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Synaptic dysfunction and loss are central to neurodegenerative diseases and correlate with cognitive decline. Synaptic Vesicle Protein 2A (SV2A) is a promising PET-imaging target for assessing synaptic density in vivo, but comprehensive mapping in the human brain is needed to validate its biomarker potential. This study used quantitative immunohistochemistry and Western blotting to map SV2A and synaptophysin (SYP) densities across six cortical regions in healthy controls and patients with early-onset Alzheimer's disease (EOAD), late-onset Alzheimer's disease (LOAD), progressive supranuclear palsy (PSP), and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-GRN). We identified region in SV2A density among controls and observed disease- and region-specific reductions, with the most severe in FTLD-GRN (up to 59.5%) and EOAD. EOAD showed a 49% reduction in the middle frontal gyrus (MFG), while LOAD had over 30% declines in the inferior frontal gyrus (IFG) and hippocampus (CA1). In PSP, smaller but significant reductions were noted in the hippocampal formation, with the inferior temporal gyrus (ITG) relatively unaffected. A strong positive correlation between SV2A and SYP densities confirmed SV2A's reliability as a synaptic integrity marker. This study supports the use of SV2A PET imaging for early diagnosis and monitoring of neurodegenerative diseases, providing essential data for interpreting in vivo PET results. Further research should explore SV2A as a therapeutic target and validate these findings in larger, longitudinal studies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Chronic demyelination and oligodendrocyte loss deprive neurons of crucial support. It is the degeneration of neurons and their connections that drives progressive disability in demyelinating disease. However, whether chronic demyelination triggers neurodegeneration and how it may do so remain unclear. We characterize two genetic mouse models of inducible demyelination, one distinguished by effective remyelination and the other by remyelination failure and chronic demyelination. While both demyelinating lines feature axonal damage, mice with blocked remyelination have elevated neuronal apoptosis and altered microglial inflammation, whereas mice with efficient remyelination do not feature neuronal apoptosis and have improved functional recovery. Remyelination incapable mice show increased activation of kinases downstream of dual leucine zipper kinase (DLK) and phosphorylation of c-Jun in neuronal nuclei. Pharmacological inhibition or genetic disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. Together, we demonstrate that remyelination is associated with neuroprotection and identify DLK inhibition as protective strategy for chronically demyelinated neurons., (© 2024. The Author(s).)

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.

Background: Preterm white matter injury (PWMI) is the most common cause of brain injury in premature neonates. PWMI involves a differentiation arrest of oligodendrocytes, the myelinating cells of the central nervous system. Clemastine was previously shown to induce oligodendrocyte differentiation and myelination in mouse models of PWMI at a dose of 10 mg/kg/day. The minimum effective dose (MED) of clemastine is unknown. Identification of the MED is essential for maximizing safety and efficacy in neonatal clinical trials. We hypothesized that the MED in neonatal mice is lower than 10 mg/kg/day., Methods: Mouse pups were exposed to normoxia or hypoxia (10% FiO2) from postnatal day 3 (P3) through P10. Vehicle or clemastine at one of four doses (0.5, 2, 7.5 or 10 mg/kg/day) was given to hypoxia-exposed pups. Myelination was assessed at age P14 and 10 weeks to determine the MED. Clemastine pharmacokinetics were evaluated at steady-state on day 8 of treatment., Results: Clemastine rescued hypoxia-induced hypomyelination with a MED of 7.5 mg/kg/day. Pharmacokinetic analysis of the MED revealed C max 44.0 ng/mL, t 1/2 4.6 h, and AUC 24 280.1 ng*hr/mL., Conclusions: Based on these results, myelination-promoting exposures should be achievable with oral doses of clemastine in neonates with PWMI., Impact: Preterm white matter injury (PWMI) is the most common cause of brain injury and cerebral palsy in premature neonates. Clemastine, an FDA-approved antihistamine, was recently identified to strongly promote myelination in a mouse model of PWMI and is a possible treatment. The minimum effective dose in neonatal rodents is unknown and is critical for guiding dose selection and balancing efficacy with toxicity in future clinical trials. We identified the minimum effective dose of clemastine and the associated pharmacokinetics in a murine chronic hypoxia model of PWMI, paving the way for a future clinical trial in human neonates., (© 2024. The Author(s).)

Chronic demyelination and oligodendrocyte loss deprive neurons of crucial support. It is the degeneration of neurons and their connections that drives progressive disability in demyelinating disease. However, whether chronic demyelination triggers neurodegeneration and how it may do so remain unclear. We characterize two genetic mouse models of inducible demyelination, one distinguished by effective remyelination and the other by remyelination failure and chronic demyelination. While both demyelinating lines feature axonal damage, mice with blocked remyelination have elevated neuronal apoptosis and altered microglial inflammation, whereas mice with efficient remyelination do not feature neuronal apoptosis and have improved functional recovery. Remyelination incapable mice show increased activation of kinases downstream of dual leucine zipper kinase (DLK) and phosphorylation of c-Jun in neuronal nuclei. Pharmacological inhibition or genetic disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. Together, we demonstrate that remyelination is associated with neuroprotection and identify DLK inhibition as protective strategy for chronically demyelinated neurons., Competing Interests: Competing Interests T.S.S. and B.E. are co-founders of Autobahn Therapeutics, B.E. has received consulting fees from Autobahn Therapeutics and T.S.S. is a Senior Advisor to Autobahn Therapeutics. B.E. and G.J.D. have received licensing fees for the use of Myrf inducible conditional knockout mice. These potential conflicts of interest have been reviewed and managed by OHSU.

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.)

