B0-insensitive image navigators for prospective motion-corrected MRS with localized second-order shimming.

PURPOSE: Localized shimming in single-voxel MRS often results in large B0 inhomogeneity outside the volume-of-interest. This causes unacceptable degradation in motion navigator images. Switching back and forth between whole-brain shim and localized shim is possible for linear shims, but not for higher-order shims. Here we propose motion navigators largely insensitive to B0 inhomogeneity for prospective motion-corrected MRS with localized higher-order shimming. METHODS: A recent fast high-resolution motion navigator based on spiral-in/out k-space trajectories and multislice-to-volume registration was modified by splitting the readout into multiple shot interleaves which shortened the echo time and reduced the effect of B0 inhomogeneity. The performance of motion correction was assessed in healthy subjects in the prefrontal cortex using a sLASER sequence at 3T (N = 5) and 7T (N = 5). RESULTS: With multiple spatial interleaves, excellent quality navigator images were acquired in the whole brain in spite of large B0 inhomogeneity outside the MRS voxel. The total duration of the navigator in sLASER remained relatively short even with multiple shots (3T: 10 spatial interleaves 94 ms per slice; 7T: 15 spatial interleaves 103 ms per slice). Prospective motion correction using the multi-shot navigators yielded comparable spectral quality (water linewidth and metabolite SNR) with and without subject motion. CONCLUSION: B0-insensitive motion navigators enable prospective motion correction for MRS with all first- and second-order shims adjusted in the MRS voxel, providing optimal spectral linewidth.

Fast high-resolution prospective motion correction for single-voxel spectroscopy.

PURPOSE: To develop a fast high-resolution image-based motion correction method using spiral navigators with multislice-to-volume registration. METHODS: A semi-LASER sequence was modified to include a multislice spiral navigator for prospective motion correction (∼305 ms including acquisition, processing, and feedback) as well as shim and frequency navigators for prospective shim and frequency correction (∼100 ms for each). MR spectra were obtained in the prefrontal cortex in five healthy subjects at 3 T with and without prospective motion and shim correction. The effect of key navigator parameters (number of slices, image resolution, and excitation flip angle) on registration accuracy was assessed using simulations. RESULTS: Without prospective motion and shim correction, spectral quality degraded significantly in the presence of voluntary motion. In contrast, with prospective motion and shim correction, spectral quality was improved (metabolite linewidth = 6.7 ± 0.6 Hz, SNR= 67 ± 9) and in good agreement with baseline data without motion (metabolite linewidth = 6.9 ± 0.9 Hz, SNR = 73 ± 9). In addition, there was no significant difference in metabolites concentrations measured without motion and with prospective motion and shim correction in the presence of motion. Simulations showed that the registration precision was comparable when using three navigator slices with 3 mm resolution and when using the entire volume (all slices) with 8 mm resolution. CONCLUSION: The proposed motion correction scheme allows fast and precise prospective motion and shim correction for single-voxel spectroscopy at 3 T. With 3 mm resolution, only a few navigator slices are necessary to achieve excellent motion correction performance.

Prospective motion correction for cervical spinal cord MRS.

PURPOSE: To develop prospective motion correction for single-voxel MRS in the human cervical spinal cord. METHODS: A motion MR navigator was implemented using reduced field-of-view 2D-selective RF excitation together with EPI readout. A short-echo semi-LASER sequence (TE = 30 ms) was updated to incorporate this real-time image-based motion navigator, as well as real-time shim and frequency navigators. Five healthy participants were studied at 3 T with a 64-channel head-neck receive coil. Single-voxel MRS data were measured in a voxel located at the C3-5 vertebrae level. The motion navigator was used to correct for translations in the X-Y plane and was validated by assessing spectral quality with and without prospective correction in the presence of subject motion. RESULTS: Without prospective correction, motion resulted in severe lipid contamination in the MR spectra. With prospective correction, the quality of spinal cord MR spectra in the presence of motion was similar to that obtained in the absence of motion, with comparable spectral signal-to-noise ratio and linewidth and no significant lipid contamination. CONCLUSION: Prospective motion and B0 correction allow acquisition of good-quality MR spectra in the human cervical spinal cord in the presence of motion. This new technique should facilitate reliable acquisition of spinal cord MR spectra in both research and clinical settings.

Brain MRI detects early-stage alterations and disease progression in Friedreich ataxia.

