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The first genome-wide significant multiple sclerosis severity locus, rs10191329, has been pathologically linked to cortical lesion load and brain atrophy. However, observational cohorts such as MSBase have not replicated associations with disability outcomes, instead finding other loci. We evaluated rs10191329 and MSBase loci in a unique cohort of 53 people followed for 30 years after a clinically isolated syndrome, with deep clinical phenotyping and MRI measures of inflammation and neurodegeneration. After 30 years, 26 had developed relapsing-remitting multiple sclerosis, 15 secondary progressive multiple sclerosis and 12 remained diagnosed with a clinically isolated syndrome. Genetic associations with disease severity (age-related multiple sclerosis severity score and Expanded Disability Status Scale), disease course and brain MRI features (white matter lesions, cortical lesions and grey matter fraction) were investigated using regression models and survival analyses. rs10191329 was not associated with multiple sclerosis severity, secondary progressive multiple sclerosis diagnosis or brain MRI features at 30 years. Similarly, MSBase loci were not associated with 30-year disease severity, although rs73091975 was significantly associated with lower 14-year age-related multiple sclerosis severity score in those developing multiple sclerosis. Given that effect sizes for both rs10191329 and rs73091975 were greatest between 14 and 20 years, these findings suggest genetic effects on multiple sclerosis severity may interact non-linearly with disease duration., Competing Interests: N.S. has been a clinical research fellow in a post supported by Merck (supervised by S.A.T. and D.C.) and subsequently by MRC (MR/W019906/1); he has received speaker honoraria from Merck. K.C. has received honoraria for participation and attendance of educational events from Novartis, Roche, Biogen and Merck; she has received honoraria for consultancy work from Novartis, Roche, Biogen, Merck and Viatris. F.P. received a Guarantors of Brain fellowship 2017–20. F.P. and B.K. are supported by the National Institute for Health Research (NIHR), Biomedical Research Centre initiative at University College London Hospitals (UCLH). A.J.T. reports personal fees paid to his institution from Eisai Ltd; is an editorial board member for The Lancet Neurology receiving a free subscription; is Editor-in-Chief for Multiple Sclerosis Journal receiving an honorarium from SAGE Publications; receives support for travel as member, from Clinical Trials Committee, from International Progressive MS Alliance and from the National MS Society (USA) as member, NMSS Research Programs Advisory Committee. S.A.T. has received honoraria from Roche, Merck, Novartis, Sanofi-Genzyme and Biogen in the last 3 years and co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, UK, which is supported by Merck. W.B. has received speaker honoraria and/or acted as a consultant for Biogen, Janssen, Merck, Neuroxpharm, Novartis, Roche, Sandoz, Sanofi and Viatris. He is supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre. O.C. is a member of an independent DSMB for Novartis, gave a teaching talk on McDonald criteria in a Merck local symposium and contributed to an Advisory Board for Biogen; she is Deputy Editor of Neurology, for which she receives an honorarium. C.T. is currently being funded by a Junior Leader La Caixa Fellowship [The project that gave rise to these results received the support of a fellowship from ‘la Caixa’ Foundation (ID 100010434), fellowship code is LCF/BQ/PI20/117600080]. She has also received the 2021 Merck’s Award for the Investigation in Multiple Sclerosis (Spain) and a grant from Instituto de Salud Carlos III (ISCIII), Spain (grant ID: PI21/01860). In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK Multiple Sclerosis Society (grant number 77). She has also received speaker honoraria from Roche and Novartis. She serves on the Editorial Board of Neurology and Multiple Sclerosis Journal. F.B. is supported by the UCLH Biomedical Research Centre. He is a steering committee or iDMC member for Biogen, Merck, Roche, EISAI and Prothena. He is a consultant for Roche, Biogen, Merck, IXICO, Jansen and Combinostics. He has research agreements with Merck, Biogen, GE Healthcare and Roche. He is co-founder and shareholder of Queen Square Analytics Ltd. D.C. is a consultant for Hoffmann-La Roche. In the last 3 years, he has been a consultant for Biogen; received research funding from Hoffmann-La Roche, the International Progressive Multiple Sclerosis Alliance, the Multiple Sclerosis Society and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre; and received speaker’s honorarium from Novartis. He co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, UK, which is supported by Merck. The remaining authors have nothing to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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

