Improvement of the thalamocortical white matter network in people with stable treated relapsing-remitting multiple sclerosis over time.

Advanced imaging techniques (tractography) enable the mapping of white matter (WM) pathways and the understanding of brain connectivity patterns. We combined tractography with a network-based approach to examine WM microstructure on a network level in people with relapsing-remitting multiple sclerosis (pw-RRMS) and healthy controls (HCs) over 2 years. Seventy-six pw-RRMS matched with 43 HCs underwent clinical assessments and 3T MRI scans at baseline (BL) and 2-year follow-up (2-YFU). Probabilistic tractography was performed, accounting for the effect of lesions, producing connectomes of 25 million streamlines. Network differences in fibre density across pw-RRMS and HCs at BL and 2-YFU were quantified using network-based statistics (NBS). Longitudinal network differences in fibre density were quantified using NBS in pw-RRMS, and were tested for correlations with disability, cognition and fatigue scores. Widespread network reductions in fibre density were found in pw-RRMS compared with HCs at BL in cortical regions, with more reductions detected at 2-YFU. Pw-RRMS had reduced fibre density at BL in the thalamocortical network compared to 2-YFU. This effect appeared after correction for age, was robust across different thresholds, and did not correlate with lesion volume or disease duration. Pw-RRMS demonstrated a robust and long-distance improvement in the thalamocortical WM network, regardless of age, disease burden, duration or therapy, suggesting a potential locus of neuroplasticity in MS. This network's role over the disease's lifespan and its potential implications in prognosis and treatment warrants further investigation.

A longitudinal analysis of brain volume changes in myelin oligodendrocyte glycoprotein antibody-associated disease.

BACKGROUND AND PURPOSE: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a relapsing demyelinating condition. There are several cross-sectional studies showing evidence of brain atrophy in people with MOGAD (pwMOGAD), but longitudinal brain volumetric assessment is still an unmet need. Current recommendations do not include monitoring with MRI and assume distinct attacks. Evidence of ongoing axon loss will have diagnostic and therapeutic implications. In this study, we assessed brain volume changes in pwMOGAD over a mean follow-up period of 2 years and compared this to changes in people with multiple sclerosis (pwMS). METHODS: This is a retrospective single-center study over a 7-year period from 2014 to 2021. MRI brain scans at the time of diagnosis and follow-up in remission were collected from 14 Caucasian pwMOGAD, confirmed by serum myelin oligodendrocyte glycoprotein immunoglobulin G antibody presence, detected by live cell-based assays. Total brain volume (TBV), white matter (WM), gray matter (GM), and demyelinating lesion volumes were assessed automatically using the Statistical Parametric Mapping and FMRIB automated segmentation tools. MRI brain scans at diagnosis and follow-up on remission were collected from 32-matched pwMS for comparison. Statistical analysis was done using analysis of variance. RESULTS: There is evidence of TBV loss, affecting particularly GM, over an approximately 2-year follow-up period in pwMOGAD (p < .05), comparable to pwMS. WM and lesion volume change over the same period were not statistically significant (p > .1). CONCLUSION: We found evidence of loss of GM and TBV over time  in pwMOGAD, similar to pwMS, although the WM and lesion volumes were unchanged.

Diffusion tensor imaging changes of the cortico-thalamic-striatal tracts correlate with fatigue and disability in people with relapsing-remitting MS.

PURPOSE: To investigate how the microstructural neural integrity of cortico-thalamic-striatal (CTS) tracts correlate with fatigue and disability over time. The primary outcome was diffusion tensor imaging (DTI) metrics change over time, and the secondary outcome was correlations with fatigue and disability in people with RRMS (pw-RRMS). METHODS: 76 clinically stable pw-RRMS and 43 matched healthy controls (HCs). The pw-RRMS cohort consisted of three different treatment subgroups. All participants underwent disability, cognitive, fatigue and mental health assessments. Structural and diffusion scans were performed at baseline (BL) and 2-year follow-up (2-YFU) for all participants. Fractional anisotropy (FA), mean, radial and axial diffusivities (MD, RD, AD) of normal-appearing white matter (NAWM) and white matter lesion (WML) in nine tracts-of-interests (TOIs) were estimated using our MRtrix3 in-house pipeline. RESULTS: We found significant BL and 2-YFU differences in most diffusion metrics in TOIs in pw-RRMS compared to HCs (pFDR ≤ 0.001; false-detection-rate (FDR)-corrected). There was a significant decrease in WML diffusivities and an increase in FA over the follow-up period in most TOIs (pFDR ≤ 0.001). Additionally, there were no differences in DTI parameters across treatment groups. AD and MD were positively correlated with fatigue scores (r ≤ 0.33, p ≤ 0.01) in NAWM-TOIs, while disability (EDSS) was negatively correlated with FA in most NAWM-TOIs (|r|≤0.31, p ≤ 0.01) at both time points. Disability scores correlated with all diffusivity parameters (r ≤ 0.29, p ≤ 0.01) in most WML-TOIs at both time points. CONCLUSION: Statistically significant changes in diffusion metrics in WML might be indicative of integrity improvement over two years in CTS tracts in clinically stable pw-RRMS. This finding represents structural changes within lesioned tracts. Measuring diffusivity in pw-RRMS affected tracts might be a relevant measure for future remyelination clinical trials.

