RENEWED: A follow-up study of the opicinumab phase 2 RENEW study in participants with acute optic neuritis.

Background: The randomized, phase 2 RENEW trial (NCT01721161) evaluated efficacy/safety of opicinumab (anti-LINGO-1) versus placebo in patients with first-episode unilateral acute optic neuritis (AON). Although no significant differences in the latency recovery of visual evoked potential (VEP) were observed between opicinumab and placebo groups in the intention to treat (ITT) population, the prespecified per-protocol (PP) population showed better recovery with opicinumab than with placebo. RENEWED (NCT02657915) was a one-visit, follow-up study 2 years after the last RENEW study visit (Week 32) designed to assess the long-term electrophysiological and clinical outcomes for participants previously enrolled and having received study treatment in RENEW.

Examining the relative contribution of slow-burning inflammation and chronic demyelination to axonal damage in chronic multiple sclerosis lesions.

Background And Objectives: Slow-burning inflammation at the edge, and chronic demyelination at the core, of established multiple sclerosis (MS) lesions are potential mediators of disease progression. However, their relative contribution to progressive axonal damage has not been explored. Therefore, in this study, we investigated the comparative contribution of slow-burning inflammation and chronic demyelination to axonal attrition within MS lesions by measuring progressive tissue rarefaction.

Quantifying chronic lesion expansion in multiple sclerosis: Exploring imaging markers for longitudinal assessment.

Objectives: Gradual expansion of multiple sclerosis lesions over time is known to have a significant impact on disease progression. However, accurately quantifying the volume changes in chronic lesions presents challenges due to their slow rate of progression and the need for longitudinal segmentation. Our study addresses this by estimating the expansion of chronic lesions using data collected over a 1-2 year period and exploring imaging markers that do not require longitudinal lesion segmentation.

Longitudinal enlargement of choroid plexus is associated with chronic lesion expansion and neurodegeneration in RRMS patients.

Background And Objective: We explored dynamic changes in the choroid plexus (CP) in patients with relapsing-remitting multiple sclerosis (RRMS) and assessed its relationship with chronic lesion expansion and atrophy in various brain compartments.

Methods: Fifty-seven RRMS patients were annually assessed for a minimum of 48 months with 3D FLAIR, pre- and post-contrast 3D T1 and diffusion-weighted magnetic resonance imaging (MRI). The CP was manually segmented at baseline and last follow-up.

A real-world clinical validation for AI-based MRI monitoring in multiple sclerosis.

Modern management of MS targets No Evidence of Disease Activity (NEDA): no clinical relapses, no magnetic resonance imaging (MRI) disease activity and no disability worsening. While MRI is the principal tool available to neurologists for monitoring clinically silent MS disease activity and, where appropriate, escalating treatment, standard radiology reports are qualitative and may be insensitive to the development of new or enlarging lesions. Existing quantitative neuroimaging tools lack adequate clinical validation.

Anti-inflammatory Effects of Siponimod in a Mouse Model of Excitotoxicity-Induced Retinal Injury.

Glaucoma is a leading cause of permanent blindness worldwide and is characterized by neurodegeneration linked to progressive retinal ganglion cell (RGC) death, axonal damage, and neuroinflammation. Glutamate excitotoxicity mediated through N-methyl-D-aspartate (NMDA) receptors plays a crucial role in glaucomatous RGC loss. Sphingosine 1-phosphate receptors (S1PRs) are important mediators of neurodegeneration and neuroinflammation in the brain and the retina.

Evaluating associations of RNFL thickness and multifocal VEP with cognitive assessment and brain MRI volumes in older adults: Optic nerve decline and cognitive change (ONDCC) initiative.

To examine the relationships of retinal structural (optical coherence tomography) and visual functional (multifocal visual evoked potentials, mfVEP) indices with neuropsychological and brain structural measurements in healthy older subjects. 95 participants (mean (SD) age 68.1 (9.

Choroid plexus volume is enlarged in clinically isolated syndrome patients with optic neuritis.

Objectives: We investigated choroid plexus (CP) volume in patients presenting with optic neuritis (ON) as a clinically isolated syndrome (CIS), compared to a cohort with established relapsing-remitting multiple sclerosis (RRMS) and healthy controls (HCs).