B cell-directed CAR T cell therapy has fundamentally changed the treatment of hematological malignancies and its scope of application is rapidly expanding to include other diseases such as solid tumors or autoimmune disorders. Therapy-refractoriness remains an important challenge in various inflammatory and non-inflammatory disorders of the CNS. The reasons for therapy failure are diverse and include limited access of current therapies to the CNS, as well as enormous inter- and intraindividual disease heterogeneity. The tissue-penetrating properties of CAR T cells make them a promising option to overcome this problem and to tackle pathologies directly within the CNS. First application of B cell-directed CAR T cells in neuromyelitis optica spectrum disorder and multiple sclerosis patients has lately revealed promising outcomes, expanding the potential of CAR T cell therapy to encompass CNS diseases. Additionally, the optimization of CAR T cells for the therapy of gliomas is a growing field. As a further perspective, pre-clinical data reveal potential benefits of CAR T cell therapy also in the treatment of primary neurodegenerative diseases such as Alzheimer's disease. Considering the biotechnological optimizations in the field of T cell engineering, such as the extension to target different antigens or the variation of the modified T cell subtype, new and promising fields of application for CAR T cells are rapidly opening up. These innovations offer the potencial to address the complex pathophysiological properties of CNS diseases. To optimally utilize CAR T cell therapy for CNS diseases in the future while minimizing therapy risks, there is a need for further mechanistic research as well as prospective controlled trials to seriously assess the disease and patient-specific risk-benefit ratio., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The interaction between ageing and multiple sclerosis is complex and carries significant implications for patient care. Managing multiple sclerosis effectively requires an understanding of how ageing and multiple sclerosis impact brain structure and function. Ageing inherently induces brain changes, including reduced plasticity, diminished grey matter volume, and ischaemic lesion accumulation. When combined with multiple sclerosis pathology, these age-related alterations may worsen clinical disability. Ageing may also influence the response of multiple sclerosis patients to therapies and/or their side effects, highlighting the importance of adjusted treatment considerations. MRI is highly sensitive to age- and multiple sclerosis-related processes. Accordingly, MRI can provide insights into the relationship between ageing and multiple sclerosis, enabling a better understanding of their pathophysiological interplay and informing treatment selection. This review summarizes current knowledge on the immunopathological and MRI aspects of ageing in the CNS in the context of multiple sclerosis. Starting from immunosenescence, ageing-related pathological mechanisms and specific features like enlarged Virchow-Robin spaces, this review then explores clinical aspects, including late-onset multiple sclerosis, the influence of age on diagnostic criteria, and comorbidity effects on imaging features. The role of MRI in understanding neurodegeneration, iron dynamics and myelin changes influenced by ageing and how MRI can contribute to defining treatment effects in ageing multiple sclerosis patients, are also discussed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The use of ultra-high-field 7-Tesla (7T) MRI in multiple sclerosis (MS) research has grown significantly over the past two decades. With recent regulatory approvals of 7T scanners for clinical use in 2017 and 2020, the use of this technology for routine care is poised to continue to increase in the coming years. In this context, the North American Imaging in MS Cooperative (NAIMS) convened a workshop in February 2023 to review the previous and current use of 7T technology for MS research and potential future research and clinical applications. In