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

Background: Inebilizumab, an anti-CD19 B-cell-depleting antibody, demonstrated safety and efficacy in neuromyelitis optica spectrum disorder in the randomised controlled period of the N-MOmentum trial. Here, end-of-study data, including the randomised controlled period and open-label extension period, are reported., Methods: In the double-blind, randomised, placebo-controlled, phase 2/3 N-MOmentum trial, adults aged 18 years and older with an neuromyelitis optica spectrum disorder diagnosis, Expanded Disability Status Scale score of 8·0 or less, and history of either at least one acute inflammatory attack requiring rescue therapy in the past year or two attacks requiring rescue therapy in the past 2 years, were recruited from 81 outpatient specialty clinics or hospitals in 24 countries. Eligible participants were randomly assigned (3:1), using a central interactive voice system or interactive web response system, and a permuted block randomisation scheme (block size of 4), to receive intravenous inebilizumab (300 mg) or identical placebo on days 1 and 15 of the randomised period, which lasted up to 197 days. Participants and all study staff were masked to treatment assignment. The primary endpoint of the randomised period of the trial was time to onset of adjudicated neuromyelitis optica spectrum disorder attack on or before day 197. Participants in the randomised controlled period who had an adjudicated attack, completed 197 days in the study, or were in the randomised controlled period when enrolment stopped, could voluntarily enter the open-label period. In the open-label period, participants either initiated inebilizumab if assigned placebo (receiving 300 mg on days 1 and 15 of the open-label period) or continued treatment if assigned inebilizumab (receiving 300 mg on day 1 and placebo on day 15, to maintain B-cell depletion and masking of the randomised controlled period). All participants subsequently received inebilizumab 300 mg every 6 months for a minimum of 2 years. The end-of-study analysis endpoints were time to adjudicated attack and annualised attack rate (assessed in all participants who received inebilizumab at any point during the randomised controlled period or open-label period [any inebilizumab population] and the aquaporin-4 [AQP4]-IgG seropositive subgroup [any inebilizumab-AQP4-IgG seropositive population]) and safety outcomes (in all participants who were exposed to inebilizumab, analysed as-treated). This study is registered with ClinicalTrials.gov, NCT02200770, and is now complete., Findings: Between Jan 6, 2015, and Sept 24, 2018, 467 individuals were screened, 231 were randomly assigned, and 230 received at least one dose of inebilizumab (n=174) or placebo (n=56). Between May 19, 2015, and Nov 8, 2018, 165 (95%) of 174 participants in the inebilizumab group and 51 (91%) of 56 in the placebo group entered the open-label period (mean age 42·9 years [SD 12·4], 197 [91%] of 216 were female, 19 [9%] were male, 115 [53%] were White, 45 [21%] were Asian, 19 [9%] were American Indian or Alaskan Native, and 19 [9%] were Black or African American). As of data cutoff for this end of study analysis (Dec 18, 2020; median exposure 1178 days [IQR 856-1538], total exposure of 730 person-years) 225 participants formed the any inebilizumab population, and 208 (92%) participants were AQP4-IgG seropositive. Overall, 63 adjudicated neuromyelitis optica spectrum disorder attacks occurred in 47 (21%) of 225 treated participants (60 attacks occurred in 44 [21%] of 208 in the AQP4-IgG seropositive subgroup); 40 (63%) of 63 attacks occurred in 34 (15%) of 225 treated participants during the first year of treatment. Of individuals who had an adjudicated attack while receiving inebilizumab, 36 (77%) of 47 were subsequently attack-free at the end of 4 years. Annualised attack rates decreased year-on-year, with end-of-study adjusted annualised attack rates being similar in the any inebilizumab-AQP4-IgG seropositive subgroup (0·097 [95% CI 0·070-0·14]) and any inebilizumab populations (0·092 [0·067-0·13]). Overall, 208 (92%) of 225 participants who received any inebilizumab had at least one treatment-emergent adverse event, the most frequent of which were urinary tract infection (59 [26%]), nasopharyngitis (47 [21%]), and arthralgia (39 [17%]). Infection rates did not increase over 4 years. Three (1%) of 225 participants in the any inebilizumab population died during the open-label period (one each due to a CNS event of unknown cause and pneumonia, respiratory insufficiency resulting from an neuromyelitis optica spectrum disorder attack and viral pneumonia related to COVID-19), all of which were deemed to be unrelated to treatment., Interpretation: Data from the end-of-study analysis of the N-MOmentum trial showed continued and sustained clinical benefits of long-term inebilizumab treatment in individuals with neuromyelitis optica spectrum disorder, which supports the role of inebilizumab as a CD19+ B-cell-depleting therapy in neuromyelitis optica spectrum disorder., Funding: MedImmune and Viela Bio/Horizon Therapeutics, now part of Amgen., Competing Interests: Declaration of interests BACC reports personal fees for consulting from Alexion, Atara, Autobahn, Avotres, Biogen, Boston Pharma, EMD Serono, Gossamer Bio, Hexal/Sandoz, Horizon Therapeutics, Neuron23, Novartis, Sanofi, Siemens, TG Therapeutics, and Therini Bio, and has received research support from Genentech. HJK has received a grant from the National Research Foundation of Korea and research support from AprilBio, Eisai, and UCB; consultancy or speaker fees from Alexion, Altos Biologics, AstraZeneca, Biogen, Daewoong Pharmaceutical, Eisai, GC Pharma, Handok Pharmaceuticals, Kaigene, Kolon Life Science, MDimune, Merck Serono, Mitsubishi Tanabe Pharma, Roche, and Sanofi Genzyme; serves on a steering committee for MedImmune/Viela Bio; and is a co-editor for the Multiple Sclerosis Journal and an associate editor for the Journal of Clinical Neurology. BGW receives payments for serving as chair of attack adjudication committees for clinical trials in neuromyelitis optica spectrum disorder for Alexion, MedImmune, UCB Bioscience, and Viela Bio/Horizon Therapeutics; has consulted with CANbridge Pharmaceuticals, Chugai, Genentech, Horizon Therapeutics, Mitsubishi Tanabe Pharma, and Roche Pharmaceuticals; has received payments for speaking for Genentech, Horizon Therapeutics, and Roche; and has a patent for NMO-IgG for diagnosis of neuromyelitis optica, with royalties paid by Hospices Civils de Lyon, MVZ Labor PD Dr Volkmann und Kollegen GbR, RSR Limited, and the University of Oxford. SJP reports grants, personal fees, and non-financial support from Alexion; grants from Autoimmune Encephalitis Alliance and Grifols; grants, personal fees, and non-financial support from MedImmune and Viela Bio/Horizon Therapeutics; consulting support from Astellas, Genentech, and Sage Therapeutics; personal fees for consulting services from for F Hoffman-La Roche AG, Genentech, and UCB; and has a patent #9,891,219 (Application#12-573942) “Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody positive”. DMW reports personal fees from Alexion, AstraZeneca, Bristol Myers Squibb, Genentech, Horizon Therapeutics, Imcyse, Merck, Novartis, and Reistone Biopharma; serves on a clinical trial adjudication committee for MedImmune, Viela Bio/Horizon Therapeutics, and UCB Pharma; and serves on a data and safety monitoring board for Alexion and Abscuro. KF serves on scientific advisory boards for Alexion, Bayer Schering, Biogen, Chugai, MedImmune, Merck Serono, Mitsubishi Tanabe Pharma, Nihon Pharmaceutical, Novartis, Ono Pharmaceutical, and Viela Bio/Horizon Therapeutics; has received funding for travel and speaker fees from Asahi Kasei Medical, Astellas, Bayer Schering, Biogen, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Mitsubishi Tanabe Pharma, Nihon Pharmaceutical, Novartis, and Takeda; and research support from Asahi Kasei Medical, Bayer Schering, Biogen, Chemo-Sero-Therapeutic Research Institute, Chugai, Genzyme Japan, the Ministry of Education, Culture, Sports, Science, and Technology of Japan, the Ministry of Health, Welfare, and Labor of Japan, Mitsubishi Tanabe Pharma, Nihon Pharmaceutical, Ono Pharmaceutical, Teijin, and Teva. FP has received research support, speaker fees, and travel reimbursement from Bayer, Biogen, Merck Serono, Novartis, Sanofi Genzyme, and Teva; is supported by the German Competence Network for Multiple Sclerosis and the German Research Council (DFG Exc 257); has received travel reimbursement from the Guthy–Jackson Charitable Foundation; and serves on the steering committee of the OCTiMS study sponsored by Novartis. GRC has received personal fees for participation on data and safety monitoring boards from AI Therapeutics, AMO Pharma, Applied Therapeutics, AstraZeneca, Avexis Pharmaceuticals, BioLineRx, Brainstorm Cell Therapeutics, Bristol Myers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Green Valley Pharma, Horizon Therapeutics, Immunic Therapeutics, Karuna Therapeutics, Mapi Pharma, Merck, Mitsubishi Tanabe Pharma, the National Heart, Lung, and Blood Institute (US; Protocol Review Committee), Novartis, OPKO Biologics, Prothena Biosciences, Reata Pharmaceuticals, Regeneron, Sanofi-Aventis, Teva Pharmaceuticals, the University of Texas Southwestern, the University of Pennsylvania, and Visioneering Technologies; personal fees for consulting or advisory board participation from Alexion, Antisense Therapeutics, Biogen, Clinical Trial Solutions, Entelexo Biotherapeutics, Genentech, Genzyme, GW Pharmaceuticals, Immunic Therapeutics, Immunosis, Klein Buendel, Merck/Serono, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Protalix BioTherapeutics, Recursion/CereXis, Regeneron, Roche, and SAB Biotherapeutics. GRC is employed by the University of Alabama at Birmingham and is President of Pythagoras, a private consulting company based in Birmingham, AL, USA. RM serves on scientific advisory boards for MedImmune and Viela Bio/Horizon Therapeutics; and has received funding for travel and fees from Alexion, Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, Teva, and Viela Bio/Horizon Therapeutics. AJG reports grants from the Conrad N Hilton Foundation and the Tom Sherak MS Hope Foundation; other financial relationships for activities as expert witness, associate editor, advisory board or steering committee participation, and endpoint adjudication with Bionure, Inception Sciences, JAMA Neurology, MedImmune/Viela Bio, Mylan, Synthon, and Trims Pharma; and personal fees from Pipeline Therapeutics. OA reports grants from the German Ministry of Education and Research (known as BMBF) and the German Research Foundation (known as DFG); grants and personal fees from Bayer HealthCare, Biogen, Genzyme, Novartis, Teva, and Viela Bio/Horizon Therapeutics; and personal fees from Alexion, Almirall, Horizon Therapeutics, Merck Serono, Roche, and Zambon. H-PH has received fees for consulting, speaking, and serving on steering committees from Bayer HealthCare, Biogen, Celgene Receptos, CSL Behring, GeNeuro, Genzyme, MedDay, MedImmune, Merck Serono, Novartis, Roche, Sanofi, TG Therapeutics, and Viela Bio with approval by the Rector of Heinrich Heine University Düsseldorf. DS, WR, MS, and DC hold stock or are employees of Viela Bio/Horizon Therapeutics, or both. EK was an employee of Viela Bio/Horizon Therapeutics during the preparation of this manuscript. JLB reports payment for study design or consultation from MedImmune/Viela Bio; personal fees from AbbVie, Alexion, Antigenomycs, BeiGene, Chugai, Clene Nanomedicine, EMD Serono, Genentech, Genzyme, Horizon Therapeutics, Mitsubishi Tanabe Pharma, Novartis, Reistone Biopharma, Roche, and TG Therapeutics; grants and personal fees from Novartis; grants from Alexion, the Guthy–Jackson Charitable Foundation, Mallinckrodt, and the National Institutes of Health; and has a patent for aquaporumab issued (US10654916B2: Compositions and methods for the treatment of neuromyelitis optica)., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

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.)