Multi-modal neuroimaging signatures predict cognitive decline in multiple sclerosis: A 5-year longitudinal study.

BACKGROUND: Cognitive impairment is a hallmark of multiple sclerosis (MS) but is usually an under-recorded symptom of disease progression. Identifying the predictive signatures of cognitive decline in people with MS (pwMS) over time is important to ensure effective preventative treatment strategies. Structural and functional brain characteristics as measured by various magnetic resonance (MR) methods have been correlated with variation in cognitive function in MS, but typically these studies are limited to a single MR modality and/or are cross-sectional designs. Here we assess the predictive value of multiple different MR modalities in relation to cognitive decline in pwMS over 5 years. METHODS: A cohort of 43 pwMS was assessed at baseline and 5 years follow-up. Baseline (input) data consisted of 70 multi-modal MRI measures for different brain regions including magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI) and standard volumetrics. Age, sex, disease duration and treatment were included as clinical inputs. Cognitive function was assessed using the Audio Recorded Cognitive Screen (ARCS) and the Symbol Digit Modalities Test (SDMT). Prediction modelling was performed using the machine learning package - GLMnet, where a penalised regression was applied to identify multi-modal signatures with the most predictive value (and the least error) for each outcome. RESULTS: The multi-modal approach to neuroimaging was able to accurately predict cognitive decline in pwMS. The best performing model for change in total ARCS (tARCS) included 16 features from across the various MR modalities and explained 54 % of the variation in change over time (R2=0.54, 95 % CI=0.48-0.51). The features included nine MRS, four volumetric and two DTI parameters. The model also selected disease duration, but not treatment, as a predictive feature. By comparison, the best model for SDMT included several of the same above features and explained 39 % of the change over time (R2=0.39, 95 % CI=0.48-0.51). Conventional volumetric measures were about half as good at predicting change in tARCS score compared to the best multi-modal model (R2=0.26 95 % CI:0.22-0.29). The clinical interpretation of the best predictive model for change in tARCS showed that cognitive decline could be predicted with >90 % accuracy in this cohort (AUC=0.92, SE=0.86 - 0.94). CONCLUSION: Multi-modal MRI signatures can predict cognitive decline in a cohort of pwMS over 5 years with high accuracy. Future studies will benefit from the inclusion of even more MR modalities e.g., functional MRI, quantitative susceptibility mapping, magnetisation transfer imaging, as well as other potential predictors e.g., genetic and environmental factors. With further validation, this signature could be used in future trials with high-risk patients to personalise the management of cognitive decline in pwMS, even in the absence of relapses.

MR myelin imaging in multiple sclerosis: A scoping review.

The inability of disease-modifying therapies to stop the progression of multiple sclerosis (MS), has led to the development of a new therapeutic strategy focussing on myelin repair. While conventional MRI lacks sensitivity for quantifying myelin damage, advanced MRI techniques are proving effective. The development of targeted therapeutics requires histological validation of myelin imaging results, alongside the crucial task of establishing correlations between myelin imaging results and clinical assessments, so that the effectiveness of therapeutic interventions can be evaluated. The aims of this scoping review were to identify myelin imaging methods - some of which have been histologically validated, and to determine how these approaches correlate with clinical assessments of people with MS (pwMS), thus allowing for effective therapeutic evaluation. A search of two databases was undertaken for publications relating to studies on adults MS using either MRI/MR-histology of the MS brain in the range 1990-to-2022. The myelin imaging methods specified were relaxometry, magnetization transfer, and quantitative susceptibility. Relaxometry was used most frequently, with myelin water fraction (MWF) being the primary metric. Studies conducted on tissue from various regions of the brain showed that MWF was significantly lower in pwMS than in healthy controls. Magnetization transfer ratio indicated that the macromolecular content of lesions was lower than that of normal-appearing tissue. Higher magnetic susceptibility of lesions were indicative of myelin breakdown and iron accumulation. Several myelin imaging metrics were correlated with disability, disease severity and duration. Many studies showed a good correlation between myelin measured histologically and by MR myelin imaging techniques.