Methods: Three-dimensional (3D) T1, T2-FLAIR and diffusion-weighted sequences were acquired from 44 ON CIS patients at baseline, 1, 3, 6 and 12 months after the onset of ON. Fifty RRMS patients and 50 HCs were also included for comparison.

S1PR1 signaling attenuates apoptosis of retinal ganglion cells via modulation of cJun/Bim cascade and Bad phosphorylation in a mouse model of glaucoma.

Glaucoma is a complex neurodegenerative disease characterized by optic nerve damage and apoptotic retinal ganglion cell (RGC) death, and is the leading cause of irreversible blindness worldwide. Among the sphingosine 1-phosphate receptors (S1PRs) family, S1PR1 is a highly expressed subtype in the central nervous system and has gained rapid attention as an important mediator of pathophysiological processes in the brain and the retina. Our recent study showed that mice treated orally with siponimod drug exerted neuroprotection via modulation of neuronal S1PR1 in experimental glaucoma.

Siponimod exerts neuroprotective effects on the retina and higher visual pathway through neuronal S1PR1 in experimental glaucoma.

Sphingosine-1-phosphate receptor (S1PR) signaling regulates diverse pathophysiological processes in the central nervous system. The role of S1PR signaling in neurodegenerative conditions is still largely unidentified. Siponimod is a specific modulator of S1P1 and S1P5 receptors, an immunosuppressant drug for managing secondary progressive multiple sclerosis.

Early predictors of visual and axonal outcomes after acute optic neuritis.

Background: Predicting long-term visual outcomes and axonal loss following acute optic neuritis (ON) is critical for choosing treatment. Predictive models including all clinical and paraclinical measures of optic nerve dysfunction following ON are lacking.

Objectives: Using a prospective study method, to identify 1 and 3 months predictors of 6 and 12 months visual outcome (low contrast letter acuity 2.

Choroid plexus volume in multiple sclerosis predicts expansion of chronic lesions and brain atrophy.

Objectives: Recent studies suggested that the expansion of long-standing multiple sclerosis (MS) lesions and an enlargement of choroid plexus may be linked to chronic inflammation and microglial activation. We investigated the potential association between plexus volume and subsequent lesion expansion in patients with relapsing-remitting MS.

Methods: Pre- and post-gadolinium 3D-T1, 3D FLAIR and diffusion tensor images were acquired from 49 patients.

Fingolimod effects on the brain are mediated through biochemical modulation of bioenergetics, autophagy, and neuroinflammatory networks.

Fingolimod (FTY720) is an oral drug approved by the Food and Drug Administration (FDA) for management of multiple sclerosis (MS) symptoms, which has also shown beneficial effects against Alzheimer's (AD) and Parkinson's (PD) diseases pathologies. Although an extensive effort has been made to identify mechanisms underpinning its therapeutic effects, much remains unknown. Here, we investigated Fingolimod induced proteome changes in the cerebellum (CB) and frontal cortex (FC) regions of the brain which are known to be severely affected in MS, using a tandem mass tag (TMT) isobaric labeling-based quantitative mass-spectrometric approach to investigate the mechanism of action of Fingolimod.

Mechanisms of central brain atrophy in multiple sclerosis.

Background: Change in ventricular volume has been suggested as surrogate measure of central brain atrophy (CBA) applicable to the everyday management of multiple sclerosis (MS) patients.

Objectives: We investigated the contribution of inflammatory activity (including the severity of lesional tissue damage) to CBA.

Methods: Fifty patients with relapsing-remitting multiple sclerosis (RRMS) were enrolled.

The expansion and severity of chronic MS lesions follows a periventricular gradient.

Background And Objectives: Expansion of chronic lesions in multiple sclerosis (MS) patients and recently described cerebrospinal fluid (CSF)-related gradient of tissue damage are linked to microglial activation. The aim of this study was to investigate whether lesion expansion is associated with proximity to ventricular CSF spaces.

Methods: Pre- and post-gadolinium three-dimensional (3D)-T1, 3D FLAIR and diffusion tensor images were acquired from 36 relapsing-remitting MS (RRMS) patients.

Analysis of Multifocal Visual Evoked Potentials Using Artificial Intelligence Algorithms.