Mutations in progranulin ( GRN ) cause frontotemporal dementia ( GRN -FTD) due to deficiency of the pleiotropic protein progranulin. GRN -FTD exhibits diverse pathologies including lysosome dysfunction, lipofuscinosis, microgliosis, and neuroinflammation. Yet, how progranulin loss causes disease remains unresolved. Here, we report that non-invasive retinal imaging of GRN -FTD patients revealed deficits in photoreceptors and the retinal pigment epithelium (RPE) that correlate with cognitive decline. Likewise, Grn -/- mice exhibit early RPE dysfunction, microglial activation, and subsequent photoreceptor loss. Super-resolution live imaging and transcriptomic analyses identified RPE mitochondria as an early driver of retinal dysfunction. Loss of mitochondrial fission protein 1 (MTFP1) in Grn -/- RPE causes mitochondrial hyperfusion and bioenergetic defects, leading to NF-kB-mediated activation of complement C3a-C3a receptor signaling, which drives further mitochondrial hyperfusion and retinal inflammation. C3aR antagonism restores RPE mitochondrial integrity and limits subretinal microglial activation. Our study identifies a previously unrecognized mechanism by which progranulin modulates mitochondrial integrity and complement-mediated neuroinflammation.

Neurofilament proteins have been validated as specific body fluid biomarkers of neuro-axonal injury. The advent of highly sensitive analytical platforms that enable reliable quantification of neurofilaments in blood samples and simplify longitudinal follow-up has paved the way for the development of neurofilaments as a biomarker in clinical practice. Potential applications include assessment of disease activity, monitoring of treatment responses, and determining prognosis in many acute and chronic neurological disorders as well as their use as an outcome measure in trials of novel therapies. Progress has now moved the measurement of neurofilaments to the doorstep of routine clinical practice for the evaluation of individuals. In this Review, we first outline current knowledge on the structure and function of neurofilaments. We then discuss analytical and statistical approaches and challenges in determining neurofilament levels in different clinical contexts and assess the implications of neurofilament light chain (NfL) levels in normal ageing and the confounding factors that need to be considered when interpreting NfL measures. In addition, we summarize the current value and potential clinical applications of neurofilaments as a biomarker of neuro-axonal damage in a range of neurological disorders, including multiple sclerosis, Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, stroke and cerebrovascular disease, traumatic brain injury, and Parkinson disease. We also consider the steps needed to complete the translation of neurofilaments from the laboratory to the management of neurological diseases in clinical practice., (© 2024. Springer Nature Limited.)

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.)

Structure-activity relationship studies led to the discovery of PIPE-3297, a fully efficacious and selective kappa opioid receptor (KOR) agonist. PIPE-3297, a potent activator of G-protein signaling (GTPγS EC 50 = 1.1 nM, 91% E max ), did not elicit a β-arrestin-2 recruitment functional response ( E max < 10%). Receptor occupancy experiments performed with the novel KOR radiotracer [ 3 H]-PIPE-3113 revealed that subcutaneous (s.c.) administration of PIPE-3297 at 30 mg/kg in mice achieved 90% occupancy of the KOR in the CNS 1 h post dose. A single subcutaneous dose of PIPE-3297 in healthy mice produced a statistically significant increase of mature oligodendrocytes ( P < 0.0001) in the KOR-enriched striatum, an effect that was not observed in animals predosed with the selective KOR antagonist norbinaltorphimine. An equivalent dose given to mice in an open-field activity-monitoring system revealed a small KOR-independent decrease in total locomotor activity versus vehicle measured between 60 and 75 min post dose. Daily doses of PIPE-3297 at both 3 and 30 mg/kg s.c. reduced the disease score in the mouse experimental autoimmune encephalomyelitis (EAE) model. Visually evoked potential (VEP) N1 latencies were also significantly improved versus vehicle in both dose groups, and latencies matched those of untreated animals. Taken together, these findings highlight the potential therapeutic value of functionally selective G-protein KOR agonists in demyelinating disease, which may avoid the sedating side effects typically associated with classical nonbiased KOR agonists.

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.)

Competing Interests: F. C. Oertel was an employee of Nocturne GmbH and receives research support by the American Academy of Neurology and National Multiple Sclerosis Society (US), unrelated to this work and funding by the German Association of Neurology (Deutsche Gesellschaft für Neurologie) in context of this project. H. G. Zimmermann reports speaking honoraria and grants from Novartis and speaking honoraria from Bayer Healthcare, unrelated to this study. C. Chien has received speaking honoraria from Bayer and research funding from Novartis, unrelated to this study. R. Marignier serves on the scientific advisory board for MedImmune and has received funding for travel and honoraria from Biogen, Merck Serono, Novartis, Sanofi- Genzyme, Roche and Teva. A. Cobo-Calvo received funding from the Instituto de Salud Carlos III (Spain) JR19/00007 unrelated to this manuscript. L. Leocani received honoraria for consulting services from Merck, Roche, Biogen and for speaking activities from Teva; research support from Merck, Biogen, Novartis; travel support from Merck, Roche, Biogen, Almirall. M. Radaelli received speaker honoraria from Novartis, Bayer, Roche, Alexion and Ipsen and travel reimbursement from Bayer, Biogen, Merz, Genzyme, Teva, Roche and Merck, none related to this study. P. Villoslada hold stocks and has received consultancy fees from Accure Therapeutics, QMENTA, CLight, NeuroPrex, Attune Neurosciences, Spiral Therapeutics and Adhera Health. M. A. Lana-Peixoto has received funding for travel and speaker honoraria from Novartis, Sanofi- Genzyme, and Roche. O. Aktas has received honoraria for speaking/consultation and travel grants from Bayer Healthcare, Biogen Idec, Chugai, Novartis, Medimmune, Merck Serono, and Teva and research grants from Bayer Healthcare, Biogen Idec, Novartis, and Teva, not related to this study. M. Ringelstein received speaker honoraria from Novartis, Bayer, Roche, Alexion, and Ipsen, and travel reimbursement from Bayer, Biogen, Merz, Genzyme, Teva, Roche, and Merck, none related to this study. P. Albrecht reports grants, personal fees, and nonfinancial support from Allergan, Biogen, Ipsen, Merz Pharmaceuticals, Novartis, and Roche, personal fees and nonfinancial support from Bayer Healthcare, and Merck, and nonfinancial support from Sanofi-Aventis/Genzyme. M. R. Yeaman is the founder and a shareholder of NovaDigm Therapeutics, Inc.; he receives funding from the United States National Institutes of Health and United States Department of Defense; he holds U.S. and international patents on immunotherapeutic and anti-infective technologies, is a member of the Genentech-Roche Scientific Advisory Committee and adviser to The Guthy-Jackson Charitable Foundation. T. J. Smith was issued US patents covering the therapeutic targeting of IGF-I receptor in autoimmune diseases. He is a paid consultant for Horizon Thera and Immunovant and is a scientific advisor to the Guthy-Jackson Charitable Foundation. He receives research funding from the National Institutes of Health. F. Paul reports research grants and speaker honoraria from Bayer, Teva, Genzyme, Merck, Novartis, MedImmune and is member of the steering committee of the OCTIMS study (Novartis), all unrelated to this work. A. U. Brandt is cofounder and shareholder of Motognosis and Nocturne. He is named as inventor on several patent applications regarding MS serum biomarkers, OCT image analysis and perceptive visual computing. E. H. Martinez-Lapiscina, S. Motamedi, M. Pisa, SvS, C. Bereuter, and M. A. Fontenelle report no conflicts of interest.