this workshop, experts were tasked with reviewing the current literature and proposing a series of consensus statements, which were reviewed and approved by the NAIMS. In this review and consensus paper, we provide background on the use of 7T MRI in MS research, highlighting this technology's promise for identification and quantification of aspects of MS pathology that are more difficult to visualize with lower-field MRI, such as grey matter lesions, paramagnetic rim lesions, leptomeningeal enhancement and the central vein sign. We also review the promise of 7T MRI to study metabolic and functional changes to the brain in MS. The NAIMS provides a series of consensus statements regarding what is currently known about the use of 7T MRI in MS, and additional statements intended to provide guidance as to what work is necessary going forward to accelerate 7T MRI research in MS and translate this technology for use in clinical practice and clinical trials. This includes guidance on technical development, proposals for a universal acquisition protocol and suggestions for research geared towards assessing the utility of 7T MRI to improve MS diagnostics, prognostics and therapeutic efficacy monitoring. The NAIMS expects that this article will provide a roadmap for future use of 7T MRI in MS., Competing Interests: D.M.H. has received research funding from EMD-Serono and Roche-Genentech, consulting fees from Horizon Therapeutics, TG Therapeutics and EMD-Serono and royalties from Up To Date, Inc. F.B. has received speaker honoraria from EMD-Serono, Sanofi and Novartis and serves/ed as site PI of multi-centre studies sponsored by EMD-Serono and Novartis and on advisory boards for Sanofi, EMD-Serono and Biogen. S.N. has received research funding from Roche-Genentech and Immunotec, consulting fees from Sana Biotechnology and personal compensation from NeuroRx Research. S.G. has received research funding from Roche-Genentech. E.S.B. has received consulting fees from EMD-Serono. .J.Z. has received research support from Novartis, I-Mab Biopharma and the Race to Erase MS Foundation. R.B. has received speaking honoraria from EMD-Serono and research support from Bristol-Myers Squibb, EMD-Serono and Novartis. A.C. was supported by the ECTRIMS post-doctoral training fellowship (2022). A.C. has received speaker honoraria from Novartis. S.Y.H. has received research funding and consulting fees from Siemens Healthineers. The University Hospital Basel (USB), as the employer of C.G., has received the following fees which were used exclusively for research support: (i) advisory board and consultancy fees from Actelion, Genzyme-Sanofi, Novartis, GeNeuro and Roche; (ii) speaker fees from Genzyme-Sanofi, Novartis, GeNeuro and Roche; and (iii) research support from Siemens, GeNeuro and Roche. E.C.K. has received research funding from Abbvie, Biogen and Genentech and consulting fees from EMD-Serono, Genentech, INmune Bio, Myrobalan Therapeutics, OM1, Inc. and TG Therapeutics. C.M. has received research funding from Genentech-Roche. C.L., J.D., M.D., D.A.R. and P.B. have no disclosures to report., (Published by Oxford University Press on behalf of the Guarantors of Brain 2024.)

Chronic active lesions (CAL) are an important manifestation of chronic inflammation in multiple sclerosis and have implications for non-relapsing biological progression. In recent years, the discovery of innovative MRI and PET-derived biomarkers has made it possible to detect CAL, and to some extent quantify them, in the brain of persons with multiple sclerosis, in vivo. Paramagnetic rim lesions on susceptibility-sensitive MRI sequences, MRI-defined slowly expanding lesions on T1-weighted and T2-weighted scans, and 18-kDa translocator protein-positive lesions on PET are promising candidate biomarkers of CAL. While partially overlapping, these biomarkers do not have equivalent sensitivity and specificity to histopathological CAL. Standardization in the use of available imaging measures for CAL identification, quantification and monitoring is lacking. To fast-forward clinical translation of CAL, the North American Imaging in Multiple Sclerosis Cooperative developed a consensus statement, which provides guidance for the radiological definition and measurement of CAL. The proposed manuscript presents this consensus statement, summarizes the multistep process leading to it, and identifies the remaining major gaps in knowledge., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. Elements of this work were written by employees of the US Government.)

