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Background Patients with neuromyelitis optica spectrum disorder (NMOSD) are often seropositive for antibodies against aquaporin-4 (AQP4). The importance of MRI monitoring in this disease requires evaluation. Purpose To profile MRI features from a large international cohort with AQP4 immunoglobulin G (IgG)-seropositive NMOSD (from the Parallel MRI in NMOSD [PAMRINO] study) and to evaluate and confirm existing knowledge regarding the incidence, location, and longitudinal development of characteristic lesions in the central nervous system associated with AQP4-IgG-seropositive NMOSD. Materials and Methods In this retrospective study (from August 2016 to January 2019), MRI and clinical data were collected from 17 NMOSD expert sites in 11 countries across four continents. Clinical features and lesions identified at cross-sectional and longitudinal MRI were assessed. No formal statistical tests were used to compare observations; however, means, SDs, and 95% CIs are reported when evaluating lesion frequencies. Results Available T1-weighted and T2-weighted MRI scans in patients with AQP4-IgG-seropositive NMOSD ( n = 525) were read. Among the 525 patients, 320 underwent cerebral MRI examinations with T2-weighted hyperintense cerebral (264 of 320; 82.5%), cerebellar (44 of 320; 13.8%), and brainstem (158 of 321 [49.2%], including one lesion observed at cervical spinal cord [SC] MRI) lesions. Lesions in the optic nerves, analyzed from 152 MRI examinations, were mainly found in the central (81 of 92; 88%) and posterior (79 of 92; 86%) sections (bilaterally in 39 of 92; 42%). Longitudinally extensive transverse myelitis was the predominant SC lesion pattern (upper compartment from 322 MRI examinations, 133 of 210 [63.3%]; and lower compartment from 301 MRI examinations, 149 of 212 [70.3%]). However, nonlongitudinal extensive transverse myelitis lesions were also observed frequently (105 of 210; 50.0%) in the cervical SC. Clinical data ( n = 349; mean age, 44 years ± 14 [SD]; 202 female patients) and acute lesions at contrast-enhanced (CE) MRI ( n = 58, performed within 30 days of the last attack) were evaluated. CE lesions were detected in the cerebrum (eight of 13; 62%), optic nerves (14 of 19; 74%), or chiasm (three of four; 75%) within 15 days of any relapse. In the upper SC (29 of 44; 66%), CE lesions were frequently observed up to 20 days after a clinical myelitis event. Conclusion A high incidence of abnormal brain MRI examinations and nonlongitudinal extensive SC lesions was found in patients in PAMRINO with AQP4-IgG-seropositive NMOSD. © RSNA, 2024 Supplemental material is available for this article.

Background and Objectives: The 2022 International Consortium for Optic Neuritis diagnostic criteria for optic neuritis (ON) include optical coherence tomography (OCT). The diagnostic value of intereye difference (IED) metrics is high for ON in patients with multiple sclerosis and aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders, but unknown in myelin oligodendrocyte glycoprotein antibody-associated ON (MOG-ON)., Methods: A multicenter validation study was conducted on the published IED cutoff values (>4% or >4 μm in the macular ganglion cell and inner plexiform layer [mGCIP] or >5% or >5 μm in the peripapillary retinal nerve fiber layer [pRNFL]) in individuals with MOG-ON and age-matched and sex-matched healthy controls (HCs). Structural data were acquired with Spectralis spectral-domain OCT >6 months after ON. We calculated sensitivity, specificity, and receiver operating characteristics for both intereye percentage (IEPD) and absolute difference (IEAD)., Results: A total of 66 individuals were included (MOG-ON N = 33; HCs N = 33). ON was unilateral in 20 and bilateral in 13 subjects. In the pooled analysis, the mGCIP IEPD was most sensitive (92%), followed by the mGCIP IEAD (88%) and pRNFL (84%). The same pattern was found for the specificity (mGCIP IEPD 82%, IEAD 82%; pRNFL IEPD 82%, IEAD 79%).In subgroup analyses, the diagnostic sensitivity was higher in subjects with unilateral ON (>99% for all metrics) compared with bilateral ON (61%-78%)., Discussion: In individuals with MOG-ON, the diagnostic accuracy of OCT-based IED metrics for ON was high, especially of mGCIP IEPD., Classification of Evidence: This study provides Class III evidence that the intereye difference on OCT can distinguish between those with MOG and normal 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.

Background and Objectives: To systematically describe the clinical picture of double-antibody seronegative neuromyelitis optica spectrum disorders (DN-NMOSD) with specific emphasis on retinal involvement., Methods: Cross-sectional data of 25 people with DN-NMOSD (48 eyes) with and without a history of optic neuritis (ON) were included in this study along with data from 25 people with aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder (AQP4-NMOSD, 46 eyes) and from 25 healthy controls (HCs, 49 eyes) for comparison. All groups were matched for age and sex and included from the collaborative retrospective study of retinal optical coherence tomography (OCT) in neuromyelitis optica (CROCTINO). Participants underwent OCT with central postprocessing and local neurologic examination and antibody testing. Retinal neurodegeneration was quantified as peripapillary retinal nerve fiber layer thickness (pRNFL) and combined ganglion cell and inner plexiform layer thickness (GCIPL)., Results: This DN-NMOSD cohort had a history of [median (inter-quartile range)] 6 (5; 9) attacks within their 5 ± 4 years since onset. Myelitis and ON were the most common attack types. In DN-NMOSD eyes after ON, pRNFL ( p < 0.001) and GCIPL ( p = 0.023) were thinner compared with eyes of HCs. Even after only one ON episode, DN-NMOSD eyes already had considerable neuroaxonal loss compared with HCs. In DN-NMOSD eyes without a history of ON, pRNFL ( p = 0.027) and GCIPL ( p = 0.022) were also reduced compared with eyes of HCs. However, there was no difference in pRNFL and GCIPL between DN-NMOSD and AQP4-NMOSD for the whole group and for subsets with a history of ON and without a history of ON-as well as between variances of retinal layer thicknesses., Discussion: DN-NMOSD is characterized by severe retinal damage after ON and attack-independent retinal neurodegeneration. Most of the damage occurs during the first ON episode, which highlights the need for better diagnostic markers in DN-NMOSD to facilitate an earlier diagnosis as well as for effective and early treatments. In this study, people with DN-NMOSD presented with homogeneous clinical and imaging findings potentially suggesting a common retinal pathology in these patients.

Retinal optical coherence tomography has been identified as biomarker for disease progression in relapsing-remitting multiple sclerosis (RRMS), while the dynamics of retinal atrophy in progressive MS are less clear. We investigated retinal layer thickness changes in RRMS, primary and secondary progressive MS (PPMS, SPMS), and their prognostic value for disease activity. Here, we analyzed 2651 OCT measurements of 195 RRMS, 87 SPMS, 125 PPMS patients, and 98 controls from five German MS centers after quality control. Peripapillary and macular retinal nerve fiber layer (pRNFL, mRNFL) thickness predicted future relapses in all MS and RRMS patients while mRNFL and ganglion cell-inner plexiform layer (GCIPL) thickness predicted future MRI activity in RRMS (mRNFL, GCIPL) and PPMS (GCIPL). mRNFL thickness predicted future disability progression in PPMS. However, thickness change rates were subject to considerable amounts of measurement variability. In conclusion, retinal degeneration, most pronounced of pRNFL and GCIPL, occurs in all subtypes. Using the current state of technology, longitudinal assessments of retinal thickness may not be suitable on a single patient level., (© 2024. The Author(s).)

This study aimed to identify quantitative biomarkers of motor function for cerebellar ataxia by evaluating gait and postural control using an RGB-depth camera-based motion analysis system. In 28 patients with degenerative cerebellar ataxia and 33 age- and sex-matched healthy controls, motor tasks (short-distance walk, closed feet stance, and stepping in place) were selected from a previously reported protocol, and scanned using Kinect V2 and customized software. The Clinical Assessment Scale for the Assessment and Rating of Ataxia (SARA) was also evaluated. Compared with the normal control group, the cerebellar ataxia group had slower gait speed and shorter step lengths, increased step width, and mediolateral trunk sway in the walk test (all P < 0.001). Lateral sway increased in the stance test in the ataxia group (P < 0.001). When stepping in place, the ataxia group showed higher arrhythmicity of stepping and increased stance time (P < 0.001). In the correlation analyses, the ataxia group showed a positive correlation between the total SARA score and arrhythmicity of stepping in place (r = 0.587, P = 0.001). SARA total score (r = 0.561, P = 0.002) and gait subscore (ρ = 0.556, P = 0.002) correlated with mediolateral truncal sway during walking. These results suggest that the RGB-depth camera-based motion analyses on mediolateral truncal sway during walking and arrhythmicity of stepping in place are useful digital motor biomarkers for the assessment of cerebellar ataxia, and could be utilized in future clinical trials., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Reproduction is a key feature of all organisms, yet the way in which it is achieved varies greatly across the tree of life. One striking example of this variation is the stick insect genus Bacillus, in which five different reproductive modes have been described: sex, facultative and obligate parthenogenesis, and two highly unusual reproductive modes: hybridogenesis and androgenesis. Under hybridogenesis, the entire genome from the paternal species is eliminated and replaced each generation by mating with the corresponding species. Under androgenesis, an egg is fertilized, but the developing diploid offspring bear two paternal genomes and no maternal genome, as a consequence of unknown mechanisms. Here, we reevaluate the previous descriptions of Bacillus lineages and the proposed F1 hybrid ancestries of the hybridogenetic and obligately parthenogenetic lineages (based on allozymes and karyotypes) from Sicily, where all these reproductive modes are found. We generate a chromosome-level genome assembly for a facultative parthenogenetic species (B. rossius) and combine extensive field sampling with RADseq and mtDNA data. We identify and genetically corroborate all previously described species and confirm the ancestry of hybrid lineages. All hybrid lineages have fully retained their F1 hybrid constitution throughout the genome, indicating that the elimination of the paternal genome in hybridogens is always complete and that obligate parthenogenesis in Bacillus hybrid species is not associated with an erosion of heterozygosity as known in other hybrid asexuals. Our results provide a stepping stone toward understanding the transitions between reproductive modes and the proximate mechanisms of genome elimination., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Society for the Study of Evolution (SSE).)