Background: The N-MOmentum trial investigated safety and efficacy of inebilizumab in participants with neuromyelitis optica spectrum disorder (NMOSD)., Objective: Evaluate the attack identification process and adjudication committee (AC) performance in N-MOmentum., Methods: Adults ( n = 230) with NMOSD and Expanded Disability Status Scale score ⩽8 were randomized (3:1) to inebilizumab 300 mg or placebo. The randomized controlled period was 28 weeks or until adjudicated attack. Attacks were adjudicated according to 18 predefined criteria. Magnetic resonance imaging (MRI) and biomarker (serum glial fibrillary acidic protein [sGFAP]) analyses were performed., Results: A total of 64 participant-reported neurological events occurred; 51 (80%) were investigator-determined to be attacks. The AC confirmed 43 of the investigator-determined attacks (84%). There was high inter- and intra-AC-member agreement. In 25/64 events (39%) and 14/43 AC-adjudicated attacks (33%), MRI was reviewed during adjudication. Retrospective analysis revealed new domain-specific T1 and T2 MRI lesions in 90% of adjudicated attacks. Increased mean sGFAP concentrations (>2-fold change) from baseline were observed in 56% of adjudicated attacks versus 14% of investigator-determined attacks rejected by the AC and 31% of participant-reported events determined not to be attacks., Conclusion: AC adjudication of NMOSD attacks according to predefined criteria appears robust. MRI lesion correlates and sGFAP elevations were found in most adjudicated attacks.

Background and Aims: To investigate the prognostic value of blood neurofilament light chain protein (NfL) levels in the acute phase of coronavirus disease 2019 (COVID-19)., Methods: We conducted an individual participant data (IPD) meta-analysis after screening on MEDLINE and Scopus to May 23rd 2022. We included studies with hospitalized adult COVID-19 patients without major COVID-19-associated central nervous system (CNS) manifestations and with a measurement of blood NfL in the acute phase as well as data regarding at least one clinical outcome including intensive care unit (ICU) admission, need of mechanical ventilation (MV) and death. We derived the age-adjusted measures NfL Z scores and conducted mixed-effects modelling to test associations between NfL Z scores and other variables, encompassing clinical outcomes. Summary receiver operating characteristic curves (SROCs) were used to calculate the area under the curve (AUC) for blood NfL., Results: We identified 382 records, of which 7 studies were included with a total of 669 hospitalized COVID-19 cases (mean age 66.2 ± 15.0 years, 68.1% males). Median NfL Z score at admission was elevated compared to the age-corrected reference population (2.37, IQR: 1.13-3.06, referring to 99th percentile in healthy controls). NfL Z scores were significantly associated with disease duration and severity. Higher NfL Z scores were associated with a higher likelihood of ICU admission, need of MV, and death. SROCs revealed AUCs of 0.74, 0.80 and 0.71 for mortality, need of MV and ICU admission, respectively., Conclusions: Blood NfL levels were elevated in the acute phase of COVID-19 patients without major CNS manifestations and associated with clinical severity and poor outcome. The marker might ameliorate the performance of prognostic multivariable algorithms in COVID-19., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: The novel optic neuritis (ON) diagnostic criteria include intereye differences (IED) of optical coherence tomography (OCT) parameters. IED has proven valuable for ON diagnosis in multiple sclerosis but has not been evaluated in aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders (AQP4+NMOSD). We evaluated the diagnostic accuracy of intereye absolute (IEAD) and percentage difference (IEPD) in AQP4+NMOSD after unilateral ON >6 months before OCT as compared with healthy controls (HC)., Methods: Twenty-eight AQP4+NMOSD after unilateral ON (NMOSD-ON), 62 HC and 45 AQP4+NMOSD without ON history (NMOSD-NON) were recruited by 13 centres as part of the international Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica study. Mean thickness of peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell and inner plexiform layer (GCIPL) were quantified by Spectralis spectral domain OCT. Threshold values of the ON diagnostic criteria (pRNFL: IEAD 5 µm, IEPD 5%; GCIPL: IEAD: 4 µm, IEPD: 4%) were evaluated using receiver operating characteristics and area under the curve (AUC) metrics., Results: The discriminative power was high for NMOSD-ON versus HC for IEAD (pRNFL: AUC 0.95, specificity 82%, sensitivity 86%; GCIPL: AUC 0.93, specificity 98%, sensitivity 75%) and IEPD (pRNFL: AUC 0.96, specificity 87%, sensitivity 89%; GCIPL: AUC 0.94, specificity 96%, sensitivity 82%). The discriminative power was high/moderate for NMOSD-ON versus NMOSD-NON for IEAD (pRNFL: AUC 0.92, specificity 77%, sensitivity 86%; GCIP: AUC 0.87, specificity 85%, sensitivity 75%) and for IEPD (pRNFL: AUC 0.94, specificity 82%, sensitivity 89%; GCIP: AUC 0.88, specificity 82%, sensitivity 82%)., Conclusions: Results support the validation of the IED metrics as OCT parameters of the novel diagnostic ON criteria in AQP4+NMOSD., Competing Interests: Competing interests: The authors have stated explicitly that there are no conflicts of interest in connection with this article., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In recent years, the ability of conventional magnetic resonance imaging (MRI), including T 1 contrast-enhanced (CE) MRI, to monitor high-efficacy therapies and predict long-term disability in multiple sclerosis (MS) has been challenged. Therefore, non-invasive methods to improve MS lesions detection and monitor therapy response are needed., Methods: We studied the combined cuprizone and experimental autoimmune encephalomyelitis (CPZ-EAE) mouse model of MS, which presents inflammatory-mediated demyelinated lesions in the central nervous system as commonly seen in MS patients. Using hyperpolarized 13 C MR spectroscopy (MRS) metabolic imaging, we measured cerebral metabolic fluxes in control, CPZ-EAE and CPZ-EAE mice treated with two clinically-relevant therapies, namely fingolimod and dimethyl fumarate. We also acquired conventional T 1 CE MRI to detect active lesions, and performed ex vivo measurements of enzyme activities and immunofluorescence analyses of brain tissue. Last, we evaluated associations between imaging and ex vivo parameters., Results: We show that hyperpolarized [1- 13 C]pyruvate conversion to lactate is increased in the brain of untreated CPZ-EAE mice when compared to the control, reflecting immune cell activation. We further demonstrate that this metabolic conversion is significantly decreased in response to the two treatments. This reduction can be explained by increased pyruvate dehydrogenase activity and a decrease in immune cells. Importantly, we show that hyperpolarized 13 C MRS detects dimethyl fumarate therapy, whereas conventional T 1 CE MRI cannot., Conclusions: In conclusion, hyperpolarized MRS metabolic imaging of [1- 13 C]pyruvate detects immunological responses to disease-modifying therapies in MS. This technique is complementary to conventional MRI and provides unique information on neuroinflammation and its modulation., (© 2023. The Author(s).)

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.)

