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Abstract The relationship between brain diffusion microstructural changes and disability in multiple sclerosis (MS) remains poorly understood. We aimed to explore the predictive value of microstructural properties in white (WM) and grey matter (GM), and identify areas associated with mid-term disability in MS patients. We studied 185 patients (71% female; 86% RRMS) with the Expanded Disability Status Scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9HPT), and Symbol Digit Modalities Test (SDMT) at two time-points. We used Lasso regression to analyse the predictive value of baseline WM fractional anisotropy and GM mean diffusivity, and to identify areas related to each outcome at 4.1 years follow-up. Motor performance was associated with WM (T25FW: RMSE = 0.524, R2 = 0.304; 9HPT dominant hand: RMSE = 0.662, R2 = 0.062; 9HPT non-dominant hand: RMSE = 0.649, R2 = 0.139), and SDMT with GM diffusion metrics (RMSE = 0.772, R2 = 0.186). Cingulum, longitudinal fasciculus, optic radiation, forceps minor and frontal aslant were the WM tracts most closely linked to motor dysfunction, and temporal and frontal cortex were relevant for cognition. Regional specificity related to clinical outcomes provide valuable information that can be used to develop more accurate predictive models that could improve therapeutic strategies.

Resumen: Introducción: Los anticuerpos IgG-NMO se han demostrado sensibles y específicos para el diagnóstico de neuromielitis óptica (NMO) y han permitido ampliar el espectro clínico a formas limitadas como neuritis óptica (NO) o mielitis longitudinalmente extensas (MLE). Objetivo: Evaluar la sensibilidad y la especificidad de nuestra técnica y describir las características de los pacientes para los que se solicita dicha determinación. Métodos: Los anticuerpos IgG-NMO se analizaron mediante inmunohistoquímica y se confirmaron sobre células HEK transfectadas con acuaporina 4. La información clínica se obtuvo mediante un cuestionario rellenado por el neurólogo remitente de la muestra. Resultados: Desde noviembre de 2005 a septiembre de 2008 se analizaron 580 muestras de 518 pacientes. Se obtuvo información de 358 (68%) pacientes. El seguimiento en los 33 casos positivos fue del 100%. De los 43 pacientes diagnosticados de NMO por los criterios de 2006, 28 (65%) eran positivos; la sensibilidad fue del 62,5% si se aplicaban estos criterios eliminando el resultado de IgG-NMO y del 57% aplicando los criterios de 1999, que tampoco incluyen los IgG-NMO. Se detectaron IgG-NMO en 3 (13%) de las MLE recurrentes y 2 (4%) de las NO recurrentes. No se detectaron IgG-NMO en el resto de los pacientes evaluados (96 finalmente diagnosticados de esclerosis múltiple; 80 mielitis; 28 NO no recurrentes; 33 con otros diagnósticos). Conclusiones: En este estudio no seleccionado y tan amplio, no se han detectado falsos positivos. Los casos positivos se asocian mayoritariamente con NMO y sólo en un pequeño porcentaje con NO o MLE recurrente. Abstract: Introduction: The description of a highly sensitive and specific biomarker for neuromyelitis optica (NMO-IgG/aquaporin-4 antibody) extended the clinical spectrum of NMO to limited forms such as optic neuritis (ON) and longitudinally extensive myelitis (LEM). Objective: To asses the sensitivity and specificity of our assay, and to describe the clinical characteristics of the patients who were tested for NMO-IgG. Methods: NMO-IgG was analysed by immunohistochemistry and confirmed by assay on HEK cells transfected with aquaporin-4. The clinical information was obtained from forms filled in by the referring neurologists. Results: A total of 580 samples from 518 patients were analysed from November 2005 to September 2008. Clinical information was available from 358 (68%) patients. All 33 (100%) positive cases were followed up. Twenty-eight of the 43 (65%) patients diagnosed with NMO by the revised criteria of 2006 were positive; the sensitivity was 62.5% when applying the same criteria, but discounting the criterion of NMO-IgG status, or 57% when applying the criteria of 1999. NMO-IgG was detected in 3 (13%) of the recurrent LEM and 2 (4%) of the recurrent ON. NMO-IgG was not detected in the remaining patients (96 with a final diagnosis of multiple sclerosis; 80 with myelitis; 28 with non-recurrent ON; and 33 other diagnosis). Conclusions: No false positive cases were found in this large and non-selected study. NMO-IgG positive cases were mostly associated with NMO, and only in a low percentage with recurrent ON or LEM. Palabras clave: Neuromielitis óptica, Esclerosis múltiple, IgG-NMO, Acuaporina 4, Mielitis transversa, Neuritis óptica, Keywords: Neuromyelitis optica, Multiple sclerosis, NMO-IgG, Aquaporin-4, Transverse myelitis, Optic neuritis

Introduction: The description of a highly sensitive and specific biomarker for neuromyelitis optica (NMO-IgG/aquaporin-4 antibody) extended the clinical spectrum of NMO to limited forms such as optic neuritis (ON) and longitudinally extensive myelitis (LEM). Objective: To asses the sensitivity and specificity of our assay, and to describe the clinical characteristics of the patients who were tested for NMO-IgG. Methods: NMO-IgG was analysed by immunohistochemistry and confirmed by assay on HEK cells transfected with aquaporin-4. The clinical information was obtained from forms filled in by the referring neurologists. Results: A total of 580 samples from 518 patients were analysed from November 2005 to September 2008. Clinical information was available from 358 (68%) patients. All 33 (100%) positive cases were followed up. Twenty-eight of the 43 (65%) patients diagnosed with NMO by the revised criteria of 2006 were positive; the sensitivity was 62.5% when applying the same criteria, but discounting the criterion of NMO-IgG status, or 57% when applying the criteria of 1999. NMO-IgG was detected in 3 (13%) of the recurrent LEM and 2 (4%) of the recurrent ON. NMO-IgG was not detected in the remaining patients (96 with a final diagnosis of multiple sclerosis; 80 with myelitis; 28 with non-recurrent ON; and 33 other diagnosis). Conclusions: No false positive cases were found in this large and non-selected study. NMO-IgG positive cases were mostly associated with NMO, and only in a low percentage with recurrent ON or LEM. Resumen: Introducción: Los anticuerpos IgG-NMO se han demostrado sensibles y específicos para el diagnóstico de neuromielitis óptica (NMO) y han permitido ampliar el espectro clínico a formas limitadas como neuritis óptica (NO) o mielitis longitudinalmente extensas (MLE). Objetivo: Evaluar la sensibilidad y la especificidad de nuestra técnica y describir las características de los pacientes para los que se solicita dicha determinación. Métodos: Los anticuerpos IgG-NMO se analizaron mediante inmunohistoquímica y se confirmaron sobre células HEK transfectadas con acuaporina 4. La información clínica se obtuvo mediante un cuestionario rellenado por el neurólogo remitente de la muestra. Resultados: Desde noviembre de 2005 a septiembre de 2008 se analizaron 580 muestras de 518 pacientes. Se obtuvo información de 358 (68%) pacientes. El seguimiento en los 33 casos positivos fue del 100%. De los 43 pacientes diagnosticados de NMO por los criterios de 2006, 28 (65%) eran positivos; la sensibilidad fue del 62,5% si se aplicaban estos criterios eliminando el resultado de IgG-NMO y del 57% aplicando los criterios de 1999, que tampoco incluyen los IgG-NMO. Se detectaron IgG-NMO en 3 (13%) de las MLE recurrentes y 2 (4%) de las NO recurrentes. No se detectaron IgG-NMO en el resto de los pacientes evaluados (96 finalmente diagnosticados de esclerosis múltiple; 80 mielitis; 28 NO no recurrentes; 33 con otros diagnósticos). Conclusiones: En este estudio no seleccionado y tan amplio, no se han detectado falsos positivos. Los casos positivos se asocian mayoritariamente con NMO y sólo en un pequeño porcentaje con NO o MLE recurrente. Keywords: Neuromyelitis optica, Multiple sclerosis, NMO-IgG, Aquaporin-4, Transverse myelitis, Optic neuritis, Palabras clave: Neuromielitis óptica, Esclerosis múltiple, IgG-NMO, Acuaporina 4, Mielitis transversa, Neuritis óptica

Background and Objectives: The role of the complement system in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is not completely understood, and studies exploring its potential utility for diagnosis and prognosis are lacking. We aimed to investigate the value of complement factors (CFs) as diagnostic and prognostic biomarkers in patients with MOGAD., Methods: Multicentric retrospective cohort study including patients with MOGAD, multiple sclerosis (MS) and aquaporin-4 seropositive neuromyelitis optica spectrum disorder (AQP4-NMOSD) with available paired serum and CSF samples. A panel of CFs were measured by multiplex ELISA, and the levels were compared between the 3 conditions. Univariable and multivariable analyses were performed to evaluate the association between levels of CFs and relapse and disability outcomes in MOGAD patients., Results: Ninety-four patients (MOGAD, n = 60; MS, n = 18; AQP4-NMOSD, n = 16) were included. Mean (SD) age at sampling was 39.4 (16.7), 40.7 (7.0), and 43.3 (21.0), respectively. Female were predominant, especially in AQP4-NMOSD (88%). Combination of the serum levels of C3a, C4a, and C3a/C3 ratio showed excellent potential to discriminate MOGAD from patients with MS (area under the curve [AUC] [95% CI] 0.95 [0.90-0.99]) and from AQP4-NMOSD (AUC 0.88 [0.76-1.00]). In patients with MOGAD, CSF levels of CFs of the classical/lectin pathway influenced relapse-related outcomes, and lower C4 levels were associated with higher number of relapses during follow-up (incidence rate ratio [95% CI] 0.88 [0.78-0.99]; p = 0.04 in multivariable analysis), and a high C4a/C4 ratio was associated with increased risk of second relapse during the first year (hazard ratio [95% CI] 3.68 [1.26-10.78]; p = 0.02 in multivariable analysis). Time to second relapse was shorter in patients with MOGAD with a high CSF C4a/C4 ratio (log-rank p = 0.01). CSF levels of the membrane attack complex SC5b9 influenced disability-related outcomes, and baseline CSF SC5b9 levels were higher in patients who reached the final Expanded Disability Status Scale (EDSS) ≥ 3.0 ( p = 0.002), and elevated SC5b9 levels were associated with increased risk of reaching EDSS ≥ 3.0 (odds ratio [95% CI] 1.79 [1.16-3.67]; p = 0.04 in multivariable analyses)., Discussion: Our results suggest that serum and CSF levels of CFs have diagnostic and prognostic value respectively in patients with MOGAD. These findings support the use of complement inhibitors as a therapeutic approach in these patients.