Purpose: Clinical trials for remyelination in multiple sclerosis (MS) require an imaging biomarker. The multifocal visual evoked potential (mfVEP) is an accurate technique for measuring axonal conduction; however, it produces large datasets requiring lengthy analysis by human experts to detect measurable responses versus noisy traces. This study aimed to develop a machine-learning approach for the identification of true responses versus noisy traces and the detection of latency peaks in measurable signals.

Impaired motion perception is associated with functional and structural visual pathway damage in multiple sclerosis and neuromyelitis optica spectrum disorders.

Background: Decreased motion perception has been suggested as a marker for visual pathway demyelination in optic neuritis (ON) and/or multiple sclerosis (MS).

Objectives: To examine the influence of neuro-axonal damage on motion perception in MS and neuromyelitis optica spectrum disorders (NMOSD).

Methods: We analysed motion perception with numbers-from-motion (NFM), visual acuity, (multifocal (mf)) VEP, optical coherence tomography in patients with MS ( = 38, confirmatory cohort = 43), NMOSD ( = 13) and healthy controls ( = 33).

Expansion of chronic MS lesions is associated with an increase of radial diffusivity in periplaque white matter.

Background: Expansion of chronic multiple sclerosis (MS) lesion is associated with slow-burning inflammation at lesion rim. However, the underlying mechanisms leading to expansion are not fully understood.

Objective: To investigate the relationship between diffusivity markers of demyelination and axonal loss in perilesional white matter and lesion expansion in relapsing-remitting MS (RRMS).

Multiple sclerosis: structural and functional integrity of the visual system following alemtuzumab therapy.

Objective: To investigate potential neuroprotective and pro-remyelinating effects of alemtuzumab in multiple sclerosis (MS), using the visual pathway as a model.

Methods: We monitored clinical, multifocal visual evoked potential (mfVEP) and MRI outcomes in 30 patients commencing alemtuzumab for relapsing MS, and a reference group of 20 healthy controls (HCs), over 24 months. Change in mfVEP latency was the primary endpoint; change in optic radiation (OR) lesion diffusion metrics and Mars letter contrast sensitivity over the course of the study were secondary endpoints.

APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies.

Objective: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations.

Methods: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method.

Interferon-β Is Less Effective Than Other Drugs in Controlling the Rate of Retinal Ganglion Cell Loss in MS.

Objective: To investigate the association between disease-modifying therapies (DMTs) and the rate of progressive retinal ganglion cell (RGC) and nerve fiber loss in MS.

Methods: One hundred five relapsing-remitting patients with MS were followed annually for a median of 4.0 years using optical coherence tomography.

Differentiating axonal loss and demyelination in chronic MS lesions: A novel approach using single streamline diffusivity analysis.

We describe a new single-streamline based approach to analyse diffusivity within chronic MS lesions. We used the proposed method to examine diffusivity profiles in 30 patients with relapsing multiple sclerosis and observed a significant increase of both RD and AD within the lesion core (0.38+/-0.

Latency of Multifocal Visual Evoked Potential in Multiple Sclerosis: A Visual Pathway Biomarker for Clinical Trials of Remyelinating Therapies.

Purpose: Acute focal demyelination is the characteristic feature of multiple sclerosis, with the majority of damaged axons undergoing limited remyelination and forming chronic lesions. Potential remyelinating agents are currently under development and there is therefore an urgent need for reliable in vivo biomarkers of remyelination. This study aimed to investigate potential changes in multifocal visual evoked potentials' (mfVEPs) latency in a cohort of relapsing-remitting multiple sclerosis (RRMS) patients.

Expansion of chronic lesions is linked to disease progression in relapsing-remitting multiple sclerosis patients.

Background: Slow-burning inflammation is putatively associated with lesion expansion and leads to progressive loss of axons and disability worsening.

Objective: To investigate the incidence and extent of chronic white matter lesion expansion in relapsing-remitting multiple sclerosis (RRMS) patients and to evaluate its relationship with biomarkers of disease progression.

Methods: Pre- and post-gadolinium T1, fluid-attenuated inversion recovery (FLAIR) and diffusion tensor images were acquired from 33 patients.