Background: Inebilizumab is an anti-CD19 antibody approved for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults with aquaporin-4 autoantibodies. The relationship between B-cell, plasma-cell (PC), and immunoglobulin depletion with longitudinal reductions in NMOSD activity after inebilizumab treatment was characterised post hoc in an exploratory analysis from the N-MOmentum study (NCT02200770)., Methods: Peripheral blood CD20+ B cells, PC gene signature, and immunoglobulin levels were assessed throughout N-MOmentum (follow-up ≥2.5 years); correlations with clinical metrics and magnetic resonance imaging (MRI) lesion activity were assessed., Findings: Inebilizumab induced durable B-cell and PC depletion within 1 week versus placebo. Although no association was observed between B-cell counts at time of attack and NMOSD activity, depth of B-cell depletion after the first dosing period correlated with clinical outcomes. All participants receiving inebilizumab demonstrated a robust long-term therapeutic response, and participants with ≤4 cells/μL after the first 6-month dosing interval had persistently deeper B-cell depletion, lower annualised attack rates (estimated rate [95% CI]: 0.034 [0.024-0.04] vs 0.086 [0.056-0.12]; p = 0.045), fewer new/enlarging T2 MRI lesions (0.49 [0.43-0.56] vs 1.36 [1.12-1.61]; p < 0.0001), and a trend towards decreased Expanded Disability Status Scale worsening (0.076 [0.06-0.10] vs 0.14 [0.10-0.18]; p = 0.093). Antibodies to inebilizumab, although present in a proportion of treated participants, did not alter outcomes., Interpretation: This analysis suggests that compared with placebo, inebilizumab can provide specific, rapid, and durable depletion of B cells in participants with NMOSD. Although deep and persistent CD20+ B-cell depletion correlates with long-term clinical stability, early, deep B-cell depletion correlates with improved disease activity metrics in the first 2 years., Funding: Horizon Therapeutics (formerly from Viela Bio/MedImmune)., Competing Interests: Declaration of interests J.L.Bennett reports payment for study design/consultation from MedImmune; personal fees from AbbVie, Alexion, Antigenomycs, BeiGene, Chugai, Clene Nanomedicine, Genentech, Genzyme, Reistone Bio, Roche, and TG; grants from Alexion, the National Institutes of Health, and Novartis. In addition, Dr Bennett has a patent ‘Compositions and methods for the treatment of neuromyelitis optica’. O.Aktas reports grants from the German Research Foundation (DFG) and the German Ministry of Education and Research (BMBF); grants and personal fees from Bayer HealthCare, Biogen, Genzyme, Horizon Therapeutics (formerly from Viela Bio), Novartis, and Teva; and personal fees from Almirall, MedImmune, Merck Serono, and Roche. W.A.Rees, M.A.Smith, D.She, and D.Cimbora are employees of Horizon Therapeutics (formerly Viela Bio) and own stock. L.Yan, M.Gunsior, and E.Katz are former employees of Horizon Therapeutics. S.J.Pittock reports grants, personal fees, and non-financial support from Alexion Pharmaceuticals, Inc.; grants from Autoimmune Encephalitis Alliance and Grifols; grants, personal fees, non-financial support, and other from Horizon Therapeutics (formerly from Viela Bio) and MedImmune; personal fees for consulting services from Astellas; grants, personal fees, non-financial support and other from Roche/Genentech; personal fees for consulting services from UCB; and has a patent #9,891,219 (Application#12-573942) ’Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody Positive’. B.G.Weinshenker received payments for serving as chair of attack adjudication committees for clinical trials in NMOSD for Alexion, MedImmune, and Viela Bio/Horizon Therapeutics; has consulted with Chugai, Genentech, Horizon Therapeutics, Mitsubishi Tanabe Pharma, and Roche Pharmaceuticals; and has a patent for NMO-IgG for diagnosis of neuromyelitis optica, with royalties paid by Hospices Civils de Lyon, MVZ Labor PD Dr. Volkmann und Kollegen GbR, University of Oxford, and RSR. F.Paul has received research support, speaker honoraria, and travel reimbursement from Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, and Teva; is supported by the German Research Council (DFG Exc 257) and the German Competence Network for Multiple Sclerosis; has received travel reimbursement from the Guthy-Jackson Charitable Foundation; and serves on the steering committee of the OCTIMS study, sponsored by Novartis. R.Marignier reports personal fees for consulting from Alexion, Horizon Therapeutics (formerly Viela Bio), Roche, and UCB. D.Wingerchuk reports personal fees from Biogen, Celgene, Genentech, MedImmune, Mitsubishi Tanabe, Novartis, Reistone Biopharma, and TG Therapeutics; research support paid to the Mayo Clinic by Alexion and Terumo BCT; and has served on a clinical trial adjudication committee for Horizon Therapeutics (formerly Viela Bio) and MedImmune. G.Cutter has received personal fees for participation on Data and Safety Monitoring Boards from AstraZeneca, Avexis Pharmaceuticals, BioLineRx, Brainstorm Cell Therapeutics, Bristol Myers Squibb/Celgene, CSL Behring, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Obesity Policy Research Unit oversight committee), Galmed Pharmaceuticals, Hisun Pharmaceutical, Horizon Pharmaceuticals (formerly Viela Bio), Mapi Pharma, Merck, Merck/Pfizer, the National Heart, Lung, and Blood Institute (Protocol Review Committee), Neurim Pharmaceuticals, Novartis, OncoImmune, OPKO Biologics, Orphazyme, Reata Pharmaceuticals, Sanofi-Aventis, Teva Pharmaceuticals, and Vivus; personal fees for consulting or advisory board participation from BioDelivery Sciences International, Biogen, Click Therapeutics, Genentech, Genzyme, GW Pharmaceuticals, Immunic, Klein Buendel, MedDay, MedImmune, NeuroGenesis, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Roche, and TG Therapeutics; is employed by the University of Alabama at Birmingham, AL, USA; and is President of Pythagoras, Inc., a private consulting company based in Birmingham, AL, USA. A.Green reports grants from the Conrad N. Hilton Foundation and the Tom Sherak MS Hope Foundation; other financial relationships (for activities as expert witness, associate editor, advisory board/steering committee participation, and endpoint adjudication) with Bionure, Inception Sciences, JAMA Neurology, MedImmune/Horizon Therapeutics (formerly Viela Bio), Mylan, Synthon, and Trims Pharma; and personal fees from and other financial relationships with Pipeline Therapeutics. H.-P.Hartung has received fees for consulting, speaking, and serving on steering committees from Bayer HealthCare, Biogen Idec, Celgene Receptos, CSL Behring, GeNeuro, Genzyme, Horizon Therapeutics (formerly Viela Bio), MedDay, MedImmune, Merck Serono, Novartis, Roche, Sanofi, and TG Therapeutics with approval by the Rector of Heinrich Heine University Düsseldorf. H.J.Kim has received a grant from the National Research Foundation of Korea; consultancy/speaker fees or research support from Alexion, AprilBio, Celltrion, Daewoong Pharmaceutical, Eisai, GC Pharma, HanAll Biopharma, Horizon Therapeutics (formerly Viela Bio), Kolon Life Science, MedImmune, Merck Serono, Mitsubishi Tanabe Pharma, Novartis, Sanofi Genzyme, Teva-Handok, and UCB; and is a co-editor for the Multiple Sclerosis Journal and an associate editor for the Journal of Clinical Neurology. K.Fujihara has received fees for consulting, speaking, and serving on steering committees from AbbVie, Alexion, Asahi Kasei Kuraray Medical Co., Biogen, Chugai/Roche, Eisai, Japan Tobacco, MedImmune/Viela Bio, Merck, Merck Biopharma, Mitsubishi Tanabe Pharma, Novartis, Teijin, Takeda Pharmaceutical Company, and UCB; and a grant-in-aid for scientific research from the Ministry of Health, Labour and Welfare of Japan. M.Levy currently receives research support from Acorda Therapeutics, Alexion, Alnylam Pharmaceuticals, ApoPharma, Maryland Technology Development Corporation, the National Institutes of Health, Sanofi Genzyme, and Shire/Takeda; has received personal compensation for consultation with Acorda Therapeutics, Alexion, and Genzyme; and serves on the scientific advisory boards for Acorda Therapeutics, Alexion, and Quest Diagnostics. B.A.C.Cree reports personal compensation for consulting from Alexion, Atara Biotherapeutics, Autobahn Therapeutics, Avotres Inc., Biogen, Boston Pharma, EMD Serono, Gossamer Bio, Hexal/Sandoz, Horizon Therapeutics, Neuron23, Novartis, Sanofi, Siemens, TG Therapeutics, and Therini Bio; and has received research support from Genentech., (Copyright © 2022 Horizon Therapeutics plc. Published by Elsevier B.V. All rights reserved.)

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.)