Disruptions to brain networks, measured using structural (sMRI), diffusion (dMRI), or functional (fMRI) MRI, have been shown in people with multiple sclerosis (PwMS), highlighting the relevance of regions in the core of the connectome but yielding mixed results depending on the studied connectivity domain. Using a multilayer network approach, we integrated these three modalities to portray an enriched representation of the brain's core-periphery organization and explore its alterations in PwMS. In this retrospective cross-sectional study, we selected PwMS and healthy controls with complete multimodal brain MRI acquisitions from 13 European centers within the MAGNIMS network. Physical disability and cognition were assessed with the Expanded Disability Status Scale (EDSS) and the symbol digit modalities test (SDMT), respectively. SMRI, dMRI, and resting-state fMRI data were parcellated into 100 cortical and 14 subcortical regions to obtain networks of morphological covariance, structural connectivity, and functional connectivity. Connectivity matrices were merged in a multiplex, from which regional coreness-the probability of a node being part of the multiplex core-and coreness disruption index (κ)-the global weakening of the core-periphery structure-were computed. The associations of κ with disease status (PwMS vs. healthy controls), clinical phenotype, level of physical disability (EDSS ≥ 4 vs. EDSS < 4), and cognitive impairment (SDMT z-score < -1.5) were tested within a linear model framework. Using random forest permutation feature importance, we assessed the relative contribution of κ in the multiplex and single-layer domains, in addition to conventional MRI measures (brain and lesion volumes), in predicting disease status, physical disability, and cognitive impairment. We studied 1048 PwMS (695F, mean ± SD age: 43.3 ± 11.4 years) and 436 healthy controls (250F, mean ± SD age: 38.3 ± 11.8 years). PwMS showed significant disruption of the multiplex core-periphery organization (κ = -0.14, Hedges' g = 0.49, p < 0.001), correlating with clinical phenotype (F = 3.90, p = 0.009), EDSS (Hedges' g = 0.18, p = 0.01), and SDMT (Hedges' g = 0.30, p < 0.001). Multiplex κ was the only connectomic measure adding to conventional MRI in predicting disease status and cognitive impairment, while physical disability also depended on single-layer contributions. In conclusion, we show that multilayer networks represent a biologically and clinically meaningful framework to model multimodal MRI data, with disruption of the core-periphery structure emerging as a potential connectomic biomarker for disease severity and cognitive impairment in PwMS., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Objectives: The impact of viral infections on disease susceptibility and progression has predominantly been studied in patients with relapse-onset MS (RMS). Here, we determined immune responses to ubiquitous viruses in patients with primary progressive MS (PPMS)., Methods: Antibody responses to Epstein-Barr virus (EBV), specifically to the latent EBV nuclear antigen 1 and the lytic viral capsid antigen VCA, human herpesvirus 6 (HHV-6), human cytomegalovirus (HCMV), and measles virus were determined in a cohort of 68 PPMS patients with a mean follow-up of 8 years and compared with 66 healthy controls matched for sex and age., Results: Compared with controls, PPMS patients showed increased humoral immune responses to the EBV-encoded nuclear antigen-1 (EBNA1), but not to the lytic EBV capsid antigen (VCA) or to other viral antigens. Seroprevalence rates for HCMV were significantly higher in PPMS. Antiviral immune responses at baseline did not correlate with disability progression over time., Discussion: Elevated immune responses toward EBNA1 are selectively increased in people with primary progressive disease, indicating a link between EBNA1-targeting immune responses and the development of both RMS and PPMS. Our data also suggest that chronic HCMV infection is associated with progressive MS., Competing Interests: Declarations. Conflicts of interest: The authors declare that they have no competing interests to declare that are relevant to the content of this article., (© 2024. The Author(s).)

Multiple sclerosis (MS) is a neurodegenerative disease that affects the central nervous system. Structures affected in MS include the corpus callosum, connecting the hemispheres. Studies have shown that in mammalian brains, structural connectivity is organized according to a conservation principle, an inverse relationship between intra- and interhemispheric connectivity. The aim of this study was to replicate this conservation principle in subjects with MS and to explore how the disease interacts with it. A multicentric dataset has been analyzed including 513 people with MS and 208 healthy controls from seven different centers. Structural connectivity was quantified through various connectivity measures, and graph analysis was used to study the behavior of intra- and interhemispheric connectivity. The association between the intra- and the interhemispheric connectivity showed a similar strength for healthy controls ( r = 0.38, p < 0.001) and people with MS ( r = 0.35, p < 0.001). Intrahemispheric connectivity was associated with white matter fraction ( r = 0.48, p < 0.0001), lesion volume ( r = -0.44, p < 0.0001), and the Symbol Digit Modalities Test ( r = 0.25, p < 0.0001). Results show that this conservation principle seems to hold for people with MS. These findings support the hypothesis that interhemispheric connectivity decreases at higher cognitive decline and disability levels, while intrahemispheric connectivity increases to maintain the balance., Competing Interests: Competing Interests: See Competing Interests section. G. Martí-Juan has received a MAGNIMS-ECTRIMS fellowship. J. Sastre-Garriga declares fees from Sanofi, Biogen, Celgene, Merck, Biopass, Novartis, and Roche and receives research support from Fondo de Investigación en Salud (PI19/00950) from Instituto de Salud Carlos III, Spain. A. Vidal-Jordana has received support for contracts from Juan Rodes (JR16/00024); receives research support from Fondo de Investigación en Salud (PI17/02162) from Instituto de Salud Carlos III, Spain; and has engaged in consulting and/or participated as a speaker in events organized by Novartis, Roche, Biogen, and Sanofi. S. Llufriu received compensation for consulting services and speaker honoraria from Biogen Idec, Novartis, TEVA, Genzyme, Sanofi and Merck. E. Martinez-Heras has nothing to disclose. S. Groppa has nothing to disclose. G. González-Escamilla has nothing to disclose. M. A. Rocca received speaker honoraria from Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva and receives research support from the MS Society of Canada and Fondazione Italiana Sclerosi Multipla. M. Filippi is the Editor in Chief of the Journal of Neurology and Associate Editor of Human Brain Mapping; received compensation for consulting services and/or speaking activities from Almiral, Alexion, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, Takeda, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). E. A. Høgestøl received honoraria for lecturing and for advisory board activity from Biogen, Merck, and Sanofi-Genzyme and has unrestricted research grant from Merck. H. F. Harbo has nothing to disclose. M. A. Foster is supported by an MRC grant (MR/S026088/1). S. Collorone is supported by the Rosetrees Trust (A1332, MS632), and she was awarded a MAGNIMS-ECTRIMS fellowship in 2016. A. Toosy has been supported by grants from MRC (MR/S026088/1), NIHR BRC (541/CAP/OC/818837), and RoseTrees Trust (A1332 and PGL21/ 10079); has had meeting expenses from Merck, Biomedia, and Biogen Idec; and was UK PI for two clinical trials sponsored by MEDDAY (MS-ON - NCT02220244 and MS-SPI2 - NCT02220244). M. M. Schoonheim serves on the editorial board of Neurology and Frontiers in Neurology; receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS, and ZonMW; and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, Genzyme, MedDay, and Merck. E. Strijbis has nothing to disclose. G. Pontillo has received research grants from ECTRIMS-MAGNIMS and ESNR. M. Petracca discloses travel/meeting expenses from Novartis, Roche, and Merck; speaking honoraria from HEALTH&LIFE S.r.l. and honoraria for consulting services from Biogen; and research grants from Baroni Foundation. A. Rovira serves/served on the scientific advisory boards for Novartis, Sanofi-Genzyme, Synthetic MR, TensorMedical, Roche, Biogen, and OLEA Medical; has received speaker honoraria from Bayer, Sanofi-Genzyme, Merck-Serono, Teva Pharmaceutical Industries Ltd., Novartis, Roche, Bristol-Myers, and Biogen; and receives research support from Fondo de Investigación en Salud (PI19/00950) from Instituto de Salud Carlos III, Spain. G. Deco has nothing to disclose. D. Pareto has received a research contract from Biogen Idec and receives research support from Fondo de Investigación en Salud (PI18/00823, PI22/01709) from Instituto de Salud Carlos III, Spain, co-funded by the European Union., (© 2024 Massachusetts Institute of Technology.)

The potential for combining serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels to predict worsening disability in multiple sclerosis remains underexplored. We aimed to investigate whether sNfL and sGFAP values identify distinct subgroups of patients according to the risk of disability worsening and their response to disease-modifying treatments (DMTs). This multicentre study, conducted across 13 European hospitals, spanned from 15 July 1994 to 18 August 2022, with follow-up until 26 September 2023. We enrolled patients with multiple sclerosis who had serum samples collected within 12 months from disease onset and before initiating DMTs. Multivariable regression models were used to estimate the risk of relapse-associated worsening (RAW), progression independent of relapse activity (PIRA) and Expanded Disability Status Scale (EDSS) score of 3. Of the 725 patients included, the median age was 34.2 (interquartile range, 27.6-42.4) years, and 509 patients (70.2%) were female. The median follow-up duration was 6.43 (interquartile range, 4.65-9.81) years. Higher sNfL values were associated with an elevated risk of RAW [hazard ratio (HR) of 1.45; 95% confidence interval (CI) 1.19-1.76; P < 0.001], PIRA (HR of 1.43; 95% CI 1.13-1.81; P = 0.003) and reaching an EDSS of 3 (HR of 1.55; 95% CI 1.29-1.85; P < 0.001). Moreover, higher sGFAP levels were linked to a higher risk of achieving an EDSS score of 3 (HR of 1.36; 95% CI 1.06-1.74; P = 0.02) and, in patients with low sNfL values, to PIRA (HR of 1.86; 95% CI 1.01-3.45; P = 0.04). We also examined the combined effect of sNfL and sGFAP levels. Patients with low sNfL and sGFAP values exhibited a low risk of all outcomes and served as a reference. Untreated patients with high sNfL levels showed a higher risk of RAW, PIRA and reaching an EDSS of 3. Injectable or oral DMTs reduced the risk of RAW in these patients but failed to mitigate the risk of PIRA and reaching an EDSS of 3. Conversely, high-efficacy DMTs counteracted the heightened risk of these outcomes, except for the risk of PIRA in patients with high sNfL and sGFAP levels. Patients with low sNfL and high sGFAP values showed an increased risk of PIRA and achieving an EDSS of 3, which remained unchanged with either high-efficacy or other DMTs. In conclusion, evaluating sNfL and sGFAP levels at disease onset in multiple sclerosis might identify distinct phenotypes associated with diverse immunological pathways of disability acquisition and therapeutic response., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Objectives: Disentangling brain aging from disease-related neurodegeneration in patients with multiple sclerosis (PwMS) is increasingly topical. The brain-age paradigm offers a window into this problem but may miss disease-specific effects. In this study, we investigated whether a disease-specific model might complement the brain-age gap (BAG) by capturing aspects unique to MS., Methods: In this retrospective study, we collected 3D T1-weighted brain MRI scans of PwMS to build (1) a cross-sectional multicentric cohort for age and disease duration (DD) modeling and (2) a longitudinal single-center cohort of patients with early MS as a clinical use case. We trained and evaluated a 3D DenseNet architecture to predict DD from minimally preprocessed images while age predictions were obtained with the DeepBrainNet model. The brain-predicted DD gap (the difference between predicted and actual duration) was proposed as a DD-adjusted global measure of MS-specific brain damage. Model predictions were scrutinized to assess the influence of lesions and brain volumes while the DD gap was biologically and clinically validated within a linear model framework assessing its relationship with BAG and physical disability measured with the Expanded Disability Status Scale (EDSS)., Results: We gathered MRI scans of 4,392 PwMS (69.7% female, age: 42.8 ± 10.6 years, DD: 11.4 ± 9.3 years) from 15 centers while the early MS cohort included 749 sessions from 252 patients (64.7% female, age: 34.5 ± 8.3 years, DD: 0.7 ± 1.2 years). Our model predicted DD better than chance (mean absolute error = 5.63 years, R 2 = 0.34) and was nearly orthogonal to the brain-age model (correlation between DD and BAGs: r = 0.06 [0.00-0.13], p = 0.07). Predictions were influenced by distributed variations in brain volume and, unlike brain-predicted age, were sensitive to MS lesions (difference between unfilled and filled scans: 0.55 years [0.51-0.59], p < 0.001). DD gap significantly explained EDSS changes ( B = 0.060 [0.038-0.082], p < 0.001), adding to BAG (Δ R 2 = 0.012, p < 0.001). Longitudinally, increasing DD gap was associated with greater annualized EDSS change ( r = 0.50 [0.39-0.60], p < 0.001), with an incremental contribution in explaining disability worsening compared with changes in BAG alone (Δ R 2 = 0.064, p < 0.001)., Discussion: The brain-predicted DD gap is sensitive to MS-related lesions and brain atrophy, adds to the brain-age paradigm in explaining physical disability both cross-sectionally and longitudinally, and may be used as an MS-specific biomarker of disease severity and progression.

