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Background and Objectives: Retinal optical coherence tomography (OCT) provides promising prognostic imaging biomarkers for future disease activity in multiple sclerosis (MS). However, raw OCT-derived measures have multiple dependencies, supporting the need for establishing reference values adjusted for possible confounders. The purpose of this study was to investigate the capacity for age-adjusted z scores of OCT-derived measures to prognosticate future disease activity and disability worsening in people with MS (PwMS)., Methods: We established age-adjusted OCT reference data using generalized additive models for location, scale, and shape for peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layer (GCIP) thicknesses, involving 910 and 423 healthy eyes, respectively. Next, we transformed the retinal layer thickness of PwMS from 3 published studies into age-adjusted z scores (pRNFL-z and GCIP-z) based on the reference data. Finally, we investigated the association of pRNFL-z or GCIP-z as predictors with future confirmed disability worsening (Expanded Disability Status Scale score increase) or disease activity (failing of the no evidence of disease activity [NEDA-3] criteria) as outcomes. Cox proportional hazards models or logistic regression analyses were applied according to the original studies. Optimal cutoffs were identified using the Akaike information criterion as well as location with the log-rank and likelihood-ratio tests., Results: In the first cohort (n = 863), 172 PwMS (24%) had disability worsening over a median observational period of 2.0 (interquartile range [IQR]:1.0-3.0) years. Low pRNFL-z (≤-2.04) were associated with an increased risk of disability worsening (adjusted hazard ratio (aHR) [95% CI] = 2.08 [1.47-2.95], p = 3.82e -5 ). In the second cohort (n = 170), logistic regression analyses revealed that lower pRNFL-z showed a higher likelihood for disability accumulation at the two-year follow-up (reciprocal odds ratio [95% CI] = 1.51[1.06-2.15], p = 0.03). In the third cohort (n = 78), 46 PwMS (59%) did not maintain the NEDA-3 status over a median follow-up of 2.0 (IQR: 1.9-2.1) years. PwMS with low GCIP-z (≤-1.03) had a higher risk of showing disease activity (aHR [95% CI] = 2.14 [1.03-4.43], p = 0.04). Compared with raw values with arbitrary cutoffs, applying the z score approach with optimal cutoffs showed better performance in discrimination and calibration (higher Harrell's concordance index and lower integrated Brier score)., Discussion: In conclusion, our work demonstrated reference cohort-based z scores that account for age, a major driver for disease progression in MS, to be a promising approach for creating OCT-derived measures useable across devices and toward individualized prognostication.

Multiple sclerosis (MS) is a chronic and debilitating neurological disease that results in inflammatory demyelination. While endogenous remyelination helps to recover function, this restorative process tends to become less efficient over time. Currently, intense efforts aimed at the mechanisms that promote remyelination are being considered promising therapeutic approaches. The M1 muscarinic acetylcholine receptor (M1R) was previously identified as a negative regulator of oligodendrocyte differentiation and myelination. Here, we validate M1R as a target for remyelination by characterizing expression in human and rodent oligodendroglial cells (including those in human MS tissue) using a highly selective M1R probe. As a breakthrough to conventional methodology, we conjugated a fluorophore to a highly M1R selective peptide (MT7) which targets the M1R in the subnanomolar range. This allows for exceptional detection of M1R protein expression in the human CNS. More importantly, we introduce PIPE-307, a brain-penetrant, small-molecule antagonist with favorable drug-like properties that selectively targets M1R. We evaluate PIPE-307 in a series of in vitro and in vivo studies to characterize potency and selectivity for M1R over M2-5R and confirm the sufficiency of blocking this receptor to promote differentiation and remyelination. Further, PIPE-307 displays significant efficacy in the mouse experimental autoimmune encephalomyelitis model of MS as evaluated by quantifying disability, histology, electron microscopy, and visual evoked potentials. Together, these findings support targeting M1R for remyelination and support further development of PIPE-307 for clinical studies., Competing Interests: Competing interests statement:M.M.P., K.I.L., K.J.S., G.C.E., A.R.B., J.R.R., J.M.B., C.S.B., A.C.C., and D.S.L. are current employees of Contineum Therapeutics and hold financial shares of Contineum Therapeutics. Contineum Therapeutics owns patent rights to PIPE-307.

Purpose: This study aimed to develop a new high-resolution MRI sequence for the imaging of the ultra-short transverse relaxation time (uT 2 ) components in the brain, while simultaneously providing proton density (PD) contrast for reference and quantification., Theory: The sequence combines low flip angle balanced SSFP (bSSFP) and UTE techniques, together with a 3D dual-echo rosette k-space trajectory for readout., Methods: The expected image contrast was evaluated by simulations. A study cohort of six healthy volunteers and eight multiple sclerosis (MS) patients was recruited to test the proposed sequence. Subtraction between two TEs was performed to extract uT 2 signals. In addition, conventional longitudinal relaxation time (T 1 ) weighted, T 2 -weighted, and PD-weighted MRI sequences were also acquired for comparison., Results: Typical PD-contrast was found in the second TE images, while uT 2 signals were selectively captured in the first TE images. The subtraction images presented signals primarily originating from uT 2 components, but only if the first TE is short enough. Lesions in the MS subjects showed hyperintense signals in the second TE images but were hypointense signals in the subtraction images. The lesions had significantly lower signal intensity in subtraction images than normal white matter (WM), which indicated a reduction of uT 2 components likely associated with myelin., Conclusion: 3D isotropic sub-millimeter (0.94 mm) spatial resolution images were acquired with the novel bSSFP UTE sequence within 3 min. It provided easy extraction of uT 2 signals and PD-contrast for reference within a single acquisition., (© 2024 International Society for Magnetic Resonance in Medicine.)

Introduction: Amelioration of disability in multiple sclerosis requires the development of complementary therapies that target neurodegeneration and promote repair. Remyelination is a promising neuroprotective strategy that may protect axons from damage and subsequent neurodegeneration., Methods: A review of key literature plus additional targeted search of PubMed and Google Scholar was conducted., Results: There has been a rapid expansion of clinical trials studying putative remyelinating candidates, but further growth of the field is limited by the lack of consensus on key aspects of trial design. We have not yet defined the ideal study population, duration of therapy, or the appropriate outcome measures to detect remyelination in humans. The varied natural history of multiple sclerosis, coupled with the short time frame of phase II clinical trials, requires that we develop and validate biomarkers of remyelination that can serve as surrogate endpoints in clinical trials., Conclusions: We propose that the visual system may be the most well-suited and validated model for the study potential remyelinating agents. In this review, we discuss the pathophysiology of demyelination and summarize the current clinical trial landscape of remyelinating agents. We present some of the challenges in the study of remyelinating agents and discuss current potential biomarkers of remyelination and repair, emphasizing both established and emerging visual outcome measures., (Copyright © 2024 by North American Neuro-Ophthalmology Society.)

Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. In this study, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster in approximately 10% of PwMS who share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active preclinical period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically or radiologically isolated neuroinflammatory syndromes., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Detection and prediction of disability progression is a significant unmet need in people with progressive multiple sclerosis (PwPMS). Government and health agencies have deemed the use of patient-reported outcomes measurements (PROMs) in clinical practice and clinical trials a major strategic priority. Nevertheless, data documenting the clinical utility of PROMs in neurological diseases is scarce. This study evaluates if assessment of PROMs could track progression in PwPMS., Methods: Emerging blood Biomarkers in Progressive Multiple Sclerosis (EmBioProMS) investigated PROMs (Beck depression inventory-II (BDI-II), multiple sclerosis impact scale-29 (MSIS-29), fatigue scale for motor and cognition (FSMC)) in PwPMS (primary [PPMS] and secondary progressive MS [SPMS]). PROMs were evaluated longitudinally and compared between participants with disability progression (at baseline; retrospective evidence of disability progression (EDP), and during follow up (FU); prospective evidence of confirmed disability progression (CDP)) and those without progression. In an independent cohort of placebo participants of the phase III ORATORIO trial in PPMS, the diagnostic and prognostic value of another PROMs score (36-Item Short Form Survey [SF-36]) regarding CDP was evaluated., Results: EmBioProMS participants with EDP in the two years prior to inclusion (n = 136/227), or who suffered from CDP during FU (number of events= 88) had worse BDI-II, MSIS-29, and FSMC scores compared to PwPMS without progression. In addition, baseline MSIS29 physical above 70th, 80th, and 90th percentiles predicted future CDP/ progression independent of relapse activity in EmBioProMS PPMS participants (HR of 3.7, 6.9, 6.7, p = 0.002, <0.001, and 0.001, respectively). In the placebo arm of ORATORIO (n = 137), the physical component score (PCS) of SF-36 worsened at week 120 compared to baseline, in cases who experienced progression over the preceding trial period (P = 0.018). Worse PCS at baseline was associated with higher hazard ratios of disability accumulation over the subsequent 120 weeks (HR: 2.01 [30 th- ], 2.11 [20 th- ], and 2.8 [10 th percentile], P = 0.007, 0.012 and 0.005, respectively)., Conclusions: PROMs could provide additional, practical, cost-efficient, and remotely accessible insight about disability progression in PMS through standardized, structured, and quantifiable patient feedback., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AA received research funding from DMSG, AMSEL, Bavarian MS Trust. MK received travel funding, speaker honoraria and research support from Bristol Myers Squibb, Merck, Novartis and Roche, all not related to this manuscript. MS received consulting and/or speaker honoraria from Alexion, Bayer, Biogen, Bristol-Myers-Squibb, Merck, Roche, and Sanofi Genzyme; none related to this work. JH reports a grant for OCT research from the Friedrich-Baur-Stiftung and Merck, personal fees and non-financial support from Merck, Alexion, Novartis, Roche, Celgene, Biogen, Bayer and Horizon and non-financial support of the Sumaira-Foundation and Guthy-Jackson Charitable Foundation, all outside the submitted work. UKZ has received speaking fees, travel support, and financial support for research activities from Alexion, Almirall, Bayer, Biogen, Celgene, Janssen, Merck Serono, Novartis, Octapharm, Roche, Sanofi Genzyme, Teva as well as EU, BMBF, BMWi and DFG. None resulted in a conflict of interest. IK has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Alexion, Almirall, Bayer, Biogen, Hexal, Horizon, Merck, Neuraxpharm, Roche/Chugai and Sanofi, all outside the submitted work. AS has no personal pecuniary interests to disclose, other than being the lead of the German MS Registry, which receives project funding from a range of public and corporate sponsors, recently including The German Innovation Fund (G-BA), The German Retirement Insurance, The German MS Trust, The German MS Society, Biogen, BMS, Merck, Novartis, Roche, and Sanofi. All outside the submitted work. AH received travel funding, consulting and/or speaker honoraria from Alexion, Argenx and Horizon; none related to this manuscript. MCK has served on advisory boards and received speaker fees / travel grants from Merck, Sanofi-Genzyme, Novartis, Biogen, Jansen, Alexion, Celgene / Bristol-Myers Squibb and Roche and received research grants from Merck, Sanofi-Genzyme and Celgene / Bristol-Myers Squibb. SG reports research support from Alnylam Pharmaceuticals, CSL Behring, Else Kröner Fresenius Foundation, Deutsche Forschungsgemeinschaft and Hannover Biomedical Research School (HBRS) and consulting and/or speaker honoraria from Alnylam Pharmaceuticals and Merck all outside the submitted work. HK was an employee and shareholder of F. Hoffmann–La Roche Ltd during completion of the work related to this manuscript. He is currently an employee and shareholder of UCB Farchim SA, Bulle, Switzerland. JO reports grants from Hoffmann La-Roche, Biogen, Novartis, and Sanofi Genzyme, personal fees from Hoffmann La-Roche, Biogen, Teva, Novartis, Celgene, Medday Pharmaceuticals, EMD Serono, Sanofi Genzyme, Web MD Global and Allergan, employment from Hoffmann La-Roche and is a shareholder of Hoffmann La-Roche. QW, SC are employee and shareholder of F. Hoffmann–La Roche Ltd. TF reports personal fees for consultancies (including data monitoring committees) in the past three years from Bayer, BiosenseWebster, Cardialysis, CSL Behring, Enanta, Fresenius Kabi, Galapagos, IQVIA, Immunic, Janssen, Kyowa Kirin, Lilly, Liva Nova, Minoryx, Mylan, Novartis, Roche, Vifor; all outside the submitted work. UZ received grants from the European Research Council (ERC), German Ministry of Education and Research (BMBF), German Research Foundation (DFG), Takeda Pharmaceutical Company Ltd., and consulting fees from CorTec GmbH, all not related to this work. TK has received speaker honoraria and/or personal fees for advisory boards from Bayer Healthcare, Merck, Novartis Pharma, Sanofi-Aventis/Genzyme, Roche Pharma, Alexion/Astra Zeneca and Biogen as well as grant support from Novartis and Chugai Pharma in the past. HT received consulting and/or speaker honoraria from Alexion, Bayer, Biogen, Celgene, GSK, Jannssen, Merck, Novartis, Roche, Sanofi Genzyme and TEVA; none related to this work. All other authors report no conflict of interest in relation to this work., (Copyright © 2023. Published by Elsevier B.V.)

Importance: Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS (MS); however, data on the association between NfL level and disability accumulation have been conflicting., Objective: To determine whether and when NfL levels are elevated in the context of confirmed disability worsening (CDW)., Design, Setting, and Participants: This study included 2 observational cohorts: results from the Expression, Proteomics, Imaging, Clinical (EPIC) study at the University of California San Francisco (since 2004) were confirmed in the Swiss Multiple Sclerosis Cohort (SMSC), a multicenter study in 8 centers since 2012. Data were extracted from EPIC in April 2022 (sampling July 1, 2004, to December 20, 2016) and SMSC in December 2022 (sampling June 6, 2012, to September 2, 2021). The study included 2 observational cohorts in tertiary MS centers. All participants of both cohorts with available NfL results were included in the study, and no eligible participants were excluded or declined to participate., Exposure: Association between NfL z scores and CDW., Main Outcome Measures: CDW was defined as Expanded Disability Status Scale (EDSS) worsening that was confirmed after 6 or more months and classified into CDW associated with clinical relapses (CDW-R) or independent of clinical relapses (CDW-NR). Visits were classified in relation to the disability worsening events into CDW(-2) for 2 visits preceding event, CDW(-1) for directly preceding event, CDW(event) for first diagnosis of EDSS increase, and the confirmation visit. Mixed linear and Cox regression models were used to evaluate NfL dynamics and to assess the association of NfL with future CDW, respectively., Results: A total of 3906 EPIC visits (609 participants; median [IQR] age, 42.0 [35.0-50.0] years; 424 female [69.6%]) and 8901 SMSC visits (1290 participants; median [IQR] age, 41.2 [32.5-49.9] years; 850 female [65.9%]) were included. In CDW-R (EPIC, 36 events; SMSC, 93 events), NfL z scores were 0.71 (95% CI, 0.35-1.07; P < .001) units higher at CDW-R(-1) in EPIC and 0.32 (95% CI, 0.14-0.49; P < .001) in SMSC compared with stable MS samples. NfL elevation could be detected preceding CDW-NR (EPIC, 191 events; SMSC, 342 events) at CDW-NR(-2) (EPIC: 0.23; 95% CI, 0.01-0.45; P = .04; SMSC: 0.28; 95% CI, 0.18-0.37; P < .001) and at CDW-NR(-1) (EPIC: 0.27; 95% CI, 0.11-0.44; P < .001; SMSC: 0.09; 95% CI, 0-0.18; P = .06). Those findings were replicated in the subgroup with relapsing-remitting MS. Time-to-event analysis confirmed the association between NfL levels and future CDW-R within approximately 1 year and CDW-NR (in approximately 1-2 years)., Conclusions and Relevance: This cohort study documents the occurrence of NfL elevation in advance of clinical worsening and may hint to a potential window of ongoing dynamic central nervous system pathology that precedes the diagnosis of CDW.

Introduction: Multiple sclerosis (MS) is a major cause of disability in young and middle-aged people, and myelin repair therapies are needed to slow or potentially reverse this damage. Bazedoxifene (BZA) is a selective estrogen receptor modulator identified in a novel high-throughput unbiased screen for its remyelinating potential, and its remyelinating effects were demonstrated in pre-clinical models., Methods: This is a single-center, double blind, randomized, controlled, delayed-start Phase 2 clinical trial (NCT04002934) investigating the remyelinating effects of BZA relative to placebo. Female patients with relapsing-remitting MS, aged 45-60 years (or > 40 if post-menopausal), and ambulatory status (EDSS 0-6 inclusive), will be recruited into a clinical trial with 2 arms of identical design, except that the "Chronic Optic Neuropathy" arm requires additional inclusion criteria of electrophysiological evidence of prior visual pathway demyelination. Clinical, electrophysiological, and imaging evaluations will occur at baseline, 3 months, and 6 months. The primary outcome is change in Myelin Water Fraction (MWF) on MRI within the corpus callosum. Secondary outcomes are: visual evoked potential (VEP) P100 latency, novel digital measures of cognition and activity, and patient reported outcomes. Tertiary outcomes are: safety and tolerability., Discussion: BZA has strong preclinical effects on myelin repair, and in the general population demonstrated benefits in treating postmenopausal osteoporosis. Together, these findings support the rationale for an RCT testing BZA in women with MS, evaluating established neuroimaging and neurovisual measures of myelin repair. Additionally, validating novel digital tools could increase sensitivity to change and inform the duration and design of future clinical trials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward-rectifying) and oligodendroglial Kir4.1 (inward-rectifying) potassium channels have important roles in regulating neuronal excitability at and around the nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE), with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs, and rescued neuronal pathology in oligodendrocyte-Kir4.1-deficient (OL-Kir4.1-deficient) mice. In summary, our findings indicate that neuron-OL compensatory interactions promoted resilience through Kv7 and Kir4.1 channels and identify pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination.