Objective: Patients with myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-associated disease (MOGAD) suffer from severe optic neuritis (ON) leading to retinal neuro-axonal loss, which can be quantified by optical coherence tomography (OCT). We assessed whether ON-independent retinal atrophy can be detected in MOGAD., Methods: Eighty patients with MOGAD and 139 healthy controls (HCs) were included. OCT data was acquired with (1) Spectralis spectral domain OCT (MOGAD: N = 66 and HCs: N = 103) and (2) Cirrus high-definition OCT (MOGAD: N = 14 and HCs: N = 36). Macular combined ganglion cell and inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) were quantified., Results: At baseline, GCIPL and pRNFL were lower in MOGAD eyes with a history of ON (MOGAD-ON) compared with MOGAD eyes without a history of ON (MOGAD-NON) and HCs (p < 0.001). MOGAD-NON eyes had lower GCIPL volume compared to HCs (p < 0.001) in the Spectralis, but not in the Cirrus cohort. Longitudinally (follow-up up to 3 years), MOGAD-ON with ON within the last 6-12 months before baseline exhibited greater pRNFL thinning than MOGAD-ON with an ON greater than 12 months ago (p < 0.001). The overall MOGAD cohort did not exhibit faster GCIPL thinning compared with the HC cohort., Interpretation: Our study suggests the absence of attack-independent retinal damage in patients with MOGAD. Yet, ongoing neuroaxonal damage or edema resolution seems to occur for up to 12 months after ON, which is longer than what has been reported with other ON forms. These findings support that the pathomechanisms underlying optic nerve involvement and the evolution of OCT retinal changes after ON is distinct in patients with MOGAD. ANN NEUROL 2022;92:476-485., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Development of novel diagnostic tools is a top research priority in vascular dementia. A major obstacle is the lack of a simple, non-invasive method to visualize cerebral arteriolar walls in vivo. Retinal arterioles offer a window into the cerebral circulation., Methods: I ntensity- b ased r etinal a rteriolar v isualization in o ptical coherence tomography (I-bRAVO) was applied to evaluate mean wall thickness (MWT) and wall-to-lumen ratio (WLR) in 250 subjects with sporadic and genetic cerebral small vessel disease (CSVD), non-vascular neurodegenerative diseases (NVND), and healthy controls (HC) in association with imaging and cognitive markers., Results: MWT and WLR were higher in CSVD, associated with severity of vascular white matter lesions, and correlated with magnetic resonance imaging-based intracranial arteriolosclerosis score. WLR correlated with gray and white matter volume and differentiated asymptomatic sporadic CSVD from HC (area under the curve = 0.82)., Discussion: I-bRAVO is a rapid, non-invasive tool. MWT and WLR were associated with imaging markers of CSVD and could contribute to early identification of sporadic CSVD., Competing Interests: The authors report no conflicts of interest related to this work. All authors report no disclosures related to this work., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Chronic demyelination is a major contributor to axonal vulnerability in multiple sclerosis (MS). Therefore, remyelination could provide a potent neuroprotective strategy. The ReBUILD trial was the first study showing evidence for successful remyelination following treatment with clemastine in people with MS (pwMS) with no evidence of disease activity or progression (NEDAP). Whether remyelination was associated with neuroprotection remains unexplored., Methods: Plasma neurofilament light chain (NfL) levels were measured from ReBUILD trial's participants. Mixed linear effect models were fit for individual patients, epoch and longitudinal measurements to compare NfL concentrations between samples collected during the active and placebo treatment period., Results: NfL concentrations were 9.6% lower in samples collected during the active treatment with clemastine (n=53, geometric mean=6.33 pg/mL) compared to samples collected during treatment with placebo (n=73, 7.00 pg/mL) (B=-0.035 [-0.068 to -0.001], p=0.041). Applying age- and body mass index-standardised NfL Z-scores and percentiles revealed similar results (0.04 vs 0.35, and 27.5 vs 33.3, p=0.023 and 0.042, respectively). Higher NfL concentrations were associated with more delayed P100 latencies (B=1.33 [0.26 to 2.41], p=0.015). In addition, improvement of P100 latencies between visits was associated with a trend for lower NfL values (B=0.003 [-0.0004 to 0.007], p=0.081). Based on a Cohen's d of 0.248, a future 1:1 parallel-arm placebo-controlled study using a remyelinating agent with comparable effect as clemastine would need 202 subjects per group to achieve 80% power., Conclusions: In pwMS, treatment with the remyelinating agent clemastine was associated with a reduction of blood NfL, suggesting that neuroprotection is achievable and measurable with therapeutic remyelination., Trial Registration Number: NCT02040298., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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.)

Introduction: Most women develop MS before menopause. Menopausal hot flashes can worsen MS symptoms, and could be relieved with hormone therapy. Our objective was to evaluate feasibility, tolerability and symptom response of Duavee® (bazedoxifene + conjugated estrogen) in a Phase Ib/IIa double-blind randomized controlled clinical trial., Methods: We randomized 24 peri/postmenopausal women with MS and symptomatic hot flashes 1:1 to Duavee® versus placebo. Evaluations occurred at baseline and 2 months., Results: Groups were balanced for age (mean 51.2 ± 3.6 years), EDSS [median 3 (IQR:2.5, 4.5)], and MS duration. 21/24 participants completed the study., Feasibility: Enrollment was protracted (34 months), partially due to concerns about hormone therapy safety., Tolerability: treatment group participants reported greater satisfaction and fewer missed doses; one participant (placebo) developed new MRI lesions; liver function testing remained normal for all patients., Symptoms: Hot Flash Related Daily Interference scale at 2 months was lower in treatment vs. placebo group [median (IQR) of 4 (0.5, 14) vs. 9 (0, 33)]. Between-group differences were not statistically significant., Conclusion: Despite perceived benefits in MS, estrogens have perceived risks that represent a hurdle to enrollment. With appropriate education and screening of participants, the favorable study retention (87%) and treatment satisfaction observed in the current study support the feasibility of a longer, powered trial to evaluate whether a proven treatment for menopausal symptoms, Duavee®, could also improve MS-related function in menopausal women with MS., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Blood-derived biomarkers for brain and spinal cord diseases are urgently needed. The introduction of highly sensitive immunoassays led to a rapid increase in the number of potential blood-derived biomarkers for diagnosis and monitoring of neurological disorders. In 2018, the FDA authorized a blood test for clinical use in the evaluation of mild traumatic brain injury (TBI). The test measures levels of the astrocytic intermediate filament glial fibrillary acidic protein (GFAP) and neuroaxonal marker ubiquitin carboxy-terminal hydrolase L1. In TBI, blood GFAP levels are correlated with clinical severity and extent of intracranial pathology. Evidence also indicates that blood GFAP levels hold the potential to reflect, and might enable prediction of, worsening of disability in individuals with progressive multiple sclerosis. A growing body of evidence suggests that blood GFAP levels can be used to detect even subtle injury to the CNS. Most importantly, the successful completion of the ongoing validation of point-of-care platforms for blood GFAP might ameliorate the decision algorithms for acute neurological diseases, such as TBI and stroke, with important economic implications. In this Review, we provide a systematic overview of the evidence regarding the utility of blood GFAP as a biomarker in neurological diseases. We propose a model for GFAP concentration dynamics in different conditions and discuss the limitations that hamper the widespread use of GFAP in the clinical setting. In our opinion, the clinical use of blood GFAP measurements has the potential to contribute to accelerated diagnosis and improved prognostication, and represents an important step forward in the era of precision medicine., (© 2022. Springer Nature Limited.)