Background and Objectives: Recovery of vision after acute optic neuritis (AON) is critical to improving the quality of life of people with demyelinating diseases. The objective of the study was to prospectively assess the changes in visual acuity, retinal layer thickness, and cortical visual network in patients with AON to identify the predictors of permanent visual disability., Methods: We studied a prospective cohort of 88 consecutive patients with AON with 6-month follow-up using high and low-contrast (2.5%) visual acuity, color vision, retinal thickness from optical coherence tomography, latencies and amplitudes of multifocal visual evoked potentials, mean deviation of visual fields, and diffusion-based structural (n = 53) and functional (n = 19) brain MRI to analyze the cortical visual network. The primary outcome was 2.5% low-contrast vision, and data were analyzed with mixed-effects and multivariate regression models., Results: We found that after 6 months, low-contrast vision and quality of vision remained moderately impaired. The thickness of the ganglion cell layer at baseline was a predictor of low-contrast vision 6 months later (ß = 0.49 [CI 0.11-0.88], p = 0.012). The structural cortical visual network at baseline predicted low-contrast vision, the best predictors being the betweenness of the right parahippocampal cortex (ß = -036 [CI -0.66 to 0.06], p = 0.021), the node strength of the right V3 (ß = 1.72 [CI 0.29-3.15], p = 0.02), and the clustering coefficient of the left intraparietal sulcus (ß = 57.8 [CI 12.3-103.4], p = 0.015). The functional cortical visual network at baseline also predicted low-contrast vision, the best predictors being the betweenness of the left ventral occipital cortex (ß = 8.6 [CI: 4.03-13.3], p = 0.009), the node strength of the right intraparietal sulcus (ß = -2.79 [CI: -5.1-0.4], p = 0.03), and the clustering coefficient of the left superior parietal lobule (ß = 501.5 [CI 50.8-952.2], p = 0.03)., Discussion: The assessment of the visual pathway at baseline predicts permanent vision disability after AON, indicating that damage is produced early after disease onset and that it can be used for defining vision impairment and guiding therapy.

Background and Objectives: The 2023 criteria for myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) perform well in adults but have not been assessed in children., Methods: This prospective observational nationwide study includes children and adults with demyelinating syndromes or encephalitis, whose serum or CSF was found MOG-immunoglobulin G (IgG) positive at Institut d'Investigacions Biomèdiques August Pi i Sunyer-Hospital Clínic of Barcelona (Spain). Exclusion criteria were lack of clinical information and follow-up <1 year, and serum unavailable for antibody testing. The primary outcome was to assess the accuracy of the 2023 MOGAD criteria, using as gold standard the most plausible diagnosis after a follow-up >1 year. MOGAD criteria were retrospectively applied assessing core syndromes, supportive clinical-radiological features, and MOG-IgG titers. Patients tested ≤3 months of a disease attack (acute phase) or afterward (remission) were considered separately. The positive predictive value (PPV) of the criteria (true-positive [patients classified as MOGAD and MOGAD diagnosis last follow-up] divided by total positive [all patients classified as MOGAD]), and its 95% CI, was calculated with the Wilson procedure., Results: A total of 257 patients (133 children) were included in the study (median age 15 years [interquartile range 6-38], 54% female). Among 202 patients assessed during a disease attack, 158 (78%) had high MOG-IgG serum titers, 36 (18%) low titers, and 8 (4%) antibodies only in CSF. No differences were identified between patients with high and low titers, but those with low titers were more likely to have an alternative diagnosis at last follow-up (2/36 [6%] vs 0/158, p = 0.012). Supportive features were present in 230 of 257 (89%) patients, regardless of age, MOG-IgG titers, and core syndromes except for optic neuritis in adults whose assessment with orbital MRI was not systematic. Overall, 240 of 257 (94%) patients were well classified by the MOGAD criteria (e.g., 236 eventually having MOGAD and 4 alternative diagnoses), and 17 were wrongly classified (e.g., 11 eventually having MOGAD and 6 alternative diagnoses). Although the criteria classified better during disease attacks than during remissions (187 [96%] vs 49 [89%] serum MOG-IgG-positive patients were well-classified, p = 0.038), the PPV was high in both settings (99% [95% CI 97-100] vs 98% [95% CI 89-100])., Discussion: The 2023 MOGAD criteria correctly identified most children and adults with MOGAD. The highest accuracy occurred when they were applied during disease attacks., Classification of Evidence: This study provides Class IV evidence that the 2023 MOGAD criteria accurately identify adults and children with MOGAD.

Objectives: In MOG antibody-associated disease (MOGAD), relapse prevention and the treatment approach to refractory symptoms are unknown. We report a patient with refractory MOGAD treated with CD19-directed CAR T-cells., Methods: CD19-directed CAR T-cells (ARI-0001) were produced in-house by lentiviral transduction of autologous fresh leukapheresis and infused after a conventional lymphodepleting regimen., Results: A 18-year-old man developed 2 episodes of myelitis associated with serum MOG-IgG, which were followed by 6 episodes of left optic neuritis (ON) and sustained the presence of MOG-IgG over 6 years despite multiple immunotherapies. After the sixth episode of ON, accompanied by severe residual visual deficits, CAR T-cell treatment was provided without complications. Follow-up of cell counts showed complete depletion of CD19 + B cells at day +7; reconstituted B cells at day +141 showing a naïve B-cell phenotype, and low or absent memory B cells and plasmablasts for 1 year. MOG-IgG titers have remained undetectable since CAR T-cell infusion. The patient had an early episode of left ON at day +29, when MOG-IgG was already negative, and since then he has remained free of relapses without immunotherapy for 1 year., Discussion: This clinical case shows that CD19-directed CAR T-cell therapy is well-tolerated and is a potential treatment for patients with refractory MOGAD., Classification of Evidence: This provides Class IV evidence. It is a single observational study without controls.

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.

Objective: To evaluate: (1) the distribution of gray matter (GM) atrophy in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), and relapsing-remitting multiple sclerosis (RRMS); and (2) the relationship between GM volumes and white matter lesions in various brain regions within each disease., Methods: A retrospective, multicenter analysis of magnetic resonance imaging data included patients with MOGAD/AQP4+NMOSD/RRMS in non-acute disease stage. Voxel-wise analyses and general linear models were used to evaluate the relevance of regional GM atrophy. For significant results (p < 0.05), volumes of atrophic areas are reported., Results: We studied 135 MOGAD patients, 135 AQP4+NMOSD, 175 RRMS, and 144 healthy controls (HC). Compared with HC, MOGAD showed lower GM volumes in the temporal lobes, deep GM, insula, and cingulate cortex (75.79 cm 3 ); AQP4+NMOSD in the occipital cortex (32.83 cm 3 ); and RRMS diffusely in the GM (260.61 cm 3 ). MOGAD showed more pronounced temporal cortex atrophy than RRMS (6.71 cm 3 ), whereas AQP4+NMOSD displayed greater occipital cortex atrophy than RRMS (19.82 cm 3 ). RRMS demonstrated more pronounced deep GM atrophy in comparison with MOGAD (27.90 cm 3 ) and AQP4+NMOSD (47.04 cm 3 ). In MOGAD, higher periventricular and cortical/juxtacortical lesions were linked to reduced temporal cortex, deep GM, and insula volumes. In RRMS, the diffuse GM atrophy was associated with lesions in all locations. AQP4+NMOSD showed no lesion/GM volume correlation., Interpretation: GM atrophy is more widespread in RRMS compared with the other two conditions. MOGAD primarily affects the temporal cortex, whereas AQP4+NMOSD mainly involves the occipital cortex. In MOGAD and RRMS, lesion-related tract degeneration is associated with atrophy, but this link is absent in AQP4+NMOSD. ANN NEUROL 2024;96:276-288., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Objectives: The complement system is known to play a role in multiple sclerosis (MS) pathogenesis. However, its contribution to disease progression remains elusive. The study investigated the role of the complement system in disability progression of patients with primary progressive MS (PPMS)., Methods: Sixty-eight patients with PPMS from 12 European MS centers were included in the study. Serum and CSF levels of a panel of complement components (CCs) were measured by multiplex enzyme-linked immunosorbent assay at a baseline time point (i.e., sampling). Mean (SD) follow-up time from baseline was 9.6 (4.8) years. Only one patient (1.5%) was treated during follow-up. Univariable and multivariable logistic regressions adjusted for age, sex, and albumin quotient were performed to assess the association between baseline CC levels and disability progression in short term (2 years), medium term (6 years), and long term (at the time of the last follow-up)., Results: In short term, CC played little or no role in disability progression. In medium term, an elevated serum C3a/C3 ratio was associated with a higher risk of disability progression (adjusted OR 2.30; 95% CI 1.17-6.03; p = 0.040). By contrast, increased CSF C1q levels were associated with a trend toward reduced risk of disability progression (adjusted OR 0.43; 95% CI 0.17-0.98; p = 0.054). Similarly, in long term, an elevated serum C3a/C3 ratio was associated with higher risk of disability progression (adjusted OR 1.81; 95% CI 1.09-3.40; p = 0.037), and increased CSF C1q levels predicted lower disability progression (adjusted OR 0.41; 95% CI 0.17-0.86; p = 0.025)., Discussion: Proteins involved in the activation of early complement cascades play a role in disability progression as risk (elevated serum C3a/C3 ratio) or protective (elevated CSF C1q) factors after 6 or more years of follow-up in patients with PPMS. The protective effects associated with C1q levels in CSF may be related to its neuroprotective and anti-inflammatory properties.