Purpose: The dietary practices (DPs) of university students are influenced by many external factors. Therefore, we investigate how the DPs of students in Germany changed during the SARS-CoV-2 pandemic, what the main motivations were for those changes, and what effect the closure of university catering had on the DPs of students., Methods: A total of 560 students from two universities in Lübeck (Germany) were surveyed online during a pilot phase. The final online questionnaire was subsequently administered at 10 other German universities (399 respondents). The questionnaire surveyed sociodemographic factors, dietary habits, food consumption frequencies, and the relevance of university catering before and during the SARS-CoV-2 pandemic., Results: Regarding changes in DPs, similarities to previous studies were found, especially positive eating behaviors and an increasing interest in health- and nutrition-related sustainability. Students prepared meals freshly more often during the pandemic; consumed legumes, plant-based meats and dairy alternatives more often; and reduced their consumption of meat and milk compared to before the pandemic. The consumption frequency of sweets also decreased. It was observed that students consider eating communal in the university canteen to be highly relevant for their social interactions, which was only possible to a limited extent during the pandemic., Conclusion: In Germany, the DPs of university students as well as criteria regarding health and sustainability changed during the first 2 years of the SARS-CoV-2 pandemic. The social aspect of DPs became evident due to closed university catering. Still, changes in dietary patterns and eating habits were positively related to health and revealed some differences in the cross section of the population., Competing Interests: The 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 © 2024 Dreyer, Brandt, Lichtenstein, Sina and Smollich.)

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.)

Objective: Retrograde trans-synaptic neuroaxonal degeneration is considered a key pathological factor of subclinical retinal neuroaxonal damage in multiple sclerosis (MS). We aim to evaluate the longitudinal association of optic radiation (OR) lesion activity with retinal neuroaxonal damage and its role in correlations between retinal and brain atrophy in people with clinically isolated syndrome and early MS (pweMS)., Methods: Eighty-five pweMS were retrospectively screened from a prospective cohort (Berlin CIS cohort). Participants underwent 3T magnetic resonance imaging (MRI) for OR lesion volume and brain atrophy measurements and optical coherence tomography (OCT) for retinal layer thickness measurements. All pweMS were followed with serial OCT and MRI over a median follow-up of 2.9 (interquartile range: 2.6-3.4) years. Eyes with a history of optic neuritis prior to study enrollment were excluded. Linear mixed models were used to analyze the association of retinal layer thinning with changes in OR lesion volume and brain atrophy., Results: Macular ganglion cell-inner plexiform layer (GCIPL) thinning was more pronounced in pweMS with OR lesion volume increase during follow-up compared to those without (Difference: -0.82 μm [95% CI:-1.49 to -0.15], p = 0.018). Furthermore, GCIPL thinning correlated with both OR lesion volume increase (β [95% CI] = -0.27 [-0.50 to -0.03], p = 0.028) and brain atrophy (β [95% CI] = 0.47 [0.25 to 0.70], p < 0.001). Correlations of GCIPL changes with brain atrophy did not differ between pweMS with or without OR lesion increase ( η p 2  = 5.92e -7 , p = 0.762)., Interpretation: Faster GCIPL thinning rate is associated with increased OR lesion load. Our results support the value of GCIPL as a sensitive biomarker reflecting both posterior visual pathway pathology and global brain neurodegeneration., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Neurodegeneration in multiple sclerosis (MS) affects the visual system but dynamics and pathomechanisms over several years especially in primary progressive MS (PPMS) are not fully understood., Methods: We assessed longitudinal changes in visual function, retinal neurodegeneration using optical coherence tomography, MRI and serum NfL (sNfL) levels in a prospective PPMS cohort and matched healthy controls. We investigated the changes over time, correlations between outcomes and with loss of visual function., Results: We followed 81 patients with PPMS (mean disease duration 5.9 years) over 2.7 years on average. Retinal nerve fibre layer thickness (RNFL) was reduced in comparison with controls (90.1 vs 97.8 µm; p<0.001). Visual function quantified by the area under the log contrast sensitivity function (AULCSF) remained stable over a continuous loss of RNFL (0.46 µm/year, 95% CI 0.10 to 0.82; p=0.015) up until a mean turning point of 91 µm from which the AULCSF deteriorated. Intereye RNFL asymmetry above 6 µm, suggestive of subclinical optic neuritis, occurred in 15 patients and was related to lower AULCSF but occurred also in 5 out of 44 controls. Patients with an AULCSF progression had a faster increase in Expanded Disability Status Scale (beta=0.17/year, p=0.043). sNfL levels were elevated in patients (12.2 pg/mL vs 8.0 pg/mL, p<0.001), but remained stable during follow-up (beta=-0.14 pg/mL/year, p=0.291) and were not associated with other outcomes., Conclusion: Whereas neurodegeneration in the anterior visual system is already present at onset, visual function is not impaired until a certain turning point. sNfL is not correlated with structural or functional impairment in the visual system., Competing Interests: Competing interests: MD has financial and intellectual property interests in and holds employment by Adaptive Sensory Technology. MAF has received honoraria as speaker and for consultation from Biogen, Lundbeck, Merck KGaA, Novartis and Roche. His research is funded by the Bundesministerium für Bildung und Forschung (BMBF), Deutsche Forschungsgemeinschaft (DFG), Landesforschungsförderung Hamburg, Gemeinnützige Hertie-Stiftung, Else Kröner-Fresenius-Stiftung, Fritz Thyssen-Stiftung, Werner Otto-Stiftung and Deutsche Multiple Sklerose-Gesellschaft. HZ received speaking honoraria from Bayer Healthcare and Novartis and research grants from Novartis., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

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

Background: In the demyelinating disease multiple sclerosis (MS), chronic-active brain inflammation, remyelination failure and neurodegeneration remain major issues despite immunotherapy. While B cell depletion and blockade/sequestration of T and B cells potently reduces episodic relapses, they act peripherally to allow persistence of chronic-active brain inflammation and progressive neurological dysfunction. N-acetyglucosamine (GlcNAc) is a triple modulator of inflammation, myelination and neurodegeneration. GlcNAc promotes biosynthesis of Asn (N)-linked-glycans, which interact with galectins to co-regulate the clustering/signaling/endocytosis of multiple glycoproteins simultaneously. In mice, GlcNAc crosses the blood brain barrier to raise N-glycan branching, suppress inflammatory demyelination by T and B cells and trigger stem/progenitor cell mediated myelin repair. MS clinical severity, demyelination lesion size and neurodegeneration inversely associate with a marker of endogenous GlcNAc, while in healthy humans, age-associated increases in endogenous GlcNAc promote T cell senescence., Objectives and Methods: An open label dose-escalation mechanistic trial of oral GlcNAc at 6 g (n = 18) and 12 g (n = 16) for 4 weeks was performed in MS patients on glatiramer acetate and not in relapse from March 2016 to December 2019 to assess changes in serum GlcNAc, lymphocyte N-glycosylation and inflammatory markers. Post-hoc analysis examined changes in serum neurofilament light chain (sNfL) as well as neurological disability via the Expanded Disability Status Scale (EDSS)., Results: Prior to GlcNAc therapy, high serum levels of the inflammatory cytokines IFNγ, IL-17 and IL-6 associated with reduced baseline levels of a marker of endogenous serum GlcNAc. Oral GlcNAc therapy was safe, raised serum levels and modulated N-glycan branching in lymphocytes. Glatiramer acetate reduces T H 1, T H 17 and B cell activity as well as sNfL, yet the addition of oral GlcNAc dose-dependently lowered serum IFNγ, IL-17, IL-6 and NfL. Oral GlcANc also dose-dependently reduced serum levels of the anti-inflammatory cytokine IL-10, which is increased in the brain of MS patients. 30% of treated patients displayed confirmed improvement in neurological disability, with an average EDSS score decrease of 0.52 points., Conclusions: Oral GlcNAc inhibits inflammation and neurodegeneration markers in MS patients despite concurrent immunomodulation by glatiramer acetate. Blinded studies are required to investigate GlcNAc's potential to control residual brain inflammation, myelin repair and neurodegeneration in MS., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Multiple sclerosis (MS) is one of the most prevalent chronic inflammatory diseases caused by demyelination and axonal damage in the central nervous system. Structural retinal imaging via optical coherence tomography (OCT) shows promise as a noninvasive biomarker for monitoring of MS. There are successful reports regarding the application of Artificial Intelligence (AI) in the analysis of cross-sectional OCTs in ophthalmologic diseases. However, the alteration of thicknesses of various retinal layers in MS is noticeably subtle compared to other ophthalmologic diseases. Therefore, raw cross-sectional OCTs are replaced with multilayer segmented OCTs for discrimination of MS and healthy controls (HCs)., Methods: To conform to the principles of trustworthy AI, interpretability is provided by visualizing the regional layer contribution to classification performance with the proposed occlusion sensitivity approach. The robustness of the classification is also guaranteed by showing the effectiveness of the algorithm while being tested on the new independent dataset. The most discriminative features from different topologies of the multilayer segmented OCTs are selected by the dimension reduction method. Support vector machine (SVM), random forest (RF), and artificial neural network (ANN) are used for classification. Patient-wise cross-validation (CV) is utilized to evaluate the performance of the algorithm, where the training and test folds contain records from different subjects., Results: The most discriminative topology is determined to square with a size of 40 pixels and the most influential layers are the ganglion cell and inner plexiform layer (GCIPL) and inner nuclear layer (INL). Linear SVM resulted in 88% Accuracy (with standard deviation (std) = 0.49 in 10 times of execution to indicate the repeatability), 78% precision (std=1.48), and 63% recall (std=1.35) in the discrimination of MS and HCs using macular multilayer segmented OCTs., Conclusion: The proposed classification algorithm is expected to help neurologists in the early diagnosis of MS. This paper distinguishes itself from other studies by employing two distinct datasets, which enhances the robustness of its findings in comparison with previous studies with lack of external validation. This study aims to circumvent the utilization of deep learning methods due to the limited quantity of the available data and convincingly demonstrates that favorable outcomes can be achieved without relying on deep learning techniques., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Functional connectome fingerprinting can identify individuals based on their functional connectome. Previous studies relied mostly on short intervals between fMRI acquisitions., Objective: This cohort study aimed to determine the stability of connectome-based identification and their underlying signatures in patients with multiple sclerosis and healthy individuals with long follow-up intervals., Methods: We acquired resting-state fMRI in 70 patients with multiple sclerosis and 273 healthy individuals with long follow-up times (up to 4 and 9 years, respectively). Using functional connectome fingerprinting, we examined the stability of the connectome and additionally investigated which regions, connections and networks supported individual identification. Finally, we predicted cognitive and behavioural outcome based on functional connectivity., Results: Multiple sclerosis patients showed connectome stability and identification accuracies similar to healthy individuals, with longer time delays between imaging sessions being associated with accuracies dropping from 89% to 76%. Lesion load, brain atrophy or cognitive impairment did not affect identification accuracies within the range of disease severity studied. Connections from the fronto-parietal and default mode network were consistently most distinctive, i.e., informative of identity. The functional connectivity also allowed the prediction of individual cognitive performances., Conclusion: Our results demonstrate that discriminatory signatures in the functional connectome are stable over extended periods of time in multiple sclerosis, resulting in similar identification accuracies and distinctive long-lasting functional connectome fingerprinting signatures in patients and healthy individuals., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article, (© The Author(s), 2023.)