Objective: A major challenge in multiple sclerosis (MS) research is the understanding of silent progression and Progressive MS. Using a novel method to accurately capture upper cervical cord area from legacy brain MRI scans we aimed to study the role of spinal cord and brain atrophy for silent progression and conversion to secondary progressive disease (SPMS)., Methods: From a single-center observational study, all RRMS (n = 360) and SPMS (n = 47) patients and 80 matched controls were evaluated. RRMS patient subsets who converted to SPMS (n = 54) or silently progressed (n = 159), respectively, during the 12-year observation period were compared to clinically matched RRMS patients remaining RRMS (n = 54) or stable (n = 147), respectively. From brain MRI, we assessed the value of brain and spinal cord measures to predict silent progression and SPMS conversion., Results: Patients who developed SPMS showed faster cord atrophy rates (-2.19%/yr) at least 4 years before conversion compared to their RRMS matches (-0.88%/yr, p < 0.001). Spinal cord atrophy rates decelerated after conversion (-1.63%/yr, p = 0.010) towards those of SPMS patients from study entry (-1.04%). Each 1% faster spinal cord atrophy rate was associated with 69% (p < 0.0001) and 53% (p < 0.0001) shorter time to silent progression and SPMS conversion, respectively., Interpretation: Silent progression and conversion to secondary progressive disease are predominantly related to cervical cord atrophy. This atrophy is often present from the earliest disease stages and predicts the speed of silent progression and conversion to Progressive MS. Diagnosis of SPMS is rather a late recognition of this neurodegenerative process than a distinct disease phase. ANN NEUROL 2022;91:268-281., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose: The purpose of this study was to characterize the benign biological variance of fixational microsaccades in a control population using a tracking scanning laser ophthalmoscope (TSLO), accounting for machine accuracy and precision, to determine ideal testing conditions to detect pathologic change in fixational eye motion (FEM)., Methods: We quantified the accuracy and precision of the TSLO, analyzing measurements made by three operators on a model eye. Repeated, 10-second retinal motion traces were then recorded in 17 controls, 3 times a day (morning, afternoon, and evening), on 3 separate days. Microsaccade metrics (MMs) of frequency, average amplitude, peak velocity, and peak acceleration were extracted. Trace to trace, interday, and intraday variability were calculated across all subjects., Results: Intra-operator and machine variation contributed minimally to total variation, with only 0.007% and 0.14% contribution for frequency and amplitude respectively. Bias was detected, with lower accuracy for higher amplitudes. Participants had an average (SD) microsaccade frequency of 0.84 Hz (0.52 Hz), amplitude of 0.32 degrees (0.11 degrees), peak velocity of 43.68 degrees/s (14.02 degrees/s), and peak acceleration of 13,920.04 degrees/s2 (4,186.84 degrees/s2). The first trace recorded within a session significantly differed from the second two in both microsaccade acceleration and velocity (P < 0.05), and frequency was 0.098 Hz higher in the evenings (P < 0.05). There was no MM difference between days and no evidence of a session-level learning effect (P > 0.05)., Conclusions: The TSLO is both accurate and precise. However, biological inter- and intra-individual variance is present. Trace to trace variability and time of day should be accounted for to optimize detection of pathologic change.