Fast WASABI post-processing: Access to rapid B0 and B1 correction in clinical routine for CEST MRI.

CEST MRI methods, such as APT and NOE imaging reveal biomarkers with significant diagnostic potential due to their ability to access molecular tissue information. Regardless of the technique used, CEST MRI data are affected by static magnetic B0 and radiofrequency B1 field inhomogeneities that degrade their contrast. For this reason, the correction of B0 field-induced artefacts is essential, whereas accounting for B1 field inhomogeneities have shown significant improvements in image readability. In a previous work, an MRI protocol called WASABI was presented, which can map simultaneously B0 and B1 field inhomogeneities, while maintaining the same sequence and readout types as used for CEST MRI. Despite the highly satisfactory quality of B0 and B1 maps computed from the WASABI data, the post-processing method is based on an exhaustive search of a four-parameter space and an additional four-parameter non-linear model fitting step. This leads to long post-processing times that are prohibitive in clinical practice. This work provides a new method for fast post-processing of WASABI data with outstanding acceleration of the parameter estimation procedure and without compromising its stability. The resulting computational acceleration makes the WASABI technique suitable for clinical use. The stability of the method is demonstrated on phantom data and clinical 3 Tesla in vivo data.

CEST 2022 - Differences in APT-weighted signal in T1 weighted isointense lesions, black holes and normal-appearing white matter in people with relapsing-remitting multiple sclerosis.

PURPOSE: To evaluate amide proton transfer weighted (APTw) signal differences between multiple sclerosis (MS) lesions and contralateral normal-appearing white matter (cNAWM). Cellular changes during the demyelination process were also assessed by comparing APTw signal intensity in T1weighted isointense (ISO) and hypointense (black hole -BH) MS lesions in relation to cNAWM. METHODS: Twenty-four people with relapsing-remitting MS (pw-RRMS) on stable therapy were recruited. MRI/APTw acquisitions were undertaken on a 3 T MRI scanner. The pre and post-processing, analysis, co-registration with structural MRI maps, and identification of regions of interest (ROIs) were all performed with Olea Sphere 3.0 software. Generalized linear model (GLM) univariate ANOVA was undertaken to test the hypotheses that differences in mean APTw were entered as dependent variables. ROIs were entered as random effect variables, which allowed all data to be included. Regions (lesions and cNAWM) and/or structure (ISO and BH) were the main factor variables. The models also included age, sex, disease duration, EDSS, and ROI volumes as covariates. Receiver operating characteristic (ROC) curve analyses were performed to evaluate the diagnostic performance of these comparisons. RESULTS: A total of 502 MS lesions manually identified on T2-FLAIR from twenty-four pw-RRMS were subcategorized as 359 ISO and 143 BH with reference to the T1-MPRAGE cerebral cortex signal. Also, 490 ROIs of cNAWM were manually delineated to match the MS lesion positions. A two-tailed t-test showed that mean APTw values were higher in females than in males (t = 3.52, p < 0.001). Additionally, the mean APTw values of MS lesions were higher than those of cNAWM after accounting for covariates (mean lesion = 0.44, mean cNAWM = 0.13, F = 44.12, p < 0.001).The mean APTw values of ISO lesions were higher than those of cNAWM after accounting for covariates (mean ISO lesions = 0.42, mean cNAWM = 0.21, F = 12.12, p < 0.001). The mean APTw values of BH were also higher than those of cNAWM (mean BH lesions = 0.47, mean cNAWM = 0.033, F = 40.3, p < 0.001). The effect size (i.e., difference between lesion and cNAWM) for BH was found to be higher than for ISO (14 vs. 2). Diagnostic performance showed that APT was able to discriminate between all lesions and cNAWM with an accuracy of >75% (AUC = 0.79, SE = 0.014). Discrimination between ISO lesions and cNAWM was accomplished with an accuracy of >69% (AUC = 0.74, SE = 0.018), while discrimination between BH lesions and cNAWM was achieved at an accuracy of >80% (AUC = 0.87, SE = 0.021). CONCLUSIONS: Our results highlight the potential of APTw imaging for use as a non-invasive technique that is able to provide essential molecular information to clinicians and researchers so that the stages of inflammation and degeneration in MS lesions can be better characterized.

Stability of longitudinal DTI metrics in MS with treatment of injectables, fingolimod and dimethyl fumarate.