Amyotrophic lateral sclerosis is a debilitating and lethal neurodegenerative disorder marked by the gradual deterioration of motor neurons. Diagnosing amyotrophic lateral sclerosis is challenging due to the lack of reliable diagnostic tools, with clinical assessment being the primary criterion. Recently, increased levels of neurofilament light chain in CSF have been considered a useful biomarker in disease, correlating with disease progression but not specific for diagnosis. This study utilized enzyme-linked immunosorbent assay to measure CSF C-X-C motif chemokine ligand 12 levels in healthy controls, amyotrophic lateral sclerosis patients and patients with amyotrophic lateral sclerosis-mimic disorders, assessing its potential as a diagnostic biomarker and comparing it with neurofilament light chain levels. Our results confirmed previous findings, showing increased C-X-C motif chemokine ligand 12 levels in amyotrophic lateral sclerosis patients compared to healthy control (797.07 ± 31.84 pg/mL versus 316.15 ± 16.6 pg/mL; P = 0.000) and increased CSF neurofilament light chain levels in amyotrophic lateral sclerosis (4565.63 ± 263.77 pg/mL) compared to healthy control (847.86 ± 214.37 pg/mL; P = 0.000). Increased C-X-C motif chemokine ligand levels were specific to amyotrophic lateral sclerosis, not seen in amyotrophic lateral sclerosis-mimic conditions like myelopathies (252.20 ± 23.16 pg/mL; P = 0.000), inflammatory polyneuropathies (270.24 ± 32.23 pg/mL; P = 0.000) and other mimic diseases (228.91 ± 29.20 pg/mL; P = 0.000). In contrast, CSF neurofilament light chain levels in amyotrophic lateral sclerosis overlapped with those in myelopathies (2900.11 ± 872.20 pg/mL; P = 0.821) and other mimic diseases (3169.75 ± 1096.65 pg/mL; P = 0.63), but not with inflammatory polyneuropathies (1156.4 ± 356.6 pg/mL; P = 0.000). Receiver operating characteristic curve analysis indicated significant differences between the area under the curve values of C-X-C motif chemokine ligand and neurofilament light chain in their diagnostic capacities. C-X-C motif chemokine ligand could differentiate between amyotrophic lateral sclerosis and myelopathies (area under the curve 0.99 ± 0.005), inflammatory polyneuropathies (area under the curve 0.962 ± 0.027) and other mimic diseases (area under the curve 1.00 ± 0.00), whereas neurofilament light chain was only effective in inflammatory polyneuropathies cases (area under the curve 0.92 ± 0.048), not in myelopathies (area under the curve 0.71 ± 0.09) or other mimic diseases (area under the curve 0.69 ± 0.14). We also evaluated C-X-C motif chemokine ligand levels in plasma [amyotrophic lateral sclerosis (2022 ± 81.8 pg/mL) versus healthy control (1739.43 ± 77.3 pg/mL; P = 0.015)] but found CSF determination (area under the curve 0.97 ± 0.012) to be more accurate than plasma determination (area under the curve 0.65 ± 0.063). In plasma, single molecule array (SIMOA) neurofilament light chain determination [amyotrophic lateral sclerosis (86.00 ± 12.23 pg/mL) versus healthy control (12.69 ± 1.15 pg/mL); P = 0.000] was more accurate than plasma C-X-C motif chemokine ligand 12 (area under the curve 0.98 ± 0.01405). These findings suggest that CSF C-X-C motif chemokine ligand 12 levels can enhance diagnostic specificity in distinguishing amyotrophic lateral sclerosis from amyotrophic lateral sclerosis-mimic disorders, compared to neurofilament light chain. Larger studies are needed to validate these results, but C-X-C motif chemokine ligand 12 determination shows promising diagnostic potential., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