Background and Objectives: With the increasing use of visually evoked potentials (VEPs) as quantitative outcome parameters for myelin in clinical trials, an in-depth understanding of longitudinal VEP latency changes and their prognostic potential for subsequent neuronal loss will be required. In this longitudinal multicenter study, we evaluated the association and prognostic potential of VEP latency for retinal neurodegeneration, measured by optical coherence tomography (OCT), in relapsing-remitting MS (RRMS)., Methods: We included 293 eyes of 147 patients with RRMS (age [years, median ± SD] 36 ± 10, male sex 35%, F/U [years, median {IQR} 2.1 {1.5-3.9}]): 41 eyes had a history of optic neuritis (ON) ≥6 months before baseline (CHRONIC-ON), and 252 eyes had no history of ON (CHRONIC-NON). P100 latency (VEP), macular combined ganglion cell and inner plexiform layer volume (GCIPL), and peripapillary retinal nerve fiber layer thickness (pRNFL) (OCT) were quantified., Results: P100 latency change over the first year predicted subsequent GCIPL loss (36 months) across the entire chronic cohort ( p = 0.001) and in (and driven by) the CHRONIC-NON subset ( p = 0.019) but not in the CHRONIC-ON subset ( p = 0.680). P100 latency and pRNFL were correlated at baseline (CHRONIC-NON p = 0.004, CHRONIC-ON p < 0.001), but change in P100 latency and pRNFL were not correlated. P100 latency did not differ longitudinally between protocols or centers., Discussion: VEP in non-ON eyes seems to be a promising marker of demyelination in RRMS and of potential prognostic value for subsequent retinal ganglion cell loss. This study also provides evidence that VEP may be a useful and reliable biomarker for multicenter studies., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Many biomarkers in clinical neuroscience lack pathological certification. This issue is potentially a significant contributor to the limited success of neuroprotective and neurorestorative therapies for human neurological disease-and is evident even in areas with therapeutic promise such as myelin repair. Despite the identification of promising remyelinating candidates, biologically validated methods to demonstrate therapeutic efficacy or provide robust preclinical evidence of remyelination in the CNS are lacking. Therapies with potential to remyelinate the CNS constitute one of the most promising and highly anticipated therapeutic developments in the pipeline to treat multiple sclerosis and other demyelinating diseases. The optic nerve has been proposed as an informative pathway to monitor remyelination in animals and human subjects. Recent clinical trials using visual evoked potential have had promising results, but without unequivocal evidence about the cellular and molecular basis for signal changes on visual evoked potential, the interpretation of these trials is constrained. The visual evoked potential was originally developed and used in the clinic as a diagnostic tool but its use as a quantitative method for assessing therapeutic response requires certification of its biological specificity. Here, using the tools of experimental pathology we demonstrate that quantitative measurements of myelination using both histopathological measures of nodal structure and ultrastructural assessments correspond to visual evoked potential latency in both inflammatory and chemical models of demyelination. Visual evoked potential latency improves after treatment with a tool remyelinating compound (clemastine), mirroring both quantitative and qualitative myelin assessment. Furthermore, clemastine does not improve visual evoked potential latency following demyelinating injury when administered to a transgenic animal incapable of forming new myelin. Therefore, using the capacity for therapeutic enhancement and biological loss of function we demonstrate conclusively that visual evoked potential measures myelin status and is thereby a validated tool for preclinical verification of remyelination., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: The timing of neurodegeneration in multiple sclerosis (MS) remains unclear. It is critical to understand the dynamics of neuroaxonal loss if we hope to prevent or forestall permanent disability in MS. We therefore used a deeply phenotyped longitudinal cohort to assess and compare rates of neurodegeneration in retina and brain throughout the MS disease course., Methods: We analyzed 597 patients with MS who underwent longitudinal optical coherence tomography imaging annually for 4.5 ± 2.4 years and 432 patients who underwent longitudinal MRI scans for 10 ± 3.4 years, quantifying macular ganglion cell-inner plexiform layer (GCIPL) volume and cortical gray matter (CGM) volume. The association between the slope of decline in the anatomical structure and the age of entry in the cohort (categorized by the MRI cohort's age quartiles) was assessed by hierarchical linear models., Results: The rate of CGM volume loss declined with increasing age of study entry (1.3% per year atrophy for the age of entry in the cohort younger than 35 years; 1.1% for older than 35 years and younger than 41; 0.97% for older than 41 years and younger than 49; 0.9% for older than 49 years) while the rate of GCIPL thinning was highest in patients in the youngest quartile, fell by more than 50% in the following age quartile, and then stabilized (0.7% per year thinning for the age of entry in the cohort younger than 35 years; 0.29% for age older than 35 and younger than 41 years; 0.34% for older than 41 and younger than 49 years; 0.33% for age older than 49 years)., Discussion: An age-dependent reduction in retinal and cortical volume loss rates during relapsing-remitting MS suggests deceleration in neurodegeneration in the earlier period of disease and further indicates that the period of greatest adaptive immune-mediated inflammatory activity is also the period with the greatest neuroaxonal loss., (© 2022 American Academy of Neurology.)

Background and Objectives: Patients with multiple sclerosis (MS) transition from oral sphingosine-1-receptor (S1P) modulators to anti-CD20 therapies for several circumstances. Optimal timing of this transition is uncertain, given competing concerns of rebound disease activity and ensuring immune reconstitution. The objective of this study was to evaluate the relationship between inflammatory activity and the transition period from fingolimod to anti-CD20 therapies in a real-world MS cohort., Methods: Medical records were reviewed for all patients at our center transitioning from fingolimod to rituximab or ocrelizumab between 2010 and October 2020. Time periods reviewed were the following: before fingolimod discontinuation, interval between fingolimod and anti-CD20 treatments, and after the first anti-CD20 infusion. The primary outcome was clinical relapses; MRI activity, time to absolute lymphocyte count (ALC) recovery, and infections were secondary. Clinical and demographic factors significant in univariable analyses were included in multivariable analyses., Results: Transition data were available for 108 patients (68.5% women, 68.5% relapsing-remitting MS, mean age 44.6 years). The median (interquartile range) interval between fingolimod and anti-CD20 therapy was 28 (1-115.2) days. Six of 51 patients (11.8%) with intervals >1 month and 0/57 patients with shorter intervals experienced a relapse (MRI confirmed) within 6 months of fingolimod discontinuation. In the year following anti-CD20 initiation, 4/108 patients (3.7%) experienced a relapse (median 214.5 days after infusion). An additional 7% of those undergoing contrast-enhanced MRIs developed Gd+ lesions. ALC normalized following treatment switch in 89/92; the interval between treatments was unrelated to ALC recovery or infection., Discussion: Delaying anti-CD20 start to monitor ALC after S1P modulator discontinuation may not be necessary and could increase rebound risk. ALC monitoring could instead occur after a rapid switch to anti-CD20 treatment., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Optical coherence tomography (OCT) is capable of quantifying retinal damage. Defining the extent of anterior visual pathway injury is important in multiple sclerosis (MS) as a way to document evidence of prior disease, including subclinical injury, and setting a baseline for patients early in the course of disease. Retinal nerve fiber layer (RNFL) thickness is typically classified as low if values fall outside of a predefined range for a healthy population. In adults, an interocular difference (IOD) in RNFL thickness greater than 5 μm identified a history of unilateral optic neuritis (ON). Through our PERCEPTION (PEdiatric Research Collaboration ExPloring Tests in Ocular Neuroimmunology) study, we explored whether RNFL IOD informs on remote ON in a multicenter pediatric-onset MS (POMS) cohort., Methods: POMS (defined using consensus criteria and first attack <18 years) patients were recruited from 4 academic centers. A clinical history of ON (>6 months prior to an OCT scan) was confirmed by medical record review. RNFL thickness was measured on Spectralis machines (Heidelberg, Germany). Using a cohort of healthy controls from our centers tested on the same machines, RNFL thickness <86 μm (<2 SDs below the mean) was defined as abnormal. Based on previously published findings in adults, an RNFL IOD >5 μm was defined as abnormal. The proportions of POMS participants with RNFL thinning (<86 μm) and abnormal IOD (>5 μm) were calculated. Logistic regression was used to determine whether IOD was associated with remote ON., Results: A total of 157 participants with POMS (mean age 15.2 years, SD 3.2; 67 [43%] with remote ON) were enrolled. RNFL thinning occurred in 45 of 90 (50%) ON eyes and 24 of 224 (11%) non-ON eyes. An IOD >5 μm was associated with a history of remote ON (P < 0.001). An IOD >5 μm occurred in 62 participants, 40 (65%) with remote ON. Among 33 participants with remote ON but normal RNFL values (≥86 μm in both eyes), 14 (42%) were confirmed to have ON by IOD criteria (>5 μm)., Conclusions: In POMS, the diagnostic yield of OCT in confirming remote ON is enhanced by considering RNFL IOD, especially for those patients with RNFL thickness for each eye in the normal range. An IOD >5 μm in patients with previous visual symptoms suggests a history of remote ON., Competing Interests: A. T. Waldman has received research support from the NIH (NINDS K23NS069806, PI); she has received research support from the NIH (R01NS071463, site investigator; U54NS115052, project PI), Biogen Idec (PI), IONIS Pharmaceuticals (PI), United Leukodystrophy Foundation, and the Children's Hospital of Philadelphia (Foerderer Award, PI), royalties from UpToDate, and served as a consultant to Optum. L. Benson does not have disclosures directly related to the content of this article; Biogen sponsored clinical trial; paid consultant for the national vaccine injury compensation program. G. W. Liu discloses her spouse's royalties for Liu, Volpe, Galetta: Neuro-Ophthalmology, Diagnosis and Management. 2010, Elsevier. A. J. Green does not have disclosures directly related to the content of this article; he has received research support from NINDS, NMSS, NINDS SBIR, Adelson Medical Research Foundation, Hilton Foundation, Hellman Family Foundation/That Many May See, and Inception Sciences (Prior); he has received fees or other compensation from Bionure, Pipeline Therapeutics, Inception Sciences and Mylan Pharma; he is an Associate Editor at JAMA Neurology and has previously served on an endpoint adjudication committee for Medimmune/Viela Bio and has intellectual property and patents related to the UCSF Small Molecule Remyelination Program. E. Waubant is the site principal investigator for ongoing trials with Genentech and Biogen; she has research funding from NIH, PCORI, NMSS, and Race to Erase MS. She has received honoraria for lectures from Medscape, The Corpus, and AAN and for consulting work from Jazz Pharmaceuticals, Emerald, and DBV; she is the cochief editor for MSARD. G. Heidary has no disclosures relevant to the content of the article; she has grant support from the Children's Tumor Foundation and NIH. J. Graves does not have disclosures directly related to the content of this article; she has received honoraria from Genzyme for nonpromotional trainee education events; she has received personal fees from Novartis and Celgene; she has received recent grant and clinical trial support from the National MS Society, Race to Erase MS, Biogen, Genentech, and Octave. B. Greenberg has received grant support from the NIH, NMSS, Transverse Myelitis Association, PCORI, Guthy Jackson Charitable Foundation, Chugai, Medimmune, Medday, and Genentech. He has received consulting fees from Alexion, Novartis, EMD Serono, Genentech, and Celgene; he is an unpaid board member of the Transverse Myelitis Association. The other authors report no conflicts of interest., (Copyright © 2020 by North American Neuro-Ophthalmology Society.)

