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Background: Cortical lesion subtypes' occurrence and distribution across networks may shed light on cognitive impairment (CI) in multiple sclerosis (MS)., Methods: In 332 people with MS, lesions were classified as intracortical, leukocortical or juxtacortical based on artificially generated double inversion-recovery images., Results: CI-related leukocortical lesion count increases were greatest within sensorimotor and cognitive networks ( p < 0.001). Only intracortical lesion count could distinguish between cognitive groups ( p = 0.024). Effect sizes were two- to four-fold larger than differences between MS phenotypes., Conclusion: In CI-MS, leukocortical lesions predominate, whereas intracortical lesions distinguish cognitive groups. Lesions' grey matter (GM) involvement might be decisive for cognition in MS, surpassing overall disease burden., 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: E.A.K. and R.K. report no disclosures relevant to the manuscript. S.N. is supported by research grants from Atara Biotherapeutics, Merck and Biogen. F.B. is part of the steering committee or Data Safety Monitoring Board member for Biogen, Merck, ATRI/ACTC and Prothena, serves as a consultant for Roche, Celltrion, Rewind Therapeutics, Merck, IXICO, Jansen, Combinostics, has research agreements with Merck, Biogen, GE Healthcare and Roche and is co-founder and shareholder of Queen Square Analytics Ltd. B.M.J.U. reports research support and/or consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Teva and Immunic Therapeutics. E.C.K. has received consulting fees from EMD Serono, Genentech, INmune Bio, Myrobalan Therapeutics, OM1 and TG Therapeutics and received research funds from Abbvie, Biogen and Genentech. M.D. Steenwijk is supported by research grants from Atara Biotherapeutics, Merck and Biogen. M.M. Schoonheim serves on the editorial board of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and ZonMW (Vidi grant, project no. 09150172010056) and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, EIP, Sanofi, MedDay and Merck. I.K. has received research grants from LabEx TRAIL (Translational Research and Advanced Imaging Laboratory) and ARSEP (Fondation pour l’Aide à la Recherche sur la Sclérose En Plaques) and speakers’ honoraria from Celgene.

Background: Thalamic volume loss is known to be associated with clinical and cognitive disability in progressive multiple sclerosis (PMS)., Objective: To investigate the treatment effect of ibudilast on thalamic atrophy more than 96 weeks in the phase 2 trial in progressive(MS Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis [SPRINT-MS])., Methods: A total of 231 participants were randomized to either ibudilast ( n = 114) or placebo ( n = 117). Thalamic volume change was computed using Bayesian Sequence Adaptive Multimodal Segmentation tool (SAMseg) incorporating T1, fluid-attenuated inversion recovery (FLAIR), and fractional anisotropy maps and analyzed with a mixed-effects repeated-measures model., Results: There was no significant difference in thalamic volumes between treatment groups. On exploratory analysis, participants with primary progressive multiple sclerosis (PPMS) on placebo had a 0.004% greater rate of thalamic atrophy than PPMS participants on ibudilast ( p = 0.058, 95% confidence interval (CI) = -0.008 to <0.001). Greater reductions in thalamic volumes at more than 96 weeks were associated with worsening multiple sclerosis functional composite (MSFC-4) scores ( p = 0.002) and worsening performance on the symbol digit modality test (SDMT) ( p < 0.001)., Conclusion: In a phase 2 trial evaluating ibudilast in PMS, no treatment effect was demonstrated in preventing thalamic atrophy. Participants with PPMS exhibited a treatment effect that trended toward significance. Longitudinal changes in thalamic volume were related to worsening of physical and cognitive disability, highlighting this outcome's clinical importance., 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: Eric Klawiter has received research funding from Abbvie, Biogen, and Genentech and has received consulting fees from Banner Life Sciences, EMD Serono, Galen/Atlantica, Genentech, Greenwich Biosciences, INmune Bio, Myrobalan Therapeutics, OM1, Inc., and TG Therapeutics.