In multiple sclerosis clinical trials, MRI outcome measures are typically extracted at a whole-brain level, but pathology is not homogeneous across the brain and so whole-brain measures may overlook regional treatment effects. Data-driven methods, such as independent component analysis, have shown promise in identifying regional disease effects but can only be computed at a group level and cannot be applied prospectively. The aim of this work was to develop a technique to extract longitudinal independent component analysis network-based measures of co-varying grey matter volumes, derived from T 1 -weighted volumetric MRI, in individual study participants, and assess their association with disability progression and treatment effects in clinical trials. We used longitudinal MRI and clinical data from 5089 participants (22 045 visits) with multiple sclerosis from eight clinical trials. We included people with relapsing-remitting, primary and secondary progressive multiple sclerosis. We used data from five negative clinical trials (2764 participants, 13 222 visits) to extract the independent component analysis-based measures. We then trained and cross-validated a least absolute shrinkage and selection operator regression model (which can be applied prospectively to previously unseen data) to predict the independent component analysis measures from the same regional MRI volume measures and applied it to data from three positive clinical trials (2325 participants, 8823 visits). We used nested mixed-effect models to determine how networks differ across multiple sclerosis phenotypes are associated with disability progression and to test sensitivity to treatment effects. We found 17 consistent patterns of co-varying regional volumes. In the training cohort, volume loss was faster in four networks in people with secondary progressive compared with relapsing-remitting multiple sclerosis and three networks with primary progressive multiple sclerosis. Volume changes were faster in secondary compared with primary progressive multiple sclerosis in four networks. In the combined positive trials cohort, eight independent component analysis networks and whole-brain grey matter volume measures showed treatment effects, and the magnitude of treatment-placebo differences in the network-based measures was consistently greater than with whole-brain grey matter volume measures. Longitudinal network-based analysis of grey matter volume changes is feasible using clinical trial data, showing differences cross-sectionally and longitudinally between multiple sclerosis phenotypes, associated with disability progression, and treatment effects. Future work is required to understand the pathological mechanisms underlying these regional changes., Competing Interests: The authors report no competing interests with respect to this research. The full disclosure statement is as follows: D.L.A. has received personal compensation for serving as a Consultant for Alexion, Biogen, Celgene, Eli Lilly, EMD Serono, Frequency Therapeutics, Genentech, Merck, Novartis, Roche, Sanofi and Shionogi and holds an equity interest in NeuroRx. F.B. has received compensation for consulting services and/or speaking activities from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Genzyme, Synthon BV, Roche, Teva, Jansen research and IXICO and is supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre. O.C. has received research grants from the Multiple Sclerosis Society of Great Britain & Northern Ireland, the NIHR UCLH Biomedical Research Centre, EUH2020, Spinal Cord Research Foundation and Rosetrees Trust. She serves as a consultant for Novartis, Teva and Roche and has received an honorarium from the American Academy of Neurology as Associate Editor of Neurology and serves on the Editorial Board of Multiple Sclerosis Journal. D.T.C. is a consultant Hoffmann-La Roche. In the last three years, he has been a consultant for Biogen and has received research funding from Hoffmann-La Roche, the International Progressive Multiple Sclerosis Alliance, the Medical Research Council, the Multiple Sclerosis Society and the NIHR UCLH Biomedical Research Centre and a speaker's honorarium from Novartis. He co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck. A.E. has received speaker's honoraria from Biogen and At The Limits educational programme. A.E. has received research grants from Medical Research Council, UK Research and Innovation's Innovate UK, Biogen, UCL Innovation and Enterprise and Roche. A.E. serves on the Editorial Board of Neurology. He has received travel