BACKGROUND AND PURPOSE: Diffusion MRI (dMRI) is sensitive to microstructural changes in white matter of people with relapse-remitting multiple sclerosis (pw-RRMS) that lead to progressive disability. The role of diffusion in assessing the efficacy of different therapies requires more investigation. This study aimed to evaluate selected dMRI metrics in normal-appearing white matter and white matter-lesion in pw-RRMS and healthy controls longitudinally and compare the effect of therapies given. MATERIAL AND METHODS: Structural and dMRI scans were acquired from 78 pw-RRMS (29 injectables, 36 fingolimod, 13 dimethyl fumarate) and 43 HCs at baseline and 2-years follow-up. Changes in dMRI metrics and correlation with clinical parameters were evaluated. RESULTS: Differences were observed in most clinical parameters between pw-RRMS and HCs at both timepoints (p ≤ 0.01). No significant differences in average changes over time were observed for any dMRI metric between treatment groups in either tissue type. Diffusion metrics in NAWM and WML correlated negatively with most cognitive domains, while FA correlated positively at baseline but only for NAWM at follow-up (p ≤ 0.05). FA correlated negatively with disability in NAWM and WML over time, while MD and RD correlated positively only in NAWM. CONCLUSIONS: This is the first DTI study comparing the effect of different treatments on dMRI parameters over time in a stable cohort of pw-RRMS. The results suggest that brain microstructural changes in a stable MS cohort are similar to HCs independent of the therapies used.

Neurometabolic changes in multiple sclerosis: Fingolimod versus beta interferon or glatiramer acetate therapy.

BACKGROUND AND PURPOSE: Fingolimod has been shown to be more effective in reducing relapse rate and disability than injectable therapies in clinical trials. An increase in N-acetylaspartate (NAA) as measured by MR spectroscopy is correlated with maintaining axonal metabolic functions. This study compared the neurometabolic and volumetric changes in relapsing-remitting multiple sclerosis (RRMS) patients on fingolimod or injectable therapies with healthy controls (HCs). METHODS: Ninety-eight RRMS (52 on fingolimod, 46 on injectable therapies (27 on glatiramer acetate and 19 on interferon) were age and sex-matched to 51 HCs. RRMS patients underwent cognitive, fatigue, and mental health assessments, as well as an Expanded disability status scale (EDSS). MRI/S was acquired from the hippocampus, posterior cingulate gyrus (PCG), and prefrontal cortex (PFC). Volumetric and neurometabolic measures were compared across cohorts using a univariate general linear model and correlated with clinical severity and neuropsychological scores. RESULTS: Clinical parameters, MR-volumetric, and neurometabolic profiles showed no differences between treatment groups (p > .05). Compared to HCs, both RRMS cohorts showed volume changes in white matter (-13%), gray matter (-16%), and cerebral spinal fluid (CSF) (+17-23%), as well as reduced NAA (-17%, p = .001, hippocampus), (-7%, p = .001, PCG), and (-9%, p = .001, PFC). MRI/S metrics in three regions were moderately correlated with cognition and fatigue functions. CONCLUSION: While both treatment arms showed overall similar volumetric and neurometabolic profiles, longitudinal studies are warranted to clarify neurometabolic changes and associations with treatment efficacy.

Effect of high-intensity interval training on hippocampal metabolism in older adolescents.

Although well-evidenced in older adults, the effects of exercise on the hippocampus in youth are relatively unknown. This study examined the impact of a 6-month school-based physical activity intervention on hippocampal metabolism in adolescents using magnetic resonance spectroscopy. A subset of lower fit older adolescents [N = 56, 61% female, 16.1 ± 0.4 years] was included from four secondary schools (10 classes) in New South Wales, Australia, who were participating in a larger cluster randomized controlled trial. Participants were randomized to the Burn 2 Learn (B2L) intervention (five classes, 30 participants) or a control group (five classes, 26 participants). Changes in hippocampal metabolism were assessed using linear mixed models adjusted for clustering at the class level. We observed group-by-time effects for the B2L intervention on N-acetylaspartate (NAA) (+2.66 mmol/L, 95% CI 0.20 to 5.11, d = 0.66) and glutamate+glutamine (Glx) (+3.38 mmol/L, 95% CI 0.34 to 6.42, d = 0.67) in the left hippocampus. Increases in left hippocampal NAA and Glx concentrations were associated with improvements in cardiorespiratory fitness (NAA: rs  = 0.52, p = .016; Glx: rs  = 0.57, p = .007), lower body muscular fitness (NAA: rs  = 0.49, p = .018; Glx: rs  = 0.59, p = .003), and working memory (NAA: rs  = 0.42, p = .032; Glx: rs  = 0.43, p = .028) in the intervention group. Our findings suggest physical activity may improve hippocampal metabolism in lower fit older adolescents with implications for working memory. Further studies involving larger samples are needed to replicate our findings.