Monoclonal antibodies (mAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) received emergency use authorization for the acute treatment of COVID-19. We are not aware of published data on their use in immunosuppressed people with multiple sclerosis (pwMS). We report 23 pwMS (mean age = 49 years, ocrelizumab ( n  = 19), fingolimod ( n  = 2), vaccinated with at least an initial series ( n  = 19)) who received mAb for acute COVID-19. Following mAb receipt, approximately half recovered in <7 days (48%). There were no adverse events or deaths. Use of mAb for pwMS treated with fingolimod or ocrelizumab was not observed to be harmful and is likely helpful for treatment of acute COVID-19.

Background: Sensitive and specific biomarkers for use in progressive multiple sclerosis (MS) have not been established. We investigate neurofilament light (NfL) as a treatment response biomarker in progressive MS., Objective: To evaluate whether ibudilast 100 mg/day alters serum and cerebrospinal fluid (CSF) levels of NfL in progressive MS., Methods: In a protocol-defined exploratory analysis from a 2-year, phase 2 clinical trial of ibudilast in progressive MS (NCT01982942), serum samples were collected from 239 subjects and a subset contributed CSF and assayed using single-molecule assay (SIMOA) immunoassay. A mixed model for repeated measurements yielded log(NfL) as the response variable., Results: The geometric mean baseline serum NfL was 31.9 and 28.8 pg/mL in placebo and ibudilast groups, respectively. The geometric mean baseline CSF NfL was 1150.8 and 1290.3 pg/mL in placebo and ibudilast groups, respectively. Serum and CSF NfL correlations were r  = 0.52 and r  = 0.78 at weeks 48 and 96, respectively. Over 96 weeks, there was no between-group difference in NfL in either serum ( p  = 0.76) or CSF ( p  = 0.46). After controlling for factors that may affect NfL, no effect of ibudilast on NfL in either serum or CSF was observed., Conclusion: Ibudilast treatment was not associated with a change in either serum or CSF NfL.

Background: The SPRINT-MS trial demonstrated benefit of ibudilast on brain atrophy over 96 weeks in progressive multiple sclerosis (MS). Optical coherence tomography (OCT) was performed in all trial participants., Objective: Report the OCT results of the SPRINT-MS trial., Methods: OCT was obtained at baseline and every 6 months using spectral domain OCT and analyzed by an OCT reading center. Change in each OCT outcome measure by treatment group was estimated using linear mixed models., Results: Change in pRNFL thickness was +0.0424 uM/year (95% confidence interval (CI): -0.3091 to 0.3939) for ibudilast versus -0.2630 uM (95% CI: -0.5973 to 0.0714) for placebo ( n  = 244, p  = 0.22). Macular volume change was -0.00503 mm 3 /year (-0.02693 to 0.01688) with ibudilast versus -0.03659 mm 3 /year (-0.05824 to -0.01494) for placebo in the Spectralis cohort ( n  = 61, p  = 0.044). For the Cirrus cohort, macular volume change was -0.00040 mm 3 /year (-0.02167, 0.020866) with ibudilast compared to -0.02083 mm 3 /year (-0.04134 to -0.00033) for placebo ( n  = 183, p  = 0.1734). Ganglion cell-inner plexiform layer thickness change, available from Cirrus, was -0.4893 uM/year (-0.9132, -0.0654) with ibudilast versus -0.9587 uM/year (-1.3677, -0.5498) with placebo ( n  = 183, p  = 0.12)., Conclusion: Retinal thinning in MS may be attenuated by ibudilast. Sample size estimates suggest OCT can be a viable outcome measure in progressive MS trials if a therapy has a large treatment effect., Trial Registration: NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942.