support from the National Multiple Sclerosis Society and honorarium from the Journal of Neurology, Neurosurgery and Psychiatry for Editorial Commentaries. A.E. and F.B. have equity stake in Queen Square Analytics. J.C. has received support from the Efficacy and Evaluation (EME) Programme, a Medical Research Council (MRC) and NIHR partnership and the Health Technology Assessment (HTA) Programme (NIHR), the UK Multiple Sclerosis Society, the US National Multiple Sclerosis Society and the Rosetrees Trust. He is supported in part by the NIHR UCLH Biomedical Research Centre. He has been a local principal investigator for a trial in Multiple Sclerosis funded by the Canadian Multiple Sclerosis Society. A local principal investigator for commercial trials was funded by Ionis, Novartis and Roche and has taken part in advisory boards/consultancy for Azadyne, Biogen, Lucid, Janssen, Merck, NervGen, Novartis and Roche. E.C. and J.S. have nothing to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

With rising life expectancy and advancements in disease management, we expect the multiple sclerosis population is getting older. However, evidence supporting this hypothesis remains sparse. Our study aimed to determine whether the mean age of the Danish multiple sclerosis population has increased and to analyse the developments in sex distribution, incidence, and prevalence, all of which affect age composition. We conducted a cohort study by linking nationwide data from the Danish Multiple Sclerosis Registry to the Population Statistics Registry, the Danish Cause of Death Registry, and the Historical Migration Registry. We included all living patients with a confirmed multiple sclerosis diagnosis who lived in Denmark on the 1st of January each year from 1950 to 2023. We calculated the mean and median age, age distribution, sex distribution, incidence, and prevalence of the Danish MS population annually from 1950 to 2023. We included 28,145 individuals with multiple sclerosis. The mean age of the Danish multiple sclerosis population increased until the late 1970s to around 52.5 years, where it stabilised until 1990. The mean age experienced a slight decline to 51.2 years in 2005, followed by a subsequent rise to its peak of 54.2 years in 2023. In 1975, females comprised 58.7% of the multiple sclerosis population, increasing to 65.7% by 2000 and 68.5% in 2023. The incidence of multiple sclerosis remained stable at around 3.5 per 100,000 until 1975 and steadily increased by more than 2.5 times in 2000 to 11.4 per 100,000. Despite fluctuations, it remained relatively stable from 2000 until 2022, showing a slight decrease in 2022 compared to the previous two decades. Both overall and sex-specific prevalence exhibited an upward trend, particularly among females. Our study demonstrates that the mean age of the Danish multiple sclerosis population has increased, although not as decisively as expected. The female proportion has grown in tandem with prevalence, while incidence appears to have stabilised in recent decades after years of increase. Denmark's robust registry data and universal healthcare system offer a unique opportunity for reliable epidemiological analysis. Our results establish a benchmark for future demographic studies in the field of multiple sclerosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The manuscript explores value-based healthcare (VBHC) and its role in assessing healthcare quality beyond clinical metrics. It identifies four value types: personal, technical, allocative, and societal. Emphasizing the integration of diverse stakeholder perspectives, including patients, families, and clinicians, the study highlights the importance of patient- and family-reported measures (PROMs and PREMs) and clinician input. Clinicians' insights on treatment feasibility and effectiveness are crucial for a holistic understanding of healthcare quality. The manuscript advocates for combining machine learning with participatory approaches to enhance data analysis and continuous quality improvement in VBHC, driving better outcomes for patients and communities., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Quality in Health Care. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Ulcerative colitis (UC) is a severe and debilitating illness that affects the quality of life and physical health of many Canadians. Given the dynamic and progressive nature of the disease, advanced therapies are required to support its long-term management. The emergence of small molecule therapies offers novel treatment options that target mechanisms central to the immunopathology of UC. Sphingosine-1-phosphate (S1P) receptor modulators and Janus-activated kinase inhibitors are 2 classes of therapies that target unique pathways to attenuate inflammation and modulate the immune response characteristic of UC. This review aims to provide practical guidance on how these therapeutic options can best be used to optimize treatment management and highlight the emerging role of small molecule therapies as a treatment strategy for UC., Competing Interests: V.J. has served as an Advisory Board Member/ Consultant for AbbVie, Alimentiv Inc. (formerly Robarts Clinical Trials Inc.), Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Avoro Capital, Celgene/BMS, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Genentech, Gilde Healthcare, Gilead, GlaxoSmithKline, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Synedgen, Takeda, TD Securities, Teva, Topivert, Ventyx, and Vividion Therapeutics. He has served as a speaker for Abbvie, Ferring, BMS, Galapagos, Janssen, Pfizer, Fresenius Kabi, and Takeda. V.J. has received research support from Celgene/BMS, Pfizer, Abbvie, Boehringer Ingelheim, Eli Lilly, Janssen, Takeda, Gilead Sciences, and Tigenix. W.A. has served as a speaker, an advisory board member, and/or a clinical investigator for Abbvie, Amgen, Bausch, BMS, Celltrion, Innomar, Janssen, Merck, Pfizer, Sanofi, and Takeda. B.B has served as an advisor/speaker for Ferring, Janssen, Abbvie, Takeda, Pfizer, BMS, Merck, Sandoz, Organon, Lifelabs, Celltrion; and as an advisor for Alimentiv, Gilead, Iterative Health, Merck, Amgen, Pendopharm, Eli Lilly, Fresenius Kabi, Mylan, Viatris, Bausch Health, Jamp Pharma, and Eupraxia. B.B. has received research support from Janssen, Abbvie, GSK, BMS, Amgen, Genentech, Merck, BI, Qu Biologic; and has stock options with Qu Biologic. J.E.P. has served as an advisor/speaker for AbbVie, Astra Zeneca, BI, BMS, Frensenius Kabi, GSK, Janssen, JMP, Lilly, Mallinckrodt Pharmaceuticals, Mitsubishi Tanabe Pharma, Novartis, Organon, Pfizer, Sandoz, Samsung, Viatris. D.S. has served as an advisor/speaker for Apotex, Bayer, Biogen, BMS, Merck, EMD Serono, Novartis, Pharma Science, Roche, Sanofi, Teva. L.T. has received grants and/or contracts from AbbVie Canada, Pfizer Canada, Takeda Canada, Fresnenius Kabi Canada, and Amgen Canada; consulting fees from Janssen Canada, AbbVie Canada, Pfizer Canada, Takeda Canada, Roche Canada, Gilead Canada, Sandoz Canada, Amgen Canada, Fresnius Kabi, and Viatris; and honoraria for advisory board participation and/or development from Janssen Canada, AbbVie Canada, Pfizer Canada, Takeda Canada, Roche Canada, Gilead Canada, Sandoz Canada, Amgen Canada, and Organon Canada. R.P. has received consulting fees from AbbVie, Abbott, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Protagonist Therapeutics, Prometheus Biocsciences, Roche, Satisfai Health, Sandoz, Shire, Sublimity Therapeutics, Theravance Biopharma, UCB, Takeda Pharmaceuticals, Trellus, Viatris, and Ventyx; speaker fees from Abbvie, Amgen, Arena Pharmaceuticals, BMS, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda Pharmaceuticals; has served on advisory boards for Abbvie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring, Galapagos, Genentech, Gilead Sciences, Glaxo-Smith Kline, Janssen, Merck, Mylan, Oppilan Pharma, Pandion Pharma, Pfizer, Sandoz, Shire, Sublimity Therapeutics, Theravance Biopharma, and Takeda Pharmaceuticals; and has received research/educational support: Abbvie, Ferring, Janssen, Pfizer, and Takeda., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology.)