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

Background and Purpose: Thinning of the retinal combined ganglion cell and inner plexiform layer (GCIP) as measured by optical coherence tomography (OCT) is a common finding in patients with multiple sclerosis. This study aimed to investigate whether a single retinal OCT analysis allows prediction of future disease activity after a first demyelinating event., Methods: This observational cohort study included 201 patients with recently diagnosed clinically isolated syndrome or relapsing-remitting multiple sclerosis from two German tertiary referral centers. Individuals underwent neurological examination, magnetic resonance imaging, and OCT at baseline and at yearly follow-up visits., Results: Patients were included at a median disease duration of 2.0 months. During a median follow-up of 59 (interquartile range = 43-71) months, 82% of patients had ongoing disease activity as demonstrated by failing the no evidence of disease activity 3 (NEDA-3) criteria, and 19% presented with confirmed disability worsening. A GCIP threshold of ≤77 μm at baseline identified patients with a high risk for NEDA-3 failure (hazard ratio [HR] = 1.7, 95% confidence interval [CI] = 1.1-2.8, p = 0.04), and GCIP measures of ≤69 μm predicted disability worsening (HR = 2.2, 95% CI = 1.2-4.3, p = 0.01). Higher rates of annualized GCIP loss increased the risk for disability worsening (HR = 2.5 per 1 μm/year increase of GCIP loss, p = 0.03)., Conclusions: Ganglion cell thickness as measured by OCT after the initial manifestation of multiple sclerosis may allow early risk stratification as to future disease activity and progression., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Retinal degeneration leading to optical coherence tomography (OCT) changes is frequent in patients with multiple sclerosis (PwMS)., Objective: To investigate associations among OCT changes, MRI measurements of global and regional brain volume loss, and physical and cognitive impairment in PwMS., Methods: 95 PwMS and 52 healthy controls underwent OCT and MRI examinations. Mean peripapillary retinal nerve fiber layer (pRNFL) thickness and ganglion cell/inner plexiform layer (GCIPL) volume were measured. In PwMS disability was quantified with the Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT). Associations between OCT, MRI, and clinical measures were investigated with multivariable regression models., Results: In PwMS, pRNFL and GCIPL were associated with the volume of whole brain (p < 0.04), total gray matter (p < 0.002), thalamus (p ≤ 0.04), and cerebral cortex (p ≤ 0.003) -both globally and regionally-, but not white matter. pRNFL and GCIPL were also inversely associated with T2-lesion volume (T2LV), especially in the optic radiations (p < 0.0001). The brain volumes associated with EDSS and SDMT significantly overlapped with those correlating with pRNFL and GCIPL., Conclusions: In PwMS, pRNFL and GCIPL reflect the integrity of clinically-relevant gray matter structures, underling the value of OCT measures as markers of neurodegeneration and disability in multiple sclerosis., (© 2023. The Author(s).)

Background: We evaluated the hydrostatic pressure of the renal pelvis (RPP) as a radiation-free alternative to fluoroscopic nephrostogram to assess ureteral patency after percutaneous nephrolithotomy (PCNL)., Methods: Retrospective non-inferiority study analyzing 248 PCNL-patients (86 female (35%) and 162 males (65%)) between 2007 and 2015. Postoperatively, RPP was measured using a central venous pressure manometer in cmH 2 O. The primary endpoint was to assess RPP depending on the patency of the ureter and the nephrostomy tube removal. Secondary, the upper limit of normal RPP of [Formula: see text] 20 cmH 2 O was assessed as an indicator of an unobstructed patency., Results: The median procedure duration was 141 min (112-171.5) with a stone free rate of 82% (n = 202). RPP was significantly higher in patients with obstructive nephrostogram with 25.0 mmH 2 O (21.0-32.0) versus 20.0 mmH 2 O (16.0-24.0; p < 0.001). The pressure was lower in successful nephrostomy removal with 18 cmH 2 O (15-21) versus 23 cmH 2 O (20-29) in the leakage group (p < 0.001). The analysis of a cut-off of [Formula: see text] 20 cmH 2 O showed a sensitivity of 76.9% (95% CI [60.7%; 88.9%]) and a specificity of 61.5% (95% CI [54.6%; 68.2%]). The negative predictive value was 93.4% (95% CI: [87.9%; 97.0%]) and the positive predictive value 27.3% (95% CI [19.2%; 36.6%]). The accuracy of the model showed an AUC = 0.795 (95% CI [0.668; 0.862])., Conclusion: The hydrostatic RPP seems to allow a bedside evaluation of ureteral patency after PCNL., (© 2023. The Author(s).)