Neural diffusion tensor imaging metrics correlate with clinical measures in people with relapsing-remitting MS.

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) can detect microstructural changes of white matter in multiple sclerosis (MS) and might clarify mechanisms responsible for disability. Thus, we aimed to compare DTI metrics in relapsing-remitting MS patients (RRMS) with healthy controls (HCs), and explore the correlations between DTI metrics, total brain white matter (TBWM) and white matter lesion (WML) with clinical parameters compared to volumetric measures. MATERIAL AND METHODS: 37 RRMS patients and 19 age/sex-matched HCs were included. All participants had clinical assessments, structural and diffusion scans on a 3T MRI. Volumetric and white matter DTI metrics; fractional anisotropy (FA), mean, radial and axial diffusivities (MD, RD and AD) were estimated and correlated with clinical parameters. The mean group differences were calculated using t-tests, and univariate correlations with Pearson correlation coefficients. RESULTS: Compared to HCs, statistically significant increases in MD (+3.6%), RD (+4.8%), AD (+2.7%) and a decrease in FA (-4.3%) for TBWM in RRMS was observed (p < .01). MD and RD in TBWM and AD in WML correlated moderately with disability status. Volumetric segmentation indicated a decrease in the total brain volume, GM and WM(-5%) with a reciprocal increase in CSF(+26%) in RRMS(p < .01). Importantly, DTI parameters showed a medium correlation with cognitive domains in contrast to white matter-related volumetric measurements in RRMS(Pearson correlation, p < .05). CONCLUSIONS: Our study shows a correlation of DTI metrics with clinical symptoms of MS, in particular cognition. More generally, these findings indicated that DTI is a useful and unique technique for evaluating the clinical features of white matter disease and warrants further investigation into its clinical role.

Altered in vivo brain GABA and glutamate levels are associated with multiple sclerosis central fatigue.

PURPOSE: Fatigue is a common symptom in patients with multiple sclerosis (MS) with unknown pathophysiology. Dysfunction of the GABAergic/glutamatergic pathways involving inhibitory and excitatory neurotransmitters such as  γ-aminobutyric acid (GABA) and glutamine + glutamate pool (Glx) have been implicated in several neurological disorders. This study is aimed to evaluate the potential role of GABA and Glx in the origin of central fatigue in relapse remitting MS (RRMS) patients. METHODS: 24 RRMS patients and 16 age- and sex-matched healthy controls (HC) were scanned using Mescher-Garwood point resolved spectroscopy (MEGA-PRESS) with a 3 T system to quantify GABA+ and Glx from prefrontal (PFC) and sensorimotor (SMC) cortices. Self-reported fatigue status was measured on all participants using the Modified Fatigue Impact Scale (MFIS). RESULTS: RRMS patients had higher fatigue scores relative to HC (p ≤  0.05). Compared to HC, Glx levels in RRMS patients were significantly decreased in SMC (p =  0.04). Significant correlations were found between fatigue scores and GABA+ (r = -0.531, p =  0.008) and Glx (r = 0.511, p =  0.018) in PFC. Physical fatigue was negatively correlated with GABA+ in SMC and PFC (r = -0.428 and -0.472 respectively, p ≤  0.04) and positively with PFC Glx (r = 0.480, p =  0.028). CONCLUSION: The associations between fatigue and GABA + and Glx suggest that there might be dysregulation of GABAergic/glutamatergic neurotransmission in the pathophysiological mechanism of central fatigue in MS.

Biochemical Correlations with Fatigue in Multiple Sclerosis Detected by MR 2D Localized Correlated Spectroscopy.

BACKGROUND AND PURPOSE: Fatigue is the common symptom in patients with multiple sclerosis (MS), yet its pathophysiological mechanism is poorly understood. We investigated the metabolic changes in fatigue in a group of relapsing-remitting MS (RRMS) patients using MR two-dimensional localized correlated spectroscopy (2D L-COSY). METHODS: Sixteen RRMS and 16 healthy controls were included in the study. Fatigue impact was assessed with the Modified Fatigue Impact Scale (MFIS). MR 2D L-COSY data were collected from the posterior cingulate cortex. Nonparametric statistical analysis was used to calculate the changes in creatine scaled metabolic ratios and their correlations with fatigue scores. RESULTS: Compared to healthy controls, the RRMS group showed significantly higher fatigue and lower metabolic ratios for tyrosine, glutathione, homocarnosine (GSH+Hca), fucose-3, glutamine+glutamate (Glx), glycerophosphocholine (GPC), total choline, and N-acetylaspartate (NAA-2), while increased levels for isoleucine and glucose (P ≤ .05). Only GPC showed positive correlation with all fatigue domains (r = .537, P ≤ .05). On the other hand, Glx-upper, NAA-2, GSH+Hca, and fucose-3 showed negative correlations with all fatigue domains (r = -.345 to -.580, P ≤ .05). While tyrosine showed positive correlation with MFIS (r = .499, P ≤ .05), cognitive fatigue was negatively correlated with total GSH (r = -.530, P ≤ .05). No correlations were found between lesion load or brain volumes with fatigue score. CONCLUSIONS: Our results suggest that fatigue in MS is strongly correlated with an imbalance in neurometabolites but not structural brain measurements.