Background: Patients with anti-aquaporin-4 antibody seropositive (AQP4-IgG+) neuromyelitis optica spectrum disorders (NMOSDs) frequently suffer from optic neuritis (ON) leading to severe retinal neuroaxonal damage. Further, the relationship of this retinal damage to a primary astrocytopathy in NMOSD is uncertain. Primary astrocytopathy has been suggested to cause ON-independent retinal damage and contribute to changes particularly in the outer plexiform layer (OPL) and outer nuclear layer (ONL), as reported in some earlier studies. However, these were limited in their sample size and contradictory as to the localisation. This study assesses outer retinal layer changes using optical coherence tomography (OCT) in a multicentre cross-sectional cohort., Method: 197 patients who were AQP4-IgG+ and 32 myelin-oligodendrocyte-glycoprotein antibody seropositive (MOG-IgG+) patients were enrolled in this study along with 75 healthy controls. Participants underwent neurological examination and OCT with central postprocessing conducted at a single site., Results: No significant thinning of OPL (25.02±2.03 µm) or ONL (61.63±7.04 µm) were observed in patients who were AQP4-IgG+ compared with patients who were MOG-IgG+ with comparable neuroaxonal damage (OPL: 25.10±2.00 µm; ONL: 64.71±7.87 µm) or healthy controls (OPL: 24.58±1.64 µm; ONL: 63.59±5.78 µm). Eyes of patients who were AQP4-IgG+ (19.84±5.09 µm, p=0.027) and MOG-IgG+ (19.82±4.78 µm, p=0.004) with a history of ON showed parafoveal OPL thinning compared with healthy controls (20.99±5.14 µm); this was not observed elsewhere., Conclusion: The results suggest that outer retinal layer loss is not a consistent component of retinal astrocytic damage in AQP4-IgG+ NMOSD. Longitudinal studies are necessary to determine if OPL and ONL are damaged in late disease due to retrograde trans-synaptic axonal degeneration and whether outer retinal dysfunction occurs despite any measurable structural correlates., Competing Interests: Competing interests: HZ reports grants from Novartis and speaking honoraria from Bayer Healthcare, unrelated to this study. EHM-L received funding from the Instituto de Salud Carlos III (Spain) and Fondo Europeo de Desarrollo Regional (FEDER-JR16/00006), Grant for MS Innovation, Fundació Privada Cellex and Marató TV3 Charitable Foundation and is a researcher in the OCTIMS study, an observational study (that involves no specific drugs) to validate SD-OCT as a biomarker for MS, sponsored by Novartis and has received honoraria and travel support for international and national meetings over the last 3 years from from Biogen, Novartis, Roche, Genzyme. She is a member of the working committee of International Multiple Sclerosis Visual System (IMSVISUAL) Consortium. MAL-P has received funding for travel and speaker honoraria from Novartis, Sanofi- Genzyme and Roche. MAF has nothing to disclose. Jacqueline Palace has received support for scientific meetings and honorariums for advisory work From Merck Serono, Novartis, Chugai, Alexion, Roche, Medimmune, Argenx, UCB, Mitsubishi, Amplo, Janssen. Grants from Alexion, Amplo biotechnology. Shares in AstraZenica. Acknowledges Partial funding by Highly specialised services NHS England. MIL reported being involved in aquaporin 4 testing, receiving salary from the National Health Service National Highly Specialised Commissioning Group for Neuromyelitis Optica, UK, being supported by the National Institute for Health Research Oxford Biomedical Research Centre, UK, and receiving speaking honoraria and travel grants from Biogen Idec, and travel grant from Novartis. SMS has nothing to disclose. AR-F is sponsored by Abide Therapeutic outside of the submitted work and reports no potential conflicts of interest. SSiritho received funding for travel and speaker honoraria from Merck Serono, Pacific Healthcare (Thailand), Menarini (Thailand), Biogen Idec, UCB (Thailand), and Novartis. AA reports personal fees from received honoraria for giving educational presentations on multiple sclerosis and neuroimmunology at several national congresses or symposia from Teva Turkey, Merck-Serono, Biogen Idec-Gen Pharma of Turkey, Roche, Novartis, Bayer, Sanofi-Genzyme. She has received travel and registration coverage for attending several national and international congresses or symposia from Merck-Serono, Biogen Idec-Gen Pharma of Turkey, Roche, Sanofi-Genzyme and Bayer. AJ has received compensation for advisory board, consulting, meeting attendance and speaking from Biogen, Terumo-BCT, Genentech, Shire and Chugai Pharmaceuticals. SH has received funding from the NMO Spectrum-UK charity and was previously funded by an MGA/Watney/NIHR Oxford Biomedical research grant. RM serves on scientific advisory board for MedImmune and has received funding for travel and honoraria from Biogen, Merck Serono, Novartis, Sanofi- Genzyme, Roche and Teva. EN has nothing to disclose. ACC received funding from the Instituto de Salud Carlos III (Spain) JR19/00007 unrelated to this manuscript. DB has received speaking/consulting honoraria from Bayer Health Care, Biogen Idec, Merck, Sanofi-Genzyme, TEVA and Roche and had travel expenses to scientific meetings sponsored by Bayer Health Care, Merck Serono, TEVA and Roche. JH reports grants for OCT research from the Friedrich-Baur-Stiftung and Merck, personal fees and non-financial support from Celgene, Merck, Alexion, Novartis, Roche, Santhera, Biogen, Heidelberg Engineering, Sanofi Genzyme and non-financial support of the Guthy-Jackson Charitable Foundation, all outside the submitted work. JH is partially funded by the German Federal Ministry of Education and Research (DIFUTURE), Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H]. LL received honoraria for consulting services from Merck, Roche, Biogen and for speaking activities from Teva; research support from Merck, Biogen, Novartis; travel support from Merck, Roche, Biogen, Almirall. MP has nothing to disclose. OA has received honoraria for speaking/consultation and travel grants from Bayer Healthcare, Biogen Idec, Chugai, Novartis, Medimmune, Merck Serono, and Teva and research grants from Bayer Healthcare, Biogen Idec, Novartis, and Teva. MR received speaker honoraria from Novartis, Bayer, Roche, Alexion and Ipsen and travel reimbursement from Bayer, Biogen, Merz, Genzyme, Teva, Roche and Merck, none related to this study. PA reports grants, personal fees and non-financial support from Allergan, Biogen, Ipsen, Merz Pharmaceuticals, Novartis, and Roche, personal fees and non-financial support from Bayer Healthcare, and Merck, and non-financial support from Sanofi-Aventis/Genzyme. HJK reports speaking and/or consulting: Bayer Schering Pharma, Biogen, Celltrion, Eisai, HanAll BioPharma, MedImmune, Merck Serono, Novartis, Sanofi Genzyme, Teva-Handok, and UCB; research support: Ministry of Science & ICT, Sanofi Genzyme, Teva-Handok, and UCB; steering committee member: MedImmune; co-editor/associated editor: MS Journal-Experimental, Translational and Clinical; and Journal of Clinical Neurology. J-WH has received a grant from the National Research Foundation of Korea. YM-D has served as a consultant and/or received grant support from: Acorda, Bayer Pharmaceutical, Biogen Idec, Celgene, EMD Serono, Genzyme, Novartis, Questor, Chugai, and Teva Neuroscience and is currently supported by grants from NIH NIAID Autoimmune Center of Excellence: UM1-AI110557; NIH NINDS R01-NS080821. HSK has nothing to disclose. IK served on scientific advisory board for Biogen Idec and Genentech and received research support from Guthy-Jackson Charitable Foundation, National Multiple Sclerosis Society, Biogen-Idec,Serono, Genzyme and Novartis. ZR has nothing to disclose. AR has nothing to disclose. MRY is founder and a shareholder of NovaDigm Therapeutics, Inc; he receives funding from the United States National Institutes of Health and United States Department of Defense; he holds US and international patents on immunotherapeutic and anti-infective technologies, is a member of the Genentech-Roche Scientific Advisory Committee and adviser to The Guthy-Jackson Charitable Foundation. TJS was issued US patents covering the therapeutic targeting of IGF-I receptor in autoimmune diseases. He is a paid consultant for Horizon Thera and Immunovant and is a scientific advisor to the Guthy-Jackson Charitable Foundation. He receives research funding from the National Institutes of Health. AP is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital National Health Service (NHS) Foundation Trust and University College London Institute of Ophthalmology. AB is cofounder and shareholder of Motognosis and Nocturne. He is named as inventor on several patent applications regarding MS serum biomarkers, OCT image analysis and perceptive visual computing. FP reports research grants and speaker honoraria from Bayer, Teva, Genzyme, Merck, Novartis, MedImmune and is member of the steering committee of the OCTIMS study (Novartis), all unrelated to this work. FCO was employee of Nocturne GmbH and receives research support by the American Academy of Neurology and National Multiple Sclerosis Society (US), unrelated to this work as well as funding by the German Association of Neurology (Deutsche Gesellschaft für Neurologie) in context of this project.CC has received a speaking honorarium from Bayer and research funding from Novartis unrelated to this publication. All other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The N-MOmentum trial, a double-blind, randomized, placebo-controlled, phase 2/3 study of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD), enrolled participants who were aquaporin-4-immunoglobulin G (AQP4-IgG)-seropositive (AQP4+) or -seronegative (AQP4-). This article reports AQP4- participant outcomes., Methods: AQP4-IgG serostatus was determined for all screened participants by a central laboratory, using a validated, fluorescence-observation cell-binding assay. Medical histories and screening data for AQP4- participants were assessed independently by an eligibility committee of three clinical experts during screening. Diagnosis of NMOSD was confirmed by majority decision using the 2006 neuromyelitis optica criteria. Myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) serology (using a clinically validated, flow cytometry assay) and annualized attack rates (AARs) were evaluated post hoc. Efficacy outcomes were assessed by comparing pre-study and on-study AARs in treated participants., Results: Only 18/50 AQP4- screened participants (36%) were initially considered eligible for randomization; 16 were randomized and received full treatment, 4 to placebo (1 MOG-IgG-seropositive [MOG+]) and 12 to inebilizumab (6 MOG+). The most common reason for failure to pass screening among prospective AQP4- participants was failure to fulfill the 2006 NMO MRI criteria. In inebilizumab-treated AQP4- participants, on-study AARs (95% confidence interval [CI]) calculated from treatment initiation (whether from randomization or when received at the start of the open-label period) to the end of study were lower than pre-study rates: for all AQP4- participants (n = 16), mean (95% CI) AAR was 0.048 (0.02-0.15) versus 1.70 (0.74-2.66), respectively. For the subset of AQP4-/MOG+ participants (n = 7), AAR was 0.043 (0.006-0.302) after treatment versus 1.93 (1.10-3.14) before the study. For the subset of AQP4-/MOG- participants (n = 9), post-treatment AAR was 0.051 (0.013-0.204) versus 1.60 (1.02-2.38). Three attacks occurred during the randomized controlled period in the AQP4- inebilizumab group and were of mild severity; no attacks occurred in the AQP4- placebo group. The low number of participants receiving placebo (n = 4) confounds direct comparison with the inebilizumab group. No attacks were seen in any AQP4- participant after the second infusion of inebilizumab. Inebilizumab was generally well tolerated by AQP4- participants and the adverse event profile observed was similar to that of AQP4+ participants., Conclusion: The high rate of rejection of AQP4- participants from enrollment into the study highlights the challenges of implementing the diagnostic criteria of AQP4- NMOSD. An apparent reduction of AAR in participants with AQP4- NMOSD who received inebilizumab warrants further investigation., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To evaluate changes over 3 years in the thickness of inner retinal layers including the peripapillary retinal nerve fiber layer (pRNFL), and combined macular ganglion cell and inner plexiform layers (mGCIPL), in individuals with relapsing-remitting multiple sclerosis (RRMS) versus healthy controls; to determine whether optical coherence tomography (OCT) is sufficiently sensitive and reproducible to detect small degrees of neuroaxonal loss over time that correlate with changes in brain volume and disability progression as measured by the Expanded Disability Status Scale (EDSS)., Methods: Individuals with RRMS from 28 centers (n = 333) were matched with 64 healthy participants. OCT scans were performed on Heidelberg Spectralis machines (at baseline; 1 month; 6 months; 6-monthly thereafter)., Results: OCT measurements were highly reproducible between baseline and 1 month (intraclass correlation coefficient >0.98). Significant inner retinal layer thinning was observed in individuals with multiple sclerosis (MS) compared with controls regardless of previous MS-associated optic neuritis--group differences (95% CI) over 3 years: pRNFL: -1.86 (-2.54, -1.17) µm; mGCIPL: -2.03 (-2.78, -1.28) µm (both p < 0.0001; effect sizes 0.39 and 0.34). Greater inner retinal layer atrophy was observed in individuals diagnosed with RRMS <3 years versus >5 years (pRNFL: p < 0.05; mGCIPL: p < 0.01). Brain volume decreased by 1.3% in individuals with MS over 3 years compared to 0.5% in control subjects (effect size 0.76). mGCIPL atrophy correlated with brain atrophy (p < 0.0001). There was no correlation of OCT data with disability progression., Interpretation: OCT has potential to estimate rates of neurodegeneration in the retina and brain. The effect size for OCT, smaller than for magnetic resonance imaging based on Heidelberg Spectralis data acquired in this study, was increased in early disease., (© 2021 Novartis Pharma AG. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

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.)

Background: In the N-MOmentum trial, the risk of an adjudicated neuromyelitis optica spectrum disorder (NMOSD) attack was significantly reduced with inebilizumab compared with placebo., Objective: To demonstrate the robustness of this finding, using pre-specified sensitivity and subgroup analyses., Methods: N-MOmentum is a prospective, randomized, placebo-controlled, double-masked trial of inebilizumab, an anti-CD19 monoclonal B-cell-depleting antibody, in patients with NMOSD. Pre-planned and post hoc analyses were performed to evaluate the primary endpoint across a range of attack definitions and demographic groups, as well as key secondary endpoints., Results: In the N-MOmentum trial (ClinicalTrials.gov: NCT02200770), 174 participants received inebilizumab and 56 received placebo. Attack risk for inebilizumab versus placebo was consistently and significantly reduced, regardless of attack definition, type of attack, baseline disability, ethnicity, treatment history, or disease course (all with hazard ratios < 0.4 favoring inebilizumab, p < 0.05). Analyses of secondary endpoints showed similar trends., Conclusion: N-MOmentum demonstrated that inebilizumab provides a robust reduction in the risk of NMOSD attacks regardless of attack evaluation method, attack type, patient demographics, or previous therapy.The N-MOmentum study is registered at ClinicalTrials.gov: NCT2200770.