Central nervous system B cells have several potential roles in multiple sclerosis (MS): secretors of proinflammatory cytokines and chemokines, presenters of autoantigens to T cells, producers of pathogenic antibodies, and reservoirs for viruses that trigger demyelination. To interrogate these roles, single-cell RNA sequencing (scRNA-Seq) was performed on paired cerebrospinal fluid (CSF) and blood from subjects with relapsing-remitting MS (RRMS; n = 12), other neurologic diseases (ONDs; n = 1), and healthy controls (HCs; n = 3). Single-cell immunoglobulin sequencing (scIg-Seq) was performed on a subset of these subjects and additional RRMS ( n = 4), clinically isolated syndrome ( n = 2), and OND ( n = 2) subjects. Further, paired CSF and blood B cell subsets (RRMS; n = 7) were isolated using fluorescence activated cell sorting for bulk RNA sequencing (RNA-Seq). Independent analyses across technologies demonstrated that nuclear factor kappa B (NF-κB) and cholesterol biosynthesis pathways were activated, and specific cytokine and chemokine receptors were up-regulated in CSF memory B cells. Further, SMAD/TGF-β1 signaling was down-regulated in CSF plasmablasts/plasma cells. Clonally expanded, somatically hypermutated IgM+ and IgG1+ CSF B cells were associated with inflammation, blood-brain barrier breakdown, and intrathecal Ig synthesis. While we identified memory B cells and plasmablast/plasma cells with highly similar Ig heavy-chain sequences across MS subjects, similarities were also identified with ONDs and HCs. No viral transcripts, including from Epstein-Barr virus, were detected. Our findings support the hypothesis that in MS, CSF B cells are driven to an inflammatory and clonally expanded memory and plasmablast/plasma cell phenotype., Competing Interests: Competing interest statement: R.D.S. served on an advisory board for Sanofi Genzyme and is currently an employee of Asceneuron SA. A.J.G. reports personal fees from Inception Sciences and Mylan Pharmaceuticals and has reported serving on an end point adjudication committee for Biogen and Medimmune. He has served on trial steering committees for Novartis and serves on the Scientific Advisory Board for Bionure. R.M.B. has received personal compensation for medical legal consulting and for consulting or serving on the advisory boards of F. Hoffmann-La Roche Ltd., Sanofi-Genzyme, and Novartis. J.M.G. has received research support to University of California, San Francisco from Genentech, personal compensation for consulting for Biogen and Alexion, and personal compensation for medical legal consulting; he has also received honoraria from Dynamed Plus for editorial work. B.A.C.C. receives personal compensation for consulting from Abbvie, Biogen, EMD Serono, GeNeuro, Novartis, and Sanofi Genzyme. S.S.Z. is Deputy Editor of Neurology, Neuroimmunology and Neuroinflammation and is an Associate Editor for Frontiers in Immunology and Frontiers in Neurology. He serves on the Advisory Committee for the American Congress on Treatment and Research in Multiple Sclerosis and on the grant review committee for the National Multiple Sclerosis Society (NMSS). Previously, he has served on the Editorial Board of the Journal of Clinical Investigation, The Journal of Immunology, and The Journal of Neurological Sciences and has been a charter member of the grant review committee for the NIH Clinical Neuroimmunology and Brain Tumors. He has served as a consultant and received honoraria from Biogen-Idec, EMD-Serono, Genzyme, Novartis, Roche/Genentech, and Teva Pharmaceuticals, Inc. and has served on Data Safety Monitoring Boards for Lilly, BioMS, Teva, and Opexa Therapeutics. Currently, S.S.Z. receives research grant support from the NIH, NMSS, Weill Institute, Race to Erase MS, and the Maisin Foundation. S.L.H. currently serves on the Scientific Advisory Board of Alector, Annexon, Bionure, and Molecular Stethoscope and on the Board of Trustees of Neurona. S.L.H. also has received travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd. and Novartis for CD20-related meetings and presentations. M.R.W. received research funding from Roche/Genentech., (Copyright © 2020 the Author(s). Published by PNAS.)

No single neuroimaging technique or sequence is capable of reflecting the functional deficits manifest in MS. Given the interest in imaging biomarkers for short- to medium-term studies, we aimed to assess which imaging metrics might best represent functional impairment for monitoring in clinical trials. Given the complexity of functional impairment in MS, however, it is useful to isolate a particular functionally relevant pathway to understand the relationship between imaging and neurological function. We therefore analyzed existing data, combining multiparametric MRI and OCT to describe MS associated visual impairment. We assessed baseline data from fifty MS patients enrolled in ReBUILD, a prospective trial assessing the effect of a remyelinating drug (clemastine). Subjects underwent 3T MRI imaging, including Neurite Orientation Dispersion and Density Imaging (NODDI), myelin content quantification, and retinal imaging, using OCT. Visual function was assessed, using low-contrast letter acuity. MRI and OCT data were studied to model visual function in MS, using a partial, least-squares, regression analysis. Measures of neurodegeneration along the entire visual pathway, described most of the observed variance in visual disability, measured by low contrast letter acuity. In those patients with an identified history of ON, however, putative myelin measures also showed correlation with visual performance. In the absence of clinically identifiable inflammatory episodes, residual disability correlates with neurodegeneration, whereas after an identifiable exacerbation, putative measures of myelin content are additionally informative., Competing Interests: The authors have read the journal’s policy and have the following potential competing interests: SLH serves on the Board of Directors for Neurona, on the Scientific Advisory Board for Alector, Annexon, Bionure, and Molecular Stethoscope, and he has also received non-financial support from F. Hoffmann-La Roche Ltd and Novartis AG. AB has received travel fees from Actelion and speaker fees from Biogen. JMG reports research support to UCSF from Genentech for a clinical trial and consulting for Biogen and Alexion. BACC has received personal compensation for consulting from Akili, Alexion, Atara, Biogen, EMD Serono, Novartis, Sanofi and TG Therapeutics. AJG has served on the Scientific Advisory Board for Bionure, Inception Sciences and Pipeline Therapeutics. He serves as an Associate Editor at JAMA Neurology. He has served on an Adjudication Committee for MedImmune/Viela Bio. He has provided expert support for Mylan, Synthon and Pharmasciences and personal fees from and other financial relationships with Pipeline Therapeutics. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare. All other authors have declared that no competing interests exist.

