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BackgroundMyelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) and pediatric-onset multiple sclerosis (POMS) share clinical and magnetic resonance imaging (MRI) features but differ in prognosis and management. Early POMS diagnosis is essential to avoid disability accumulation. Central vein sign (CVS), paramagnetic rim lesions (PRLs), and central core lesions (CCLs) are susceptibility-based imaging (SbI)-related signs understudied in pediatric populations that may help discerning POMS from MOGAD.MethodsT2-FLAIR and SbI (three-dimensional echoplanar imaging (3D-EPI)/susceptibility-weighted imaging (SWI) or similar) were acquired on 1.5T/3T scanners. Two readers assessed CVS-positive rate (%CVS+), and their average score was used to build a receiver operator curve (ROC) assessing the ability to discriminate disease type. PRLs and CCLs were identified using a consensual approach.ResultsThe %CVS+ distinguished 26 POMS cases (mean age 13.7 years, 63% females, median EDSS 1.5) from 14 MOGAD cases (10.8 years, 35% females, EDSS 1.0) with ROC = 1, p < 0.0001, (cutoff 41%). PRLs were only detectable in POMS participants (mean 2.1±2.3, range 1-10), discriminating the two conditions with a sensitivity of 69% and a specificity of 100%. CCLs were more sensitive (81%) but less specific (71.43%).ConclusionThe %CVS+ and PRLs are highly specific markers of POMS. After proper validation on larger multicenter cohorts, consideration should be given to including such imaging markers for diagnosing POMS at disease onset.

Myelin repair is an unrealized therapeutic goal in the treatment of multiple sclerosis (MS). Uncertainty remains about the optimal techniques for assessing therapeutic efficacy and imaging biomarkers are required to measure and corroborate myelin restoration. We analyzed myelin water fraction imaging from ReBUILD, a double-blind, randomized placebo-controlled (delayed treatment) remyelination trial, that showed a significant reduction in VEP latency in patients with MS. We focused on brain regions rich in myelin. Fifty MS subjects in two arms underwent 3T MRI at baseline and months 3 and 5. Half of the cohort was randomly assigned to receive treatment from baseline through 3 mo, whereas the other half received treatment from 3 mo to 5 mo post-baseline. We computed myelin water fraction changes occurring in normal-appearing white matter of corpus callosum, optic radiations, and corticospinal tracts. An increase in myelin water fraction was documented in the normal-appearing white matter of the corpus callosum, in correspondence with the administration of the remyelinating treatment clemastine. This study provides direct, biologically validated imaging-based evidence of medically induced myelin repair. Moreover, our work strongly suggests that significant myelin repair occurs outside of lesions. We therefore propose myelin water fraction within the normal-appearing white matter of the corpus callosum as a biomarker for clinical trials looking at remyelination.

BackgroundRemote activity monitoring has the potential to evaluate real-world, motor function, and disability at home. The relationships of daily physical activity with spinal cord white matter and gray matter (GM) areas, multiple sclerosis (MS) disability and leg function, are unknown.ObjectiveEvaluate the association of structural central nervous system pathology with ambulatory disability.MethodsFifty adults with progressive or relapsing MS with motor disability who could walk >2 minutes were assessed using clinician-evaluated, patient-reported outcomes, and quantitative brain and spinal cord magnetic resonance imaging (MRI) measures. Fitbit Flex2, worn on the non-dominant wrist, remotely assessed activity over 30 days. Univariate and multivariate analyses were performed to assess correlations between physical activity and other disability metrics.ResultsMean age was 53.3 years and median Expanded Disability Status Scale (EDSS) was 4.0. Average daily step counts (STEPS) were highly correlated with EDSS and walking measures. Greater STEPS were significantly correlated with greater C2-C3 spinal cord GM areas (ρ = 0.39, p = 0.04), total cord area (TCA; ρ = 0.35, p = 0.04), and cortical GM volume (ρ = 0.32, p = 0.04).ConclusionThese results provide preliminary evidence that spinal cord GM area is a neuroanatomical substrate associated with STEPS. STEPS could serve as a proxy to alert clinicians and researchers to possible changes in structural nervous system pathology.