Friedreich ataxia is a progressive neurodegenerative disorder characterized by cerebellar and spinal atrophy. However, studies to elucidate the longitudinal progression of the pathology in the brain are somewhat inconsistent and limited, especially for early-stage Friedreich ataxia. Using a multimodal neuroimaging protocol, combined with advanced analysis methods, we sought to identify macrostructural and microstructural alterations in the brain of patients with early-stage Friedreich ataxia to better understand its distribution patterns and progression. We enrolled 28 patients with Friedreich ataxia and 20 age- and gender-matched controls. Longitudinal clinical and imaging data were collected in the patients at baseline, 12, 24 and 36 months. Macrostructural differences were observed in patients with Friedreich ataxia, compared to controls, including lower volume of the cerebellar white matter (but not cerebellar grey matter), superior cerebellar peduncle, thalamus and brainstem structures, and higher volume of the fourth ventricle. Diffusion tensor imaging and fixel-based analysis metrics also showed microstructural differences in several brain regions, especially in the cerebellum and corticospinal tract. Over time, many of these macrostructural and microstructural alterations progressed, especially cerebellar grey and white matter volumes, and microstructure of the superior cerebellar peduncle, posterior limb of the internal capsule and superior corona radiata. In addition, linear regressions showed significant associations between many of those imaging metrics and clinical scales. This study provides evidence of early-stage macrostructural and microstructural alterations and of progression over time in the brain in Friedreich ataxia. Moreover, it allows to non-invasively map such brain alterations over a longer period (3 years) than any previous study, and identifies several brain regions with significant involvement in the disease progression besides the cerebellum. We show that fixel-based analysis of diffusion MRI data is particularly sensitive to longitudinal change in the cerebellar peduncles, as well as motor and sensory white matter tracts. In combination with other morphometric measures, they may therefore provide sensitive imaging biomarkers of disease progression for clinical trials.

Multimodal MRI improves diagnostic accuracy and sensitivity to longitudinal change in amyotrophic lateral sclerosis.

BACKGROUND: Recent advances in MRI acquisitions and image analysis have increased the utility of neuroimaging in understanding disease-related changes. In this work, we aim to demonstrate increased sensitivity to disease progression as well as improved diagnostic accuracy in Amyotrophic lateral sclerosis (ALS) with multimodal MRI of the brain and cervical spinal cord. METHODS: We acquired diffusion MRI data from the brain and cervical cord, and T1 data from the brain, of 20 participants with ALS and 20 healthy control participants. Ten ALS and 14 control participants, and 11 ALS and 13 control participants were re-scanned at 6-month and 12-month follow-ups respectively. We estimated cross-sectional differences and longitudinal changes in diffusion metrics, cortical thickness, and fixel-based microstructure measures, i.e. fiber density and fiber cross-section. RESULTS: We demonstrate improved disease diagnostic accuracy and sensitivity through multimodal analysis of brain and spinal cord metrics. The brain metrics also distinguished lower motor neuron-predominant ALS participants from control participants. Fiber density and cross-section provided the greatest sensitivity to longitudinal change. We demonstrate evidence of progression in a cohort of 11 participants with slowly progressive ALS, including in participants with very slow change in ALSFRS-R. More importantly, we demonstrate that longitudinal change is detectable at a six-month follow-up visit. We also report correlations between ALSFRS-R and the fiber density and cross-section metrics. CONCLUSIONS: Our findings suggest that multimodal MRI is useful in improving disease diagnosis, and fixel-based measures may serve as potential biomarkers of disease progression in ALS clinical trials.

ALS is a disease affecting the brain and spinal cord which leads to weakness and muscle wasting. It is important to be able to measure disease-related changes whilst clinical trials are ongoing to assess whether the treatments being tested are working. We imaged the brain and spinal cord of people with and without ALS at 3 time points over a year. We found changes in the brain and spine over time. This study demonstrates that brain imaging could be potentially used to assess changes in disease progression during clinical trials, giving an indication of whether the treatments being tested are having an effect.

Progressive Spinal Cord Degeneration in Friedreich's Ataxia: Results from ENIGMA-Ataxia.

