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Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER, "Otra manera de hacer Europa", "Investing in your future"); Red Española de Esclerosis Múltiple (REEM - RD16/0015/0002, RD16/0015/0003, RD12/0032/0002, RD12/0060/01-02); TEVA Spain; Fundación Merck Salud (Ayudas Merck de Investigación 2017); Proyecto Societat Catalana Neurologia 2017; CIBERNED program (Program 1, Alzheimer Disease and SIGNAL study); National Institutes of Health (NIA grants 1R01AG056850-01A1, R21AG056974, R01AG061566;, Fundació La Marató de TV3 (20142030, 20141210); Fundació Catalana Síndrome de Down; Fundació Víctor Grífols i Lucas; Generalitat de Catalunya (SLT006/17/00119); Universitat de Barcelona (APIF Pre-doctoral grant); Hospital Clinic Emili Letang). The spatio-temporal characteristics of grey matter (GM) impairment in multiple sclerosis (MS) are poorly understood. We used a new surface-based diffusion MRI processing tool to investigate regional modifications of microstructure, and we quantified volume loss in GM in a cohort of patients with MS classified into three groups according to disease duration. Additionally, we investigated the relationship between GM changes with disease severity. We studied 54 healthy controls and 247 MS patients classified regarding disease duration: MS1 (less than 5 years, n = 67); MS2 (5-15 years, n = 107); and MS3 (more than15 years, n = 73). We compared GM mean diffusivity (MD), fractional anisotropy (FA) and volume between groups, and estimated their clinical associations. Regional modifications in diffusion measures (MD and FA) and volume did not overlap early in the disease, and became widespread in later phases. We found higher MD in MS1 group, mainly in the temporal cortex, and volume reduction in deep GM and left precuneus. Additional MD changes were evident in cingulate and occipital cortices in the MS2 group, coupled to volume reductions in deep GM and parietal and frontal poles. Changes in MD and volume extended to more than 80% of regions in MS3 group. Conversely, increments in FA, with very low effect size, were observed in the parietal cortex and thalamus in MS1 and MS2 groups, and extended to the frontal lobe in the later group. MD and GM changes were associated with white matter lesion load and with physical and cognitive disability. Microstructural integrity loss and atrophy present differential spatial predominance early in MS and accrual over time, probably due to distinct pathogenic mechanisms that underlie tissue damage.

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.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.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.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.

Background: Serum neurofilament light (sNfL) chain is a promising biomarker reflecting neuro-axonal injury in multiple sclerosis (MS). However, the ability of sNfL to predict outcomes in real-world MS cohorts requires further validation. Objective: The aim of the study is to investigate the associations of sNfL concentration, magnetic resonance imaging (MRI) and retinal optical coherence tomography (OCT) markers with disease worsening in a longitudinal European multicentre MS cohort. Methods: MS patients ( n = 309) were prospectively enrolled at four centres and re-examined after 2 years ( n = 226). NfL concentration was measured by single molecule array assay in serum. The patients’ phenotypes were thoroughly characterized with clinical examination, retinal OCT and MRI brain scans. The primary outcome was disease worsening at median 2-year follow-up. Results: Patients with high sNfL concentrations (⩾8 pg/mL) at baseline had increased risk of disease worsening at median 2-year follow-up (odds ratio (95% confidence interval) = 2.8 (1.5–5.3), p = 0.001). We found no significant associations of MRI or OCT measures at baseline with risk of disease worsening. Conclusion: Serum NfL concentration was the only factor associated with disease worsening, indicating that sNfL is a useful biomarker in MS that might be relevant in a clinical setting.

Background:Prognostic markers are needed to guide multiple sclerosis (MS) management in the context of large availability of disease-modifying drugs (DMDs).Objective:To investigate the role of cerebrospinal fluid (CSF) markers to inform long-term MS outcomes.Methods:Demographic features, IgM index, oligoclonal IgM bands (OCMB), lipid-specific OCMB, CSF neurofilament light chain protein levels, expanded disability status scale (EDSS), relapses and DMD use over the study period and peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell plus inner plexiform layer (GCIPL) thicknesses in non-optic neuritis eyes (end of follow-up) were collected from relapsing MS (RMS) patients with CSF obtained ⩽2 years after MS onset prospectively followed at the Hospital Clinic of Barcelona. We assessed associations between CSF markers and MS outcomes using multivariable models.Results:A total of 89 patients (71 females; median 32.9 years of age) followed over a median of 9.6 years were included. OCMB were associated with a 33% increase in the annualized relapse rate (ARR; p = 0.06), higher odds for high-efficacy DMDs use (OR = 4.8; 95% CI = (1.5, 16.1)), thinner pRNFL (β = −4.4; 95% CI = (−8.6, −0.2)) and GCIPL (β = −2.9; 95% CI = (−5.9, +0.05)), and higher rates to EDSS ⩾ 3.0 (HR = 4.4; 95% CI = (1.6, 11.8)) and EDSS ⩾ 4.0 (HR = 5.4; 95% CI = (1.1, 27.1)). No overall associations were found for other CSF markers.Conclusion:The presence of OCMB was associated with unfavorable long-term outcomes. OCMB should be determined in RMS to inform long-term prognosis.