Background: Thalamic pathology is a marker for neurodegeneration and multiple sclerosis (MS) disease progression., Objective: To characterize (1) the morphology of thalamic lesions, (2) their relation to cortical and white matter (WM) lesions, and (3) clinical measures, and to assess (4) the imaging correlates of thalamic atrophy., Methods: A total of 90 MS patients and 44 healthy controls underwent acquisition of 7 Tesla images for lesion segmentation and 3 Tesla scans for atrophy evaluation. Thalamic lesions were classified according to the shape and the presence of a central venule. Regression analysis identified the predictors of (1) thalamic atrophy, (2) neurological disability, and (3) information processing speed., Results: Thalamic lesions were mostly ovoid than periventricular, and for the great majority (78%) displayed a central venule. Lesion volume in the thalamus, cortex, and WM did not correlate with each other. Thalamic atrophy was only associated with WM lesion volume ( p  = 0.002); subpial and WM lesion volumes were associated with neurological disability ( p  = 0.016; p  < 0.001); and WM and thalamic lesion volumes were related with cognitive impairment ( p  < 0.001; p  = 0.03)., Conclusion: Thalamic lesions are unrelated to those in the cortex and WM, suggesting that they may not share common pathogenic mechanisms and do not contribute to thalamic atrophy. Combined WM, subpial, and thalamic lesion volumes at 7 Tesla contribute to the disease severity.

Background: The importance of supporting pregnancy-related decisions in multiple sclerosis (MS) patients has increasingly been recognized and hence the need for prospective data on pregnancy and pediatric outcomes in this patient population., Objective: To assess prospective growth and developmental outcomes of infants born to mothers with multiple sclerosis (IMS)., Methods: PREG-MS is a prospective multicenter cohort study in New England, United States. We followed 65 women with MS and their infants with up to 12 months consistent pediatric follow-up. Pediatric, neurologic, and demographic information was obtained via structured telephone interviews and validated with medical records., Results: No differences in infant weights and lengths with World Health Organization (WHO) 50th percentile standards were observed ( p  > 0.05). However, larger head circumference (HC) measurements than WHO standards were reported in cohort infants ( p  < 0.05). There was no association between HC and markers of maternal MS activity, demographic, or social factors. No irreversible pediatric developmental abnormalities were observed., Conclusion: This first prospective study on pediatric anthropometry in IMS suggests a possible increase in HC compared to WHO standards without an increase in irreversible developmental abnormalities. The observations are exploratory and require confirmation with larger prospective studies in diverse groups of MS patients.

Background: Neuroinflammation with microglia activation is thought to be closely related to cortical multiple sclerosis (MS) lesion pathogenesis., Objective: Using 11 C-PBR28 and 7 Tesla (7T) imaging, we assessed in 9 relapsing-remitting multiple sclerosis (RRMS) and 10 secondary progressive multiple sclerosis (SPMS) patients the following: (1) microglia activation in lesioned and normal-appearing cortex, (2) cortical lesion inflammatory profiles, and (3) the relationship between neuroinflammation and cortical integrity., Methods: Mean 11 C-PBR28 uptake was measured in focal cortical lesions, cortical areas with 7T quantitative T 2 * (q-T 2 *) abnormalities, and normal-appearing cortex. The relative difference in cortical 11 C-PBR28 uptake between patients and 14 controls was used to classify cortical lesions as either active or inactive. Disease burden was investigated according to cortical lesion inflammatory profiles. The relation between q-T 2 * and 11 C-PBR28 uptake along the cortex was assessed., Results: 11 C-PBR28 uptake was abnormally high in cortical lesions in RRMS and SPMS; in SPMS, tracer uptake was significantly increased also in normal-appearing cortex. 11 C-PBR28 uptake and q-T 2 * correlated positively in many cortical areas, negatively in some regions. Patients with high cortical lesion inflammation had worse clinical outcome and higher intracortical lesion burden than patients with low inflammation., Conclusion: 11 C-PBR28 and 7T imaging reveal distinct profiles of cortical inflammation in MS, which are related to disease burden.