BACKGROUND: Spinal cord damage is a hallmark of Friedreich's ataxia (FRDA), but its progression and clinical correlates remain unclear. OBJECTIVE: The objective of this study was to perform a characterization of cervical spinal cord structural damage in a large multisite FRDA cohort. METHODS: We performed a cross-sectional analysis of cervical spinal cord (C1-C4) cross-sectional area (CSA) and eccentricity using magnetic resonance imaging data from eight sites within the ENIGMA-Ataxia initiative, including 256 individuals with FRDA and 223 age- and sex-matched control subjects. Correlations and subgroup analyses within the FRDA cohort were undertaken based on disease duration, ataxia severity, and onset age. RESULTS: Individuals with FRDA, relative to control subjects, had significantly reduced CSA at all examined levels, with large effect sizes (d > 2.1) and significant correlations with disease severity (r < -0.4). Similarly, we found significantly increased eccentricity (d > 1.2), but without significant clinical correlations. Subgroup analyses showed that CSA and eccentricity are abnormal at all disease stages. However, although CSA appears to decrease progressively, eccentricity remains stable over time. CONCLUSIONS: Previous 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 the DC and damage to CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, while 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. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A natural history study to track brain and spinal cord changes in individuals with Friedreich's ataxia: TRACK-FA study protocol.

INTRODUCTION: Drug development for neurodegenerative diseases such as Friedreich's ataxia (FRDA) is limited by a lack of validated, sensitive biomarkers of pharmacodynamic response in affected tissue and disease progression. Studies employing neuroimaging measures to track FRDA have thus far been limited by their small sample sizes and limited follow up. TRACK-FA, a longitudinal, multi-site, and multi-modal neuroimaging natural history study, aims to address these shortcomings by enabling better understanding of underlying pathology and identifying sensitive, clinical trial ready, neuroimaging biomarkers for FRDA. METHODS: 200 individuals with FRDA and 104 control participants will be recruited across seven international study sites. Inclusion criteria for participants with genetically confirmed FRDA involves, age of disease onset ≤ 25 years, Friedreich's Ataxia Rating Scale (FARS) functional staging score of ≤ 5, and a total modified FARS (mFARS) score of ≤ 65 upon enrolment. The control cohort is matched to the FRDA cohort for age, sex, handedness, and years of education. Participants will be evaluated at three study visits over two years. Each visit comprises of a harmonized multimodal Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) scan of the brain and spinal cord; clinical, cognitive, mood and speech assessments and collection of a blood sample. Primary outcome measures, informed by previous neuroimaging studies, include measures of: spinal cord and brain morphometry, spinal cord and brain microstructure (measured using diffusion MRI), brain iron accumulation (using Quantitative Susceptibility Mapping) and spinal cord biochemistry (using MRS). Secondary and exploratory outcome measures include clinical, cognitive assessments and blood biomarkers. DISCUSSION: Prioritising immediate areas of need, TRACK-FA aims to deliver a set of sensitive, clinical trial-ready neuroimaging biomarkers to accelerate drug discovery efforts and better understand disease trajectory. Once validated, these potential pharmacodynamic biomarkers can be used to measure the efficacy of new therapeutics in forestalling disease progression. CLINICAL TRIAL REGISTRATION: ClinicalTrails.gov Identifier: NCT04349514.

Spinal cord magnetic resonance imaging and spectroscopy detect early-stage alterations and disease progression in Friedreich ataxia.

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.

Corrigendum: Assessment of cerebral and cerebellar white matter microstructure in spinocerebellar ataxias 1, 2, 3, and 6 using diffusion MRI.

[This corrects the article DOI: 10.3389/fneur.2020.00411.].

Multiparametric characterization of white matter alterations in early stage Huntington disease.

Huntington's disease (HD) is a monogenic, fully penetrant neurodegenerative disorder. Widespread white matter damage affects the brain of patients with HD at very early stages of the disease. Fixel-based analysis (FBA) is a novel method to investigate the contribution of individual crossing fibers to the white matter damage and to detect possible alterations in both fiber density and fiber-bundle morphology. Diffusion-weighted magnetic resonance spectroscopy (DW-MRS), on the other hand, quantifies the motion of brain metabolites in vivo, thus enabling the investigation of microstructural alteration of specific cell populations. The aim of this study was to identify novel specific microstructural imaging markers of white matter degeneration in HD, by combining FBA and DW-MRS. Twenty patients at an early stage of HD and 20 healthy controls were recruited in a monocentric study. Using diffusion imaging we observed alterations to the brain microstructure and their morphology in patients with HD. Furthermore, FBA revealed specific fiber populations that were affected by the disease. Moreover, the mean diffusivity of the intra-axonal metabolite N-acetylaspartate, co-measured with N-acetylaspartylglutamate (tNAA), was significantly reduced in the corpus callosum of patients compared to controls. FBA and DW-MRS of tNAA provided more specific information about the biological mechanisms underlying HD and showed promise for early investigation of white matter degeneration in HD.