Viruses are the most abundant components of the microbiome in human beings with a significant impact on health and disease. However, the impact of human immunodeficiency virus (HIV) infection on gut virome has been scarcely analyzed. On the other hand, several studies suggested that not all antiretrovirals for treating HIV infection exert similar effects on the gut bacteriome, being the integrase strand transfers inhibitors (INSTIs) —first-choice treatment of naive HIV-infected patients nowadays— those associated with a healthier gut. Thus, the aim of this study was to evaluate the effects of HIV infection and INSTIs in first line of treatment on gut virome composition. To accomplish this objective, 26 non-HIV-infected volunteers, 15 naive HIV-infected patients and 15 INSTIs-treated HIV-infected patients were recruited and gut virome composition was analysed using shotgun sequencing. The results showed that bacteriophages are the most abundant and diverse viruses in the gut independent from the HIV-status and the use of treatment. HIV infection was accompanied by a decrease in phage richness which was reverted after INSTIs-based treatment (pvs. control Richness index and pvs. control Fisher’s alpha index). β-diversity of phages revealed that samples from HIV-infected samples clustered separately from those belonging to the control group (padjvs. control and padjvs. control). However, it is worth mentioning that samples coming from INSTIs-treated patients were more grouped than those from naive patients. Differential abundant analysis of phages showed an increase of Caudoviricetes class in the naive group compared to control the group (padjMalgrandaviricetes class in the INSTIs-treated group compared to the control group (padjvs. control) or to modify the decrease observed on the relative abundance of Proteobacteria-infecting phages (pvs. control). To sum up, our study describes for the first time the impact of HIV and INSTIs on gut virome and demonstrates that INSTIs-based treatments are able to partially restore gut dysbiosis not only at bacterial but also at viral level, which opens several opportunities for new studies focused on microbiota-based therapies.Author summaryThe impact of human immunodeficiency virus (HIV) infection and the effects of integrase strand transfer inhibitors (INSTIs)-based treatments —first-choice treatment of naive HIV-infected patients nowadays— on gut virome are unknown. In this study, we have confirmed that phages are the most abundant viral component of the human gut virome. Besides, we have described for the first time that INSTIs-based treatments are able to partially restore gut dysbiosis induced by HIV infection not only at bacteria but also at viral level. This fact opens new opportunities for future studies and approaches focused on microbiota-based therapies in the context of HIV infection and treatment.

Immunotherapies for multiple sclerosis (MS) significantly decrease the risk of new relapses. However, the chronic compartmentalized inflammation and neurodegeneration that define progressive MS are not prevented by these therapies and so significant damage to the brain and spinal cord and resulting disability ensues. Hence, the possibility of combining current immunotherapies with neuroprotective, remyelinating or regenerative therapies should be pursued.This article sheds light on neuroprotective, remyelination and neurorepair strategies for MS, the numerous mechanisms for therapeutic targeting and the new candidates for combination therapies. We searched PubMed for articles with the terms, 'neuroprotection', remyelination' or 'regeneration' and 'therapies' or 'drugs' and 'Multiple Sclerosis'.An enriched understanding of the neurobiology and molecular changes that are activated by inflammatory CNS damage will provide new opportunities for the identification of neuroprotective, remyelinating and regenerative therapies. Success will depend on the improvement of CNS drug delivery, the identification of new predictive biomarkers, the optimization of clinical trials by assessment of the damage to the visual pathway and the testing of novel therapies in acute optic neuritis.

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.

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.

Significance Multiple sclerosis is an autoimmune disease shaped by genetic and environmental factors. Because of the heterogeneity of the human population, it has been difficult to identify “immune signatures” of the disease. Here we investigated a cohort of identical twin pairs who are discordant for multiple sclerosis. In each twin pair, the immune signatures were remarkably similar, pointing to a strong influence of shared genetic and environmental factors. However, when we focused on a subgroup of seemingly healthy cotwins who showed subtle signs of “subclinical neuro-inflammation,” we identified a distinct signature of memory T cells. Insight into the immunological mechanisms associated with the initiation of the disease is relevant not only to the therapy but also for prevention of the disease., The tremendous heterogeneity of the human population presents a major obstacle in understanding how autoimmune diseases like multiple sclerosis (MS) contribute to variations in human peripheral immune signatures. To minimize heterogeneity, we made use of a unique cohort of 43 monozygotic twin pairs clinically discordant for MS and searched for disease-related peripheral immune signatures in a systems biology approach covering a broad range of adaptive and innate immune populations on the protein level. Despite disease discordance, the immune signatures of MS-affected and unaffected cotwins were remarkably similar. Twinship alone contributed 56% of the immune variation, whereas MS explained 1 to 2% of the immune variance. Notably, distinct traits in CD4+ effector T cell subsets emerged when we focused on a subgroup of twins with signs of subclinical, prodromal MS in the clinically healthy cotwin. Some of these early-disease immune traits were confirmed in a second independent cohort of untreated early relapsing-remitting MS patients. Early involvement of effector T cell subsets thus points to a key role of T cells in MS disease initiation.

Objective To determine the optimal thresholds for intereye differences in retinal nerve fiber and ganglion cell + inner plexiform layer thicknesses for identifying unilateral optic nerve lesions in multiple sclerosis. Current international diagnostic criteria for multiple sclerosis do not include the optic nerve as a lesion site despite frequent involvement. Optical coherence tomography detects retinal thinning associated with optic nerve lesions. Methods In this multicenter international study at 11 sites, optical coherence tomography was measured for patients and healthy controls as part of the International Multiple Sclerosis Visual System Consortium. High- and low-contrast acuity were also collected in a subset of participants. Presence of an optic nerve lesion for this study was defined as history of acute unilateral optic neuritis. Results Among patients (n = 1,530), receiver operating characteristic curve analysis demonstrated an optimal peripapillary retinal nerve fiber layer intereye difference threshold of 5μm and ganglion cell + inner plexiform layer threshold of 4μm for identifying unilateral optic neuritis (n = 477). Greater intereye differences in acuities were associated with greater intereye retinal layer thickness differences (p ≤ 0.001). Interpretation Intereye differences of 5μm for retinal nerve fiber layer and 4μm for macular ganglion cell + inner plexiform layer are robust thresholds for identifying unilateral optic nerve lesions. These thresholds may be useful in establishing the presence of asymptomatic and symptomatic optic nerve lesions in multiple sclerosis and could be useful in a new version of the diagnostic criteria. Our findings lend further validation for utilizing the visual system in a multiple sclerosis clinical trial setting. Ann Neurol 2019;85:618-629.