Spiral MRSI and tissue segmentation of normal-appearing white matter and white matter lesions in relapsing remitting multiple sclerosis patients☆.

PURPOSE: To evaluate the performance of novel spiral MRSI and tissue segmentation pipeline of the brain, to investigate neurometabolic changes in normal-appearing white matter (NAWM) and white matter lesions (WML) of stable relapsing remitting multiple sclerosis (RRMS) compared to healthy controls (HCs). METHODS: Spiral 3D MRSI using LASER-GOIA-W [16,4] was undertaken on 16 RRMS patients and 9 HCs, to acquire MRSI data from a large volume of interest (VOI) 320 cm3 and analyzed using LCModel. MRSI data and voxel tissue segmentation were compared between the two cohorts using t-tests. Support vector machine (SVM) was used to classify tissue types and assessed by accuracy, sensitivity and specificity. RESULTS: Compared to HCs, RRMS demonstrated a statistically significant reduction in all mean brain tissues and increase in CSF volume. Within VOI, WM decreased (-10%) and CSF increased (41%) in RRMS compared to HCs (p < 0.001). MRSI revealed that total creatine (tCr) ratios of N-acetylaspartate and glutamate+glutamine in WML were significantly lower than NAWM-MS (-9%, -8%) and HCs (-14%, -10%), respectively. Myo-inositol/tCr in WML was significantly higher than NAWM-MS (14%) and HCs (10%). SVM of MRSI yielded accuracy, sensitivity and specificity of 86%, 95%, and 70%, respectively for HCs vs WML, which were higher than HC vs NAWM and WML vs NAWM models. CONCLUSION: This study demonstrates the benefit of MRSI in evaluating MS neurometabolic changes in NAWM. SVM of MRSI data in the MS brain may be suited for clinical monitoring and progression of MS patients. Longitudinal MRSI studies are warranted.

2D in-vivo L-COSY spectroscopy identifies neurometabolite alterations in treated multiple sclerosis.

BACKGROUND: We have applied in vivo two-dimensional (2D) localized correlation spectroscopy (2D L-COSY), in treated relapsing relapsing-remitting multiple sclerosis (RRMS) to identify novel biomarkers in normal-appearing brain parenchyma. METHODS: 2D L-COSY magnetic resonance spectroscopy (MRS) spectra were prospectively acquired from the posterior cingulate cortex (PCC) in 45 stable RRMS patients undergoing treatment with Fingolimod, and 40 age and sex-matched healthy control (HC) participants. Average metabolite ratios and clinical symptoms including, disability, cognition, fatigue, and mental health parameters were measured, and compared using parametric and nonparametric tests. Whole brain volume and MRS voxel morphometry were evaluated using SIENAX and the SPM LST toolbox. RESULTS: Despite the mean whole brain lesion volume being low in this RRMS group (6.8 ml) a significant reduction in PCC metabolite to tCr ratios were identified for multiple N-acetylaspartate (NAA) signatures, gamma-aminobutyric acid (GABA), glutamine and glutamate (Glx), threonine, and isoleucine/lipid. Of the clinical symptoms measured, visuospatial function, attention, and memory were correlated with NAA signatures, Glx, and isoleucine/lipid in the brain. CONCLUSIONS: 2D L-COSY has the potential to detect metabolic alterations in the normal-appearing MS brain. Despite examining only a localised region, we could detect metabolic variability associated with symptoms.

Supervised risk predictor of central gland lesions in prostate cancer using 1 H MR spectroscopic imaging with gradient offset-independent adiabaticity pulses.