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

Serum antibodies directed against myelin oligodendrocyte glycoprotein (MOG) are found in patients with acquired CNS demyelinating syndromes that are distinct from multiple sclerosis and aquaporin-4-seropositive neuromyelitis optica spectrum disorder. Based on an extensive literature review and a structured consensus process, we propose diagnostic criteria for MOG antibody-associated disease (MOGAD) in which the presence of MOG-IgG is a core criterion. According to our proposed criteria, MOGAD is typically associated with acute disseminated encephalomyelitis, optic neuritis, or transverse myelitis, and is less commonly associated with cerebral cortical encephalitis, brainstem presentations, or cerebellar presentations. MOGAD can present as either a monophasic or relapsing disease course, and MOG-IgG cell-based assays are important for diagnostic accuracy. Diagnoses such as multiple sclerosis need to be excluded, but not all patients with multiple sclerosis should undergo screening for MOG-IgG. These proposed diagnostic criteria require validation but have the potential to improve identification of individuals with MOGAD, which is essential to define long-term clinical outcomes, refine inclusion criteria for clinical trials, and identify predictors of a relapsing versus a monophasic disease course., Competing Interests: Declaration of interests BB has or will potentially receive financial compensation for consultancy effort for Novartis, Roche, UCB, Horizon Therapeutics, Biogen, and Immunic Therapeutics for advice on clinical trial design. BB is funded by the National Multiple Sclerosis Society, National Institute of Health, and has been previously funded by the Canadian Multiple Sclerosis Society. JLB has received research grants from Novartis, Mallinckrodt Pharmaceuticals, Alexion, and the National Institutes of Health, license fees from a US patent (2014/0170140); consulting fees from Horizon Therapeutics, Alexion, BeiGene Chugai Pharmaceutical, Genentech, Genzyme, Mitsubishi-Tanabe Pharma, Reistone Biopharma, Roche, and AbbVie; and serves on Data Safety Monitoring Boards for Roche, Genentech, and Clene Nanomedicine. RM reports personal fees from Horizon Therapeutics, Alexion, Roche, and UCB and non-financial support from Horizon Therapeutics, Merck, Biogen, and Roche, outside the submitted work. HJK received a grant from the National Research Foundation of Korea and research support from Aprilbio and Eisai; received consultancy and speaker fees from Alexion, Aprilbio, Altos Biologics, Biogen, Celltrion, Daewoong, Eisai, GC Pharma, HanAll BioPharma, Handok, Horizon Therapeutics (formerly Viela Bio), Kolon Life Science, Mdimune, Merck Serono, Mitsubishi Tanabe Pharma, Novartis, Roche, Sanofi Genzyme, Teva-Handok, and UCB; and is a co-editor for the Multiple Sclerosis Journal and an associated editor for the Journal of Clinical Neurology. FB has received research funding from the National Health and Medical Research Council (Australia), Multiple Sclerosis Research Australia, New South Wales Health, Novartis, and the University of Sydney (Sydney, NSW, Australia). She has received speaker honoraria from Novartis, Biogen, Merck, and Limbic Neurology, and has been on advisory boards for Merck and Novartis. She works at the University of Sydney and at the Children's Hospital at Westmead, Westmead, New South Wales, Australia, which offers MOG-IgG testing. EPF has served on advisory boards for Alexion, Genentech, and Horizon Therapeutics. He has received speaker honoraria from Pharmacy Times and royalties from UpToDate for a topic on MOGAD. He was a site primary investigator in a randomised clinical trial on inebilizumab in neuromyelitis optica spectrum disorder run by Horizon Therapeutics. He is principal investigator on an RO1 on MOG-IgG disease. He works at Mayo Clinic, Rochester, MN, USA, which offers commercial MOG-IgG testing but he receives no royalties from such testing. SR has received research funding from the National Health and Medical Research Council (Australia), the Brain Foundation (Australia), the Royal Australasian College of Physicians, and the University of Sydney. She was supported by an National Health and Medicine Research Council Neil Hamilton Fairley Early Career Fellowship (APP1141169) and is currently supported by an NHMRC Emerging Leadership (EL2) Investigator Grant (APP2008339). She serves as a consultant on an advisory board for UCB and Limbic Neurology, and has been an invited speaker for Biogen, Limbic Neurology, and Excemed. PW has received research grants from Euroimmun AG, Commonwealth Serum Laboratories Behring and patent royalties for antibody testing (W02010046716A1). He is the co-director of the Oxford Autoimmune Neurology Diagnostic Laboratory (Oxford University, Oxford, UK) where MOG-IgG1 autoantibodies are tested and both he and the University of Oxford receive royalties (for antibody tests for LGI1 and CASPR2, W02010046716A1). He has received honoraria or consulting fees from Biogen Idec, F Hoffmann La-Roche, Mereo BioPharma, Retrogenix, UBC, Euroimmun AG, University of British Columbia, and Alexion; and travel grants from the Guthy-Jackson Charitable Foundation. Work in the Oxford Autoimmune Neurology Diagnostic Laboratory is supported by the UK National Health Service Commissioning service for NMOSD. ST has received speaker and consulting fees from Biogen-Idec Argentina, Merck SA, Genzyme-Sanofi, Roche, Novartis Argentina, and Novartis Pharma. She serves as a consultant on an advisory board for Genentech-Roche. and Alexion Pharmaceuticals. JSG has grant or contract research support from the National Multiple Sclerosis Society, Biogen, and Octave Biosciences for work unrelated to the present project. She serves on a steering committee for a trial supported by Novartis. She has received speaker fees from Alexion and Bristol Myers Sqiuibb, and served on an advisory board for Genentech. TC has received compensation for consulting from Biogen, Novartis Pharmaceuticals, Roche, Genentech, and Sanofi Genzyme. She has received research support from the National Institutes of Health, National Multiple Sclerosis Society, US Department of Defense, EMD Serono, Guthy-Jackson Charitable Foundation, I-Mab Biopharma, Mallinckrodt Pharmaceuticals, Novartis, Octave Bioscience, Roche Genentech, The Sumaira Foundation, and Tiziana Life Sciences. AUB has received grant support from Moore Foundation, Clinical and Trnaslational Awards Program, German Federal Ministry of Education and Research (BMBF). He has been named as inventor on several patents and patent applications describing multiple sclerosis serological biomarkers, drug targets for remyelination therapy, marker-less motor function analysis, and retinal image analysis methods. He serves on the Observational Study Monitoring Board for CAVS-MS. He is cofounder, board member, and currently serving as secretary treasurer of IMSVISUAL. He is cofounder and holds stocks of technology startups Motognosis GmbH and Nocturne GmbH. Motognosis GmbH develops and sells systems for assessing motor dysfunction in patients with neurological disorders. Nocturne GmbH offers analysis services for retinal optical coherence tomography. Both companies' products and services are relevant for neurology in general, but not specific to MOGAD. CH reports grant support from the Medical Research Council, Multiple Sclerosis Society, and Vasculitis UK. She serves as a consultant to Novartis, Biogen, Roche, UCB, Viela Bio, and Sanofi. She participated on an independent data safety monitoring board for the Wellcome Trust. RN reports grant support from Multiple Sclerosis Research Foundation (Netherlands). He has participated on a data safety monitoring board or advisory board for EXCEL study (neurofibromatosis). He is board member of the Dutch Pediatric Neurology Society. LP has received speaker honoraria and travel grants from Biogen, and has consulted for Biogen, Novartis, and Sanofi. Her university holds a patent for her invention: Live cell based assay for detection of autoantibodies for NMOSD and related disorders (Indian patent number 202141055841). MR is supported by research grants from the Austrian Science Fund (FWF project P32699), the Austrian Research Promotion Agency, Euroimmun, and Roche, and consulting fees and advisory board from Roche (to institution). MR works at the Clinical Department of the Medical University of Innsbruck (Innsbruck, Austria), which offers diagnostic testing for MOG-IgG and other autoantibodies. AS received personal compensation for consulting, serving on a scientific advisory board, speaking activities with Merck, Sanofi, Biogen, Roche, TEVA Pharmaceuticals, Novartis, Alexion, and Janssen. DKS has received research support from National council for Scientific and Technological Development CNPq Brazil (425331/2016-4 and 308636/2019-8), Fundacao de Amparo Pesquisa do Estado do Rio Grande do Sul (17/2551-0001391-3 and 21/2551-0000077-5), TEVA Pharmaceuticals, Merck, Biogen, and Euroimmun AG; speaker honoraria from Biogen, Novartis, Genzyme, TEVA Pharmaceuticals, Merck, Roche, and Bayer; and participates in advisory boards for Biogen, Roche, and Merck. KR has been an invited speaker for Merck and serves as a consultant for an advisory board for Roche. FP has received honoraria and research support from Alexion, Bayer, Biogen, Chugai, MerckSerono, Novartis, Genyzme, MedImmune, Shire, and Teva Pharmaceuticals, and serves on scientific advisory boards for Alexion, MedImmune, Novartis, and UCB. He has received funding from Deutsche Forschungsgemeinschaft (DFG Exc 257), Bundesministerium für Bildung und Forschung (Competence Network Multiple Sclerosis), Guthy-Jackson Charitable Foundation, EU Framework Program 7, and National Multiple Sclerosis Society of the USA. He serves on the steering committee of the N-Momentum study with inebilizumab (Horizon Therapeutics) and the OCTiMS Study (Novartis). He is an associatee editor with Neurology, Neuroimmunology, and Neuroinflammation and academic editor with PloS One. SJP reports grants, personal fees, and non-financial support from Alexion Pharmaceuticals; grants, personal fees, and non-financial support from MedImmune /Viela Bio; and personal fees for consulting from Genentech, Roche, UCB, and Astellas. He has two patents issued (8889102; application 12-678350; Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia; and 9891219B2; application 12-573942; Methods for Treating Neuromyelitis Optica [NMO] by Administration of Eculizumab to an individual that is Aquaporin-4 [AQP4]-IgG Autoantibody positive). SJP also has patents pending for IgGs to the following proteins as biomarkers of autoimmune neurological disorders: septin-5, kelch-like protein 11, GFAP, PDE10A, and MAP1B. He works at Mayo Clinic, which offers commercial MOG-IgG testing. He receives no royalties from the sale of tests done at the neuroimmunology Laboratory at Mayo Clinic. KF serves as an advisor or on scientific advisory boards for Biogen, Mitsubishi Tanabe, Novartis, Chugai, Roche, Alexion, VielaBio/Horizon Therapeutics, UCB, Merck Biopharma, Japan Tobacco and Abbvie; has received funding for travel and speaker honoraria from Biogen, Eisai, Mitsubishi Tanabe, Novartis, Chugai, Roche, Alexion, VielaBio, Teijin, Asahi Kasei Medical, Merck, and Takeda; and has received the Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan. JP has received consulting fees from Merck, Novartis, Roche, Mitsubishi Tnabe Pharma, UCB, Alexion, Vitaccess, and Argenx, and MRI support from Medimmune, Merck, and Roche. She has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck, VielaBio, Roche and Alexion. She has participated on a data safety monitoring board or advisory board for Novartis, Roche, Argenx, UCB, Alexion, and Sanofi. She is member of the Charcot Foundation Board, Magnetic Resonance in Multiple Sclerosis steering committee, and National Health Service England Intravenous Immune Globulin Committee. She holds stock for AstraZeneca for a product that is not related to MOG-antibody associated disease. She has a patent for Diagnosing Multiple Sclerosis (application no PCT/GB2013/050285, final patent number 13704627.2–1408; client reference 4440; MS reference P37347WO; patent published Sept 13, 2021)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Large-scale disease overarching longitudinal data are rare in the field of neuroimmunology. However, such data could aid early disease stratification, understanding disease etiology and ultimately improve treatment decisions. The Berlin Registry of Neuroimmunological Entities (BERLimmun) is a longitudinal prospective observational study, which aims to identify diagnostic, disease activity and prognostic markers and to elucidate the underlying pathobiology of neuroimmunological diseases., Methods: BERLimmun is a single-center prospective observational study of planned 650 patients with neuroimmunological disease entity (e.g. but not confined to: multiple sclerosis, isolated syndromes, neuromyelitis optica spectrum disorders) and 85 healthy participants with 15 years of follow-up. The protocol comprises annual in-person visits with multimodal standardized assessments of medical history, rater-based disability staging, patient-report of lifestyle, diet, general health and disease specific symptoms, tests of motor, cognitive and visual functions, structural imaging of the neuroaxis and retina and extensive sampling of biological specimen., Discussion: The BERLimmun database allows to investigate multiple key aspects of neuroimmunological diseases, such as immunological differences between diagnoses or compared to healthy participants, interrelations between findings of functional impairment and structural change, trajectories of change for different biomarkers over time and, importantly, to study determinants of the long-term disease course. BERLimmun opens an opportunity to a better understanding and distinction of neuroimmunological diseases., (© 2022. The Author(s).)