The pathophysiological mechanisms for classical plaque characteristics and their predictive value for clinical course and outcome in multiple sclerosis is unclear. Connectivity-based approaches incorporating the distribution and magnitude of the extended brain network aberrations caused by lesions may offer higher sensitivity for axonal damage. Using individual brain disconnectome mapping, we tested the longitudinal associations between putative brain network aberrations and levels of serum neurofilament light chain (sNfL) as a neuroaxonal injury biomarker.Multiple sclerosis patients (n= 328, mean age 42.9 years, 71 % female) were prospectively enrolled at four European multiple sclerosis centres, and reassessed after two years (n = 280). Post-processing of 3 Tesla (3T) MRI data was performed at one centre using a harmonized pipeline, and disconnectome maps were calculated using BCBtoolkit based on individual lesion maps. Global disconnectivity (GD) was defined as the average disconnectome probability in each patient’s white matter. Serum NfL concentrations were measured by single molecule array (Simoa). Robust linear mixed models (rLMM) with GD or T2-lesion volume (T2LV) as dependent variables, patient and centre as a random factor, sNfL, age, sex, timepoint for visit, diagnosis, and treatment as fixed factors were run.Robust LMM revealed significant associations between higher levels of GD and increased sNfL (t= 2.30,β= 0.03,p= 0.02), age (t= 5.01,β= 0.32,p< 5.5 × 10−7), and diagnosis progressive multiple sclerosis (PMS);t= 1.97,β= 1.06,p= 0.05), but not for sex (t= 0.78,p= 0.43), treatments (effective;t= 0.85,p= 0.39, highly-effective;t= 0.86,p= 0.39) or sNfL change between base line and two-year follow up (t= −1.65,p= 0.10). Voxel-wise analyses revealed distributed associations in cerebellar and brainstem regions.In our prospective multi-site multiple sclerosis cohort, rLMMs demonstrated that the extent of global brain disconnectivity is sensitive to a systemic biomarker of axonal damage, sNfL, in patients with multiple sclerosis. These findings provide a neuropathological correlate of advanced disconnectome mapping and provide a platform for further investigations of the functional and clinical relevance in patients with brain disorders.

The spatio-temporal characteristics of grey matter (GM) impairment in multiple sclerosis (MS) are poorly understood. We used a surface-based diffusion MRI processing tool to investigate regional modifications of microstructure and volume loss in GM at different time-points of the disease, and their relationship to disability. We studied 54 healthy controls and 247 MS patients classified according to disease duration: MS1 (less than 5 years, n=67); MS2 (5-15 years, n=107); and MS3 (more than15 years, n=73). We compared GM mean diffusivity (MD) and volume between groups, and estimated their clinical correlations. Regional modifications in MD and volume did not overlap early in the disease, and became widespread in later phases. We found higher MD in MS1 group, mainly in the temporal cortex, and volume reduction in right putamen. Additional MD changes were evident in cingulate and occipital cortices in the MS2 group, coupled to volume reductions in deep GM and parietal and frontal poles. Changes extended to more than 80% of regions in MS3 group. Clinical disability was correlated with GM changes. Microstructural integrity loss and atrophy present differential spatial predominance early in MS and accrual over time, probably due to distinct pathogenic mechanisms that underlie tissue damage.

Coronavirus disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to scale and threaten human health and public safety. It is essential to identify those risk factors that lead to a poor prognosis of the disease. A predisposing host genetic background could be one of these factors that explain the interindividual variability to COVID-19 severity. Thus, we have studied whether the rs4341 and rs4343 polymorphisms of the angiotensin converting enzyme (ACE) gene, key regulator of the renin-aldosterone-angiotensin system (RAAS), could explain the different outcomes of 128 COVID-19 patients with diverse degree of severity (33 asymptomatic or mildly asymptomatic, 66 hospitalized in the general ward, and 29 admitted to the ICU). We found that G allele of rs4341 and rs4343 was associated with severe COVID-19 in hypertensive patients, independently of gender (pp< 0.05) and higher severity of COVID-19 in dyslipidemic (pp< 0.01).In conclusion, our preliminary study suggests that the G-containing genotypes of rs4341 and rs4343 confer an additional risk of adverse COVID-19 prognosis. Thus, rs4341 and rs4343 polymorphisms of ACE could be predictive markers of severity of COVID-19 in those patients with hypertension, dyslipidemia or diabetes. The knowledge of these genetic data could contribute to precision management of SARS-CoV-2 infected patients when admitted to hospital.

OBJECTIVE: To evaluate whether a retinal spectral-domain optical coherence tomography (SD-OCT) assessment at baseline is associated with long-term disability worsening in people with multiple sclerosis (PwMS), we performed SD-OCT and Expanded Disability Status Scale (EDSS) assessments among 132 PwMS at baseline and at a median of 10 years later. METHODS: In this prospective, longitudinal study, participants underwent SD-OCT, EDSS, and visual acuity (VA) assessments at baseline and at follow-up. Statistical analyses were performed using generalized linear regression models, adjusted for age, sex, race, multiple sclerosis (MS) subtype, and baseline disability. We defined clinically meaningful EDSS worsening as an increase of ≥2.0 if baseline EDSS score was

This work was supported by the European Union 7FP-Programme (CombiMS, grant No 305397) and the European Sys4MS project (Horizon2020: Eracosysmed: ID-43). RM and the Section for Neuroimmunology and MS Research, University Zurich (UZH), have been supported by a European Research Council Advanced Grant (ERC 340733-HLA-DR15 in MS), by a Clinical Research Priority Project - disease heterogeneity of MS (CRPPMS; UZH), by the Swiss National Science Foundation and the Swiss MS Society. Open Access funding enabled and organized by Projekt DEAL.

Background To better understand the biology of COVID-19, we have explored the behavior of calcitonin gene-related peptide (CGRP), an angiogenic, vasodilating, and immune modulating peptide, in severe acute respiratory syndrome coronavirus 2 positive patients. Methods Levels of CGRP in the serum of 57 COVID-19 patients (24 asymptomatic, 23 hospitalized in the general ward, and 10 admitted to the intensive care unit) and healthy donors (n = 24) were measured by enzyme-linked immunosorbent assay (ELISA). In addition, to better understand the physiological consequences of the observed variations, we investigated by immunofluorescence the distribution of receptor activity modifying protein 1 (RAMP1), one of the components of the CGRP receptor, in autopsy lung specimens. Results CGRP levels were greatly decreased in COVID-19 patients (P < 0.001) when compared to controls, and there were no significant differences due to disease severity, sex, age, or comorbidities. We found that COVID-19 patients treated with proton pump inhibitors had lower levels of CGRP than other patients not taking this treatment (P = 0.001). RAMP1 immunoreactivity was found in smooth muscle cells of large blood vessels and the bronchial tree and in the airways´ epithelium. In COVID-19 samples, RAMP1 was also found in proliferating type II pneumocytes, a common finding in these patients. Conclusions The lower levels of CGRP should negatively impact the respiratory physiology of COVID-19 patients due to vasoconstriction, improper angiogenesis, less epithelial repair, and faulty immune response. Therefore, restoring CGRP levels in these patients may represent a novel therapeutic approach for COVID-19.