Oxidative stress is a central part of innate immune-induced neurodegeneration. However, the transcriptomic landscape of central nervous system (CNS) innate immune cells contributing to oxidative stress is unknown, and therapies to target their neurotoxic functions are not widely available. Here, we provide the oxidative stress innate immune cell atlas in neuroinflammatory disease and report the discovery of new druggable pathways. Transcriptional profiling of oxidative stress-producing CNS innate immune cells identified a core oxidative stress gene signature coupled to coagulation and glutathione-pathway genes shared between a microglia cluster and infiltrating macrophages. Tox-seq followed by a microglia high-throughput screen and oxidative stress gene network analysis identified the glutathione-regulating compound acivicin, with potent therapeutic effects that decrease oxidative stress and axonal damage in chronic and relapsing multiple sclerosis models. Thus, oxidative stress transcriptomics identified neurotoxic CNS innate immune populations and may enable discovery of selective neuroprotective strategies.

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Objective tools for prognosis and disease progression monitoring in multiple sclerosis (MS) are lacking. The visuomotor system could be used to track motor dysfunction at the micron scale through the monitoring of fixational microsaccades., Aims: The aim of this study was to evaluate whether microsaccades are correlated with standard MS disability metrics and to assess whether these methods play a predictive role in MS disability., Method: We used a custom-built retinal eye tracker, the tracking scanning laser ophthalmoscope (TSLO), to record fixation in 111 participants with MS and 100 unaffected controls., Results: In MS participants, a greater number of microsaccades showed significant association with higher Expanded Disability Status Scale score (EDSS, p  < 0.001), nine-hole peg test (non-dominant: p  = 0.006), Symbol Digit Modalities Test (SMDT, p  = 0.014), and Functional Systems Scores (FSS) including brainstem ( p  = 0.005), cerebellar ( p  = 0.011), and pyramidal ( p  = 0.009). Both brainstem FSS and patient-reported fatigue showed significant associations with microsaccade number, amplitude, and peak acceleration. Participants with MS showed a statistically different average number ( p  = 0.020), peak vertical acceleration ( p  = 0.003), and vertical amplitude ( p  < 0.001) versus controls. Logistic regression models for MS disability were created using TSLO microsaccade metrics and paraclinical tests with ⩾80% accuracy., Conclusion: Microsaccades provide objective measurements of MS disability level and disease worsening.

Background: Remote assessment of neurological disability in people with multiple sclerosis (MS) could improve access to clinical care and efficiency of clinical research., Objective: To develop and validate a telemedicine-based MS disability examination that does not require an in-home examiner., Methods: Adults with MS were recruited after a standardized in-person Expanded Disability Status Scale (EDSS) evaluation, and within 1 week underwent a blinded televideo-enabled EDSS examination with a different clinician. EDSS and tele-EDSS scores were compared., Results: Overall, 41 adults participated (mean (standard deviation (SD)) age: 47.0 years (11.6); median EDSS: 2 (range: 0-7)); 37 required no in-home assistance for the tele-EDSS evaluation (e.g. help positioning camera). Mean difference between EDSS and tele-EDSS was 0.34 (95% confidence interval (CI): 0.07-0.61). For 88% of evaluations, tele-EDSS and EDSS scores were within 1 point (similar to reported in-person inter-rater differences). Unweighted kappa for agreement within 0.5 point was 0.72. Correlation for individual functional systems (FS) ranged from modest (vision: 0.37) to high (bowel/bladder: 0.79). Overall correlation between EDSS and tele-EDSS was 0.89 ( p  < 0.0001); and 0.98 ( p < 0.0001) at EDSS range: 4-7., Conclusion: In this proof of principle study, disability evaluation in mild to moderate MS is feasible using telemedicine without an aide at the patient's location.

Multiple sclerosis is a heterogeneous disease with an unpredictable course and a wide range of severity; some individuals rapidly progress to a disabled state whereas others experience only mild symptoms. Though genetic studies have identified variants that are associated with an increased risk of developing multiple sclerosis, no variants have been consistently associated with multiple sclerosis severity. In part, the lack of findings is related to inherent limitations of clinical rating scales; these scales are insensitive to early degenerative changes that underlie disease progression. Optical coherence tomography imaging of the retina and low-contrast letter acuity correlate with and predict clinical and imaging-based outcomes in multiple sclerosis. Therefore, they may serve as sensitive phenotypes to discover genetic predictors of disease course. We conducted a set of genome-wide association studies of longitudinal structural and functional visual pathway phenotypes in multiple sclerosis. First, we assessed genetic predictors of ganglion cell/inner plexiform layer atrophy in a discovery cohort of 374 patients with multiple sclerosis using mixed-effects models adjusting for age, sex, disease duration, optic neuritis and genetic ancestry and using a combination of single-variant and network-based analyses. For candidate variants identified in discovery, we conducted a similar set of analyses of ganglion cell/inner plexiform layer thinning in a replication cohort (n = 376). Second, we assessed genetic predictors of sustained loss of 5-letters in low-contrast letter acuity in discovery (n = 582) using multivariable-adjusted Cox proportional hazards models. We then evaluated candidate variants/pathways in a replication cohort. (n = 253). Results of both studies revealed novel subnetworks highly enriched for connected genes in early complement activation linked to measures of disease severity. Within these networks, C3 was the gene most strongly associated with ganglion cell/inner plexiform layer atrophy (P = 0.004) and C1QA and CR1 were top results in analysis of sustained low-contrast letter acuity loss. Namely, variant rs158772, linked to C1QA, and rs61822967, linked to CR1, were associated with 71% and 40% increases in risk of sustained LCLA loss, respectively, in meta-analysis pooling discovery and replication cohorts (rs158772: hazard ratio: 1.71; 95% confidence interval 1.30-2.25; P = 1.3 × 10-4; rs61822967: hazard ratio: 1.40; 95% confidence interval: 1.16-1.68; P = 4.1 × 10-4). In conclusion, early complement pathway gene variants were consistently associated with structural and functional measures of multiple sclerosis severity. These results from unbiased analyses are strongly supported by several prior reports that mechanistically implicated early complement factors in neurodegeneration., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Electronic medical records (EMR) data are increasingly used in research, but no studies have yet evaluated similarity between EMR and research-quality data and between characteristics of an EMR multiple sclerosis (MS) population and known natural MS history., Objectives: To (1) identify MS patients in an EMR system and extract clinical data, (2) compare EMR-extracted data with gold-standard research data, and (3) compare EMR MS population characteristics to expected MS natural history., Methods: Algorithms were implemented to identify MS patients from the University of California San Francisco EMR, de-identify the data and extract clinical variables. EMR-extracted data were compared to research cohort data in a subset of patients., Results: We identified 4142 MS patients via search of the EMR and extracted their clinical data with good accuracy. EMR and research values showed good concordance for Expanded Disability Status Scale (EDSS), timed-25-foot walk, and subtype. We replicated several expected MS epidemiological features from MS natural history including higher EDSS for progressive versus relapsing-remitting patients and for male versus female patients and increased EDSS with age at examination and disease duration., Conclusion: Large real-world cohorts algorithmically extracted from the EMR can expand opportunities for MS clinical research.

Importance: Disability measures in multiple sclerosis (MS) fail to capture potentially important variability in walking behavior. More sensitive and ecologically valid outcome measures are needed to advance MS research., Objectives: To assess continuous step count activity remotely among individuals with MS for 1 year and determine how average daily step count is associated with other measures of MS disability., Design, Setting, and Participants: In a prospective longitudinal observational cohort study, 95 adults with relapsing or progressive MS who were able to walk more than 2 minutes with or without an assistive device were recruited between June 15, 2015, and August 8, 2016, and remotely monitored in their natural environment for 1 year. Patients were excluded if they had a clinical relapse within 30 days or comorbidity contributing to ambulatory impairment. Longitudinal analysis was performed from October 2017 to March 2018. Revised analysis was performed in December 2018., Intervention: Activity monitoring of step count using a wrist-worn accelerometer., Main Outcomes and Measures: Average daily step count compared with in-clinic assessments and patient-reported outcomes., Results: Of the 95 participants recruited (59 women and 36 men; mean [SD] age, 49.6 [13.6] years [range, 22.0-74.0 years]), 35 (37%) had progressive MS, and the median baseline Expanded Disability Status Scale score was 4.0 (range, 0-6.5). At 1 year, 79 participants completed follow-up (83% retention). There was a modest reduction in accelerometer use during the 1 year of the study. A decreasing average daily step count during the study was associated with worsening of clinic-based outcomes (Timed 25-Foot Walk, β = -13.09; P < .001; Timed-Up-and-Go, β = -9.25; P < .001) and patient-reported outcomes (12-item Multiple Sclerosis Walking Scale, β = -17.96; P < .001). A decreasing average daily step count occurred even when the Expanded Disability Status Scale score remained stable, and 12 of 25 participants (48%) with a significant decrease in average daily step count during the study did not have a reduction on other standard clinic-based metrics. Participants with a baseline average daily step count below 4766 (cohort median) had higher odds of clinically meaningful disability (Expanded Disability Status Scale score) worsening at 1 year, adjusting for age, sex, and disease duration (odds ratio, 4.01; 95% CI, 1.17-13.78; P = .03)., Conclusions and Relevance: Continuous remote activity monitoring of individuals with MS for 1 year appears to be feasible. In this study, a decreasing average daily step count during a 1-year period was associated with worsening of standard ambulatory measures but could also occur even when traditional disability measures remained stable. These results appear to support the prospect of using the average daily step count as a sensitive longitudinal outcome measure in MS and as a clinically relevant metric for targeted intervention.

