of spurious echo artifacts in single-voxel MRS using sensitivity encoding.

PURPOSE: In localized MRS, spurious echo artifacts commonly occur when unsuppressed signal outside the volume of interest is excited and refocused. In the spectral domain, these signals often overlap with metabolite resonances and hinder accurate quantification. Because the artifacts originate from regions separate from the target MRS voxel, this work proposes that sensitivity encoding based on receive-coil sensitivity profiles may be used to separate these signal contributions. METHODS: Numerical simulations were performed to explore the effect of sensitivity-encoded separation for unknown artifact regions. An imaging-based approach was developed to identify regions that may contribute to spurious echo artifacts, and tested for sensitivity-based unfolding of signal on six data sets from three brain regions. Spectral data reconstructed using the proposed method ("ERASE") were compared with the standard coil combination. RESULTS: The method was able to fully unfold artifact signals if regions were known a priori. Mismatch between estimated and true artifact regions reduced the efficiency of removal, yet metabolite signals were unaffected. Water suppression imaging was able to identify regions of unsuppressed signal, and ERASE (from up to eight regions) led to visible removal of artifacts relative to standard reconstruction. Fitting errors across major metabolites were also lower; for example, Cramér-Rao lower bounds of myo-inositol were 13.7% versus 17.5% for ERASE versus standard reconstruction, respectively. CONCLUSION: The ERASE reconstruction tool was demonstrated to reduce spurious echo artifacts in single-voxel MRS. This tool may be incorporated into standard workflows to improve spectral quality when hardware limitations or other factors result in out-of-voxel signal contamination.

Calibration-free regional RF shims for MRS.

PURPOSE: Achieving a desired RF transmit field ( B1+ ) in small regions of interest is critical for single-voxel MRS at ultrahigh field. Radio-frequency (RF) shimming, using parallel transmission, requires B1+ mapping and optimization, which limits its ease of use. This work aimed to generate calibration-free RF shims for predefined target regions of interest, which can be applied to any participant, to produce a desired absolute magnitude B1+ (| B1+ |). METHODS: The RF shims were found offline by joint optimization on a database comprising B1+ maps from 11 subjects, considering regions of interest in occipital cortex, hippocampus and posterior cingulate, as well as whole brain. The | B1+ | achieved was compared with a tailored shimming approach, and MR spectra were acquired using tailored and calibration-free shims in 4 participants. Global and local 10g specific-absorption-rate deposition were estimated using Duke and Ella dielectric models. RESULTS: There was no difference in the mean | B1+ | produced using calibration-free versus tailored RF shimming in the occipital cortex (p = .15), hippocampus (p = .5), or posterior cingulate (p = .98), although differences were observed in the RMS error | B1+ |. Spectra acquired using calibration-free shims had similar SNR and low residual water signal. Under identical power settings, specific-absorption-rate deposition was lower compared with operating in quadrature mode. For example, the total head specific absorption rate was around 35% less for the occipital cortex. CONCLUSION: This work demonstrates that static RF shims, optimized offline for small regions, avoid the need for B1+ mapping and optimization for each region of interest and participant. Furthermore, power settings may be increased when using calibration-free shims, to better take advantage of RF shimming.

Comparison of different linear-combination modeling algorithms for short-TE proton spectra.

Short-TE proton MRS is used to study metabolism in the human brain. Common analysis methods model the data as a linear combination of metabolite basis spectra. This large-scale multi-site study compares the levels of the four major metabolite complexes in short-TE spectra estimated by three linear-combination modeling (LCM) algorithms. 277 medial parietal lobe short-TE PRESS spectra (TE = 35 ms) from a recent 3 T multi-site study were preprocessed with the Osprey software. The resulting spectra were modeled with Osprey, Tarquin and LCModel, using the same three vendor-specific basis sets (GE, Philips and Siemens) for each algorithm. Levels of total N-acetylaspartate (tNAA), total choline (tCho), myo-inositol (mI) and glutamate + glutamine (Glx) were quantified with respect to total creatine (tCr). Group means and coefficient of variations of metabolite estimates agreed well for tNAA and tCho across vendors and algorithms, but substantially less so for Glx and mI, with mI systematically estimated as lower by Tarquin. The cohort mean coefficient of determination for all pairs of LCM algorithms across all datasets and metabolites was R2¯ = 0.39, indicating generally only moderate agreement of individual metabolite estimates between algorithms. There was a significant correlation between local baseline amplitude and metabolite estimates (cohort mean R2¯ = 0.10). While mean estimates of major metabolite complexes broadly agree between linear-combination modeling algorithms at group level, correlations between algorithms are only weak-to-moderate, despite standardized preprocessing, a large sample of young, healthy and cooperative subjects, and high spectral quality. These findings raise concerns about the comparability of MRS studies, which typically use one LCM software and much smaller sample sizes.

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

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

Water and lipid suppression techniques for advanced 1 H MRS and MRSI of the human brain: Experts' consensus recommendations.

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.

Comparison of Multivendor Single-Voxel MR Spectroscopy Data Acquired in Healthy Brain at 26 Sites.