BACKGROUND: Due to the histological heterogeneity of the central gland, accurate detection of central gland prostate cancer remains a challenge. PURPOSE: To evaluate the efficacy of in vivo 3D 1 H MR spectroscopic imaging (3D 1 H MRSI) with a semi-localized adiabatic selective refocusing (sLASER) sequence and gradient-modulated offset-independent adiabatic (GOIA) pulses for detection of central gland prostate cancer. Additionally four risk models were developed to differentiate 1) normal vs. cancer, 2) low- vs. high-risk cancer, 3) low- vs. intermediate-risk cancer, and 4) intermediate- vs. high-risk cancer voxels. STUDY TYPE: Prospective. SUBJECTS: Thirty-six patients with biopsy-proven central gland prostate cancer. FIELD STRENGTH/SEQUENCE: 3T MRI / 3D 1 H MRSI using GOIA-sLASER. ASSESSMENT: Cancer and normal regions of interest (ROIs) were selected by an experienced radiologist and 1 H MRSI voxels were placed within the ROIs to calculate seven metabolite signal ratios. Voxels were split into two subsets, 80% for model training and 20% for testing. STATISTICAL TESTS: Four support vector machine (SVM) models were built using the training dataset. The accuracy, sensitivity, and specificity for each model were calculated for the testing dataset. RESULTS: High-quality MR spectra were obtained for the whole central gland of the prostate. The normal vs. cancer diagnostic model achieved the highest predictive performance with an accuracy, sensitivity, and specificity of 96.2%, 95.8%, and 93.1%, respectively. The accuracy, sensitivity, and specificity of the low- vs. high-risk cancer and low- vs. intermediate-risk cancer models were 82.5%, 89.2%, 70.2%, and 73.0%, 84.7%, 60.8%, respectively. The intermediate- vs. high-risk cancer model yielded an accuracy, sensitivity, and specificity lower than 55%. DATA CONCLUSION: The GOIA-sLASER sequence with an external phased-array coil allows for fast assessment of central gland prostate cancer. The classification offers a promising diagnostic tool for discriminating normal vs. cancer, low- vs. high-risk cancer, and low- vs. intermediate-risk cancer. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1926-1936.

Diurnal variability of cerebral metabolites in healthy human brain with 2D localized correlation spectroscopy (2D L-COSY).

BACKGROUND: Two-dimensional localized correlation spectroscopy (2D L-COSY) is a research tool that has been applied to evaluate in vivo metabolic activity in many neurological and oncological disorders. Circadian mediators such as brain temperature, hydration, and osmotic regulation have been claimed to change metabolic profiles. PURPOSE: To evaluate the diurnal variability of neuro-metabolites with 2D L-COSY in healthy subjects using a 3 T scanner. STUDY TYPE: Crossover. POPULATION/PHANTOM: Ten healthy subjects and magnetic resonance spectroscopy-high definition (MRS-HD) sphere or "Braino." Field Strength/Sequence: 3 T/2D L-COSY MRS. ASSESSMENT: In vivo 2D L-COSY measurements were performed on ten healthy subjects (5 M/5F, mean age 36.1 ± 7.7 years) repeatedly at three timepoints (0700, 1200, and 1700) on the same day. in vitro evaluations were performed in a similar fashion as in vivo on Braino containing selected brain metabolites at physiological concentrations and pH. 2D L-COSY was acquired from a 27 cm3 voxel located in the posterior cingulate cortex. A total of 75 resonances were included in the analysis and spectral peak volumes were normalized to creatine. STATISTICAL TEST: One-way repeated measured analysis of variance with Bonferroni post-hoc adjustment using SPSS software. RESULTS: In vitro data showed no statistically significant differences between different scans (P > 0.12). in vivo results showed statistically significant diurnal variations (P ≤ 0.05, F > 3.88) for 22 resonances. Bonferroni post-hoc testing showed there was statistically significant increases in metabolite ratios between 0700 and 1700 and these include different moieties of N-acetylaspartate, creatine, choline, myo-inositol, lipids, fucose, glutathione, and homocarnosine. DATA CONCLUSION: 2D L-COSY can detect diurnal physiological variability in neuro-metabolite levels. Thus, time of the day should be considered when planning MRS studies to avoid confounding results. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2019;50:592-601.

Diurnal stability and long-term repeatability of neurometabolites using single voxel 1H magnetic resonance spectroscopy.