Background: Efferent visual dysfunction in children could lead to impaired quality of life at home and school. Eye-tracking can detect subtle efferent dysfunction missed on bedside examination but has not been validated in the pediatric multiple sclerosis population., Objective: We sought to determine the feasibility of eye-tracking in children and associations with multiple sclerosis., Methods: Participants meeting criteria for pediatric multiple sclerosis without acute efferent vision abnormalities and healthy controls were recruited. Multiple sclerosis participants underwent a clinical assessment and saccade and antisaccade testing paradigms. Intraclass correlation coefficients were generated for intertest repeatability. Adjusting for age and intereye correlations, generalized estimating equations compared latencies with case status, Expanded Disability Status Scale and Symbol Digit Modalities Test (SDMT) scores., Results: We eye-tracked 15 children with multiple sclerosis (n = 30 eyes, mean age 15.6 ± 2.1, mean disease duration 3.9 years, median Expanded Disability Status Scale 1.5) compared to 6 healthy controls (n = 12 eyes, age 14.3 ± .95). The intraclass correlation coefficient for repeated trials was 0.85. Adjusting for age, saccadic latency was 60 milliseconds (ms) longer for cases than controls (95% confidence interval = 26.4, 93.8; P = .0005). For antisaccadic latency, we observed a similar trend of 60 ms longer for cases than controls ( P = .06)., Conclusion: Eye-tracking is a short noninvasive examination, and high intertest repeatability supports use of eye-tracking technology in pediatric multiple sclerosis. Longer saccadic latencies were seen in children with multiple sclerosis despite short disease duration and low Expanded Disability Status Scale scores.

: BACKGROUND:: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system causing the immune-mediated demyelination of the brain, optic nerve, and spinal cord and resulting in ultimate axonal loss and permanent neurological disability. Ocular motor dysfunction is commonly observed in MS but can be frequently overlooked or underappreciated by nonspecialists. Therefore, detailed and quantitative assessment of eye movement function has significant potential for optimization of patient care, especially for clinicians interested in treating visual symptoms or tracking disease progression. METHODS:: A brief history of eye tracking technology followed by a contextualized review of the methods that can be used to assess ocular motor dysfunction in MS-including a discussion of each method's strengths and limitations. We discuss the rationale for interest in this area and describe new tools capable of tracking eye movements as a possible means of monitoring disease. RESULTS/CONCLUSIONS:: This overview should inform clinicians working with patients with MS of how ocular motor deficits can best be assessed and monitored in this population. It also provides a rationale for interest in this field with insights regarding which techniques should be used for studying which classes of eye movements and related dysfunction in the disease.

Background: Multiple sclerosis is a degenerative inflammatory disease of the CNS characterised by immune-mediated destruction of myelin and progressive neuroaxonal loss. Myelin in the CNS is a specialised extension of the oligodendrocyte plasma membrane and clemastine fumarate can stimulate differentiation of oligodendrocyte precursor cells in vitro, in animal models, and in human cells. We aimed to analyse the efficacy and safety of clemastine fumarate as a treatment for patients with multiple sclerosis., Methods: We did this single-centre, 150-day, double-blind, randomised, placebo-controlled, crossover trial (ReBUILD) in patients with relapsing multiple sclerosis with chronic demyelinating optic neuropathy on stable immunomodulatory therapy. Patients who fulfilled international panel criteria for diagnosis with disease duration of less than 15 years were eligible. Patients were randomly assigned (1:1) via block randomisation using a random number generator to receive either clemastine fumarate (5·36 mg orally twice daily) for 90 days followed by placebo for 60 days (group 1), or placebo for 90 days followed by clemastine fumarate (5·36 mg orally twice daily) for 60 days (group 2). The primary outcome was shortening of P100 latency delay on full-field, pattern-reversal, visual-evoked potentials. We analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT02040298., Findings: Between Jan 1, 2014, and April 11, 2015, we randomly assigned 50 patients to group 1 (n=25) or group 2 (n=25). All patients completed the study. The primary efficacy endpoint was met with clemastine fumarate treatment, which reduced the latency delay by 1·7 ms/eye (95% CI 0·5-2·9; p=0·0048) when analysing the trial as a crossover. Clemastine fumarate treatment was associated with fatigue, but no serious adverse events were reported., Interpretation: To our knowledge, this is the first randomised controlled trial to document efficacy of a remyelinating drug for the treatment of chronic demyelinating injury in multiple sclerosis. Our findings suggest that myelin repair can be achieved even following prolonged damage., Funding: University of California, San Francisco and the Rachleff Family., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We have witnessed major successes in the development of effective immunomodulatory therapies capable of reducing adaptive immune-mediated myelin damage in MS over the last 30 years. However, until it is possible to prevent MS or initiate treatment before it has already caused lesions there is a need to repair myelin damage to prevent further axonal loss. The past decade has brought remarkable advances in our understanding of oligodendrocyte biology and the related search for remyelinating therapies in humans. In this review, we first outline the basic biology of central nervous system myelin and remyelination, including a discussion of the major identified pathways and targets that might help yield CNS remyelinating drugs. In conjunction, we provide an overview of techniques that have helped identify compounds capable of promoting oligodendrocyte precursor cell differentiation and myelination. This includes the methods for both initial in vitro screening and subsequent in vivo confirmation of the target. We then review methods proposed to quantify human remyelination in vivo, including visual evoked potentials and putative imaging modalities. As the remyelination era approaches, with the announcement of the first positive trial in remyelination, we are now tasked with answering new questions regarding patient-specific factors (e.g., age) that may influence the extent and optimal therapeutic window for remyelination.

Background: Structural retinal imaging biomarkers are important for early recognition and monitoring of inflammation and neurodegeneration in multiple sclerosis. With the introduction of spectral domain optical coherence tomography (SD-OCT), supervised automated segmentation of individual retinal layers is possible. We aimed to investigate which retinal layers show atrophy associated with neurodegeneration in multiple sclerosis when measured with SD-OCT., Methods: In this systematic review and meta-analysis, we searched for studies in which SD-OCT was used to look at the retina in people with multiple sclerosis with or without optic neuritis in PubMed, Web of Science, and Google Scholar between Nov 22, 1991, and April 19, 2016. Data were taken from cross-sectional cohorts and from one timepoint from longitudinal studies (at least 3 months after onset in studies of optic neuritis). We classified data on eyes into healthy controls, multiple-sclerosis-associated optic neuritis (MSON), and multiple sclerosis without optic neuritis (MSNON). We assessed thickness of the retinal layers and we rated individual layer segmentation performance by random effects meta-analysis for MSON eyes versus control eyes, MSNON eyes versus control eyes, and MSNON eyes versus MSON eyes. We excluded relevant sources of bias by funnel plots., Findings: Of 25 497 records identified, 110 articles were eligible and 40 reported data (in total 5776 eyes from patients with multiple sclerosis [1667 MSON eyes and 4109 MSNON eyes] and 1697 eyes from healthy controls) that met published OCT quality control criteria and were suitable for meta-analysis. Compared with control eyes, the peripapillary retinal nerve fibre layer (RNFL) showed thinning in MSON eyes (mean difference -20·10 μm, 95% CI -22·76 to -17·44; p<0·0001) and in MSNON eyes (-7·41 μm, -8·98 to -5·83; p<0·0001). The macula showed RNFL thinning of -6·18 μm (-8·07 to -4·28; p<0·0001) in MSON eyes and -2·15 μm (-3·15 to -1·15; p<0·0001) in MSNON eyes compared with control eyes. Atrophy of the macular ganglion cell layer and inner plexiform layer (GCIPL) was -16·42 μm (-19·23 to -13·60; p<0·0001) for MSON eyes and -6·31 μm (-7·75 to -4·87; p<0·0001) for MSNON eyes compared with control eyes. A small degree of inner nuclear layer (INL) thickening occurred in MSON eyes compared with control eyes (0·77 μm, 0·25 to 1·28; p=0·003). We found no statistical difference in the thickness of the combined outer nuclear layer and outer plexiform layer when we compared MSNON or MSON eyes with control eyes, but we found a small degree of thickening of the combined layer when we compared MSON eyes with MSNON eyes (1·21 μm, 0·24 to 2·19; p=0·01)., Interpretation: The largest and most robust differences between the eyes of people with multiple sclerosis and control eyes were found in the peripapillary RNFL and macular GCIPL. Inflammatory disease activity might be captured by the INL. Because of the consistency, robustness, and large effect size, we recommend inclusion of the peripapillary RNFL and macular GCIPL for diagnosis, monitoring, and research., Funding: None., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To assess retinal ganglion cell (RGC) injury and sex differences in axon loss in pediatric multiple sclerosis (MS)., Methods: This is a cross-sectional evaluation of consecutive pediatric MS subjects and controls. Eyes with acute optic neuritis (ON) within 6 months of visit were excluded. Spectral domain optical coherence tomography (OCT) included peripapillary ring and macular scans with post-acquisition segmentation of retinal layers using automated software (Heidelberg v1.8.6.0). Generalized estimating equations (GEEs) measured associations of sex, history of ON, disease duration, and age with OCT outcomes., Results: In all, 53 MS subjects (100 eyes, median disease duration = 1.0 years, interquartile range (IQR) = 0.3, 2.5) were compared to 19 control subjects (38 eyes). Eyes with history of ON showed reduced retinal nerve fiber layer (RNFL: -26.8 µm, 95% confidence interval (CI) = -38.9, -14.8, p < 0.001) and 26% lower ganglion cell layer (GCL) volumes (-0.12 mm 3 , 95% CI = -0.16, -0.072, p < 0.001) compared to control eyes. Non-ON MS eyes had lower temporal RNFL (-11.9 µm, 95% CI = -18.6, -5.3, p < 0.001) and GCL volumes (-0.036 mm 3 , 95% CI = -0.06, -0.011, p = 0.004) than control eyes. In MS eyes, males versus females had lower global RNFL (-9.4 µm, 95% CI = -17.4, -1.33, p = 0.022) and in ON eyes had lower temporal quadrant RNFL (-9.6 µm, 95% CI = -15.1, -4.15, p = 0.001)., Conclusion: Subclinical retinal injury occurs in pediatric-onset MS patients without a history of ON. As in adult-onset MS, substantial GCL thinning is present in eyes with prior ON. Finally, greater retinal axonal injury occurs in boys compared to girls.