BackgroundTo better understand the biology of COVID-19, we have explored the behavior of calcitonin gene-related peptide (CGRP), an angiogenic, vasodilating, and immune modulating peptide, in SARS-CoV-2 positive patients.MethodsLevels of CGRP in the serum of 57 COVID-19 patients (24 asymptomatic, 23 hospitalized in the general ward, and 10 admitted to the intensive care unit) and healthy donors (n=24) were measured by ELISA. In addition, to better understand the physiological consequences of the observed variations, we investigated by immunofluorescence the distribution of RAMP1, one of the components of the CGRP receptor, in autopsy lung specimens.ResultsCGRP levels greatly decreased in COVID-19 patients (pConclusionsThe lower levels of CGRP should negatively impact the respiratory physiology of COVID-19 patients due to vasoconstriction, improper angiogenesis, less epithelial repair, and faulty immune response. Therefore, restoring CGRP levels in these patients may represent a novel therapeutic approach for COVID-19.

Understanding of the role of focal inflammation, a treatable feature, on neuro-axonal injury, is paramount to optimize neuroprotective strategy in MS. To quantify the impact of focal inflammatory activity on the rate of neuro-axonal injury over the MS course. We quantified the annualized rates of change in peripapillary retinal nerve fiber layer, ganglion cell plus inner plexiform layer (GCIPL), whole-brain, gray matter and thalamic volumes in patients with and without focal inflammatory activity in 161 patients followed over 5 years. We used mixed models including focal inflammatory activity (the presence of at least one relapse or a new/enlarging T2-FLAIR or gadolinium- enhancing lesion), and its interaction with time adjusted by age, sex, use of disease-modifying therapies and steroids, and prior optic neuritis. The increased rate of neuro-axonal injury during the first five years after onset was more prominent among active patients, as reflected by the changes in GCIPL thickness (p = 0.02), whole brain (p = 0.002) and thalamic volumes (p

Care of patients with multiple sclerosis (MS) has evolved in the last decade to shorten the time to confirm the diagnosis of clinically definite MS and to start disease-modifying drugs as soon as possible to decrease permanent disability and the risk of progressive disease. Such trends have been achieved by improving our understanding of the role of paraclinical tests such as the presence of oligoclonal bands on CSF examination, visual evoked potentials, or MRI imaging of the brain or spinal cord. Recently, the evidence that retinal damage detected with optical coherence tomography (OCT) is a sensitive test for identifying MS-related damage in the anterior visual pathway has been added to the diagnostic armamentarium.1,2 However, symptomatic or subclinical optic nerve lesion as evidence of dissemination in space has not been included in the 2017 MS diagnostic criteria because the available data concerning the diagnostic specificity and sensitivity were considered to be insufficient to justify its inclusion at that time.3 Despite the fact that optic neuritis is one of the most characteristic findings of MS, the optic nerve has not been designated as a fifth lesion site3 because imaging and other data were unavailable to support its inclusion. Recently, Brownlee et al.4 found that the inclusion of symptomatic optic nerve involvement in patients with optic neuritis from their clinically isolated syndrome (CIS) cohort improved the accuracy of 2017 MS diagnostic criteria. This study did not include OCT. Today, evidence of optic neuritis may be confirmed clinically by visual evoked potentials or by imaging with MRI or OCT. Subclinical or oligosymptomatic cases can be confirmed with these complementary tests, and new technologies such as OCT can help to characterize the underlying conditions producing optic neuritis. Further refinement of the diagnosis of optic neuritis is now possible with the introduction of the aquaporin 4, glial fibrillary acid protein, and myelin oligodendrocyte protein antibodies, which help to exclude variants of optic nerve inflammation. Therefore, it is time to re-evaluate the inclusion of optic nerve as a fifth lesion site for dissemination in space for the diagnosis of MS.

The use of optical coherence tomography (OCT) has been suggested as a potential biomarker for Alzheimer’s Disease based on previously reported thinning of the retinal nerve fiber layer (RNFL) in Alzheimer’s disease’s (AD) and Mild Cognitive Impairment (MCI). However, other studies have not shown such results. 930 individuals (414 cognitively healthy individuals, 192 probable amnestic MCI and 324 probable AD) attending a memory clinic were consecutively included and underwent spectral domain OCT (Maestro, Topcon) examinations to assess differences in peripapillary RNFL thickness, using a design of high ecological validity. Adjustment by age, education, sex and OCT image quality was performed. We found a non-significant decrease in mean RNFL thickness as follows: control group: 100,20 ± 14,60 µm, MCI group: 98,54 ± 14,43 µm and AD group: 96,61 ± 15,27 µm. The multivariate adjusted analysis revealed no significant differences in mean overall (p = 0.352), temporal (p = 0,119), nasal (p = 0,151), superior (p = 0,435) or inferior (p = 0,825) quadrants between AD, MCI and control groups. These results do not support the usefulness of peripapillary RNFL analysis as a marker of cognitive impairment or in discriminating between cognitive groups. The analysis of other OCT measurements in other retinal areas and layers as biomarkers for AD should be tested further.

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

Human immunodeficiency virus (HIV) infection is associated with premature aging and the development of aging-related comorbidities, such as cardiovascular disease (CVD). Gut microbiota (GM) disturbance is involved in these comorbidities and there is currently interest in strategies focused on modulating GM composition and/or functionality. Scientific evidence based on well-designed clinical trials is needed to support the use of prebiotics, probiotics, symbiotics, and fecal transplantation (FT) to modify the GM and reduce the incidence of CVD in HIV-infected patients. We reviewed the data obtained from three clinical trials focused on prebiotics, 25 trials using probiotics, six using symbiotics, and four using FT. None of the trials investigated whether these compounds could reduce CVD in HIV patients. The huge variability observed in the type of compound as well as the dose and duration of administration makes it difficult to adopt general recommendations and raise serious questions about their application in clinical practice.