Background The hardware and software differences between MR vendors and individual sites influence the quantification of MR spectroscopy data. An analysis of a large data set may help to better understand sources of the total variance in quantified metabolite levels. Purpose To compare multisite quantitative brain MR spectroscopy data acquired in healthy participants at 26 sites by using the vendor-supplied single-voxel point-resolved spectroscopy (PRESS) sequence. Materials and Methods An MR spectroscopy protocol to acquire short-echo-time PRESS data from the midparietal region of the brain was disseminated to 26 research sites operating 3.0-T MR scanners from three different vendors. In this prospective study, healthy participants were scanned between July 2016 and December 2017. Data were analyzed by using software with simulated basis sets customized for each vendor implementation. The proportion of total variance attributed to vendor-, site-, and participant-related effects was estimated by using a linear mixed-effects model. P values were derived through parametric bootstrapping of the linear mixed-effects models (denoted Pboot). Results In total, 296 participants (mean age, 26 years ± 4.6; 155 women and 141 men) were scanned. Good-quality data were recorded from all sites, as evidenced by a consistent linewidth of N-acetylaspartate (range, 4.4-5.0 Hz), signal-to-noise ratio (range, 174-289), and low Cramér-Rao lower bounds (≤5%) for all of the major metabolites. Among the major metabolites, no vendor effects were found for levels of myo-inositol (Pboot > .90), N-acetylaspartate and N-acetylaspartylglutamate (Pboot = .13), or glutamate and glutamine (Pboot = .11). Among the smaller resonances, no vendor effects were found for ascorbate (Pboot = .08), aspartate (Pboot > .90), glutathione (Pboot > .90), or lactate (Pboot = .28). Conclusion Multisite multivendor single-voxel MR spectroscopy studies performed at 3.0 T can yield results that are coherent across vendors, provided that vendor differences in pulse sequence implementation are accounted for in data analysis. However, the site-related effects on variability were more profound and suggest the need for further standardization of spectroscopic protocols. © RSNA, 2020 Online supplemental material is available for this article.

Effects of different macromolecular models on reproducibility of FID-MRSI at 7T.

PURPOSE: A properly characterized macromolecular (MM) contribution is essential for accurate metabolite quantification in FID-MRSI. MM information can be included into the fitting model as a single component or parameterized and included over several individual MM resonances, which adds flexibility when pathologic changes are present but is prone to potential overfitting. This study investigates the effects of different MM models on MRSI reproducibility. METHODS: Clinically feasible, high-resolution FID-MRSI data were collected in ~5 min at 7 Tesla from 10 healthy volunteers and quantified via LCModel (version 6.3) with 3 basis sets, each with a different approach for how the MM signal was handled: averaged measured whole spectrum (full MM), 9 parameterized components (param MM) with soft constraints to avoid overparameterization, or without any MM information included in the fitting prior knowledge. The test-retest reproducibility of MRSI scans was assessed voxel-wise using metabolite coefficients of variation and intraclass correlation coefficients and compared between the basis sets. Correlations of concentration estimates were investigated for the param MM fitting model. RESULTS: The full MM model provided the most reproducible quantification of total NAA, total Cho, myo-inositol, and glutamate + glutamine ratios to total Cr (coefficients of variations ≤ 8%, intraclass correlation coefficients ≥ 0.76). Using the param MM model resulted in slightly lower reproducibility (up to +3% higher coefficients of variations, up to -0.1 decreased intraclass correlation coefficients). The quantification of the parameterized macromolecules did not affect quantification of the overlapping metabolites. CONCLUSION: Clinically feasible FID-MRSI with an experimentally acquired MM spectrum included in prior knowledge provides highly reproducible quantification for the most common neurometabolites in healthy volunteers. Parameterization of the MM spectrum may be preferred as a compromise between quantification accuracy and reproducibility when the MM content is expected to be pathologically altered.

Water removal in MR spectroscopic imaging with L2 regularization.

PURPOSE: An L2-regularization based postprocessing method is proposed and tested for removal of residual or unsuppressed water signals in proton MR spectroscopic imaging (MRSI) data recorded from the human brain at 3T. METHODS: Water signals are removed by implementation of the L2 regularization using a synthesized water-basis matrix that is orthogonal to metabolite signals of interest in the spectral dimension. Simulated spectra with variable water amplitude and in vivo brain MRSI datasets were used to demonstrate the proposed method. Results were compared with two commonly-used postprocessing methods for removing water signals. RESULTS: The L2 method yielded metabolite signals that were close to true values for the simulated spectra. Residual/unsuppressed water signals in human brain short- and long-echo time MRSI datasets were efficiently removed by the proposed method allowing good quality metabolite maps to be reconstructed with minimized contamination from water signals. Significant differences of the creatine signal were observed between brain long-echo time MRSI without and with water saturation, attributable to the previously described magnetization transfer effect. CONCLUSIONS: With usage of a synthesized water matrix generated based on reasonable prior knowledge about water and metabolite resonances, the L2 method is shown to be an effective way to remove water signals from MRSI of the human brain.