The objective of the study was to investigate the timing of central nervous system tissue atrophy in MS by evaluating longitudinal retinal volume changes in a broadly representative cohort with disease duration across the entire arc of disease. In this longitudinal study, 135 patients with MS and 16 healthy reference subjects underwent spectral-domain optical coherence tomography (OCT) at baseline and 2 years later. Following OCT quality control, automated segmentation of the peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell-inner plexiform layer (mGCIPL) and macular inner nuclear layer (mINL) was performed. Generalized estimation equations were used to analyze longitudinal changes and associations with disease duration and clinical measures. Participants had a median disease duration at baseline of 16.4 years (range 0.1-45.4). Nearly half (44 %) of the MS patients had previously experienced MS-related optic neuritis (MSON) more than 6 months prior. The MS patients demonstrated a significant decrease over 2 years of the pRNFL (-1.1 µm, 95 % CI 1.4-0.7, p < 0.001) and mGCIPL (-1.1 µm, 95 % CI -1.4 to -0.8, p < 0.001). This thinning was most pronounced early in the course of disease. These findings were irrespective of previous episodes of MSON. No consistent pattern of change was observed for the mINL (-0.03 µm, 95 % CI -0.2 to 0.2, p = 0.795). This longitudinal study demonstrated that injury of the innermost retinal layers is found in MS and that this damage occurs most rapidly during the early stages of disease. The attenuation of atrophy with longer disease duration is suggestive of a plateau effect. These findings emphasize the importance of early intervention to prevent such injury.

Background: Most patients with multiple sclerosis without previous optic neuritis have thinner retinal layers than healthy controls. We assessed the role of peripapillary retinal nerve fibre layer (pRNFL) thickness and macular volume in eyes with no history of optic neuritis as a biomarker of disability worsening in a cohort of patients with multiple sclerosis who had at least one eye without optic neuritis available., Methods: In this multicentre, cohort study, we collected data about patients (age ≥16 years old) with clinically isolated syndrome, relapsing-remitting multiple sclerosis, and progressive multiple sclerosis. Patients were recruited from centres in Spain, Italy, France, Germany, Czech Republic, Netherlands, Canada, and the USA, with the first cohort starting in 2008 and the latest cohort starting in 2013. We assessed disability worsening using the Expanded Disability Status Scale (EDSS). The pRNFL thickness and macular volume were assessed once at study entry (baseline) by optical coherence tomography (OCT) and was calculated as the mean value of both eyes without optic neuritis for patients without a history of optic neuritis or the value of the non-optic neuritis eye for patients with previous unilateral optic neuritis. Researchers who did the OCT at baseline were masked to EDSS results and the researchers assessing disability with EDSS were masked to OCT results. We estimated the association of pRNFL thickness or macular volume at baseline in eyes without optic neuritis with the risk of subsequent disability worsening by use of proportional hazards models that included OCT metrics and age, disease duration, disability, presence of previous unilateral optic neuritis, and use of disease-modifying therapies as covariates., Findings: 879 patients with clinically isolated syndrome (n=74), relapsing-remitting multiple sclerosis (n=664), or progressive multiple sclerosis (n=141) were included in the primary analyses. Disability worsening occurred in 252 (29%) of 879 patients with multiple sclerosis after a median follow-up of 2·0 years (range 0·5-5 years). Patients with a pRNFL of less than or equal to 87 μm or less than or equal to 88 μm (measured with Spectralis or Cirrus OCT devices) had double the risk of disability worsening at any time after the first and up to the third years of follow-up (hazard ratio 2·06, 95% CI 1·36-3·11; p=0·001), and the risk was increased by nearly four times after the third and up to the fifth years of follow-up (3·81, 1·63-8·91; p=0·002). We did not identify meaningful associations for macular volume., Interpretation: Our results provide evidence of the usefulness of monitoring pRNFL thickness by OCT for prediction of the risk of disability worsening with time in patients with multiple sclerosis., Funding: Instituto de Salud Carlos III., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Importance: In multiple sclerosis (MS), upper cervical cord gray matter (GM) atrophy correlates more strongly with disability than does brain or cord white matter (WM) atrophy. The corresponding relationships in the thoracic cord are unknown owing to technical difficulties in assessing GM and WM compartments by conventional magnetic resonance imaging techniques., Objectives: To investigate the associations between MS disability and disease type with lower thoracic cord GM and WM areas using phase-sensitive inversion recovery magnetic resonance imaging at 3 T, as well as to compare these relationships with those obtained at upper cervical levels., Design, Setting, and Participants: Between July 2013 and March 2014, a total of 142 patients with MS (aged 25-75 years; 86 women) and 20 healthy control individuals were included in this cross-sectional observational study conducted at an academic university hospital., Main Outcomes and Measures: Total cord areas (TCAs), GM areas, and WM areas at the disc levels C2/C3, C3/C4, T8/9, and T9/10. Area differences between groups were assessed, with age and sex as covariates., Results: Patients with relapsing MS (RMS) had smaller thoracic cord GM areas than did age- and sex-matched control individuals (mean differences [coefficient of variation (COV)]: 0.98 mm2 [9.2%]; P = .003 at T8/T9 and 0.93 mm2 [8.0%]; P = .01 at T9/T10); however, there were no significant differences in either the WM area or TCA. Patients with progressive MS showed smaller GM areas (mean differences [COV]: 1.02 mm2 [10.6%]; P < .001 at T8/T9 and 1.37 mm2 [13.2%]; P < .001 at T9/T10) and TCAs (mean differences [COV]: 3.66 mm2 [9.0%]; P < .001 at T8/T9 and 3.04 mm2 [7.2%]; P = .004 at T9/T10) compared with patients with RMS. All measurements (GM, WM, and TCA) were inversely correlated with Expanded Disability Status Scale score. Thoracic cord GM areas were correlated with lower limb function. In multivariable models (which also included cord WM areas and T2 lesion number, brain WM volumes, brain T1 and fluid-attenuated inversion recovery lesion loads, age, sex, and disease duration), cervical cord GM areas had the strongest correlation with Expanded Disability Status Scale score followed by thoracic cord GM area and brain GM volume., Conclusions and Relevance: Thoracic cord GM atrophy can be detected in vivo in the absence of WM atrophy in RMS. This atrophy is more pronounced in progressive MS than RMS and correlates with disability and lower limb function. Our results indicate that remarkable cord GM atrophy is present at multiple cervical and lower thoracic levels and, therefore, may reflect widespread cord GM degeneration.