Introduction: Precision medicine is an approach to disease prevention and treatment that takes into account individual variability in terms of genetics, environment and lifestyle. This approach depends on clinical, imaging and biological markers to define the optimal therapeutic approach for a given patient.Areas covered: Although many biomarkers have been proposed for MS, at present only oligoclonal bands (OCBs), magnetic resonance imaging, optical coherent tomography measurements and the JCv antibody index have been implemented in clinical practice.Expert commentary: Validation of biomarkers in multicentric prospective studies is necessary to improve the application of precision medicine for MS patients. New tools will open new avenues to improve our ability to provide personalized therapy to individuals with MS, including those aimed at the extraction of medical information from electronic health records, or those involving the application of machine learning tools to combine different types of...

Multiple Sclerosis (MS) is an autoimmune disease in which axons and myelin of the central nervous system (CNS) are damaged by inflammation and degenerative processes leading to significant disability. The course of the MS is hard to predict, limiting the decision making process for patient management and therapeutic options. Many genetic, lifestyle and environmental factors could influence the risks of MS development. Subtle abnormalities in the control of the immune response can be amplified and deregulated decades later suggesting that MS and other autoimmune diseases can be envisioned as dynamic diseases. Based on this premise, mathematical modeling of MS pathogenesis is an approach that would bring this dynamic concept to the understanding of the disease and therefore be useful for improving our understanding for the application of precision medicine. Modeling can be focused on different biological scales from genes and signaling pathways to cell–cell interactions, interplay between inflammatory and degenerative processes at tissue level, and predictions of clinical outcomes. Models of the autoimmune process as well as the damage of the CNS has been developed using ordinary differential equations and fitted parameters with experimental datasets. Simulations support the concept of MS as a dynamic disease that is being produced by subtle differences in the molecular and cellular control of the immune-nervous interplay amplified along time. These new systems medicine tools can now be applied for patient stratification and personalized medicine.

Background Methylthioadenosine is a metabolite of the polyamine pathway that modulates methyltransferase activity, thereby influencing DNA and protein methylation. Since methylthioadenosine produces neuroprotection in models of inflammation, ischemia and epilepsy, we set out to evaluate the role of methylthioadenosine in promoting remyelination, a process that will protect axons in demyelinating diseases and that will aid functional recovery. Methods The effect of methylthioadenosine in promoting remyelination was tested in mouse cerebellum organotypic cultures that were exposed to lipopolysaccharide to induce neuroinflammation, or lysolecithin to induce chemical demyelination. In addition methylthioadenosine administration was also tested in vivo, using the cuprizone model of demyelination. The molecular pathways involved in this methylthioadenosine activity were evaluated in primary cortical mouse astrocytes. Results In models of neuroinflammation or chemical demyelination, methylthioadenosine prevented the loss of myelin and promoted remyelination in vitro by increasing the number of mature myelinating oligodendrocytes. Methylthioadenosine enhanced myelin production in the cuprizone model, in conjunction with a clinical improvement. Methylthioadenosine enhanced STAT-3 phosphorylation in astrocytes in vitro, and the production of ciliary neurotrophic factor (CNTF), a trophic factor known to promote oligodendrocyte maturation and differentiation, as well as remyelination. Conclusions The remyelination promoted by methylthioadenosine suggests a role for the polyamine pathway in oligodendrocyte maturation and survival, paving the way for new therapeutic strategies to promote regeneration in Multiple Sclerosis and other demyelinating diseases.

Attention and executive deficits are disabling symptoms in multiple sclerosis (MS) that have been related to disconnection mechanisms. We aimed to investigate changes in structural connectivity in MS and their association with attention and executive performance applying an improved framework that combines high order probabilistic tractography and anatomical exclusion criteria postprocessing. We compared graph theory metrics of structural networks and fractional anisotropy (FA) of white matter (WM) connections or edges between 72 MS subjects and 38 healthy volunteers (HV) and assessed their correlation with cognition. Patients displayed decreased network transitivity, global efficiency and increased path length compared with HV (p, Highlights • High order tractography and anatomical exclusion criteria improve connectivity analyses. • Structural connectivity is less efficient in multiple sclerosis. • Attentional and executive functions relate to integrity of strategic networks. • Increased connectivity suggests structural reorganization mechanisms.

Neuropathologies can be classified, on the basis of post-mortem histopathology and by using machine learning, into six transdiagnostic clusters associated with clinical phenotypes.

Objectives and design Neuronal responses adapt to familiar and repeated sensory stimuli. Enhanced synchrony across wide brain systems has been postulated as a potential mechanism for this adaptation phenomenon. Here, we used recently developed graph theory methods to investigate hidden connectivity features of dynamic synchrony changes during a visual repetition paradigm. Particularly, we focused on strength connectivity changes occurring at local and distant brain neighborhoods. Principal observations We found that connectivity reorganization in visual modal cortex-such as local suppressed connectivity in primary visual areas and distant suppressed connectivity in fusiform areas-is accompanied by enhanced local and distant connectivity in higher cognitive processing areas in multimodal and association cortex. Moreover, we found a shift of the dynamic functional connections from primary-visual-fusiform to primary-multimodal/association cortex. Conclusions These findings suggest that repetition-suppression is made possible by reorganization of functional connectivity that enables communication between low- and high-order areas. Hum Brain Mapp 38:1965-1976, 2017. © 2017 Wiley Periodicals, Inc.