We aimed to compare the ability of diffusion tensor imaging and multi-compartment spherical mean technique to detect focal tissue damage and in distinguishing between different connectivity patterns associated with varying clinical outcomes in multiple sclerosis (MS). Seventy-six people diagnosed with MS were scanned using a SIEMENS Prisma Fit 3T magnetic resonance imaging (MRI), employing both conventional (T1w and fluid-attenuated inversion recovery) and advanced diffusion MRI sequences from which fractional anisotropy (FA) and microscopic FA (μFA) maps were generated. Using automated fiber quantification (AFQ), we assessed diffusion profiles across multiple white matter (WM) pathways to measure the sensitivity of anisotropy diffusion metrics in detecting localized tissue damage. In parallel, we analyzed structural brain connectivity in a specific patient cohort to fully grasp its relationships with cognitive and physical clinical outcomes. This evaluation comprehensively considered different patient categories, including cognitively preserved (CP), mild cognitive deficits (MCD), and cognitively impaired (CI) for cognitive assessment, as well as groups distinguished by physical impact: those with mild disability (Expanded Disability Status Scale [EDSS] <=3) and those with moderate-severe disability (EDSS >3). In our initial objective, we employed Ridge regression to forecast the presence of focal MS lesions, comparing the performance of μFA and FA. μFA exhibited a stronger association with tissue damage and a higher predictive precision for focal MS lesions across the tracts, achieving an R-squared value of .57, significantly outperforming the R-squared value of .24 for FA (p-value <.001). In structural connectivity, μFA exhibited more pronounced differences than FA in response to alteration in both cognitive and physical clinical scores in terms of effect size and number of connections. Regarding cognitive groups, FA differences between CP and MCD groups were limited to 0.5% of connections, mainly around the thalamus, while μFA revealed changes in 2.5% of connections. In the CP and CI group comparison, which have noticeable cognitive differences, the disparity was 5.6% for FA values and 32.5% for μFA. Similarly, μFA outperformed FA in detecting WM changes between the MCD and CI groups, with 5% versus 0.3% of connections, respectively. When analyzing structural connectivity between physical disability groups, μFA still demonstrated superior performance over FA, disclosing a 2.1% difference in connectivity between regions closely associated with physical disability in MS. In contrast, FA spotted a few regions, comprising only 0.6% of total connections. In summary, μFA emerged as a more effective tool than FA in predicting MS lesions and identifying structural changes across patients with different degrees of cognitive and global disability, offering deeper insights into the complexities of MS-related impairments., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Clinical research emphasizes the implementation of rigorous and reproducible study designs that rely on between-group matching or controlling for sources of biological variation such as subject's sex and age. However, corrections for body size (i.e. height and weight) are mostly lacking in clinical neuroimaging designs. This study investigates the importance of body size parameters in their relationship with spinal cord (SC) and brain magnetic resonance imaging (MRI) metrics. Data were derived from a cosmopolitan population of 267 healthy human adults (age 30.1±6.6 years old, 125 females). We show that body height correlated strongly or moderately with brain gray matter (GM) volume, cortical GM volume, total cerebellar volume, brainstem volume, and cross-sectional area (CSA) of cervical SC white matter (CSA-WM; 0.44≤r≤0.62). In comparison, age correlated weakly with cortical GM volume, precentral GM volume, and cortical thickness (-0.21≥r≥-0.27). Body weight correlated weakly with magnetization transfer ratio in the SC WM, dorsal columns, and lateral corticospinal tracts (-0.20≥r≥-0.23). Body weight further correlated weakly with the mean diffusivity derived from diffusion tensor imaging (DTI) in SC WM (r=-0.20) and dorsal columns (-0.21), but only in males. CSA-WM correlated strongly or moderately with brain volumes (0.39≤r≤0.64), and weakly with precentral gyrus thickness and DTI-based fractional anisotropy in SC dorsal columns and SC lateral corticospinal tracts (-0.22≥r≥-0.25). Linear mixture of sex and age explained 26±10% of data variance in brain volumetry and SC CSA. The amount of explained variance increased at 33±11% when body height was added into the mixture model. Age itself explained only 2±2% of such variance. In conclusion, body size is a significant biological variable. Along with sex and age, body size should therefore be included as a mandatory variable in the design of clinical neuroimaging studies examining SC and brain structure., Competing Interests: Declaration of interests Since June 2022, Dr. A.K. Smith has been employed by GE HealthCare. This article was co-authored by Dr. Smith in his personal capacity. The opinions expressed in the article are his in and do not necessarily reflect the views of GE HealthCare. Since August 2022, Dr. M. M. Laganà has been employed by Canon Medical Systems srl, Rome, Italy. This article was co-authored by Dr. M. M. Laganà in her personal capacity. The opinions expressed in the article are her own and do not necessarily reflect the views of Canon Medical Systems. Since September 2023, Dr. Papp has been an employee of Siemens Healthcare AB, Sweden. This article was co-authored by Dr. Papp in his personal capacity. The views and opinions expressed in this article are his own and do not necessarily reflect the views of Siemens Healthcare AB, or Siemens Healthineers AG. Since January 2024, Dr. Barry has been employed by the National Institute of Biomedical Imaging and Bioengineering at the NIH. This article was co-authored by Robert Barry in his personal capacity. The opinions expressed in the article are his own and do not necessarily reflect the views of the NIH, the Department of Health and Human Services, or the United States government. Guillaume Gilbert is an employee of Philips Healthcare. S Llufriu received compensation for consulting services and speaker honoraria from Biogen Idec, Novartis, Bristol Myer Squibb Genzyme, Sanofi Jansen and Merck. The Max Planck Institute for Human Cognitive and Brain Sciences and Wellcome Centre for Human Neuroimaging have institutional research agreements with Siemens Healthcare. NW holds a patent on acquisition of MRI data during spoiler gradients (US 10,401,453 B2). NW was a speaker at an event organized by Siemens Healthcare and was reimbursed for the travel expenses. The other authors declare no competing interests.

Background: We aimed to investigate the potential of serum biomarker levels to predict disability progression in a multicentric real-world cohort of patients with primary progressive multiple sclerosis (PPMS)., Methods: A total of 141 patients with PPMS from 18 European MS centres were included. Disability progression was investigated using change in Expanded Disability Status Scale (EDSS) score over three time intervals: baseline to 2 years, 6 years and to the last follow-up. Serum levels of neurofilament light chain (sNfL), glial fibrillar acidic protein (sGFAP) and chitinase 3-like 1 (sCHI3L1) were measured using single-molecule array assays at baseline. Correlations between biomarker levels, and between biomarkers and age were quantified using Spearman's r. Univariable and multivariable linear models were performed to assess associations between biomarker levels and EDSS change over the different time periods., Results: Median (IQR) age of patients was 52.9 (46.4-58.5) years, and 58 (41.1%) were men. Median follow-up time was 9.1 (7.0-12.6) years. Only 8 (5.7%) patients received treatment during follow-up. sNfL and sGFAP levels were moderately correlated (r=0.43) and both weakly correlated with sCHI3L1 levels (r=0.19 and r=0.17, respectively). In multivariable analyses, levels of the three biomarkers were associated with EDSS changes across all time periods. However, when analysis was restricted to non-inflammatory patients according to clinical and radiological parameters (n=64), only sCHI3L1 levels remained associated with future EDSS change., Conclusions: Levels of sNfL, sGFAP and sCHI3L1 are prognostic biomarkers associated with disability progression in patients with PPMS, being CHI3L1 findings less dependent on the inflammatory component associated with disease progression., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We investigated the association between changes in retinal thickness and cognition in people with MS (PwMS), exploring the predictive value of optical coherence tomography (OCT) markers of neuroaxonal damage for global cognitive decline at different periods of disease., Method: We quantified the peripapillary retinal nerve fibre (pRFNL) and ganglion cell-inner plexiform (GCIPL) layers thicknesses of 207 PwMS and performed neuropsychological evaluations. The cohort was divided based on disease duration (≤5 years or >5 years). We studied associations between changes in OCT and cognition over time, and assessed the risk of cognitive decline of a pRFNL≤88 µm or GCIPL≤77 µm and its predictive value., Results: Changes in pRFNL and GCIPL thickness over 3.2 years were associated with evolution of cognitive scores, in the entire cohort and in patients with more than 5 years of disease (p<0.01). Changes in cognition were related to less use of disease-modifying drugs, but not OCT metrics in PwMS within 5 years of onset. A pRFNL≤88 µm was associated with earlier cognitive disability (3.7 vs 9.9 years) and higher risk of cognitive deterioration (HR=1.64, p=0.022). A GCIPL≤77 µm was not associated with a higher risk of cognitive decline, but a trend was observed at ≤91.5 µm in PwMS with longer disease (HR=1.81, p=0.061)., Conclusions: The progressive retinal thinning is related to cognitive decline, indicating that cognitive dysfunction is a late manifestation of accumulated neuroaxonal damage. Quantifying the pRFNL aids in identifying individuals at risk of cognitive dysfunction., Competing Interests: Competing interests: ES received travel reimbursement from Sanofi, Merck and ECTRIMS. EL-S holds a predoctoral grant from the University of Barcelona (APIF) and she received travel support from Sanofi, IP-V received travel reimbursement from Roche and Genzyme, and she holds stock options in Aura Innovative Robotics. Currently, she is an employee at UCB Pharma, her contribution to this work is associated with her previous work at IDIBAPS; MA holds equity shares of Bionure, S.L. and Goodgut S.L. and stock options of Attune Neurosciences. He is currently an employee of Roche, although his contribution to this work is associated with his previous work at IDIBAPS; MS received speaker honoraria from Genzyme, Novartis and Biogen; JMC received speaker honoraria from Sanfi; EF received funding for an ECTRIMS Clinical Training Fellowship Programme; AC is supported by the ECTRIMS post-doc fellowship (2022), previously received a UK MS Society PhD studentship (2020), a Guarantors of Brain “Entry” clinical fellowship (2019), and an ECTRIMS-MAGNIMS fellowship (2018). He received travel reimbursement from UK MS society, ECTRIMS, NAIMS. AS received compensation for consulting services and speaker honoraria from Bayer-Schering, Merck-Serono, Biogen-Idec, Sanofi-Aventis, TEVA, Novartis and Roche; EHML received travel support for international and national meetings from Roche and Sanofi-Genzyme, and honoraria for consultancies from Novartis, Roche and Sanofi before 16 April 2019. She is currently employed by the European Medicines Agency (Human Medicines) since 16 April 2019. This article is related to her activity under Hospital Clinic of Barcelona/IDIBAPS affiliation and consequently, as external activity, it does not represent the views of the Agency or its Committees. She is a member of the International Multiple Sclerosis Visual System (IMSVISUAL) Consortium; PV is a shareholder and has received consultancy fees from Accure Therapeutics SL, Attune Neurosciences, QMenta, Spiral Therapeutix, CLight and NeuroPrex, as well as having held grants from the Instituto de Salud Carlos III and the European Commissions; YB received speaking honoraria from Biogen, Novartis and Genzyme; BS-D received compensation for consulting services and speaker honoraria from Chiesi and Sanofi-Genzyme and holds equity shares of Accure Therapeutics S.L. SL received compensation for consulting services and speaker honoraria from Biogen Idec, Novartis, TEVA, Genzyme, Sanofi, Merck and Bristol-Myers Squibb, and holds grants from the Instituto de Salud Carlos III., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Multiple sclerosis patients would benefit from machine learning algorithms that integrates clinical, imaging and multimodal biomarkers to define the risk of disease activity., Methods: We have analysed a prospective multi-centric cohort of 322 MS patients and 98 healthy controls from four MS centres, collecting disability scales at baseline and 2 years later. Imaging data included brain MRI and optical coherence tomography, and omics included genotyping, cytomics and phosphoproteomic data from peripheral blood mononuclear cells. Predictors of clinical outcomes were searched using Random Forest algorithms. Assessment of the algorithm performance was conducted in an independent prospective cohort of 271 MS patients from a single centre., Results: We found algorithms for predicting confirmed disability accumulation for the different scales, no evidence of disease activity (NEDA), onset of immunotherapy and the escalation from low- to high-efficacy therapy with intermediate to high-accuracy. This accuracy was achieved for most of the predictors using clinical data alone or in combination with imaging data. Still, in some cases, the addition of omics data slightly increased algorithm performance. Accuracies were comparable in both cohorts., Conclusion: Combining clinical, imaging and omics data with machine learning helps identify MS patients at risk of disability worsening., (© 2023. The Author(s).)