Multiparametric in vivo analyses of the brain and spine identify structural and metabolic biomarkers in men with adrenomyeloneuropathy.

OBJECTIVE: Progressive myelopathy causes severe handicap in men with adrenomyeloneuropathy (AMN), an X-linked disorder due to ABCD1 pathogenic variants. At present, treatments are symptomatic but disease-modifying therapies are under evaluation. Given the small effect size of clinical scales in AMN, biomarkers with higher effect size are needed. Here we used high-resolution magnetic resonance techniques to identify non-invasive in vivo biomarkers of the brain and spine with high effect sizes. METHODS: We performed a multiparametric imaging and spectroscopy study in 23 male patients with AMN (age: 44 ± 11) and 23 male controls (age: 43 ± 11) of similar age and body-mass index. We combined (i) macrostructural analyses of the spine, using cross-sectional area (CSA) and magnetization transfer ratio (MTR), (ii) microstructural analyses of the spine and the brain, using diffusion tensor and the newly developed fixel-based analysis, and (iii) advanced metabolic analyses of the spine using metabolite cycling coupled to a semi-LASER sequences. RESULTS: Macrostructural alterations (decrease in CSA and MTR) were observed in patients at all spinal cord levels studied (C1-T2 for CSA and C1-C5 for MTR) (p < 0.001). Microstructural alterations were observed in the spine and brain on diffusion tensor and fixel-based metrics though the latter showed higher effect sizes. Metabolic alterations were observed in patients as a decreased total N-acetylaspartate/myo-inositol ratio (p < 0.001). Overall, MTR showed the highest effect size. CONCLUSION: This cross-sectional study supports the use of multiparametric techniques that elucidate the structural, microstructural and metabolic alterations in AMN. These outcome measures should be tested longitudinally and in clinical trials.

Assessment of Cerebral and Cerebellar White Matter Microstructure in Spinocerebellar Ataxias 1, 2, 3, and 6 Using Diffusion MRI.

Development of imaging biomarkers for rare neurodegenerative diseases such as spinocerebellar ataxia (SCA) is important to non-invasively track progression of disease pathology and monitor response to interventions. Diffusion MRI (dMRI) has been shown to identify cross-sectional degeneration of white matter (WM) microstructure and connectivity between healthy controls and patients with SCAs, using various analysis methods. In this paper, we present dMRI data in SCAs type 1, 2, 3, and 6 and matched controls, including longitudinal acquisitions at 12-24-month intervals in a subset of the cohort, with up to 5 visits. The SCA1 cohort also contained 3 premanifest patients at baseline, with 2 showing ataxia symptoms at the time of the follow-up scans. We focused on two aspects: first, multimodal evaluation of the dMRI data in a cross-sectional approach, and second, longitudinal trends in dMRI data in SCAs. Three different pipelines were used to perform cross-sectional analyses in WM: region of interest (ROI), tract-based spatial statistics (TBSS), and fixel-based analysis (FBA). We further analyzed longitudinal changes in dMRI metrics throughout the brain using ROI-based analysis. Both ROI and TBSS analyses identified higher mean (MD), axial (AD), and radial (RD) diffusivity and lower fractional anisotropy (FA) in the cerebellum for all SCAs compared to controls, as well as some cerebral alterations in SCA1, 2, and 3. FBA showed lower fiber density (FD) and fiber crossing (FC) regions similar to those identified by ROI and TBSS analyses. FBA also highlighted corticospinal tract (CST) abnormalities, which was not detected by the other two pipelines. Longitudinal ROI-based analysis showed significant increase in AD in the middle cerebellar peduncle (MCP) for patients with SCA1, suggesting that the MCP may be a good candidate region to monitor disease progression. The patient who remained symptom-free throughout the study displayed no microstructural abnormalities. On the other hand, the two patients who were at the premanifest stage at baseline, and showed ataxia symptoms in their follow-up visits, displayed AD values in the MCP that were already in the range of symptomatic patients with SCA1 at their baseline visit, demonstrating that microstructural abnormalities are detectable prior to the onset of ataxia.