Objective: To assess the decision-making impairment in patients with multiple sclerosis (MS) and how they relate to other cognitive domains. Methods: We performed a cross-sectional analysis in 84 patients with MS, and 21 matched healthy controls using four tasks taken from behavioral economics: (1) risk preferences, (2) choice consistency, (3) delay of gratification, and (4) rate of learning. All tasks were conducted using real-world reward outcomes (food or money) in different real-life conditions. Participants underwent cognitive examination using the Brief Repeatable Battery-Neuropsychology. Results: Patients showed higher risk aversion (general propensity to choose the lottery was 0.51 vs 0.64, p = 0.009), a trend to choose more immediate rewards over larger but delayed rewards ( p = 0.108), and had longer reactions times ( p = 0.033). Choice consistency and learning rates were not different between groups. Progressive patients chose slower than relapsing patients. In relation to general cognitive impairments, we found correlations between impaired decision-making and impaired verbal memory ( r = 0.29, p = 0.009), visual memory ( r = −0.37, p = 0.001), and reduced processing speed ( r = −0.32, p = 0.001). Normalized gray matter volume correlated with deliberation time ( r = −0.32, p = 0.005). Conclusion: Patients with MS suffer significant decision-making impairments, even at the early stages of the disease, and may affect patients’ quality and social life.

Trials of antigen-specific tolerance have been undertaken in the clinic for over fifty years and the results of these antigen-specific clinical trials are described in this review. Antigen-specific tolerization of the immune system in protein replacement therapy for hemophilia A is an accepted treatment. Clinical trials are ongoing for autoimmune conditions such as type 1 diabetes, multiple sclerosis, neuromyelitis optica, and rheumatoid arthritis with various antigen-specific strategies. Trials for tolerization in celiac disease aim for antigen specific tolerance to gluten, an environmental trigger, which may then halt the progression to autoimmunity targeting a self-antigen, tissue transglutaminase. Although many promising approaches have been demonstrated in pre-clinical models, this review will focus primarily on clinical trials of antigen-specific tolerance that have been taken to the clinic and with initial results reported in the peer reviewed literature. A separate article on approaches with CAR-T cells appears in this volume.

Inner nuclear layer; Multiple sclerosis; Optical coherence tomography Capa nuclear interna; Esclerosis múltiple; Tomografía de coherencia óptica Capa nuclear interior; Esclerosi múltiple; Tomografia de coherència òptica Background: The association of peripapillary retinal nerve fibre layer (pRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness with neurodegeneration in multiple sclerosis (MS) is well established. The relationship of the adjoining inner nuclear layer (INL) with inflammatory disease activity is less well understood. Objective: The objective of this paper is to investigate the relationship of INL volume changes with inflammatory disease activity in MS. Methods In this longitudinal, multi-centre study, optical coherence tomography (OCT) and clinical data (disability status, relapses and MS optic neuritis (MSON)) were collected in 785 patients with MS (68.3% female) and 92 healthy controls (63.4% female) from 11 MS centres between 2010 and 2017 and pooled retrospectively. Data on pRNFL, GCIPL and INL were obtained at each centre. Results: There was a significant increase in INL volume in eyes with new MSON during the study (N=61/1562, β=0.01mm3, p

Dysregulation of signaling pathways in multiple sclerosis (MS) can be analyzed by phosphoproteomics in peripheral blood mononuclear cells (PBMCs). We performed in vitro kinetic assays on PBMCs in 195 MS patients and 60 matched controls and quantified the phosphorylation of 17 kinases using xMAP assays. Phosphoprotein levels were tested for association with genetic susceptibility by typing 112 single-nucleotide polymorphisms (SNPs) associated with MS susceptibility. We found increased phosphorylation of MP2K1 in MS patients relative to the controls. Moreover, we identified one SNP located in the PHDGH gene and another on IRF8 gene that were associated with MP2K1 phosphorylation levels, providing a first clue on how this MS risk gene may act. The analyses in patients treated with disease-modifying drugs identified the phosphorylation of each receptor’s downstream kinases. Finally, using flow cytometry, we detected in MS patients increased STAT1, STAT3, TF65, and HSPB1 phosphorylation in CD19 + cells. These findings indicate the activation of cell survival and proliferation (MAPK), and proinflammatory (STAT) pathways in the immune cells of MS patients, primarily in B cells. The changes in the activation of these kinases suggest that these pathways may represent therapeutic targets for modulation by kinase inhibitors.

The development of neuroprotective therapies is a sought-after goal. By screening combinatorial chemical libraries using in vitro assays, we identified the small molecule BN201 that promotes the survival of cultured neural cells when subjected to oxidative stress or when deprived of trophic factors. Moreover, BN201 promotes neuronal differentiation, the differentiation of precursor cells to mature oligodendrocytes in vitro, and the myelination of new axons. BN201 modulates several kinases participating in the insulin growth factor 1 pathway including serum-glucocorticoid kinase and midkine, inducing the phosphorylation of NDRG1 and the translocation of the transcription factor Foxo3 to the cytoplasm. In vivo, BN201 prevents axonal and neuronal loss, and it promotes remyelination in models of multiple sclerosis, chemically induced demyelination, and glaucoma. In summary, we provide a new promising strategy to promote neuroaxonal survival and remyelination, potentially preventing disability in brain diseases., This work was supported by the Fundación Ramon Areces,Madrid, Spain, and the Instituto de Salud Carlos III, Madrid Spain(RD07/0060 and PI12/01823) to PVand AM and by an unrestricted grantfrom Bionure SL, Barcelona, Spain.

The use of optical coherence tomography (OCT) has been suggested as a potential biomarker for Alzheimer's Disease based on previously reported thinning of the retinal nerve fiber layer (RNFL) in Alzheimer's disease's (AD) and Mild Cognitive Impairment (MCI). However, other studies have not shown such results. 930 individuals (414 cognitively healthy individuals, 192 probable amnestic MCI and 324 probable AD) attending a memory clinic were consecutively included and underwent spectral domain OCT (Maestro, Topcon) examinations to assess differences in peripapillary RNFL thickness, using a design of high ecological validity. Adjustment by age, education, sex and OCT image quality was performed. We found a non-significant decrease in mean RNFL thickness as follows: control group: 100,20 ± 14,60 µm, MCI group: 98,54 ± 14,43 µm and AD group: 96,61 ± 15,27 µm. The multivariate adjusted analysis revealed no significant differences in mean overall (p = 0.352), temporal (p = 0,119), nasal (p = 0,151), superior (p = 0,435) or inferior (p = 0,825) quadrants between AD, MCI and control groups. These results do not support the usefulness of peripapillary RNFL analysis as a marker of cognitive impairment or in discriminating between cognitive groups. The analysis of other OCT measurements in other retinal areas and layers as biomarkers for AD should be tested further.