BackgroundAmbulatory disability is common in people with multiple sclerosis (MS). Remote monitoring using average daily step count (STEPS) can assess physical activity (activity) and disability in MS. STEPS correlates with conventional metrics such as the expanded disability status scale (Expanded Disability Status Scale; EDSS), Timed-25 Foot walk (T25FW) and timed up and go (TUG). However, while STEPS as a summative measure characterizes the number of steps taken over a day, it does not reflect variability and intensity of activity.ObjectivesNovel analytical methods were developed to describe how individuals spends time in various activity levels (e.g., continuous low versus short bouts of high) and the proportion of time spent at each activity level.Methods94 people with MS spanning the range of ambulatory impairment (unaffected to requiring bilateral assistance) were recruited into FITriMS study and asked to wear a Fitbit continuously for 1-year. Parametric distributions were fit to minute-by-minute step data. Adjusted R2 values for regressions between distributional fit parameters and STEPS with EDSS, TUG, T25FW and the patient-reported 12-item MS Walking scale (MSWS-12) were calculated over the first 4-weeks, adjusting for sex, age and disease duration.ResultsDistributional fits determined that the best statistically-valid model across all subjects was a 3-compartment Gaussian Mixture Model (GMM) that characterizes the step behavior within 3 levels of activity: high, moderate and low. The correlation of GMM parameters for baseline step count measures with clinical assessments was improved when compared with STEPS (adjusted R2 values GMM vs. STEPS: TUG: 0.536 vs. 0.419, T25FW: 0.489 vs. 0.402, MSWS-12: 0.383 vs. 0.378, EDSS: 0.557 vs. 0.465). The GMM correlated more strongly (Kruskal-Wallis: p = 0.0001) than STEPS and gave further information not included in STEPS.ConclusionsIndividuals' step distributions follow a 3-compartment GMM that better correlates with clinic-based performance measures compared with STEPS. These data support the existence of high-moderate-low levels of activity. GMM provides an interpretable framework to better understand the association between different levels of activity and clinical metrics and allows further analysis of walking behavior that takes step distribution and proportion of time at three levels of intensity into account.

Myelin loss is associated with axonal damage in established multiple sclerosis. This relationship is challenging to study in vivo in early disease. Here, we ask whether myelin loss is associated with axonal damage at diagnosis by combining non-invasive neuroimaging and blood biomarkers. We performed quantitative microstructural MRI and single-molecule ELISA plasma neurofilament measurement in 73 patients with newly diagnosed, immunotherapy naïve relapsing-remitting multiple sclerosis. Myelin integrity was evaluated using aggregate g-ratios, derived from magnetization transfer saturation and neurite orientation dispersion and density imaging diffusion data. We found significantly higher g-ratios within cerebral white matter lesions (suggesting myelin loss) compared with normal-appearing white matter (0.61 versus 0.57, difference 0.036, 95% CI: 0.029-0.043, P < 0.001). Lesion volume (Spearman's rho rs= 0.38, P < 0.001) and g-ratio (rs= 0.24, P < 0.05) correlated independently with plasma neurofilament. In patients with substantial lesion load (n = 38), those with higher g-ratio (defined as greater than median) were more likely to have abnormally elevated plasma neurofilament than those with normal g-ratio (defined as less than median) [11/23 (48%) versus 2/15 (13%), P < 0.05]. These data suggest that, even at multiple sclerosis diagnosis, reduced myelin integrity is associated with axonal damage. MRI-derived g-ratio may provide useful additional information regarding lesion severity and help to identify individuals with a high degree of axonal damage at disease onset.

ObjectiveTo assess feasibility, tolerability, and safety of N-acetyl cysteine (NAC) for fatigue in progressive MS. Secondary objectives evaluated changes in fatigue and oxidative pathway biomarkers on NAC versus placebo.MethodsIndividuals with progressive MS with Modified Fatigue Impact Scale (MFIS) > t38 were randomized 2:1 to NAC 1250mg TID or placebo for 4 weeks. The primary outcome was tolerability and safety. The secondary outcome to evaluate efficacy was MFIS change from baseline to week 4 between groups. Exploratory biomarker outcomes included change in blood GSH/GSSG ratio (reduced-to-oxidized glutathione (GSH)) and in vivo relative GSH using 7T MR spectroscopy (MRS) between groups. Fisher exact test was used for categorical and rank sum for continuous outcomes.ResultsFifiteen were randomized (10 NAC, 5 placebo; mean age 56.1 years, 80% female, median EDSS 6.0). At least one adverse event (AE) occurred in 60% on NAC versus 80% on placebo (p = 0.75). There were two AEs attributed to NAC in one patient (abdominal pain and constipation), with 94% adherence to NAC. MFIS decreased in both groups at week 4, with the mean improvement of 11-points on NAC versus 18-points on placebo (p = 0.33). GSH/GSSG ratio decreased on placebo (-0.6) and NAC (-0.1) (p = 0.18). Change in GSH levels to total creatine in anterior and posterior cingulate cortex, insula, caudate, putamen, and thalamus did not differ between groups.InterpretationNAC was well-tolerated in progressive MS, although reduction in fatigue on NAC was similar to placebo. Antioxidant blood and MRS biomarkers were not significantly altered by NAC, which could be due to dose, route of administration, time of sample collection, short half-life, or lack of effect. REGISTERED: clinicaltrials.gov NCT02804594.