PURPOSE: This study was designed to evaluate the diurnal stability and long-term repeatability and reliability of one-dimensional (1D) hydrogen magnetic resonance spectroscopy (1H-MRS) in vitro and in vivo at 3 T. MATERIAL AND METHOD: A standard brain phantom was used for in vitro study. In vivo diurnal evaluation involved ten healthy subjects, while repeatability study involved six subjects. MRS was acquired from posterior cingulate gyrus (PCG), and processed with LCModel. Diurnal effects were assessed with repeated measures ANOVAs, repeatability was evaluated using coefficient of variation (CV), while reliability was assessed with standard error measurement (SEM) and intra-class correlation coefficient (ICC). RESULTS: Diurnal metabolic changes in vitro were non-significant. The intra/inter-in vitro CVs for the major metabolites; N-acetylaspartate (NAA), creatine (Cr), myo-inositol (mI), glutamate + glutamine (Glx) and total choline (tCho) were 1-3%/2-6%, respectively. Statistically significant in vivo diurnal effects were only seen for glycerophosphocholine (GPC, +10%, F = 10.6, p = 0.001) and Glx (+6%, F = 5.1, p = 0.018). The intra/inter-subject CVs for the major metabolites ranged from 2-5%/ 5-9%, respectively. The major metabolites displayed ICC ranging from 0.5-0.7 and low SEM (0.001-0.078) reflecting high reliability in detecting neurometabolites. The inter-week interval for in vivo measurements had minimal effect on metabolite ratios (F = 1.4, p = 0.09). CONCLUSION: In vitro MRS showed no diurnal effects and minimal variation in metabolite levels. Most PCG metabolites are not altered diurnally. The low in vivo variability of metabolite concentration supports the use of localised MRS on clinical 3 T scanners for reliable neurometabolic profiling of the brain.

Reliability of neurometabolite detection with two-dimensional localized correlation spectroscopy at 3T.

BACKGROUND: Two-dimensional localized correlational spectroscopy (2D L-COSY) has been applied in vivo to investigate metabolic profiles in many disorders due to its ability to detect several metabolites simultaneously. Successful application of this technique depends on the reliability of the detection and understanding of the variability result from test-retest measurements. PURPOSE: To evaluate the test-retest repeatability/reliability of 2D L-COSY in detecting brain metabolites in a phantom and healthy subjects in a 3T scanner. STUDY TYPE: Test-retest. POPULATION/PHANTOM: Six healthy subjects and magnetic resonance spectroscopy-high definition (MRS-HD) sphere or "Braino". FIELD STRENGTH/SEQUENCE: 3T/2D L-COSY MRS. ASSESSMENT: Healthy subjects underwent eight weekly experiments over a period of 3 months with an intersession delay of 1 month after the first four measurements. Twenty-nine neurometabolite resonances (8 diagonal, 14 cross, and 7 composite resonances) were studied using a 27 cm3 voxel from the posterior cingulate cortex. In vitro evaluations were performed in a similar manner as in vivo on a Braino phantom containing brain metabolites at physiological concentrations and pH. STATISTICAL TESTS: Intra- and intersubject variability were measured. Test-retest repeatability was calculated using coefficient of variation (CV), and reliability was assessed with standard error measurement (SEM) and intraclass correlation coefficient (ICC), using SPSS software. RESULTS: The intra/inter CV for in vitro and in vivo data ranged from 0.01-0.23%/0.02-0.29% and 0.03-0.23%/0.04-0.39%, respectively. The major diagonal peaks showed ICC ranging from 0.31 to 0.93, while the ICC for cross peaks were 0.09-0.87. The SEM for in vivo data ranged from 0.0016 to 0.08. The interweek interval may have a positive effect on metabolite ratios (P = 0.08; F = 1.78). DATA CONCLUSION: The low variability in metabolite concentration in this study shows a high level of reliability of 2D L-COSY in the human brain. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;48:1559-1569.

Fast magnetic resonance spectroscopic imaging techniques in human brain- applications in multiple sclerosis.

Multi voxel magnetic resonance spectroscopic imaging (MRSI) is an important imaging tool that combines imaging and spectroscopic techniques. MRSI of the human brain has been beneficially applied to different clinical applications in neurology, particularly in neurooncology but also in multiple sclerosis, stroke and epilepsy. However, a major challenge in conventional MRSI is the longer acquisition time required for adequate signal to be collected. Fast MRSI of the brain in vivo is an alternative approach to reduce scanning time and make MRSI more clinically suitable.Fast MRSI can be categorised into spiral, echo-planar, parallel and turbo imaging techniques, each with its own strengths. After a brief introduction on the basics of non-invasive examination (1H-MRS) and localization techniques principles, different fast MRSI techniques will be discussed from their initial development to the recent innovations with particular emphasis on their capacity to record neurochemical changes in the brain in a variety of pathologies.The clinical applications of whole brain fast spectroscopic techniques, can assist in the assessment of neurochemical changes in the human brain and help in understanding the roles they play in disease. To give a good example of the utilities of these techniques in clinical context, MRSI application in multiple sclerosis was chosen. The available up to date and relevant literature is discussed and an outline of future research is presented.