Fractal analysis represents a promising new approach to structural neuroimaging data, yet systematic evaluation of the fractal dimension (FD) as a marker of structural brain complexity is scarce. Here we present in-depth methodological assessment of FD estimation in structural brain MRI. On the computational side, we show that spatial scale optimization can significantly improve FD estimation accuracy, as suggested by simulation studies with known FD values. For empirical evaluation, we analyzed two recent open-access neuroimaging data sets (MASSIVE and Midnight Scan Club), stratified by fundamental image characteristics including registration, sequence weighting, spatial resolution, segmentation procedures, tissue type, and image complexity. Deviation analyses showed high repeated-acquisition stability of the FD estimates across both data sets, with differential deviation susceptibility according to image characteristics. While less frequently studied in the literature, FD estimation in T2-weighted images yielded robust outcomes. Importantly, we observed a significant impact of image registration on absolute FD estimates. Applying different registration schemes, we found that unbalanced registration induced i) repeated-measurement deviation clusters around the registration target, ii) strong bidirectional correlations among image analysis groups, and iii) spurious associations between the FD and an index of structural similarity, and these effects were strongly attenuated by reregistration in both data sets. Indeed, differences in FD between scans did not simply track differences in structure per se, suggesting that structural complexity and structural similarity represent distinct aspects of structural brain MRI. In conclusion, scale optimization can improve FD estimation accuracy, and empirical FD estimates are reliable yet sensitive to image characteristics.

Significance Application of antigen-specific immune tolerance in autoimmune disease is a long-sought goal. We studied diseases with abundant information on the autoimmune target: in multiple sclerosis (MS), various myelin antigens are known targets of T cells and antibodies, whereas in neuromyelitis optica (NMO), the aquaporin-4 channel is attacked by T cells and antibodies. We tested whether engineered dendritic cells might induce a tolerogenic immune response in these two conditions. In this in-human clinical study, individual regulatory T cells, secreting IL-10, a key tolerogenic cytokine, were detected after treatment. These results might lead to more extensive trials with this approach in autoimmune conditions where the antigenic target has been identified, including MS, NMO, myasthenia gravis, and Graves disease., There are adaptive T-cell and antibody autoimmune responses to myelin-derived peptides in multiple sclerosis (MS) and to aquaporin-4 (AQP4) in neuromyelitis optica spectrum disorders (NMOSDs). Strategies aimed at antigen-specific tolerance to these autoantigens are thus indicated for these diseases. One approach involves induction of tolerance with engineered dendritic cells (tolDCs) loaded with specific antigens. We conducted an in-human phase 1b clinical trial testing increasing concentrations of autologous tolDCs loaded with peptides from various myelin proteins and from AQP4. We tested this approach in 12 patients, 8 with MS and 4 with NMOSD. The primary end point was the safety and tolerability, while secondary end points were clinical outcomes (relapses and disability), imaging (MRI and optical coherence tomography), and immunological responses. Therapy with tolDCs was well tolerated, without serious adverse events and with no therapy-related reactions. Patients remained stable clinically in terms of relapse, disability, and in various measurements using imaging. We observed a significant increase in the production of IL-10 levels in PBMCs stimulated with the peptides as well as an increase in the frequency of a regulatory T cell, known as Tr1, by week 12 of follow-up. In this phase 1b trial, we concluded that the i.v. administration of peptide-loaded dendritic cells is safe and feasible. Elicitation of specific IL-10 production by peptide-specific T cells in MS and NMOSD patients indicates that a key element in antigen specific tolerance is activated with this approach. The results warrant further clinical testing in larger trials.

Purpose Raman spectroscopy allows molecular changes to be quantified in vivo from the tissues like the retina. Here we aimed to assess the metabolic changes in the retina of patients with multiple sclerosis (MS). Methods We built a Raman spectroscopy prototype by connecting a scanning laser ophthalmoscope to a spectrophotometer. We defined the spectra of 10 molecules participating on energy supply, axon biology, or synaptic damage, which have been shown to be altered in the brain of patients with MS: cytochrome C, flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide (NADH), N-acetyl-aspartate (NAA), excitotoxicity, glutamate, amyloid β (Aβ), τ and α-synuclein (SNCA), phosphatidyl-ethanolamine, and phosphatidyl-choline. We studied these molecules in a prospective cohort of patients with MS, either in the chronic phase or during relapses of acute optic neuritis (AON). Results Significant changes to all these molecules were associated with age in healthy individuals. There was a significant decrease in NADH and a trend toward a decrease in NAA in patients with MS, as well as an increase in Aβ compared with healthy controls. Moreover, NADH and FAD increased over time in a longitudinal analysis of patients with MS, whereas Aβ diminished. In patients with acute retinal inflammation due to AON, there was a significant increase in FAD and a decrease in SNCA in the affected retina. Moreover, glutamate levels increased in the affected eyes after a 6-month follow-up. Conclusions Alterations of molecules related to axonal degeneration are observed during neuroinflammation and show dynamic changes over time, suggesting progressive neurodegeneration.

Objective: To develop consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results.Methods: A panel of experienced OCT researchers (including 11 neurologists, 2 ophthalmologists, and 2 neuroscientists) discussed requirements for performing and reporting quantitative analyses of retinal morphology and developed a list of initial recommendations based on experience and previous studies. The list of recommendations was subsequently revised during several meetings of the coordinating group.Results: We provide a 9-point checklist encompassing aspects deemed relevant when reporting quantitative OCT studies. The areas covered are study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition data analysis, recommended nomenclature, and statistical analysis.Conclusions: The Advised Protocol for OCT Study Terminology and Elements recommendations include core items to standardize and improve quality of reporting in quantitative OCT studies. The recommendations will make reporting of quantitative OCT studies more consistent and in line with existing standards for reporting research in other biomedical areas. The recommendations originated from expert consensus and thus represent Class IV evidence. They will need to be regularly adjusted according to new insights and practices.

