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.
Objective
In patients suffering multiple sclerosis activity despite treatment with interferon β or glatiramer acetate, clinicians often switch therapy to either natalizumab or fingolimod. However, no ...studies have directly compared the outcomes of switching to either of these agents.
Methods
Using MSBase, a large international, observational, prospectively acquired cohort study, we identified patients with relapsing–remitting multiple sclerosis experiencing relapses or disability progression within the 6 months immediately preceding switch to either natalizumab or fingolimod. Quasi‐randomization with propensity score–based matching was used to select subpopulations with comparable baseline characteristics. Relapse and disability outcomes were compared in paired, pairwise‐censored analyses.
Results
Of the 792 included patients, 578 patients were matched (natalizumab, n = 407; fingolimod, n = 171). Mean on‐study follow‐up was 12 months. The annualized relapse rates decreased from 1.5 to 0.2 on natalizumab and from 1.3 to 0.4 on fingolimod, with 50% relative postswitch difference in relapse hazard (p = 0.002). A 2.8 times higher rate of sustained disability regression was observed after the switch to natalizumab in comparison to fingolimod (p < 0.001). No difference in the rate of sustained disability progression events was observed between the groups. The change in overall disability burden (quantified as area under the disability–time curve) differed between natalizumab and fingolimod (−0.12 vs 0.04 per year, respectively, p < 0.001).
Interpretation
This study suggests that in active multiple sclerosis during treatment with injectable disease‐modifying therapies, switching to natalizumab is more effective than switching to fingolimod in reducing relapse rate and short‐term disability burden. Ann Neurol 2015;77:425–435
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.
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.
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.
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
ABSTRACT
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.
Fatigue is a common and debilitating symptom in multiple sclerosis (MS). Over the past decade, a growing body of research has focussed on the pathophysiological mechanisms underlying central ...(cognitive and physical) fatigue in MS. The precise mechanisms causing fatigue in MS patients are complex and poorly understood, and may differ between patients. Advanced quantitative magnetic resonance imaging (MRI) techniques allow for objective assessment of disease pathology and have been used to characterise the pathophysiology of central fatigue in MS.
To systematically review the existing literature of MRI-based studies assessing the pathophysiological mechanisms of MS-related central fatigue.
A systematic literature search of four major databases (PubMed, Medline, Embase, Scopus and Google Scholar) was conducted to identify MRI-based studies of MS-related fatigue published in the past 20 years. Studies using the following MRI-based methods were included: structural (lesion load/atrophy), T1 relaxation time/magnetisation transfer ratio (MTR), diffusion tensor imaging (DTI), functional MRI (fMRI) and magnetic resonance spectroscopy (MRS).
A total of 92 studies were identified as meeting the search criteria and included for review. Structurally, regional gray/white matter atrophy, cortical thinning, decreased T1 relaxation times and reduced fractional anisotropy were associated with central fatigue in MS. Functionally, hyperactivity and reduced functional connectivity in several regional areas of frontal, parietal, occipital, temporal and cerebellum were suggested as causes of central fatigue. Biochemically, a reduction in N-acetyl aspartate/creatine and increased (glutamine+glutamate)/creatine ratios were correlated with fatigue severity in MS.
Several advanced quantitative MRI methods have been employed in the study of central fatigue in MS. Central fatigue in MS is associated with macro/microstructural and functional changes within specific brain regions (frontal, parietal, temporal and deep gray matter) and specific pathways/networks (cortico-cortical and cortico-subcortical). Alternations in the cortico-striatal-thalamocortical (CSTC) loop are correlated with the development of fatigue in MS patients.
•Central fatigue in multiple sclerosis (MS) is complex and poorly understood.•A wide range of MRI methods are being used in the study of central fatigue including advanced quantitative measures.•Structural/functional alterations in several interconnected brain regions may possibly explain central fatigue in MS.•Cortico-striato-thalamo-cortical loop appears to be the neural network that has close correlations with central fatigue.•Advanced quantitative MRI has potential role in understanding the pathophysiological mechanism of central fatigue in MS.
Objective
To compare treatment efficacy and persistence in patients who switched to natalizumab versus those who switched between glatiramer acetate (GA) and interferon‐beta (IFNβ) after an ...on‐treatment relapse on IFNβ or GA using propensity score matched real‐world datasets.
Methods
Patients included were registered in MSBase or the TYSABRI Observational Program (TOP), had relapsed on IFNβ or GA within 12 months prior to switching to another therapy, and had initiated natalizumab or IFNβ/GA treatment ≤6 months after discontinuing prior therapy. Covariates were balanced across post switch treatment groups by propensity score matching at treatment initiation. Relapse, persistence, and disability measures were compared between matched treatment arms in the total population (n = 869/group) and in subgroups defined by prior treatment history (IFNβ only n = 578/group, GA only n = 165/group, or both IFNβ and GA n = 176/group).
Results
Compared to switching between IFNβ and GA, switching to natalizumab reduced annualized relapse rate in year one by 65–75%, the risk of first relapse by 53–82% (mean follow‐up 1.7–2.2 years) and treatment discontinuation events by 48–65% (all P ≤ 0.001). In the total population, switching to natalizumab reduced the risk of confirmed disability progression by 26% (P = 0.036) and decreased the total disability burden by 1.54 EDSS‐years (P < 0.0001) over the first 24 months post switch.
Interpretation
Using large, real‐world, propensity‐matched datasets we demonstrate that after a relapse on IFNβ or GA, switching to natalizumab (rather than between IFNβ and GA) led to superior outcomes for patients in all measures assessed. Results were consistent regardless of the prior treatment identity.
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