Background: Spectral-domain (SD-) optical coherence tomography (OCT) can reliably measure axonal (peripapillary retinal nerve fiber layer [pRNFL]) and neuronal (macular ganglion cell + inner plexiform layer [GCIPL]) thinning in the retina. Measurements from 2 commonly used SD-OCT devices are often pooled together in multiple sclerosis (MS) studies and clinical trials despite software and segmentation algorithm differences; however, individual pRNFL and GCIPL thickness measurements are not interchangeable between devices. In some circumstances, such as in the absence of a consistent OCT segmentation algorithm across platforms, a conversion equation to transform measurements between devices may be useful to facilitate pooling of data. The availability of normative data for SD-OCT measurements is limited by the lack of a large representative world-wide sample across various ages and ethnicities. Larger international studies that evaluate the effects of age, sex, and race/ethnicity on SD-OCT measurements in healthy control participants are needed to provide normative values that reflect these demographic subgroups to provide comparisons to MS retinal degeneration., Methods: Participants were part of an 11-site collaboration within the International Multiple Sclerosis Visual System (IMSVISUAL) consortium. SD-OCT was performed by a trained technician for healthy control subjects using Spectralis or Cirrus SD-OCT devices. Peripapillary pRNFL and GCIPL thicknesses were measured on one or both devices. Automated segmentation protocols, in conjunction with manual inspection and correction of lines delineating retinal layers, were used. A conversion equation was developed using structural equation modeling, accounting for clustering, with healthy control data from one site where participants were scanned on both devices on the same day. Normative values were evaluated, with the entire cohort, for pRNFL and GCIPL thicknesses for each decade of age, by sex, and across racial groups using generalized estimating equation (GEE) models, accounting for clustering and adjusting for within-patient, intereye correlations. Change-point analyses were performed to determine at what age pRNFL and GCIPL thicknesses exhibit accelerated rates of decline., Results: The healthy control cohort (n = 546) was 54% male and had a wide distribution of ages, ranging from 18 to 87 years, with a mean (SD) age of 39.3 (14.6) years. Based on 346 control participants at a single site, the conversion equation for pRNFL was Cirrus = -5.0 + (1.0 × Spectralis global value). Based on 228 controls, the equation for GCIPL was Cirrus = -4.5 + (0.9 × Spectralis global value). Standard error was 0.02 for both equations. After the age of 40 years, there was a decline of -2.4 μm per decade in pRNFL thickness ( P < 0.001, GEE models adjusting for sex, race, and country) and -1.4 μm per decade in GCIPL thickness ( P < 0.001). There was a small difference in pRNFL thickness based on sex, with female participants having slightly higher thickness (2.6 μm, P = 0.003). There was no association between GCIPL thickness and sex. Likewise, there was no association between race/ethnicity and pRNFL or GCIPL thicknesses., Conclusions: A conversion factor may be required when using data that are derived between different SD-OCT platforms in clinical trials and observational studies; this is particularly true for smaller cross-sectional studies or when a consistent segmentation algorithm is not available. The above conversion equations can be used when pooling data from Spectralis and Cirrus SD-OCT devices for pRNFL and GCIPL thicknesses. A faster decline in retinal thickness may occur after the age of 40 years, even in the absence of significant differences across racial groups., (Copyright © 2022 by North American Neuro-Ophthalmology Society.)

Background: The diagnosis of multiple sclerosis (MS) requires demyelinating events that are disseminated in time and space. Peripapillary retinal nerve fiber layer (pRNFL) thickness as measured by optical coherence tomography (OCT) distinguishes eyes with a prior history of acute optic neuritis (ON) and may provide evidence to support a demyelinating attack., Objective: To investigate whether a deep learning (DL)-based network can distinguish between eyes with prior ON and healthy control (HC) eyes using peripapillary ring scans., Methods: We included 1033 OCT scans from 415 healthy eyes (213 HC subjects) and 510 peripapillary ring scans from 164 eyes with prior acute ON (140 patients with MS). Data were split into 70% training, 15% validation, and 15% test data. We included 102 OCT scans from 80 healthy eyes (40 HC) and 61 scans from 40 ON eyes (31 MS patients) from an independent second center. Receiver operating characteristic curve analyses with area under the curve (AUC) were used to investigate performance., Results: We used a dilated residual convolutional neural network for the classification. The final network had an accuracy of 0.85 and an AUC of 0.86, whereas pRNFL only had an AUC of 0.77 in recognizing ON eyes. Using data from a second center, the network achieved an accuracy of 0.77 and an AUC of 0.90 compared to pRNFL, which had an AUC of 0.84., Interpretation: DL-based disease classification of prior ON is feasible and has the potential to outperform thickness-based classification of eyes with and without history of prior ON., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Aquaporin-4 immunoglobulin-G positive (AQP4-IgG + ) neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy associated with optic neuritis (ON). Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an oligodendrocytopathy with a similar phenotype. Serum glial fibrillary acidic protein (sGFAP), an astrocyte-derived protein, is associated with disease severity in AQP4-IgG + NMOSD. Serum neurofilament light (sNfL) indicates neuroaxonal damage. The objective was to investigate the association of sGFAP and sNfL with subclinical afferent visual system damage in clinically stable AQP4-IgG + NMOSD and MOGAD patients., Methods: In this cross-sectional study, clinically stable patients with AQP4-IgG + NMOSD (N = 33) and MOGAD (N = 16), as diseased controls, underwent sGFAP and sNfL measurements by single molecule array, retinal optical coherence tomography and visually evoked potentials., Results: Higher sGFAP concentrations were associated with thinner ganglion cell-inner plexiform layer (β (95% confidence interval (CI)) = -0.75 (-1.23 to -0.27), p = 0.007) and shallower fovea (average pit depth: β (95%CI) = -0.59 (-0.63 to -0.55), p = 0.020) in NMOSD non-ON eyes. Participants with pathological P100 latency had higher sGFAP (median [interquartile range]: 131.32 [81.10-179.34] vs. 89.50 [53.46-121.91] pg/ml, p = 0.024). In MOGAD, sGFAP was not associated with retinal structural or visual functional measures., Conclusions: The association of sGFAP with structural and functional markers of afferent visual system damage in absence of ON suggests that sGFAP may be a sensitive biomarker for chronic disease severity in clinically stable AQP4-IgG + NMOSD., Competing Interests: Declaration of Competing Interest T.-Y. Lin, P. Schindler, U. Grittner, A. Lu, A.S. Duchow, S. Jarius, J. Kuhle, P. Benkert and T. Schmitz-Hübsch report no relevant disclosures. F.C. Oertel was an employee of Nocturne GmbH and receives research support by the American Academy of Neurology, the National Multiple Sclerosis Society and Deutsche Gesellschaft für Neurologie (German Neurology Society), unrelated to this work. S. Motamedi is named as co-inventor on the patent application for the foveal shape analysis method used by this manuscript (“Method for estimating shape parameters of the fovea by optical coherence tomography”, International Publication Number: “WO 2019/016319 A1”). S.K. Yadav is named as co-inventor on the patent application for the foveal shape analysis method used by this manuscript (“Method for estimating shape parameters of the fovea by optical coherence tomography”, International Publication Number: “WO 2019/016319 A1”) and a cofounder of medical technology companies Nocturne GmbH. A.U. Brandt is cofounder and shareholder of medical technology companies Nocturne GmbH and Motognosis GmbH. He is named as inventor on several patent applications describing MS biomarkers, visual perceptive computing based motor function analysis, and retinal image analysis. J. Bellmann-Strobl has received speaking honoraria and travel grants from Bayer Healthcare, and sanofi-aventis/Genzyme, in addition received compensation for serving on a scientific advisory board of Roche, unrelated to the presented work. F. Paul 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. K. Ruprecht received research support from Novartis, Merck Serono, German Ministry of Education and Research, European Union (821283-2), Stiftung Charité (BIH Clinical Fellow Program) and Arthur Arnstein Foundation; received travel grants from Guthy-Jackson Charitable Foundation. H.G. Zimmermann received research grants from Novartis and speaking honoraria from Bayer Healthcare and Novartis., (Copyright © 2022. Published by Elsevier B.V.)

Optic neuritis (ON) in neuromyelitis optica spectrum disorders (NMOSD) regularly leads to more profound vision loss compared to multiple sclerosis (MS) and myelin-oligodendrocyte-glycoprotein-antibody associated disease (MOGAD). Here we investigate ON-related vision loss in NMOSD compared to MS and MOGAD in order to identify neuroaxonal and retinal contributors to visual dysfunction. In this retrospective study we included patients with aquaporin-4-antibody seropositive NMOSD (n = 28), MOGAD (n = 14), MS (n = 29) and controls (n = 14). We assessed optic nerve damage and fovea morphometry by optical coherence tomography. Visual function was assessed as high (HCVA) and low contrast visual acuity (LCVA), and visual fields' mean deviation (MD). In all diseases, lower visual function was associated with peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell and inner plexiform layer (GCIP) thinning following a broken stick model, with pRNFL and GCIP cutoff point at ca. 60 µm. HCVA loss per µm pRNFL and GCIP thinning was stronger in NMOSD compared with MOGAD. Foveal inner rim volume contributed to MD and LCVA in NMOSD eyes, only. Together these data supports that visual dysfunction in NMOSD is associated with neuroaxonal damage beyond the effect seen in MS and MOGAD. A primary retinopathy, respectively Müller cell pathology, may contribute to this effect., (© 2022. The Author(s).)

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

Background and Objectives: Recent studies have suggested that intereye differences (IEDs) in peripapillary retinal nerve fiber layer (pRNFL) or ganglion cell + inner plexiform (GCIPL) thickness by spectral domain optical coherence tomography (SD-OCT) may identify people with a history of unilateral optic neuritis (ON). However, this requires further validation. Machine learning classification may be useful for validating thresholds for OCT IEDs and for examining added utility for visual function tests, such as low-contrast letter acuity (LCLA), in the diagnosis of people with multiple sclerosis (PwMS) and for unilateral ON history., Methods: Participants were from 11 sites within the International Multiple Sclerosis Visual System consortium. pRNFL and GCIPL thicknesses were measured using SD-OCT. A composite score combining OCT and visual measures was compared individual measurements to determine the best model to distinguish PwMS from controls. These methods were also used to distinguish those with a history of ON among PwMS. Receiver operating characteristic (ROC) curve analysis was performed on a training data set (2/3 of cohort) and then applied to a testing data set (1/3 of cohort). Support vector machine (SVM) analysis was used to assess whether machine learning models improved diagnostic capability of OCT., Results: Among 1,568 PwMS and 552 controls, variable selection models identified GCIPL IED, average GCIPL thickness (both eyes), and binocular 2.5% LCLA as most important for classifying PwMS vs controls. This composite score performed best, with area under the curve (AUC) = 0.89 (95% CI 0.85-0.93), sensitivity = 81%, and specificity = 80%. The composite score ROC curve performed better than any of the individual measures from the model ( p < 0.0001). GCIPL IED remained the best single discriminator of unilateral ON history among PwMS (AUC = 0.77, 95% CI 0.71-0.83, sensitivity = 68%, specificity = 77%). SVM analysis performed comparably with standard logistic regression models., Discussion: A composite score combining visual structure and function improved the capacity of SD-OCT to distinguish PwMS from controls. GCIPL IED best distinguished those with a history of unilateral ON. SVM performed as well as standard statistical models for these classifications., Classification of Evidence: This study provides Class III evidence that SD-OCT accurately distinguishes multiple sclerosis from normal controls as compared with clinical criteria., (© 2022 American Academy of Neurology.)