Complex diseases such as Multiple Sclerosis (MS) cover a wide range of biological scales, from genes and proteins to cells and tissues, up to the full organism. In fact, any phenotype for an organism is dictated by the interplay among these scales. We conducted a multilayer network analysis and deep phenotyping with multi-omics data (genomics, phosphoproteomics and cytomics), brain and retinal imaging, and clinical data, obtained from a multicenter prospective cohort of 328 patients and 90 healthy controls. Multilayer networks were constructed using mutual information for topological analysis, and Boolean simulations were constructed using Pearson correlation to identified paths within and among all layers. The path more commonly found from the Boolean simulations connects protein MK03, with total T cells, the thickness of the retinal nerve fiber layer (RNFL), and the walking speed. This path contains nodes involved in protein phosphorylation, glial cell differentiation, and regulation of stress-activated MAPK cascade, among others. Specific paths identified were subsequently analyzed by flow cytometry at the single-cell level. Combinations of several proteins (GSK3AB, HSBP1 or RS6) and immune cells (Th17, Th1 non-classic, CD8, CD8 Treg, CD56 neg, and B memory) were part of the paths explaining the clinical phenotype. The advantage of the path identified from the Boolean simulations is that it connects information about these known biological pathways with the layers at higher scales (retina damage and disability). Overall, the identified paths provide a means to connect the molecular aspects of MS with the overall phenotype., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: KK reports no disclosures. NKdR reports no disclosures. AU received grants and contracts from FISM, Novartis, Biogen, Merck, Fondazione Cariplo, Italian Ministry of Health, received honoraria, or consultation fees from Biogen, Roche, Teva, Merck, Genzyme, Novartis. FI reports no disclosures. MC reports no disclosures. HFH has received honoraria for lecturing or advice from Biogen, Merck, Roche, Novartis and Sanofi. TB has received unrestricted research grants from Biogen and Sanofi-Genzyme. SDB reports no disclosures. EH received honoraria for lecturing and advisory board activity from Biogen, Merck and Sanofi-Genzyme and unrestricted research grant from Merck. SBI reports no disclosures. SAdRB reports no disclosures. FP received honoraria and research support from Alexion, Bayer, Biogen, Chugai, Merck Serono, Novartis, Genzyme, MedImmune, Shire, Teva, and serves on scientific advisory boards for Alexion, MedImmune, and Novartis. He has received funding from Deutsche Forschungsgemeinschaft (DFG Exc 257), Bundesministerium fu?r Bildung und Forschung (Competence Network Multiple Sclerosis), Guthy Jackson Charitable Foundation, EU Framework Program 7, National Multiple Sclerosis Society of the USA. AUB is named as inventor on multiple patents and patents pending owned by Charité - Universitätsmedizin Berlin and/or University of California Irvine for visual computing-based motor function analysis, multiple sclerosis serum biomarkers, and retinal image analysis. He is cofounder and holds shares of Motognosis GmbH and Nocturne GmbH. He serves on the executive board and is Treasurer/Secretary of IMSVISUAL. He received research support from BMWi, BMBF, NIH ICTS, the Kathleen C. Moore Foundation and the Guthy- Jackson Charitable Foundation. Priscilla Ba?cker-Koduah is funded by the DFG Excellence grant to FP (DFG exc 257) and is a Junior scholar of the Einstein Foundation. CC received honoraria for speaking from Bayer and research funding from Novartis, unrelated to this study. SA received a conference grant from Celgene and honoraria for speaking from Alexion, Bayer and Roche. JB reports no disclosures. JSR declares funding from GSK & Sanofi and fees from Travere Therapeutics & Singularity Bio. MR reports no disclosures. LGA is founder and hold stocks at ProtATonce. MA is an employee of Hoffman-La Roche AG, yet this article is related to his activity at the Hospital Clinic of Barcelona. EHML is an employee of the European Medicines Agency (Human Medicines) since 16 April 2019, yet this article is related to her activity at the Hospital Clinic of Barcelona and consequently, it does not in any way represent the views of the Agency or its Committees. SL received compensation for consulting services and speaker honoraria from Biogen Idec, Novartis, TEVA, Genzyme, Sanofi and Merck. AS received compensation for consulting services and speaker honoraria from Bayer-Schering, Merck- Serono, Biogen-Idec, Sanofi-Aventis, TEVA, Novartis and Roche. EMH reports no disclosures. Elisabeth Solana received travel reimbursement from Sanofi and ECTRIMS and reports personal fees from Roche Spain. IPV is currently an employee of UCB pharma, yet this article is related to her activity at the Hospital Clinic of Barcelona. She has received travel reimbursement from Roche Spain and Genzyme-Sanofi, European Academy of Neurology, and European Committee for Treatment and Research in Multiple Sclerosis for international and national meetings over the last 3 years; she holds a patent for an affordable eye-tracking system to measure eye movement in neurologic diseases, and she holds stock in Aura Innovative Robotics. JGO reports no disclosures. PV has received consultancy fees and held stocks from Accure Therapeutics SL, Attune Neurosciences Inc, Spiral Therapeutics Inc, QMenta Inc, CLight Inc, NeuroPrex Inc, StimuSIL and Adhera Health Inc, (Copyright: © 2024 Kennedy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: We aimed to describe the severity of the changes in brain diffusion-based connectivity as multiple sclerosis (MS) progresses and the microstructural characteristics of these networks that are associated with distinct MS phenotypes., Methods: Clinical information and brain MRIs were collected from 221 healthy individuals and 823 people with MS at 8 MAGNIMS centres. The patients were divided into four clinical phenotypes: clinically isolated syndrome, relapsing-remitting, secondary progressive and primary progressive. Advanced tractography methods were used to obtain connectivity matrices. Then, differences in whole-brain and nodal graph-derived measures, and in the fractional anisotropy of connections between groups were analysed. Support vector machine algorithms were used to classify groups., Results: Clinically isolated syndrome and relapsing-remitting patients shared similar network changes relative to controls. However, most global and local network properties differed in secondary progressive patients compared with the other groups, with lower fractional anisotropy in most connections. Primary progressive participants had fewer differences in global and local graph measures compared with clinically isolated syndrome and relapsing-remitting patients, and reductions in fractional anisotropy were only evident for a few connections. The accuracy of support vector machine to discriminate patients from healthy controls based on connection was 81%, and ranged between 64% and 74% in distinguishing among the clinical phenotypes., Conclusions: In conclusion, brain connectivity is disrupted in MS and has differential patterns according to the phenotype. Secondary progressive is associated with more widespread changes in connectivity. Additionally, classification tasks can distinguish between MS types, with subcortical connections being the most important factor., Competing Interests: Competing interests: ES and EL-S received travel reimbursement from Sanofi and ECTRIMS; AC received support from the ECTRIMS-MAGNIMS fellowship (2018) and, was granted a postdoctoral fellowship from ECTRIMS in 2022; AS received compensation for consulting services and speaker honoraria from Merck, Biogen-Idec, Sanofi, Novartis, Roche, Janssen and Horizon Therapeutics; YB received speaking honoraria from Biogen, Novartis and Genzyme; SL received compensation for consulting services and speaker honoraria from Biogen Idec, Novartis, TEVA, Genzyme, Sanofi and Merck. MMS serves on the editorial board of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and ZonMW and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, Genzyme, MedDay and Merck. HV has received research grants from Pfizer, Merck Serono, Novartis. and Teva; speaker honoraria from Novartis; and consulting fees from Merck Serono, all paid directly to his institution. FB: Steering committee and iDMC member for Biogen, Merck, Roche, EISAI. Consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics. Research agreements with Novartis, Merck, Biogen, GE, Roche. Co-founder and shareholder of Queen Square Analytics LTD. MAR received speaker honoraria from Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva and research support from the Canadian MS Society and Fondazione Italiana Sclerosi Multipla. MF is editor-in-chief of the Journal of Neurology and Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology, received compensation for consulting services and/or speaking activities from Alexion, Almirall, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, Takeda, and Teva Pharmaceutical Industries, and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, the Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). BB received financial support by the German Federal Ministry for Education and Research, BMBF, German Competence Network Multiple Sclerosis (KKNMS), grant no.01GI1601I. CL received a research grant by the German Federal Ministry for Education and Research, BMBF, German Competence Network Multiple Sclerosis (KKNMS), grant no.01GI1601I, has received consulting and speaker’s honoraria from Biogen Idec, Bayer Schering, Daiichi Sanykyo, Merck Serono, Novartis, Sanofi, Genzyme and TEVA. AR serves on scientific advisory boards for Novartis, Sanofi-Genzyme, Synthetic MR, TensorMedical, Roche, Biogen, and OLEA Medical, and has received speaker honoraria from Bayer, Sanofi-Genzyme, Merck-Serono, Teva Pharmaceutical Industries, Novartis, Roche, Bristol-Myers and Biogen. JS-G serves as co-editor for Europe on the editorial board of Multiple Sclerosis Journal and as editor-in-chief in Revista de Neurología, receives research support from Fondo de Investigaciones Sanitarias (19/950) and has served as a consultant/speaker for Biogen, Celgene/Bristol Meyers Squibb, Genzyme, Novartis, Merck and Roche. AT has been supported by grants from MRC (MR/S026088/1), NIHR BRC (541/CAP/OC/818837) and RoseTrees Trust (A1332 and PGL21/10079), has had meeting expenses from Merck, Biomedia and Biogen Idec and was UK PI for two clinical trials sponsored by MEDDAY (MS-ON-NCT02220244 and MS-SPI2-NCT02220244). OC acts as a consultant for Novartis and Merck, and has received research funding from: NIHR, UK MS Society, NIHR UCLH BRC, MRC, Rosetrees Trust., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Autoimmune neurological diseases (ANDs) are a specific type of autoimmune disease that affect cells within the central and peripheral nervous system. ANDs trigger various physical/neuropsychiatric symptoms. However, language impairments in people with ANDs are not well characterized. Here we aimed to determine the kinds of language impairment that most commonly emerge in 10 ANDs, the characteristics of the patients (demographic, neurological damage), and the assessment methods used., Methods: We followed the PRISMA Extension for Scoping Reviews (PRISMA-ScR). PubMed and Google Scholar were searched. We used a list of search terms containing 10 types of ANDs (e.g., multiple sclerosis, acute disseminated encephalomyelitis) in combination with the terms aphasia, dysphasia, fluency, language, listening, morphology, phonology, pragmatics, reading, semantics, speaking, syntax, writing. The reference lists and citations of the relevant papers were also investigated. The type of AND, patient characteristics, neurological damage and examination technique, language tests administered, and main findings were noted for each study meeting the inclusion criteria., Results: We found 171 studies meeting our inclusion criteria. These comprised group studies and case studies. Language impairments differed largely among types of ANDs. Neurological findings were mentioned in most of the papers, but specific language tests were rarely used., Conclusions: Language symptoms in people with ANDs are commonly reported. These are often not full descriptions or only focus on specific time points in the course of the disease. Future research needs to assess specific language functions in people with ANDs and relate their language impairments to brain damage at different stages of disease evolution., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Background and Objective: In people with multiple sclerosis (pwMS), concern for potential disease exacerbation or triggering of other autoimmune disorders contributes to vaccine hesitancy. We assessed the humoral and T-cell responses to SARS-CoV-2 after mRNA vaccination, changes in disease activity, and development of antibodies against central or peripheral nervous system antigens., Methods: This was a prospective 1-year longitudinal observational study of pwMS and a control group of patients with other inflammatory neurologic disorders (OIND) who received an mRNA vaccine. Blood samples were obtained before the first dose (T1), 1 month after the first dose (T2), 1 month after the second dose (T3), and 6 (T4), 9 (T5), and 12 (T6) months after the first dose. Patients were assessed for the immune-specific response, annualized relapse rate (ARR), and antibodies to onconeuronal, neural surface, glial, ganglioside, and nodo-paranodal antigens., Results: Among 454 patients studied, 390 had MS (22 adolescents) and 64 OIND; the mean (SD) age was 44 (14) years; 315 (69%) were female; and 392 (87%) were on disease-modifying therapies. Antibodies to the receptor-binding domain were detected in 367 (86%) patients at T3 and 276 (83%) at T4. After a third dose, only 13 (22%) of 60 seronegative patients seroconverted, and 255 (92%) remained seropositive at T6. Cellular responses were present in 381 (93%) patients at T3 and in 235 (91%) patients at T6 including all those receiving anti-CD20 therapies and in 79% of patients receiving fingolimod. At T3 (429 patients) or T6 (395 patients), none of the patients had developed CNS autoantibodies. Seven patients had neural antibodies that were already present before immunization (3 adult patients with MS had MOG-IgG, 2 with MG and 1 with MS had neuronal cell surface antibodies [unknown antigen], and 1 with MS had myelin antibody reactivity [unknown antigen]. Similarly, no antibodies against PNS antigens were identified at T3 (427 patients). ARR was lower in MS and not significantly different in patients with OIND. Although 182 (40%) patients developed SARS-CoV-2 infection, no cases of severe COVID-19 or serious adverse events occurred., Discussion: In this study, mRNA COVID-19 vaccination was safe and did not exacerbate the autoimmune disease nor triggered neural autoantibodies or immune-mediated neurologic disorders. The outcome of patients who developed SARS-CoV-2 infection was favorable., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction: Magnetic resonance imaging (MRI) is widely used for the diagnosis and follow-up of patients with multiple sclerosis (MS). Coordination between neurology and neuroradiology departments is crucial for performing and interpreting radiological studies as efficiently and as accurately as possible. However, improvements can be made in the communication between these departments in many Spanish hospitals., Methods: A panel of 17 neurologists and neuroradiologists from 8 Spanish hospitals held in-person and online meetings to draft a series of good practice guidelines for the coordinated management of MS. The drafting process included 4 phases: 1) establishing the scope of the guidelines and the methodology of the study; 2) literature review on good practices or recommendations on the use of MRI in MS; 3) discussion and consensus between experts; and 4) validation of the contents., Results: The expert panel agreed a total of 9 recommendations for improving coordination between neurology and neuroradiology departments. The recommendations revolve around 4 main pillars: 1) standardising the process for requesting and scheduling MRI studies and reports; 2) designing common protocols for MRI studies; 3) establishing multidisciplinary committees and coordination meetings; and 4) creating formal communication channels between both departments., Conclusions: These consensus recommendations are intended to optimise coordination between neurologists and neuroradiologists, with the ultimate goal of improving the diagnosis and follow-up of patients with MS., (Copyright © 2021 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: On 4 and 5 November 2022, Madrid hosted the 15th edition of the Post-ECTRIMS Meeting, where neurologists specialised in multiple sclerosis outlined the latest developments presented at the 2022 ECTRIMS Congress, held in Amsterdam from 26 to 28 October., Aim: To synthesise the content presented at the 15th edition of the Post-ECTRIMS Meeting, in an article broken down into two parts., Development: This second part describes the new developments in terms of therapeutic strategies for escalation and de-escalation of disease-modifying therapies (DMT), when and in whom to initiate or switch to highly effective DMT, the definition of therapeutic failure, the possibility of treating radiologically isolated syndrome and the future of personalised treatment and precision medicine. It also considers the efficacy and safety of autologous haematopoietic stem cell transplantation, different approaches in clinical trial design and outcome measures to assess DMT in progressive stages, challenges in the diagnosis and treatment of cognitive impairment, and treatment in special situations (pregnancy, comorbidity and the elderly). In addition, results from some of the latest studies with oral cladribine and evobrutinib presented at ECTRIMS 2022 are shown.