Autosomal dominant cerebellar ataxias: Imaging biomarkers with high effect sizes.

Objective: As gene-based therapies may soon arise for patients with spinocerebellar ataxia (SCA), there is a critical need to identify biomarkers of disease progression with effect sizes greater than clinical scores, enabling trials with smaller sample sizes. Methods: We enrolled a unique cohort of patients with SCA1 (n = 15), SCA2 (n = 12), SCA3 (n = 20) and SCA7 (n = 10) and 24 healthy controls of similar age, sex and body mass index. We collected longitudinal clinical and imaging data at baseline and follow-up (mean interval of 24 months). We performed both manual and automated volumetric analyses. Diffusion tensor imaging (DTI) and a novel tractography method, called fixel-based analysis (FBA), were assessed at follow-up. Effect sizes were calculated for clinical scores and imaging parameters. Results: Clinical scores worsened as atrophy increased over time (p < 0.05). However, atrophy of cerebellum and pons showed very large effect sizes (>1.2) compared to clinical scores (<0.8). FBA, applied for the first time to SCA, was sensitive to microstructural cross-sectional differences that were not captured by conventional DTI metrics, especially in the less studied SCA7 group. FBA also showed larger effect sizes than DTI metrics. Conclusion: This study showed that volumetry outperformed clinical scores to measure disease progression in SCA1, SCA2, SCA3 and SCA7. Therefore, we advocate the use of volumetric biomarkers in therapeutic trials of autosomal dominant ataxias. In addition, FBA showed larger effect size than DTI to detect cross-sectional microstructural alterations in patients relative to controls.

Expanded neurochemical profile in the early stage of Huntington disease using proton magnetic resonance spectroscopy.

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 31 P magnetic resonance spectroscopy (31 P MRS). We therefore sought to further characterize these metabolic alterations with 1 H 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 1 H 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 1 H 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.

A strategy for multimodal data integration: application to biomarkers identification in spinocerebellar ataxia.

The growing number of modalities (e.g. multi-omics, imaging and clinical data) characterizing a given disease provides physicians and statisticians with complementary facets reflecting the disease process but emphasizes the need for novel statistical methods of data analysis able to unify these views. Such data sets are indeed intrinsically structured in blocks, where each block represents a set of variables observed on a group of individuals. Therefore, classical statistical tools cannot be applied without altering their organization, with the risk of information loss. Regularized generalized canonical correlation analysis (RGCCA) and its sparse generalized canonical correlation analysis (SGCCA) counterpart are component-based methods for exploratory analyses of data sets structured in blocks of variables. Rather than operating sequentially on parts of the measurements, the RGCCA/SGCCA-based integrative analysis method aims at summarizing the relevant information between and within the blocks. It processes a priori information defining which blocks are supposed to be linked to one another, thus reflecting hypotheses about the biology underlying the data blocks. It also requires the setting of extra parameters that need to be carefully adjusted.Here, we provide practical guidelines for the use of RGCCA/SGCCA. We also illustrate the flexibility and usefulness of RGCCA/SGCCA on a unique cohort of patients with four genetic subtypes of spinocerebellar ataxia, in which we obtained multiple data sets from brain volumetry and magnetic resonance spectroscopy, and metabolomic and lipidomic analyses. As a first step toward the extraction of multimodal biomarkers, and through the reduction to a few meaningful components and the visualization of relevant variables, we identified possible markers of disease progression.

Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1 deficiency.

OBJECTIVE: On the basis of our previous work with triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets. METHODS: We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7-47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional (31)P-NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus. RESULTS: Patients with GLUT1-DS experienced a mean of 30.8 (± 27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (± 2.9, 76% motor events) during the treatment phase (p = 0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (± 21.9, 52% motor events; p = 0.043). Furthermore, brain energy metabolism normalised with triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p = 0.021), and deteriorated when triheptanoin was withdrawn. CONCLUSIONS: Treatment with triheptanoin resulted in a 90% clinical improvement in non-epileptic paroxysmal manifestations and a normalised brain bioenergetics profile in patients with GLUT1-DS. TRIAL REGISTRATION NUMBER: NCT02014883.

In vivo neurometabolic profiling in patients with spinocerebellar ataxia types 1, 2, 3, and 7.

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 ((1) H 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.

Two-site reproducibility of cerebellar and brainstem neurochemical profiles with short-echo, single-voxel MRS at 3T.

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.