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

Purpose: To test the hypothesis that newly developed shape measures using optical coherence tomography (OCT) macular volume scans can discriminate patients with perimetric glaucoma from healthy subjects., Methods: OCT structural measures defining macular topography and volume were recently developed based on cubic Bézier curves. We exported macular volume scans from 135 eyes with glaucoma (133 patients) and 155 healthy eyes (85 subjects) and estimated global and quadrant-based measures. The best subset of measures to predict glaucoma was explored with a gradient boost model (GBM) with subsequent logistic regression. Accuracy and area under receiver operating curves (AUC) were the primary metrics. In addition, we separately investigated model performance in 66 eyes with mild glaucoma (mean deviation ≥ -6 dB)., Results: Average (±SD) 24-2 mean deviation was -8.2 (±6.1) dB in eyes with glaucoma. The main predictive measures for glaucoma were temporal inferior rim height, nasal inferior pit volume, and temporal inferior pit depth. Lower values for these measures predicted higher risk of glaucoma. Sensitivity, specificity, and AUC for discriminating between healthy and glaucoma eyes were 81.5% (95% CI = 76.6-91.9%), 89.7% (95% CI = 78.7-94.2%), and 0.915 (95% CI = 0.882-0.948), respectively. Corresponding metrics for mild glaucoma were 84.8% (95% CI = 72.1%-95.5%), 85.8% (95% CI = 87.1%-97.4%), and 0.913 (95% CI = 0.867-0.958), respectively., Conclusions: Novel macular shape biomarkers detect early glaucoma with clinically relevant performance. Such biomarkers do not depend on intraretinal segmentation accuracy and may be helpful in eyes with suboptimal macular segmentation., Translational Relevance: Macular shape biomarkers provide valuable information for detection of early glaucoma and may provide additional information beyond thickness measurements.

Reliable biomarkers quantifying neurodegeneration and neuroinflammation in central nervous system disorders such as Multiple Sclerosis, Alzheimer's dementia or Parkinson's disease are an unmet clinical need. Intraretinal layer thicknesses on macular optical coherence tomography (OCT) images are promising noninvasive biomarkers querying neuroretinal structures with near cellular resolution. However, changes are typically subtle, while tissue gradients can be weak, making intraretinal segmentation a challenging task. A robust and efficient method that requires no or minimal manual correction is an unmet need to foster reliable and reproducible research as well as clinical application. Here, we propose and validate a cascaded two-stage network for intraretinal layer segmentation, with both networks being compressed versions of U-Net (CCU-INSEG). The first network is responsible for retinal tissue segmentation from OCT B-scans. The second network segments eight intraretinal layers with high fidelity. At the post-processing stage, we introduce Laplacian-based outlier detection with layer surface hole filling by adaptive non-linear interpolation. Additionally, we propose a weighted version of focal loss to minimize the foreground-background pixel imbalance in the training data. We train our method using 17,458 B-scans from patients with autoimmune optic neuropathies, i.e., multiple sclerosis, and healthy controls. Voxel-wise comparison against manual segmentation produces a mean absolute error of 2.3 μm, outperforming current state-of-the-art methods on the same data set. Voxel-wise comparison against external glaucoma data leads to a mean absolute error of 2.6 μm when using the same gold standard segmentation approach, and 3.7 μm mean absolute error in an externally segmented data set. In scans from patients with severe optic atrophy, 3.5% of B-scan segmentation results were rejected by an experienced grader, whereas this was the case in 41.4% of B-scans segmented with a graph-based reference method. The validation results suggest that the proposed method can robustly segment macular scans from eyes with even severe neuroretinal changes.

Background: The standardized T1-weighted/T2-weighted (sT1w/T2w) ratio for the middle cerebellar peduncle (MCP) has been reported to be sensitive for detecting degenerative changes in the cerebellar subtype of multiple system atrophy (MSA-C), even in the early stages. We aimed to investigate the diagnostic value of the MCP sT1w/T2w ratio for differentiating between MSA-C and spinocerebellar ataxia (SCA)., Methods: We included 32 MSA-C, 8 SCA type 3 (SCA3), 16 SCA type 6 (SCA6) patients, and 17 controls, and the MCP sT1w/T2w ratio was analyzed using a region-of-interest approach. The diagnostic performance of the MCP sT1w/T2w ratio in discriminating among MSA-C, SCA3, and SCA6 was assessed and compared with diagnosis based on visual interpretation of MCP hyperintensities and the "hot cross bun" (HCB) sign., Results: MCP sT1w/T2w ratio values were markedly lower in patients with MSA-C than in those with SCA3, those with SCA6, and controls (p < 0.001). The MCP sT1w/T2w ratio showed high diagnostic accuracy for distinguishing MSA-C from SCA3 (area under curve = 0.934), SCA6 (area under curve = 0.965), and controls (area under curve = 0.980). The diagnostic accuracy of the MCP sT1w/T2w ratio for differentiating MSA-C from SCA3 or SCA6 (90.0% for MSA-C vs. SCA3, and 91.7% for MSA-C vs. SCA6) was comparable to or superior than that of visual interpretation of MCP hyperintensities (80.0-87.5% in MSA-C vs. SCA3 and 87.6-97.9% in MSA-C vs. SCA6) or the HCB sign (72.5-80.0% in MSA-C vs. SCA3 and 77.1-93.8% in MSA-C vs. SCA6)., Conclusions: The MCP sT1w/T2w ratio might be a sensitive imaging-based marker for detecting MSA-C-related changes and differentiating MSA-C from SCA3 or SCA6., Competing Interests: The authors have declared that no competing interests exist.

Epidemiological, clinical and neuroscientific studies support a link between psychobiological stress and multiple sclerosis. Neuroimaging suggests that blunted central stress processing goes along with higher multiple sclerosis severity, neuroendocrine studies suggest that blunted immune system sensitivity to stress hormones is linked to stronger neuroinflammation. Until now, however, no effort has been made to elucidate whether central stress processing and immune system sensitivity to stress hormones are related in a disease-specific fashion, and if so, whether this relation is clinically meaningful. Consequently, we conducted two functional MRI analyses based on a total of 39 persons with multiple sclerosis and 25 healthy persons. Motivated by findings of an altered interplay between neuroendocrine stress processing and T-cell glucocorticoid sensitivity in multiple sclerosis, we searched for neural networks whose stress task-evoked activity is differentially linked to peripheral T-cell glucocorticoid signalling in patients versus healthy persons as a potential indicator of disease-specific CNS-immune crosstalk. Subsequently, we tested whether this activity is simultaneously related to disease severity. We found that activity of a network comprising right anterior insula, right fusiform gyrus, left midcingulate and lingual gyrus was differentially coupled to T-cell glucocorticoid signalling across groups. This network's activity was simultaneously linked to patients' lesion volume, clinical disability and information-processing speed. Complementary analyses revealed that T-cell glucocorticoid signalling was not directly linked to disease severity. Our findings show that alterations in the coupling between central stress processing and T-cell stress hormone sensitivity are related to key severity measures of multiple sclerosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Decreased motion perception has been suggested as a marker for visual pathway demyelination in optic neuritis (ON) and/or multiple sclerosis (MS)., Objectives: To examine the influence of neuro-axonal damage on motion perception in MS and neuromyelitis optica spectrum disorders (NMOSD)., Methods: We analysed motion perception with numbers-from-motion (NFM), visual acuity, (multifocal (mf)) VEP, optical coherence tomography in patients with MS ( n = 38, confirmatory cohort n = 43), NMOSD ( n = 13) and healthy controls ( n = 33)., Results: NFM was lower compared with controls in MS ( B = -12.37, p < 0.001) and NMOSD ( B = -34.5, p < 0.001). NFM was lower in ON than in non-ON eyes ( B = -30.95, p = 0.041) in NMOSD, but not MS. In MS and NMOSD, lower NFM was associated with worse visual acuity ( B = -139.4, p < 0.001/ B = -77.2, p < 0.001) and low contrast letter acuity ( B = 0.99, p = 0.002/ B = 1.6, p < 0.001), thinner peripapillary retinal nerve fibre layer ( B = 1.0, p < 0.001/ B = 0.92, p = 0.016) and ganglion cell/inner plexiform layer ( B = 64.8, p < 0.001/ B = 79.5, p = 0.006), but not with VEP P100 latencies. In the confirmatory MS cohort, lower NFM was associated with thinner retinal nerve fibre layer ( B = 1.351, p < 0.001) and increased mfVEP P100 latencies ( B = -1.159, p < 0.001)., Conclusions: Structural neuro-axonal visual pathway damage is an important driver of motion perception impairment in MS and NMOSD.

Background: Instrumented assessment of motor symptoms has emerged as a promising extension to the clinical assessment of several movement disorders. The use of mobile and inexpensive technologies such as some markerless motion capture technologies is especially promising for large-scale application but has not transitioned into clinical routine to date. A crucial step on this path is to implement standardized, clinically applicable tools that identify and control for quality concerns., Objective: The main goal of this study comprises the development of a systematic quality control (QC) procedure for data collected with markerless motion capture technology and its experimental implementation to identify specific quality concerns and thereby rate the usability of recordings., Methods: We developed a post hoc QC pipeline that was evaluated using a large set of short motor task recordings of healthy controls (2010 recordings from 162 subjects) and people with multiple sclerosis (2682 recordings from 187 subjects). For each of these recordings, 2 raters independently applied the pipeline. They provided overall usability decisions and identified technical and performance-related quality concerns, which yielded respective proportions of their occurrence as a main result., Results: The approach developed here has proven user-friendly and applicable on a large scale. Raters' decisions on recording usability were concordant in 71.5%-92.3% of cases, depending on the motor task. Furthermore, 39.6%-85.1% of recordings were concordantly rated as being of satisfactory quality whereas in 5.0%-26.3%, both raters agreed to discard the recording., Conclusions: We present a QC pipeline that seems feasible and useful for instant quality screening in the clinical setting. Results confirm the need of QC despite using standard test setups, testing protocols, and operator training for the employed system and by extension, for other task-based motor assessment technologies. Results of the QC process can be used to clean existing data sets, optimize quality assurance measures, as well as foster the development of automated QC approaches and therefore improve the overall reliability of kinematic data sets., (©Hanna Marie Röhling, Patrik Althoff, Radina Arsenova, Daniel Drebinger, Norman Gigengack, Anna Chorschew, Daniel Kroneberg, Maria Rönnefarth, Tobias Ellermeyer, Sina Cathérine Rosenkranz, Christoph Heesen, Behnoush Behnia, Shigeki Hirano, Satoshi Kuwabara, Friedemann Paul, Alexander Ulrich Brandt, Tanja Schmitz-Hübsch. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 01.04.2022.)