The relationship between structural connectivity (SC) and functional connectivity (FC) captured from magnetic resonance imaging, as well as its interaction with disability and cognitive impairment, is not well understood in people with multiple sclerosis (pwMS). The Virtual Brain (TVB) is an open-source brain simulator for creating personalized brain models using SC and FC. The aim of this study was to explore SC-FC relationship in MS using TVB. Two different model regimes have been studied: stable and oscillatory, with the latter including conduction delays in the brain. The models were applied to 513 pwMS and 208 healthy controls (HC) from 7 different centers. Models were analyzed using structural damage, global diffusion properties, clinical disability, cognitive scores, and graph-derived metrics from both simulated and empirical FC. For the stable model, higher SC-FC coupling was associated with pwMS with low Single Digit Modalities Test (SDMT) score (F=3.48, P$\lt$0.05), suggesting that cognitive impairment in pwMS is associated with a higher SC-FC coupling. Differences in entropy of the simulated FC between HC, high and low SDMT groups (F=31.57, P$\lt$1e-5), show that the model captures subtle differences not detected in the empirical FC, suggesting the existence of compensatory and maladaptive mechanisms between SC and FC in MS., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

MRI and clinical features of myelin oligodendrocyte glycoprotein (MOG)-antibody disease may overlap with those of other inflammatory demyelinating conditions posing diagnostic challenges, especially in non-acute phases and when serologic testing for MOG antibodies is unavailable or shows uncertain results. We aimed to identify MRI and clinical markers that differentiate non-acute MOG-antibody disease from aquaporin 4 (AQP4)-antibody neuromyelitis optica spectrum disorder and relapsing remitting multiple sclerosis, guiding in the identification of patients with MOG-antibody disease in clinical practice. In this cross-sectional retrospective study, data from 16 MAGNIMS centres were included. Data collection and analyses were conducted from 2019 to 2021. Inclusion criteria were: diagnosis of MOG-antibody disease; AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis; brain and cord MRI at least 6 months from relapse; and Expanded Disability Status Scale (EDSS) score on the day of MRI. Brain white matter T2 lesions, T1-hypointense lesions, cortical and cord lesions were identified. Random forest models were constructed to classify patients as MOG-antibody disease/AQP4-neuromyelitis optica spectrum disorder/multiple sclerosis; a leave one out cross-validation procedure assessed the performance of the models. Based on the best discriminators between diseases, we proposed a guide to target investigations for MOG-antibody disease. One hundred and sixty-two patients with MOG-antibody disease [99 females, mean age: 41 (±14) years, median EDSS: 2 (0-7.5)], 162 with AQP4-neuromyelitis optica spectrum disorder [132 females, mean age: 51 (±14) years, median EDSS: 3.5 (0-8)], 189 with multiple sclerosis (132 females, mean age: 40 (±10) years, median EDSS: 2 (0-8)] and 152 healthy controls (91 females) were studied. In young patients (<34 years), with low disability (EDSS < 3), the absence of Dawson's fingers, temporal lobe lesions and longitudinally extensive lesions in the cervical cord pointed towards a diagnosis of MOG-antibody disease instead of the other two diseases (accuracy: 76%, sensitivity: 81%, specificity: 84%, P < 0.001). In these non-acute patients, the number of brain lesions < 6 predicted MOG-antibody disease versus multiple sclerosis (accuracy: 83%, sensitivity: 82%, specificity: 83%, P < 0.001). An EDSS < 3 and the absence of longitudinally extensive lesions in the cervical cord predicted MOG-antibody disease versus AQP4-neuromyelitis optica spectrum disorder (accuracy: 76%, sensitivity: 89%, specificity: 62%, P < 0.001). A workflow with sequential tests and supporting features is proposed to guide better identification of patients with MOG-antibody disease. Adult patients with non-acute MOG-antibody disease showed distinctive clinical and MRI features when compared to AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis. A careful inspection of the morphology of brain and cord lesions together with clinical information can guide further analyses towards the diagnosis of MOG-antibody disease in clinical practice., (© 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.)