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

Monitoring disease burden is an unmeet need in multiple sclerosis (MS). Identifying patients at high risk of disability progression will be useful for improving clinical-therapeutic decisions in clinical routine. To evaluate the role of visual field testing in non-optic neuritis eyes (non-ON eyes) as a biomarker of disability progression in MS. In 109 patients of the MS-VisualPath cohort, we evaluated the association between visual field abnormalities and global and cognitive disability markers and brain and retinal imaging markers of neuroaxonal injury using linear regression models adjusted for sex, age, disease duration and use of disease-modifying therapies. We evaluated the risk of disability progression associated to have baseline impaired visual field after 3 years of follow-up. Sixty-two percent of patients showed visual field defects in non-ON eyes. Visual field mean deviation was statistically associated with global disability; brain (normalized brain parenchymal, gray matter volume and lesion load) and retinal (peripapillary retinal nerve fiber layer thickness and macular ganglion cell complex thickness) markers of neuroaxonal damage. Patients with impaired visual field had statistically significative greater disability, lower normalized brain parenchymal volume and higher lesion volume than patients with normal visual field testing. MS patients with baseline impaired VF tripled the risk of disability progression during follow-up [OR = 3.35; 95 % CI (1.10-10.19); p = 0.033]. The association of visual field impairment with greater disability and neuroaxonal injury and higher risk of disability progression suggest that VF could be used to monitor MS disease burden.

Objective: To establish cytometry profiles associated with disease stages and immunotherapy in MS. Methods: Demographic/clinical data and peripheral blood samples were collected from 227 patients with MS and 82 sex- and age-matched healthy controls (HCs) enrolled in a cross-sectional study at 4 European MS centers (Spain, Italy, Germany, and Norway). Flow cytometry of isolated peripheral blood mononuclear cells was performed in each center using specifically prepared antibody-cocktail Lyotubes; data analysis was centralized at the Genoa center. Differences in immune cell subsets were assessed between groups of untreated patients with relapsing-remitting or progressive MS (RRMS or PMS) and HCs and between groups of patients with RRMS taking 6 commonly used disease-modifying drugs. Results: In untreated patients with MS, significantly higher frequencies of Th17 cells in the RRMS population compared with HC and lower frequencies of B-memory/B-regulatory cells as well as higher percentages of B-mature cells in patients with PMS compared with HCs emerged. Overall, the greatest deviation in immunophenotype in MS was observed by treatment rather than disease course, with the strongest impact found in fingolimod-treated patients. Fingolimod induced a decrease in total CD4+ T cells and in B-mature and B-memory cells and increases in CD4+ and CD8+ T-regulatory and B-regulatory cells. Conclusions: Our highly standardized, multisite cytomics data provide further understanding of treatment impact on MS immunophenotype and could pave the way toward monitoring immune cells to help clinical management of MS individuals. This work was supported by the European Commission (ERACOSYSMED ERA-Net program, Sys4MS project, id:43), Instituto de Salud Carlos III, Spain (AC1500052), the Italian Ministry of Health (WFR-PER-2013-02361136), the German Ministry of Science (Deutsches Teilprojekt B “Förderkennzeichen: 031L0083B”), and the Norwegian Research Council (project 257955).

IMPORTANCE: Neuroprotective and remyelinating therapies are required for multiple sclerosis (MS), and acute optic neuritis (AON) is a potential condition to evaluate such treatments. OBJECTIVE: To comprehensively assess key biological and methodological aspects of AON trials for testing neuroprotection and remyelination in MS. DESIGN, SETTING, AND PARTICIPANTS: The AON-VisualPath prospective cohort study was conducted from February 2011 to November 2018 at the Hospital Clinic of University of Barcelona, Barcelona, Spain. Consecutive patients with AON were prospectively enrolled in the cohort and followed up for 18 months. Data analyses occurred from November 2018 to February 2019. EXPOSURES: Participants were followed up for 18 months using optical coherence tomography, visual acuity tests, and in a subset of 25 participants, multifocal visual evoked potentials. MAIN OUTCOMES AND MEASURES: Dynamic models of retinal changes and nerve conduction and their associations with visual end points; and eligibility criteria, stratification, and sample-size estimation for future trials. RESULTS: A total of 60 patients (50 women [83%]; median age, 34 years) with AON were included. The patients studied displayed early and intense inner retinal thinning, with a thinning rate of approximately 2.38 μm per week in the ganglion cell plus inner plexiform layer (GCIPL) during the first 4 weeks. Eyes with AON displayed a 6-month change in latency of about 20 milliseconds, while the expected change in the eyes of healthy participants by random variability was 0.13 (95% CI, −0.80 to 1.06) milliseconds. The strongest associations with visual end points were for the 6-month intereye difference in 2.5% low-contrast letter acuity, which was correlated with the peripapillary retinal nerve fiber layer thinning (adjusted R(2), 0.57), GCIPL thinning (adjusted R(2), 0.50), and changes in mfVEP latency (adjusted R(2), 0.26). A 5-letter increment in high-contrast visual acuity at presentation (but not sex or age) was associated with 6-month retinal thinning (1.41 [95% CI, 0.60-2.23] μm less peripapillary retinal nerve fiber layer thinning thinning; P = .001; adjusted R(2), 0.20; 0.86 [95% CI, 0.35-1.37] μm less GCIPL thinning; P = .001; adjusted R(2), 0.19) but not any change in multifocal visual evoked potential latency. To demonstrate 50% efficacy in GCIPL thinning or change in multifocal visual evoked potential latency, a 6-month, 2-arm, parallel-group trial would need 37 or 50 participants per group to test a neuroprotective or remyelinating drug, respectively (power, 80%; α, .05). CONCLUSIONS AND RELEVANCE: Acute optic neuritis is a suitable condition to test neuroprotective and remyelinating therapies after acute inflammation, providing sensitive markers to assess the effects on both processes and prospective visual recovery within a manageable timeframe and with a relatively small sample size.