Background and Objectives: The choroid plexus has been shown to play a crucial role in CNS inflammation. Previous studies found larger choroid plexus in multiple sclerosis (MS) compared with healthy controls. However, it is not clear whether the choroid plexus is similarly involved in MS and in neuromyelitis optica spectrum disorder (NMOSD). Thus, the aim of this study was to compare the choroid plexus volume in MS and NMOSD., Methods: In this retrospective, cross-sectional study, patients were included by convenience sampling from 4 international MS centers. The choroid plexus of the lateral ventricles was segmented fully automatically on T1-weighted MRI sequences using a deep learning algorithm (Multi-Dimensional Gated Recurrent Units). Uni- and multivariable linear models were applied to investigate associations between the choroid plexus volume, clinically meaningful disease characteristics, and MRI parameters., Results: We studied 180 patients with MS and 98 patients with NMOSD. In total, 94 healthy individuals and 47 patients with migraine served as controls. The choroid plexus volume was larger in MS (median 1,690 µL, interquartile range [IQR] 648 µL) than in NMOSD (median 1,403 µL, IQR 510 µL), healthy individuals (median 1,533 µL, IQR 570 µL), and patients with migraine (median 1,404 µL, IQR 524 µL; all p < 0.001), whereas there was no difference between NMOSD, migraine, and healthy controls. This was also true when adjusted for age, sex, and the intracranial volume. In contrast to NMOSD, the choroid plexus volume in MS was associated with the number of T2-weighted lesions in a linear model adjusted for age, sex, total intracranial volume, disease duration, relapses in the year before MRI, disease course, Expanded Disability Status Scale score, disease-modifying treatment, and treatment duration (beta 4.4; 95% CI 0.78-8.1; p = 0.018)., Discussion: This study supports an involvement of the choroid plexus in MS in contrast to NMOSD and provides clues to better understand the respective pathogenesis., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Retinal optical coherence tomography (OCT) with intraretinal layer segmentation is increasingly used not only in ophthalmology but also for neurological diseases such as multiple sclerosis (MS). Signal quality influences segmentation results, and high-quality OCT images are needed for accurate segmentation and quantification of subtle intraretinal layer changes. Among others, OCT image quality depends on the ability to focus, patient compliance and operator skills. Current criteria for OCT quality define acceptable image quality, but depend on manual rating by experienced graders and are time consuming and subjective. In this paper, we propose and validate a standardized, grader-independent, real-time feedback system for automatic quality assessment of retinal OCT images. We defined image quality criteria for scan centering, signal quality and image completeness based on published quality criteria and typical artifacts identified by experienced graders when inspecting OCT images. We then trained modular neural networks on OCT data with manual quality grading to analyze image quality features. Quality analysis by a combination of these trained networks generates a comprehensive quality report containing quantitative results. We validated the approach against quality assessment according to the OSCAR-IB criteria by an experienced grader. Here, 100 OCT files with volume, circular and radial scans, centered on optic nerve head and macula, were analyzed and classified. A specificity of 0.96, a sensitivity of 0.97 and an accuracy of 0.97 as well as a Matthews correlation coefficient of 0.93 indicate a high rate of correct classification. Our method shows promising results in comparison to manual OCT grading and may be useful for real-time image quality analysis or analysis of large data sets, supporting standardized application of image quality criteria., (Copyright © 2021. Published by Elsevier Ltd.)

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

Background and Objectives: Connectivity-based approaches incorporating the distribution and magnitude of the extended brain network aberrations caused by lesions may offer higher sensitivity for axonal damage in patients with multiple sclerosis (MS) than conventional lesion characteristics. Using individual brain disconnectome mapping, we tested the longitudinal associations between putative imaging-based brain network aberrations and levels of serum neurofilament light chain (NfL) as a neuroaxonal injury biomarker., Methods: MS patients (n = 312, mean age 42.9 years, 71 % female) and healthy controls (HC) (n = 59, mean age 39.9 years, 78 % female) were prospectively enrolled at four European MS centres, and reassessed after two years (MS, n = 242; HC, n = 30). Post-processing of 3 Tesla (3 T) MRI data was performed at one centre using a harmonized pipeline, and disconnectome maps were calculated using BCBtoolkit based on individual lesion maps. Global disconnectivity (GD) was defined as the average disconnectome probability in each patient's white matter. Serum NfL concentrations were measured by single molecule array (Simoa). Robust linear mixed models (rLMM) with GD or T2-lesion volume (T2LV) as dependent variables, patient as a random factor, serum NfL, age, sex, timepoint for visit, diagnosis, treatment, and center as fixed factors were run., Results: rLMM revealed significant associations between GD and serum NfL (t = 2.94, p = 0.003), age (t = 4.21, p = 2.5 × 10 -5 ), and longitudinal changes in NfL (t = -2.29, p = 0.02), but not for sex (t = 0.63, p = 0.53) or treatments (t = 0.80-0.83, p = 0.41-0.42). Voxel-wise analyses revealed significant associations between dysconnectivity in cerebellar and brainstem regions and serum NfL (t = 7.03, p < 0.001)., Discussion: In our prospective multi-site MS cohort, rLMMs demonstrated that the extent of global and regional brain disconnectivity is sensitive to a systemic biomarker of axonal damage, serum NfL, in patients with MS. These findings provide a neuroaxonal correlate of advanced disconnectome mapping and provide a platform for further investigations of the functional and potential clinical relevance of brain disconnectome mapping in patients with brain disorders., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cross-sectional studies suggest normal appearing white matter (NAWM) integrity loss may lead to cortical atrophy in late-stage relapsing-remitting multiple sclerosis (MS)., Objective: To investigate the relationship between NAWM integrity and cortical thickness from first clinical presentation longitudinally., Methods: NAWM integrity and cortical thickness were assessed with 3T magnetic resonance imaging (MRI) in 102 patients with clinically isolated syndrome or early MS (33.2 (20.1-60.1) years old, 68% female) from first clinical presentation over 2.8 ± 1.6 years. Fifty healthy controls (HCs) matched for age and sex were included. NAWM integrity was evaluated using the standardized T1w/T2w ratio (sT1w/T2w). The association between sT1w/T2w and cortical thickness was assessed using linear mixed models. The effect of disease activity was investigated using the No Evidence of Disease Activity (NEDA-3) criteria., Results: At baseline, sT1w/T2w ( p  = 0.152) and cortical thickness ( p  = 0.489) did not differ from HCs. Longitudinally, decreasing sT1w/T2w was associated with cortical thickness and increasing lesion burden (marginal R 2  = 0.061). The association was modulated by failing NEDA-3 (marginal R 2  = 0.097)., Conclusion: sT1w/T2w may be a useful MRI biomarker for early MS, detecting relevant NAWM damage over time using conventional MRI scans, although with less sensitivity compared to quantitative measures.

Health-related quality of life (HRQoL) is an essential complementary parameter in the assessment of disease burden and treatment outcome in multiple sclerosis (MS) and can be affected by neuropsychiatric symptoms, which in turn are sensitive to psychological stress. However, until now, the impact of neurobiological stress and relaxation on HRQoL in MS has not been investigated. We thus evaluated whether the activity of neural networks triggered by mild psychological stress (elicited in an fMRI task comprising mental arithmetic with feedback) or by stress termination (i.e., relaxation) at baseline (T0) predicts HRQoL variations occurring between T0 and a follow-up visit (T1) in 28 patients using a robust regression and permutation testing. The median delay between T0 and T1 was 902 (range: 363-1,169) days. We assessed HRQoL based on the Hamburg Quality of Life Questionnaire in MS (HAQUAMS) and accounted for the impact of established HRQoL predictors and the cognitive performance of the participants. Relaxation-triggered activity of a widespread neural network predicted future variations in overall HRQoL ( t = 3.68, p family-wise error [FWE] -corrected = 0.008). Complementary analyses showed that relaxation-triggered activity of the same network at baseline was associated with variations in the HAQUAMS mood subscale on an α FWE = 0.1 level ( t = 3.37, p FWE = 0.087). Finally, stress-induced activity of a prefronto-limbic network predicted future variations in the HAQUAMS lower limb mobility subscale ( t = -3.62, p FWE = 0.020). Functional neural network measures of psychological stress and relaxation contain prognostic information for future HRQoL evolution in MS independent of clinical predictors., Competing Interests: The 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 © 2021 Meyer-Arndt, Schmitz-Hübsch, Bellmann-Strobl, Brandt, Haynes, Gold, Paul and Weygandt.)