Importance: The value of serum neurofilament light chain (sNfL) levels for predicting long-term disability in patients with multiple sclerosis (MS) remains controversial., Objective: To assess whether high sNfL values are associated with disability worsening in patients who underwent their first demyelinating MS event., Design, Setting, and Participants: This multicenter cohort study included patients who underwent their first demyelinating event suggestive of MS at Hospital Universitario Ramón y Cajal (development cohort; June 1, 1994, to September 31, 2021, with follow-up until August 31, 2022) and 8 Spanish hospitals (validation cohort; October 1, 1995, to August 4, 2020, with follow-up until August 16, 2022)., Exposures: Clinical evaluations at least every 6 months., Main Outcomes and Measures: The main outcomes were 6-month confirmed disability worsening (CDW) and an Expanded Disability Status Scale (EDSS) score of 3. Levels of sNfL were measured in blood samples obtained within 12 months after disease onset using a single molecule array kit. The cutoffs used were sNfL level of 10 pg/mL and a standardized score (z score) of 1.5. Multivariable Cox proportional hazards regression models were used to evaluate outcomes., Results: Of the 578 patients included in the study, 327 were in the development cohort (median age at sNfL analysis, 34.1 years [IQR, 27.2-42.7 years]; 226 female [69.1%]) and 251 patients were in the validation cohort (median age at sNfL analysis, 33.3 years [IQR, 27.4-41.5 years]; 184 female [73.3%]). The median follow-up was 7.10 years (IQR, 4.18-10.0 years). Levels of sNfL greater than 10 pg/mL were independently associated with higher risk of 6-month CDW and an EDSS of 3 in the development cohort (6-month CDW: hazard ratio [HR], 2.39; 95% CI, 1.39-4.12; P = .002; EDSS of 3: HR, 4.12; 95% CI, 2.18-7.77; P < .001) and the validation cohort (6-month CDW: HR, 1.61; 95% CI, 1.07-2.42; P = .02; EDSS of 3: HR, 2.03; 95% CI, 1.23-3.33; P = .005). Highly effective disease-modifying treatments were associated with lower risks of 6-month CDW and an EDSS of 3 in patients with high baseline sNfL values., Conclusions and Relevance: This cohort study found that high sNfL values obtained within the first year of disease were associated with long-term disability worsening in MS, suggesting that sNfL level measurement may help identify optimal candidates for highly effective disease-modifying treatments.

Optic neuritis (ON) often occurs at the presentation of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). The recommended treatment of high-dose corticosteroids for ON is based on a North American study population, which did not address treatment timing or antibody serostatus. The Acute Optic Neuritis Network (ACON) presents a global, prospective, observational study protocol primarily designed to investigate the effect of time to high-dose corticosteroid treatment on 6-month visual outcomes in ON. Patients presenting within 30 days of the inaugural ON will be enrolled. For the primary analysis, patients will subsequently be assigned into the MS-ON group, the aquapotin-4-IgG positive ON (AQP4-IgG+ON) group or the MOG-IgG positive ON (MOG-IgG+ON) group and then further sub-stratified according to the number of days from the onset of visual loss to high-dose corticosteroids ( days-to-Rx ). The primary outcome measure will be high-contrast best-corrected visual acuity (HC-BCVA) at 6 months. In addition, multimodal data will be collected in subjects with any ON (CIS-ON, MS-ON, AQP4-IgG+ON or MOG-IgG+ON, and seronegative non-MS-ON), excluding infectious and granulomatous ON. Secondary outcomes include low-contrast best-corrected visual acuity (LC-BCVA), optical coherence tomography (OCT), magnetic resonance imaging (MRI) measurements, serum and cerebrospinal fluid (CSF) biomarkers (AQP4-IgG and MOG-IgG levels, neurofilament, and glial fibrillary protein), and patient reported outcome measures (headache, visual function in daily routine, depression, and quality of life questionnaires) at presentation at 6-month and 12-month follow-up visits. Data will be collected from 28 academic hospitals from Africa, Asia, the Middle East, Europe, North America, South America, and Australia. Planned recruitment consists of 100 MS-ON, 50 AQP4-IgG+ON, and 50 MOG-IgG+ON. This prospective, multimodal data collection will assess the potential value of early high-dose corticosteroid treatment, investigate the interrelations between functional impairments and structural changes, and evaluate the diagnostic yield of laboratory biomarkers. This analysis has the ability to substantially improve treatment strategies and the accuracy of diagnostic stratification in acute demyelinating ON., Trial Registration: ClinicalTrials.gov, identifier: NCT05605951., Competing Interests: SA has received speaker honoraria from Alexion, Bayer, and Roche. JB reports payment for consultation from Horizon Therapeutics, Alexion, Antigenomycs, BeiGene, Chugai, Clene Nanomedicine, Genentech, Reistone Bio, Roche, Imcyse, and TG; grants from Alexion, Novartis, and the National Institutes of Health. In addition, JB has a patent on Compositions and methods for the treatment of neuromyelitis optica. YB has received speaker honoraria from Novartis, Roche, Genzyme-Sanofi, Merck, and Biogen. EC has received reimbursement for developing educational presentations, educational and research grants, consultation fees, and/or travel stipends from Biogen Argentina, Genzyme Argentina, Merck Argentina and LATAM, Roche Argentina and LATAM, Raffo, Novartis Argentina, LACTRIMS, and The Guthy-Jackson Charitable Foundation. JC has served on advisory boards for Horizon, Roche, and UCB. CC has received honoraria for speaking from Bayer and research funding from Novartis. JD has received royalties from Wolters Kluwer, Neurology—UpToDate and from Medlink Neurology as contributing author, from Athena Diagnostics for the use of Ma2 as an autoantibody test, and from Euroimmun for the use of NMDA-receptor, GABA(B)-receptor, GABA(A)-receptor, DPPX, and IgLON5 as autoantibody tests and has received research support from Advance Medical (allosteric modulation of NMDAR) SAGE Therapeutics, Instituto Carlos III/FEDER (FIS PI20/00197, CIBERER CB15/00010, Proyectos Integrados de Excelencia, PIE 16/00014 and AC18/00009), Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR), CERCA Programme Generalitat de Catalunya, ERA-NET NEURON, La Caixa Foundation Health Research Award, Pablove Foundation Childhood Cancer Grant, Safra Foundation, Sage therapeutics, Cellex Foundation, and La Caixa Health Foundation. EF has served on advisory boards for Alexion, Genentech, Horizon Therapeutics, and UCB. He has received speaker honoraria from Pharmacy Times. He received royalties from up-to-date. EF was a site primary investigator in a randomized clinical trial on Inebilizumab in neuromyelitis optica spectrum disorder run by Medimmune/Viela-Bio/Horizon Therapeutics. EF has received funding from the NIH (R01NS113828). EF is a member of the medical advisory board of the MOG project. EF is an editorial board member of the Journal of the Neurological Sciences and Neuroimmunology Reports. A patent has been submitted on DACH1-IgG as a biomarker of paraneoplastic autoimmunity. CF participates in a regional medical board advisory of Alexion. CG-A has received grants from Biogen Colombia. JH reports grants for OCT research from the Friedrich-Baur-Stiftung and Merck, personal fees, and non-financial support from Celgene, Janssen, Bayer, Merck, Alexion, Horizon, Novartis, Roche, Biogen, and non-financial support of the Guthy-Jackson Charitable Foundation, all outside the submitted work. JH was partially funded by the German Federal Ministry of Education and Research [(DIFUTURE), Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H]]. HK has received a grant from the National Research Foundation of Korea; consultancy/speaker fees or research support from Alexion, Aprilbio, Altos Biologics, Biogen, Celltrion, Daewoong, Eisai, GC Pharma, HanAll BioPharma, Handok, Horizon Therapeutics (formerly Viela Bio), Kolon Life Science, MDimune, Mitsubishi Tanabe Pharma, Merck Serono, Novartis, Roche, Sanofi Genzyme, Teva-Handok, and UCB; and is a coeditor for the Multiple Sclerosis Journal and an associated editor for the Journal of Clinical Neurology. CLM reports consultancy fees for Chiesi Farmaceutici, Regulatory PharmaNet, and Thenewway Srl and received speaker honoraria and/or travel support for meetings from Santhera Pharmaceuticals, Chiesi Farmaceutici, Regulatory Pharma Net, Thenewway Srl, First Class Srl, and Biologix. ML-P has received funding for travel and speaker honoraria from Novartis, Biogen, and Roche. MLei was funded by NHS (Myasthenia and Related Disorders Service and National Specialized Commissioning Group for Neuromyelitis Optica, UK) and by the University of Oxford, UK. She has been awarded research grants from the UK association for patients with myasthenia—Myaware and the University of Oxford. She has received speaker honoraria or travel grants from Biogen Idec, Novartis, Argenx, UCB, and the Guthy–Jackson Charitable Foundation. MLei serves on scientific or educational advisory boards for UCB Pharma, Argenx, and Viela/Horizon. SL has received consulting fees and speaker honoraria from Biogen, Novartis, TEVA, Genzyme, Sanofy, and Merck. PL has received reimbursement for developing educational presentations, educational and research grants, consultation fees, and/or travel stipends from Biogen Argentina and LATAM, Genzyme Argentina, Merck Argentina, Roche Argentina, Novartis Argentina, and LACTRIMS. AL has served as a Biogen, Bristol Myers Squibb, Merck Serono, Novartis, Roche, Sanofi/Genzyme, and Teva Advisory Board Member, has received congress and travel/accommodation expense compensations, or speaker honoraria from Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi/Genzyme, Teva, and Fondazione Italiana Sclerosi Multipla (FISM), her institutions received research grants from Novartis and Sanofi/Genzyme. SMo reports consultancy fees (Invex Therapeutics); advisory board fees (Invex therapeutics, Gensight); and speaker fees (Heidelberg engineering, Chugai-Roche Ltd., Allergan, Santen, Chiesi, and Santhera), all outside the submitted work. RM serves on scientific advisory boards for Alexion, Horizon Therapeutics, Roche, and UCB has received speaker honoraria from Alexion, Biogen, Horizon Therapeutics, Novartis, Roche, and Sanofi Genzyme, has received support for attending scientific meetings by Merck and Euroimmun, has received speaker honoraria from Biogen and Novartis. SMa received speaker honoraria for presenting at scientific meetings by Novartis and Biogen. SMo reports consultancy fees (Invex Therapeutics); advisory board fees (Invex therapeutics, Gensight); and speaker fees (Heidelberg engineering, Chugai-Roche Ltd., Allergan, Santen, Chiesi, and Santhera). All outside the submitted work. FC receives ongoing research support from the National Multiple Sclerosis Society (NMSS), the American Academy of Neurology (AAN), and Deutsche Gesellschaft für Neurologie (DGN). JPa has received support for scientific meetings and honorariums for advisory work from Merck Serono, Novartis, Chugai, Alexion, Roche, Medimmune, Argenx, UCB, Mitsubishi, Amplo, Janssen, and Sanofi. Grants from Alexion, Roche, Medimmune, UCB, and Amplo biotechnology. Patent ref P37347WO and license agreement Numares multimarker MS diagnostics Shares in AstraZeneca. Acknowledges Partial funding by Highly specialized services NHS England. SP is a named inventor on filed patents that relate to functional AQP4/NMO-IgG assays and NMO-IgG as a cancer marker, was consulted for Alexion and MedImmune, has received research support from Grifols, MedImmune, and Alexion, all compensation for consulting activities is paid directly to Mayo Clinic. SR has received research funding from the National Health and Medical Research Council (Australia), the Petre Foundation, the Brain Foundation (Australia), the Royal Australasian College of Physicians, and the University of Sydney. She was supported by an NHMRC Investigator Grant (GNT2008339). She serves as a consultant on an advisory board for UCB and Limbic Neurology and has been an invited speaker for Biogen, Excemed, and Limbic Neurology. AS received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck-Serono, Sanofi, Biogen, Roche, Novartis, Alexion, Janssen, and Horizon Therapeutics. DS received a grant from the National Multiple Sclerosis Society and serves on several advisory committees for the Multiple Sclerosis International Federation in unpaid roles. MS received speaker honoraria from Teva Pharmaceuticals and has received funding from the German Research Foundation, Federal Ministry of Education and Research and Federal Ministry for Economic Affairs and Energy, Volkswagen Stiftung, and Berlin Institute of Health. He is holding patents for the 3D printing of computed tomography models and is a shareholder of PhantomX and MSC3D. All unrelated to this work. PSu has served on advisory boards for Horizon Therapeutics, Viridian Therapeutics, Invex Therapeutics, Kriya Therapeutics, and GenSight Biologics. He receives research support from the NIH, DOD, Horizon, Invex, and Viridian. AM has received a grant for Biopas Laboratories and reports speaking fees from Chiesi. HZ received research grants from Novartis and speaking fees from Bayer Healthcare, unrelated to this project. FP served on the scientific advisory boards of Novartis and MedImmune; received travel funding and/or speaker honoraria from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, and Shire; is an associate editor of Neurology: Neuroimmunology & Neuroinflammation; is an academic editor of PLoS ONE; consulted for Sanofi Genzyme, Biogen, MedImmune, Shire, and Alexion; received research support from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Geynzme, Alexion, and Merck Serono; and received research support from the German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, EU FP7 Framework Program, Arthur Arnstein Foundation Berlin, Guthy-Jackson Charitable Foundation, and NMSS. HS-K received speaker honoraria from Roche. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Asseyer, Asgari, Bennett, Bialer, Blanco, Bosello, Camos-Carreras, Carnero Contentti, Carta, Chen, Chien, Chomba, Dale, Dalmau, Feldmann, Flanagan, Froment Tilikete, Garcia-Alfonso, Havla, Hellmann, Kim, Klyscz, Konietschke, La Morgia, Lana-Peixoto, Leite, Levin, Levy, Llufriu, Lopez, Lotan, Lugaresi, Marignier, Mariotto, Mollan, Ocampo, Cosima Oertel, Olszewska, Palace, Pandit, Peralta Uribe, Pittock, Ramanathan, Rattanathamsakul, Saiz, Samadzadeh, Sanchez-Dalmau, Saylor, Scheel, Schmitz-Hübsch, Shifa, Siritho, Sperber, Subramanian, Tiosano, Vaknin-Dembinsky, Mejia Vergara, Wilf-Yarkoni, Zarco, Zimmermann, Paul and Stiebel-Kalish.)