Objectives: To quantify brain microstructural changes in recently diagnosed relapsing-remitting multiple sclerosis (RRMS) using longitudinal T1 measures, and determine their associations with clinical disability. Methods: Seventy-nine people with recently diagnosed (< 6 months) RRMS were recruited from a single-centre cohort sub-study, and underwent baseline and 1-year brain MRI, including variable flip angle T1 mapping. Median T1 was measured in white matter lesions (WML), normal-appearing white matter (NAWM), cortical/deep grey matter (GM), thalami, basal ganglia and medial temporal regions. Prolonged T1 (≥ 2.00 s) and supramedian T1 (relative to cohort WML values) WML voxel counts were also measured. Longitudinal change was assessed with paired t-tests and compared with Bland-Altman limits of agreement from healthy control test-retest data. Regression analyses determined relationships with Expanded Disability Status Scale (EDSS) score and dichotomised EDSS outcomes (worsening or stable/improving). Results: Sixty-two people with RRMS (mean age 37.2 ± 10.9 [standard deviation], 48 female) and 11 healthy controls (age 44 ± 11, 7 female) contributed data. Prolonged and supramedian T1 WML components increased longitudinally (176 and 463 voxels, respectively; p <.001), and were associated with EDSS score at baseline (p <.05) and follow-up (supramedian: p <.01; prolonged: p <.05). No cohort-wide median T1 changes were found; however, increasing T1 in WML, NAWM, cortical/deep GM, basal ganglia and thalami was positively associated with EDSS worsening (p <.05). Conclusion: T1 is sensitive to brain microstructure changes in early RRMS. Prolonged WML T1 components and subtle changes in NAWM and GM structures are associated with disability. Clinical relevance statement: MRI T1 brain mapping quantifies disability-associated white matter lesion heterogeneity and subtle microstructural damage in normal-appearing brain parenchyma in recently diagnosed RRMS, and shows promise for early objective disease characterisation and stratification. Key Points: • Quantitative T1 mapping detects brain microstructural damage and lesion heterogeneity in recently diagnosed relapsing-remitting multiple sclerosis. • T1 increases in lesions and normal-appearing parenchyma, indicating microstructural damage, are associated with worsening disability. • Brain T1 measures are objective markers of disability-relevant pathology in early multiple sclerosis. [ABSTRACT FROM AUTHOR]

Background: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) and pediatric-onset multiple sclerosis (POMS) share clinical and magnetic resonance imaging (MRI) features but differ in prognosis and management. Early POMS diagnosis is essential to avoid disability accumulation. Central vein sign (CVS), paramagnetic rim lesions (PRLs), and central core lesions (CCLs) are susceptibility-based imaging (SbI)-related signs understudied in pediatric populations that may help discerning POMS from MOGAD., Methods: T2-FLAIR and SbI (three-dimensional echoplanar imaging (3D-EPI)/susceptibility-weighted imaging (SWI) or similar) were acquired on 1.5T/3T scanners. Two readers assessed CVS-positive rate (%CVS+), and their average score was used to build a receiver operator curve (ROC) assessing the ability to discriminate disease type. PRLs and CCLs were identified using a consensual approach., Results: The %CVS+ distinguished 26 POMS cases (mean age 13.7 years, 63% females, median EDSS 1.5) from 14 MOGAD cases (10.8 years, 35% females, EDSS 1.0) with ROC = 1, p < 0.0001, (cutoff 41%). PRLs were only detectable in POMS participants (mean 2.1±2.3, range 1-10), discriminating the two conditions with a sensitivity of 69% and a specificity of 100%. CCLs were more sensitive (81%) but less specific (71.43%)., Conclusion: The %CVS+ and PRLs are highly specific markers of POMS. After proper validation on larger multicenter cohorts, consideration should be given to including such imaging markers for diagnosing POMS at disease onset., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SS, NP, VAS, AA, HZ, JA, WAS, JC, JH, SSZ, PS, RGH, and EW have no disclosures relevant to this study.AV is supported by a Biogen Fellowship.