Sex strongly impacts genome evolution via recombination and segregation. In the absence of these processes, haplotypes within lineages of diploid organisms are predicted to accumulate mutations independently of each other and diverge over time. This so-called "Meselson effect" is regarded as a strong indicator of the long-term evolution under obligate asexuality. Here, we present genomic and transcriptomic data of three populations of the asexual oribatid mite species Oppiella nova and its sexual relative Oppiella subpectinata We document strikingly different patterns of haplotype divergence between the two species, strongly supporting Meselson effect-like evolution and long-term asexuality in O. nova : I) variation within individuals exceeds variation between populations in O. nova but vice versa in O. subpectinata ; II) two O. nova sublineages feature a high proportion of lineage-specific heterozygous single-nucleotide polymorphisms (SNPs), indicating that haplotypes continued to diverge after lineage separation; III) the deepest split in gene trees generally separates the two haplotypes in O. nova , but populations in O. subpectinata ; and IV) the topologies of the two haplotype trees match each other. Our findings provide positive evidence for the absence of canonical sex over evolutionary time in O. nova and suggest that asexual oribatid mites can escape the dead-end fate usually associated with asexual lineages., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Background and Objectives: To determine optic nerve and retinal damage in aquaporin-4 antibody (AQP4-IgG)-seropositive neuromyelitis optica spectrum disorders (NMOSD) in a large international cohort after previous studies have been limited by small and heterogeneous cohorts., Methods: The cross-sectional Collaborative Retrospective Study on retinal optical coherence tomography (OCT) in neuromyelitis optica collected retrospective data from 22 centers. Of 653 screened participants, we included 283 AQP4-IgG-seropositive patients with NMOSD and 72 healthy controls (HCs). Participants underwent OCT with central reading including quality control and intraretinal segmentation. The primary outcome was thickness of combined ganglion cell and inner plexiform (GCIP) layer; secondary outcomes were thickness of peripapillary retinal nerve fiber layer (pRNFL) and visual acuity (VA)., Results: Eyes with ON (NMOSD-ON, N = 260) or without ON (NMOSD-NON, N = 241) were assessed compared with HCs (N = 136). In NMOSD-ON, GCIP layer (57.4 ± 12.2 μm) was reduced compared with HC (GCIP layer: 81.4 ± 5.7 μm, p < 0.001). GCIP layer loss (-22.7 μm) after the first ON was higher than after the next (-3.5 μm) and subsequent episodes. pRNFL observations were similar. NMOSD-NON exhibited reduced GCIP layer but not pRNFL compared with HC. VA was greatly reduced in NMOSD-ON compared with HC eyes, but did not differ between NMOSD-NON and HC., Discussion: Our results emphasize that attack prevention is key to avoid severe neuroaxonal damage and vision loss caused by ON in NMOSD. Therapies ameliorating attack-related damage, especially during a first attack, are an unmet clinical need. Mild signs of neuroaxonal changes without apparent vision loss in ON-unaffected eyes might be solely due to contralateral ON attacks and do not suggest clinically relevant progression but need further investigation., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To investigate the association of combined serum neurofilament light chain (sNfL) and retinal optical coherence tomography (OCT) measurements with future disease activity in patients with early multiple sclerosis (MS)., Methods: We analyzed sNfL by single molecule array technology and performed OCT measurements in a prospective cohort of 78 patients with clinically isolated syndrome and early relapsing-remitting MS with a median (interquartile range) follow-up of 23.9 (23.3-24.7) months. Patients were grouped into those with abnormal or normal sNfL levels, defined as sNfL ≥/<80th percentile of age-corrected reference values. Likewise, patients were grouped by a median split into those with thin or thick ganglion cell and inner plexiform layer (GCIP), peripapillary retinal nerve fiber layer, and inner nuclear layer in nonoptic neuritis eyes. Outcome parameters were violation of no evidence of disease activity (NEDA-3) criteria or its components., Results: Patients with abnormal baseline sNfL had a higher risk of violating NEDA-3 (hazard ratio [HR] 2.28, 95% CI 1.27-4.09, p = 0.006) and developing a new brain lesion (HR 2.47, 95% CI 1.30-4.69, p = 0.006), but not for a new relapse (HR 2.21, 95% CI 0.97-5.03, p = 0.058). Patients with both abnormal sNfL and thin GCIP had an even higher risk for NEDA-3 violation (HR 3.61, 95% CI 1.77-7.36, p = 4.2e -4 ), new brain lesion (HR 3.19, 95% CI 1.51-6.76, p = 0.002), and new relapse (HR 5.38, 95% CI 1.61-17.98, p = 0.006) than patients with abnormal sNfL alone., Conclusions: In patients with early MS, the presence of both abnormal sNfL and thin GCIP is a stronger risk factor for future disease activity than the presence of each parameter alone., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations., Methods: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes., Results: A total of 116 authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans, and suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%., Conclusions: The modified Delphi method resulted in an expert-led guideline (evidence Class III; Grading of Recommendations, Assessment, Development and Evaluations [GRADE] criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition analysis, nomenclature and abbreviations, and statistical approach. It will be essential to update these recommendations to new research and practices regularly., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Artificial intelligence (AI)-based diagnostic algorithms have achieved ambitious aims through automated image pattern recognition. For neurological disorders, this includes neurodegeneration and inflammation. Scalable imaging technology for big data in neurology is optical coherence tomography (OCT). We highlight that OCT changes observed in the retina, as a window to the brain, are small, requiring rigorous quality control pipelines. There are existing tools for this purpose. Firstly, there are human-led validated consensus quality control criteria (OSCAR-IB) for OCT. Secondly, these criteria are embedded into OCT reporting guidelines (APOSTEL). The use of the described annotation of failed OCT scans advances machine learning. This is illustrated through the present review of the advantages and disadvantages of AI-based applications to OCT data. The neurological conditions reviewed here for the use of big data include Alzheimer disease, stroke, multiple sclerosis (MS), Parkinson disease, and epilepsy. It is noted that while big data is relevant for AI, ownership is complex. For this reason, we also reached out to involve representatives from patient organizations and the public domain in addition to clinical and research centers. The evidence reviewed can be grouped in a five-point expansion of the OSCAR-IB criteria to embrace AI (OSCAR-AI). The review concludes by specific recommendations on how this can be achieved practically and in compliance with existing guidelines., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Purpose: Foveal changes were reported in aquaporin-4 antibody (AQP4-Ab) seropositive neuromyelitis optica spectrum disorder (NMOSD) patients; however, it is unclear whether they are independent of optic neuritis (ON), stem from subclinical ON or crossover from ON in fellow eyes. Fovea morphometry and a statistical classification approach were used to investigate if foveal changes in NMOSD are independent of ON and progressive., Methods: This was a retrospective longitudinal study of 27 AQP4-IgG + NMOSD patients (49 eyes; 15 ON eyes and 34 eyes without a history of ON [NON eyes]), follow-up median (first and third quartile) 2.32 (1.33-3.28), and 38 healthy controls (HCs) (76 eyes), follow-up median (first and third quartile) 1.95 (1.83-2.54). The peripapillary retinal nerve fibre layer thickness and the volume of combined ganglion cell and inner plexiform layer as measures of neuroaxonal damage from ON were determined by optical coherence tomography. Nineteen foveal morphometry parameters were extracted from macular optical coherence tomography volume scans. Data were analysed using orthogonal partial least squares discriminant analysis and linear mixed effects models., Results: At baseline, foveal shape was significantly altered in ON eyes and NON eyes compared to HCs. Discriminatory analysis showed 81% accuracy distinguishing ON vs. HCs and 68% accuracy in NON vs. HCs. NON eyes were distinguished from HCs by foveal shape parameters indicating widening. Orthogonal partial least squares discriminant analysis discriminated ON vs. NON with 76% accuracy. In a follow-up of 2.4 (20.85) years, no significant time-dependent foveal changes were found., Conclusion: The parafoveal area is altered in AQP4-Ab seropositive NMOSD patients suggesting independent neuroaxonal damage from subclinical ON. Longer follow-ups are needed to confirm the stability of the parafoveal structure over time., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Importance: N-glycan branching modulates cell surface receptor availability, and its deficiency in mice promotes inflammatory demyelination, reduced myelination, and neurodegeneration. N-acetylglucosamine (GlcNAc) is a rate-limiting substrate for N-glycan branching, but, to our knowledge, endogenous serum levels in patients with multiple sclerosis (MS) are unknown., Objective: To investigate a marker of endogenous serum GlcNAc levels in patients with MS., Design, Setting, and Participants: A cross-sectional discovery study and cross-sectional confirmatory study were conducted at 2 academic MS centers in the US and Germany. The discovery study recruited 54 patients with MS from an outpatient clinic as well as 66 healthy controls between April 20, 2010, and June 21, 2013. The confirmatory study recruited 180 patients with MS from screening visits at an academic MS study center between April 9, 2007, and February 29, 2016. Serum samples were analyzed from December 2, 2013, to March 2, 2015. Statistical analysis was performed from February 23, 2020, to March 18, 2021., Main Outcomes and Measures: Serum levels of GlcNAc plus its stereoisomers, termed N-acetylhexosamine (HexNAc), were assessed using targeted tandem mass spectroscopy. Secondary outcomes (confirmatory study) comprised imaging and clinical disease markers., Results: The discovery cohort included 66 healthy controls (38 women; mean [SD] age, 42 [20] years), 33 patients with relapsing-remitting MS (RRMS; 25 women; mean [SD] age, 50 [11] years), and 21 patients with progressive MS (PMS; 14 women; mean [SD] age, 55 [7] years). The confirmatory cohort included 125 patients with RRMS (83 women; mean [SD] age, 40 [9] years) and 55 patients with PMS (22 women; mean [SD] age, 49 [80] years). In the discovery cohort, the mean (SD) serum level of GlcNAc plus its stereoisomers (HexNAc) was 710 (174) nM in healthy controls and marginally reduced in patients with RRMS (mean [SD] level, 682 [173] nM; P = .04), whereas patients with PMS displayed markedly reduced levels compared with healthy controls (mean [SD] level, 548 [101] nM; P = 9.55 × 10-9) and patients with RRMS (P = 1.83 × 10-4). The difference between patients with RRMS (mean [SD] level, 709 [193] nM) and those with PMS (mean [SD] level, 405 [161] nM; P = 7.6 × 10-18) was confirmed in the independent confirmatory cohort. Lower HexNAc serum levels correlated with worse expanded disability status scale scores (ρ = -0.485; P = 4.73 × 10-12), lower thalamic volume (t = 1.7; P = .04), and thinner retinal nerve fiber layer (B = 0.012 [SE = 7.5 × 10-11]; P = .008). Low baseline serum HexNAc levels correlated with a greater percentage of brain volume loss at 18 months (t = 1.8; P = .04)., Conclusions and Relevance: This study suggests that deficiency of GlcNAc plus its stereoisomers (HexNAc) may be a biomarker for PMS. Previous preclinical, human genetic, and ex vivo human mechanistic studies revealed that N-glycan branching and/or GlcNAc may reduce proinflammatory responses, promote myelin repair, and decrease neurodegeneration. Combined, the data suggest that GlcNAc deficiency may be associated with progressive disease and neurodegeneration in patients with MS.