Background: The relation of fatigue in multiple sclerosis (MS) to the visual system, an emerging structural and functional surrogate in MS, has not been well established., Objective: We examined how physical and cognitive fatigue could be associated with visual dysfunction and neurologic impairment., Methods: At a single time-point, we assessed 143 patients with: Low-contrast letter acuity (LCLA) and high-contrast visual acuity (VA) testing, the 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and Neuro-Ophthalmic Supplement, the Modified Fatigue Impact Scale (MFIS), the MS Functional Composite (MSFC), and the Expanded Disability Status Scale (EDSS)., Results: Worse binocular LCLA scores were associated with increased levels of total and physical fatigue (p≤0.026). Greater levels of fatigue were also associated with reduced vision-specific QOL (p<0.001). Patients with more physical, but not cognitive, fatigue had greater levels of impairment by the Timed 25-Foot Walk (T25W, r=0.39, p<0.001), 9-Hole Peg Test (9HP r=0.22, p=0.011) and EDSS (r=0.45, p<0.001)., Conclusions: Reduced vision in MS is highly associated with physical fatigue and could be used to capture more global, difficult to describe, symptoms. The potential differences in physical vs. cognitive fatigue and their correlates may begin to provide insight into their underlying mechanisms., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: To determine whether African American (AA) multiple sclerosis (MS) patients exhibit more retinal damage and visual impairment compared to Caucasian American (CA) MS patients., Methods: A total of 687 MS patients (81 AAs) and 110 healthy control (HC) subjects (14 AAs) were recruited at 3 academic hospitals between 2008 and 2012. Using mixed effects regression models, we compared high- and low-contrast visual acuity (HCVA and LCVA) and high-definition spectral domain optical coherence tomography measures of retinal architecture between MS patients of self-identified AA and CA ancestry., Results: In HCs, baseline peripapillary retinal nerve fiber layer (RNFL) thickness was 6.1µm greater in AAs (p = 0.047), whereas ganglion cell/inner plexiform layer (GCIP) thickness did not differ by race. In MS patients, baseline RNFL did not differ by race, and GCIP was 3.98µm thinner in AAs (p = 0.004). AAs had faster RNFL and GCIP thinning rates compared to CAs (p = 0.004 and p = 0.046, respectively). AA MS patients had lower baseline HCVA (p = 0.02) and worse LCVA per year of disease duration (p = 0.039). Among patients with an acute optic neuritis (AON) history, AAs had greater loss of HCVA than CA patients (p = 0.012)., Interpretation: This multicenter investigation provides objective evidence that AA MS patients exhibit accelerated retinal damage compared to CA MS patients. Self-identified AA ancestry is associated with worse MS-related visual disability, particularly in the context of an AON history, suggesting a more aggressive inflammatory disease course among AA MS patients or a subpopulation therein., (© 2014 American Neurological Association.)

Introduction: The assumption that multiple sclerosis (MS) is purely a white matter disease has been challenged in recent years by observations of axonal damage and neuronal loss in gray matter of the cortex, subcortex, and spinal cord., Methods: We report the case of a 71-year-old man with primary progressive MS and longstanding right arm weakness who presented with intermittent right arm pain., Results: Neurological examination showed atrophy, weakness, and hyporeflexia, and electromyography (EMG) showed acute and chronic partial denervation in multiple segments of the right arm. Magnetic resonance imaging (MRI) demonstrated asymmetric volume loss and increased T2 signal in the right anterior spinal cord from C3 to C7, with no evidence of nerve root compression., Conclusions: Lower motor neuron involvement of his right arm was caused by MS with involvement of either the anterior horn cells or the intraspinal motor nerve roots., (© 2014 Wiley Periodicals, Inc.)

We present a precision medicine application developed for multiple sclerosis (MS): the MS BioScreen. This new tool addresses the challenges of dynamic management of a complex chronic disease; the interaction of clinicians and patients with such a tool illustrates the extent to which translational digital medicine-that is, the application of information technology to medicine-has the potential to radically transform medical practice. We introduce 3 key evolutionary phases in displaying data to health care providers, patients, and researchers: visualization (accessing data), contextualization (understanding the data), and actionable interpretation (real-time use of the data to assist decision making). Together, these form the stepping stones that are expected to accelerate standardization of data across platforms, promote evidence-based medicine, support shared decision making, and ultimately lead to improved outcomes., (© 2014 American Neurological Association.)

Objectives: To study the association between changes in brain magnetic resonance imaging (MRI) and clinical outcomes in early MS., Methods: MS patients within 12 months of onset were enrolled and followed up to 3 years. Clinical measures included Symbol Digit Modalities Test (SDMT), MS Functional Composite (MSFC) and low contrast letter acuity (LCLA). MRI outcomes included brain volume changes measured by SIENA and SIENAX normalized measurements [brain parenchymal volume (BPV), normal-appearing white and gray matter volume (NAWMV and GMV) and T2 lesion volume (T2LV)]. Mixed model regression measured time trends and associations between imaging and clinical outcome., Results: Forty-three patients were enrolled within 7.5±4.9 months of onset. Baseline T2 lesion volume predicted subsequent changes in Paced Auditory Serial Addition Test (PASAT) (p=0.004), whereas baseline measures of atrophy including BPV, GMV, and NAWMV predicted longitudinal changes in MSFC (p=0.016, p=0.040, p=0.021, respectively) and Timed-25 Foot Walk (p<0.05). Each 1% decrease in SIENA was associated with 1.14 point decrease in SDMT score (p=0.03). Each 1% decrease in brain volume SIENA was associated with almost 1.5 letters decrease on LCLA (p=0.02)., Conclusion: Measures of lesion volume and overall brain volume were associated with different long-term clinical outcome measures in early MS., (Copyright © 2014. Published by Elsevier B.V.)

Objective: In multiple sclerosis (MS), cerebral gray matter (GM) atrophy correlates more strongly than white matter (WM) atrophy with disability. The corresponding relationships in the spinal cord (SC) are unknown due to technical limitations in assessing SC GM atrophy. Using phase-sensitive inversion recovery (PSIR) magnetic resonance imaging, we determined the association of the SC GM and SC WM areas with MS disability and disease type., Methods: A total of 113 MS patients and 20 healthy controls were examined at 3T with a PSIR sequence acquired at the C2/C3 disk level. Two independent, clinically masked readers measured the cord WM and GM areas. Correlations between cord areas and Expanded Disability Status Score (EDSS) were determined. Differences in areas between groups were assessed with age and sex as covariates., Results: Relapsing MS (RMS) patients showed smaller SC GM areas than age- and sex-matched controls (p = 0.008) without significant differences in SC WM areas. Progressive MS patients showed smaller SC GM and SC WM areas compared to RMS patients (all p ≤ 0.004). SC GM, SC WM, and whole cord areas inversely correlated with EDSS (rho: -0.60, -0.32, -0.42, respectively; all p ≤ 0.001). The SC GM area was the strongest correlate of disability in multivariate models including brain GM and WM volumes, fluid-attenuated inversion recovery lesion load, T1 lesion load, SC WM area, number of SC T2 lesions, age, sex, and disease duration. Brain and spinal GM independently contributed to EDSS., Interpretation: SC GM atrophy is detectable in vivo in the absence of WM atrophy in RMS. It is more pronounced in progressive MS than RMS and contributes more to patient disability than SC WM or brain GM atrophy., (© 2014 American Neurological Association.)

Functional screening for compounds that promote remyelination represents a major hurdle in the development of rational therapeutics for multiple sclerosis. Screening for remyelination is problematic, as myelination requires the presence of axons. Standard methods do not resolve cell-autonomous effects and are not suited for high-throughput formats. Here we describe a binary indicant for myelination using micropillar arrays (BIMA). Engineered with conical dimensions, micropillars permit resolution of the extent and length of membrane wrapping from a single two-dimensional image. Confocal imaging acquired from the base to the tip of the pillars allows for detection of concentric wrapping observed as 'rings' of myelin. The platform is formatted in 96-well plates, amenable to semiautomated random acquisition and automated detection and quantification. Upon screening 1,000 bioactive molecules, we identified a cluster of antimuscarinic compounds that enhance oligodendrocyte differentiation and remyelination. Our findings demonstrate a new high-throughput screening platform for potential regenerative therapeutics in multiple sclerosis.

Objective: To describe a novel neurophysiologic signature of the retinal ganglion cell and to elucidate its relationship to abnormalities in validated structural and functional measures of the visual system., Methods: We used multifocal electroretinogram-generated optic nerve head component (ONHC) responses from normal subjects (n = 18), patients with multiple sclerosis (MS) (n = 18), and those with glaucoma (n = 3). We then characterized the relationship between ONHC response abnormalities and performance on low-contrast visual acuity, multifocal visual-evoked potential-induced cortical responses, and average and quadrant retinal nerve fiber layer (RNFL) thicknesses, as measured by spectral-domain optical coherence tomography., Results: Compared with the eyes of normal subjects, the eyes of patients with MS exhibited an increased number of abnormal or absent ONHC responses (p < 0.0001). For every 7-letter reduction in low-contrast letter acuity, there were corresponding 4.6 abnormal ONHC responses at 2.5% contrast (p < 0.0001) and 6.6 abnormalities at the 1.25% contrast level (p < 0.0001). Regarding average RNFL thickness, for each 10-μm thickness reduction, we correspondingly observed 6.8 abnormal ONHC responses (p = 0.0002). The most robust association was between RNFL thinning in the temporal quadrant and ONHC response abnormalities (p < 0.0001)., Conclusion: Further characterization of ONHC abnormalities (those that are reversible and irreversible) may contribute to the development of novel neurotherapeutic strategies aimed at achieving neuroprotective, and perhaps even neurorestorative, effects in disorders that target the CNS in general, and MS in particular., (© 2014 American Academy of Neurology.)