Background: Activated microglia, which can be detected in vivo by 11 C-PBR28 positron emission tomography (PET), represent a main component of MS pathology in the brain. Their role in the cerebellum is still unexplored, although cerebellar involvement in MS is frequent and accounts for disability progression., Objectives: We aimed at characterizing cerebellar neuroinflammation in MS patients compared to healthy subjects by combining 11 C-PBR28 MRI-Positron Emission Tomography (MR-PET) with 7 Tesla (T) MRI and assessing its relationship with brain neuroinflammation and clinical outcome measures., Methods: Twenty-eight MS patients and 16 healthy controls underwent 11 C-PBR28 MR-PET to measure microglia activation in normal appearing cerebellum and lesions segmented from 7 T scans. Patients were evaluated using the Expanded Disability Status Scale and Symbol Digit Modalities Test. 11 C-PBR28 binding was assessed in regions of interest using 60-90 minutes standardized uptake values normalized by a pseudo-reference region in the brain normal appearing white matter. Multilinear regression was used to compare tracer uptake in MS and healthy controls and assess correlations with clinical scores., Results: In all cerebellar regions examined, MS patients showed abnormally increased tracer uptake, which correlated with cognitive and neurological disability., Conclusion: Neuroinflammation is widespread in the cerebellum of patients with MS and related to neurological disability and cognitive impairment.

Background: Cerebellar lesions are often reported in relapsing-remitting multiple sclerosis (RRMS) and have been associated with impaired motor function and cognitive status. However, prior research has primarily focused on summary measures of cerebellar involvement (e.g. total lesion load, gray/white matter volume) and not on the effect of lesion load within specific regions of cerebellar white matter., Objective: Spatially map the probability of cerebellar white matter lesion (CWML) occurrence in RRMS and explore the relationship between cognitive impairment and lesion (CWML) location within the cerebellum., Methods: High-resolution structural magnetic resonance imaging (MRI) was acquired on 16 cognitively impaired (CI) and 15 cognitively preserved (CP) RRMS subjects at 3T and used for lesion identification and voxel-based lesion-symptom mapping (VLSM)., Results: CI RRMS demonstrated a predilection for the middle cerebellar peduncle (MCP). VLSM results indicate that lesions of the MCP are significantly associated with CI in RRMS. Measures of cerebellar lesion load were correlated with age at disease onset but not disease duration., Conclusion: A specific pattern of cerebellar lesions involving the MCP, rather than the total CWML load, contributes to cognitive dysfunction in RRMS. Cerebellar lesion profiles may provide a biomarker of current or evolving risk for cognitive status change in RRMS.

CXCL13, a B-cell chemokine, has been proposed as a biomarker in a variety of conditions, some of which can mimic multiple sclerosis and can have very high levels. In this case-control study, cerebrospinal fluid (CSF) CXCL13 was elevated in multiple sclerosis, neuromyelitis optica and other inflammatory neurological controls compared with noninflammatory controls. Levels did not differentiate disease groups. For all subjects taken together, CSF CXCL13 correlated with CSF WBC, oligoclonal band numbers, CSF protein, EDSS, and neurofilament levels. In subgroup analyses, CSF CXCL13 correlated with CSF WBC in neuromyelitis optica and IgG index in multiple sclerosis. Additionally, serum CXCL13 was elevated in neuromyelitis optica.

Background: Multiple sclerosis (MS) and neuromyelitis optica (NMO) both affect spinal cord with notable differences in pathology., Objective: Determine the utility of diffusion tensor imaging (DTI) to differentiate the spinal cord lesions of NMO from MS within and outside T2 lesions., Methods: Subjects greater than or equal to 12 months from a clinical episode of transverse myelitis underwent a novel transaxial cervical spinal cord DTI sequence. Ten subjects with NMO, 10 with MS and 10 healthy controls were included., Results: Within T2 affected white matter regions, radial diffusivity was increased in both NMO and MS compared with healthy controls (p<0.001, respectively), and to a greater extent in NMO than MS (p<0.001). Axial diffusivity was decreased in T2 lesions in both NMO and MS compared with controls (p<0.001, p=0.001), but did not differ between the two diseases. Radial diffusivity and fractional anisotropy within white matter regions upstream and downstream of T2 lesions were different from controls in each disease., Conclusions: Higher radial diffusivity within spinal cord white matter tracts derived from diffusion tensor imaging were appreciated in NMO compared with MS, consistent with the known greater tissue destruction seen in NMO. DTI also detected tissue alterations outside T2 lesions and may be a surrogate of anterograde and retrograde degeneration.