Multisite machine-learning neuroimaging studies, such as those conducted by the ENIGMA Consortium, need to remove the differences between sites to avoid effects of the site (EoS) that may prevent or fraudulently help the creation of prediction models, leading to impoverished or inflated prediction accuracy. Unfortunately, we have shown earlier that current Methods Aiming to Remove the EoS (MAREoS, e.g., ComBat) cannot remove complex EoS (e.g., including interactions between regions). And complex EoS may bias the accuracy. To overcome this hurdle, groups worldwide are developing novel MAREoS. However, we cannot assess their effectiveness because EoS may either inflate or shrink the accuracy, and MAREoS may both remove the EoS and degrade the data. In this work, we propose a strategy to measure the effectiveness of a MAREoS in removing different types of EoS. FOR MAREOS DEVELOPERS, we provide two multisite MRI datasets with only simple true effects (i.e., detectable by most machine-learning algorithms) and two with only simple EoS (i.e., removable by most MAREoS). First, they should use these datasets to fit machine-learning algorithms after applying the MAREoS. Second, they should use the formulas we provide to calculate the relative accuracy change associated with the MAREoS in each dataset and derive an EoS-removal effectiveness statistic. We also offer similar datasets and formulas for complex true effects and EoS that include first-order interactions. FOR MACHINE-LEARNING RESEARCHERS, we provide an extendable benchmark website to show: a) the types of EoS they should remove for each given machine-learning algorithm and b) the effectiveness of each MAREoS for removing each type of EoS. Relevantly, a MAREoS only able to remove the simple EoS may suffice for simple machine-learning algorithms, whereas more complex algorithms need a MAREoS that can remove more complex EoS. For instance, ComBat removes all simple EoS as needed for predictions based on simple lasso algorithms, but it leaves residual complex EoS that may bias the predictions based on standard support vector machine algorithms., (Copyright © 2022. Published by Elsevier Inc.)

T 2 -hyperintense lesions are the key imaging marker of multiple sclerosis (MS). Previous studies have shown that the white matter surrounding such lesions is often also affected by MS. Our aim was to develop a new method to visualize and quantify the extent of white matter tissue changes in MS based on relaxometry properties. We applied a fast, multi-parametric quantitative MRI approach and used a multi-component MR Fingerprinting (MC-MRF) analysis. We assessed the differences in the MRF component representing prolongedrelaxation time between patients with MS and controls and studied the relation between this component's volume and structural white matter damage identified on FLAIR MRI scans in patients with MS. A total of 48 MS patients at two different sites and 12 healthy controls were scanned with FLAIR and MRF-EPI MRI scans. MRF scans were analyzed with a joint-sparsity multi-component analysis to obtain magnetization fraction maps of different components, representing tissues such as myelin water, white matter, gray matter and cerebrospinal fluid. In the MS patients, an additional component was identified with increased transverse relaxation times compared to the white matter, likely representing changes in free water content. Patients with MS had a higher volume of the long- component in the white matter of the brain compared to healthy controls (B (95%-CI) = 0.004 (0.0006-0.008), p = 0.02). Furthermore, this MRF component had a moderate correlation (correlation coefficient R 0.47) with visible structural white matter changes on the FLAIR scans. Also, the component was found to be more extensive compared to structural white matter changes in 73% of MS patients. In conclusion, our MRF acquisition and analysis captured white matter tissue changes in MS patients compared to controls. In patients these tissue changes were more extensive compared to visually detectable white matter changes on FLAIR scans. Our method provides a novel way to quantify the extent of white matter changes in MS patients, which is underestimated using only conventional clinical MRI scans., 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 Author(s). Published by Elsevier Inc. All rights reserved.)

The consequences of extremely intense long-term exercise for brain health remain unknown. We studied the effects of strenuous exercise on brain structure and function, its dose-response relationship, and mechanisms in a rat model of endurance training. Five-week-old male Wistar rats were assigned to moderate (MOD) or intense (INT) exercise or a sedentary (SED) group for 16 weeks. MOD rats showed the highest motivation and learning capacity in operant conditioning experiments; SED and INT presented similar results. In vivo MRI demonstrated enhanced global and regional connectivity efficiency and clustering as well as a higher cerebral blood flow (CBF) in MOD but not INT rats compared with SED. In the cortex, downregulation of oxidative phosphorylation complex IV and AMPK activation denoted mitochondrial dysfunction in INT rats. An imbalance in cortical antioxidant capacity was found between MOD and INT rats. The MOD group showed the lowest hippocampal brain-derived neurotrophic factor levels. The mRNA and protein levels of inflammatory markers were similar in all groups. In conclusion, strenuous long-term exercise yields a lesser improvement in learning ability than moderate exercise. Blunting of MOD-induced improvements in CBF and connectivity efficiency, accompanied by impaired mitochondrial energetics and, possibly, transient local oxidative stress, may underlie the findings in intensively trained rats., (© 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences.)

This study describes the clinical characteristics, diagnostic results, treatment regimens, and clinical course of a cohort of patients with Susac syndrome (SS). It is a retrospective observational study of all patients with the diagnosis of SS evaluated at the Hospital Clinic (Barcelona, Spain) between March 2006 and November 2020. Nine patients were diagnosed with SS. The median time from the onset of the symptoms to diagnosis was five months (IQR 9.0), and the median follow-up time was 44 months (IQR 63.5). There was no clear predominance of sex, and mean age of symptoms onset was 36 years (range 19-59). Six patients (67%) presented with incomplete classical clinical triad, but this eventually developed in six patients during the disease course. Encephalopathy, focal neurological signs, visual disturbances, and hearing loss were the most frequent manifestations. Brain magnetic resonance imaging showed callosal lesions in all patients. Most were in remission within two years. Only four patients met the proposed criteria for definite SS. When SS is suspected, a detailed diagnostic workup should be performed and repeated over time to identify the clinical manifestations that will lead to a definite diagnosis.

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by demyelinating lesions that are often visible on magnetic resonance imaging (MRI). Segmentation of these lesions can provide imaging biomarkers of disease burden that can help monitor disease progression and the imaging response to treatment. Manual delineation of MRI lesions is tedious and prone to subjective bias, while automated lesion segmentation methods offer objectivity and speed, the latter being particularly important when analysing large datasets. Lesion segmentation can be broadly categorised into two groups: cross-sectional methods, which use imaging data acquired at a single time-point to characterise MRI lesions; and longitudinal methods, which use imaging data from the same subject acquired at two or more different time-points to characterise lesions over time. The main objective of longitudinal segmentation approaches is to more accurately detect the presence of new MS lesions and the growth or remission of existing lesions, which may be effective biomarkers of disease progression and treatment response. This paper reviews articles on longitudinal MS lesion segmentation methods published over the past 10 years. These are divided into traditional machine learning methods and deep learning techniques. PubMed articles using longitudinal information and comparing fully automatic two time point segmentations in any step of the process were selected. Nineteen articles were reviewed. There is an increasing number of deep learning techniques for longitudinal MS lesion segmentation that are promising to help better understand disease progression., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)