In preclinical models of multiple sclerosis, systemic inflammation has an impact on the compartmentalized inflammatory process within the central nervous system and results in axonal loss. It remains to be shown whether this is the case in humans, specifically whether systemic inflammation contributes to spinal cord or brain atrophy in multiple sclerosis. Hence, an observational longitudinal study was conducted to delineate the relationship between systemic inflammation and atrophy using magnetic resonance imaging: the SIMS (Systemic Inflammation in Multiple Sclerosis) study. Systemic inflammation and progression were assessed in people with progressive multiple sclerosis ( n = 50) over two and a half years. Eligibility criteria included: (i) primary or secondary progressive multiple sclerosis; (ii) age ≤ 70; and (iii) Expanded Disability Status Scale ≤ 6.5. First morning urine was collected weekly to quantify systemic inflammation by measuring the urinary neopterin-to-creatinine ratio using a validated ultra-performance liquid chromatography mass spectrometry technique. The urinary neopterin-to-creatinine ratio temporal profile was characterized by short-term responses overlaid on a background level of inflammation, so these two distinct processes were considered as separate variables: background inflammation and inflammatory response. Participants underwent MRI at the start and end of the study, to measure cervical spinal cord and brain atrophy. Brain and cervical cord atrophy occurred on the study, but the most striking change was seen in the cervical spinal cord, in keeping with the corticospinal tract involvement that is typical of progressive disease. Systemic inflammation predicted cervical cord atrophy. An association with brain atrophy was not observed in this cohort. A time lag between systemic inflammation and cord atrophy was evident, suggesting but not proving causation. The association of the inflammatory response with cord atrophy depended on the level of background inflammation, in keeping with experimental data in preclinical models where the effects of a systemic inflammatory challenge on tissue injury depended on prior exposure to inflammation. A higher inflammatory response was associated with accelerated cord atrophy in the presence of background systemic inflammation below the median for the study population. Higher background inflammation, while associated with cervical cord atrophy itself, subdued the association of the inflammatory response with cord atrophy. Findings were robust to sensitivity analyses adjusting for potential confounders and excluding cases with new lesion formation. In conclusion, systemic inflammation associates with, and precedes, multiple sclerosis progression. Further work is needed to prove causation since targeting systemic inflammation may offer novel treatment strategies for slowing neurodegeneration in multiple sclerosis., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Neurofilament light chain is an established marker of neuroaxonal injury that is elevated in CSF and blood across various neurological diseases. It is increasingly used in clinical practice to aid diagnosis and monitor progression and as an outcome measure to assess safety and efficacy of disease-modifying therapies across the clinical translational neuroscience field. Quantitative methods for neurofilament light chain in human biofluids have relied on immunoassays, which have limited capacity to describe the structure of the protein in CSF and how this might vary in different neurodegenerative diseases. In this study, we characterized and quantified neurofilament light chain species in CSF across neurodegenerative and neuroinflammatory diseases and healthy controls using targeted mass spectrometry. We show that the quantitative immunoprecipitation-tandem mass spectrometry method developed in this study strongly correlates to single-molecule array measurements in CSF across the broad spectrum of neurodegenerative diseases and was replicable across mass spectrometry methods and centres. In summary, we have created an accurate and cost-effective assay for measuring a key biomarker in translational neuroscience research and clinical practice, which can be easily multiplexed and translated into clinical laboratories for the screening and monitoring of neurodegenerative disease or acute brain injury., Competing Interests: H.Z. has served at scientific advisory boards and/or as a consultant for AbbVie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). R.J.B. and R.W.P. lead The Neurofilament Light Consortium, an industry academic collaboration that is supported by AbbVie, Bristol Myers Squibb, Biogen and Roche. R.W.P. has received honoraria from GE Healthcare for educational talks, which is used to support academic work. R.J.B. has received research funding from Avid Radiopharmaceuticals, Janssen, Roche/Genentech, Eli Lilly, Eisai, Biogen, AbbVie, Bristol Myers Squibb and Novartis. Washington University and R.J.B. have equity ownership interest in C2N Diagnostics and receive income based on technology (neurofilament light chain assays and materials) licenced by Washington University to C2N Diagnostics. R.J.B. receives income from C2N Diagnostics for serving on the scientific advisory board. R.J.B. serves on the Roche Gantenerumab Steering Committee as an unpaid member. J.C. has received support from the Health Technology Assessment (HTA) Programme (National Institute for Health Research, NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust. He is supported in part by the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in multiple sclerosis funded by the Multiple Sclerosis Society of Canada. A local principal investigator for commercial trials was funded by Ionis, Novartis and Roche and has taken part in advisory boards/consultancy for Azadyne, Biogen, Lucid, Janssen, Merck, NervGen, Novartis and Roche. The MS-SMART trial was funded by the Efficacy and Mechanism Evaluation programme as project number 11/30/11. MS-SMART is an investigator-led project sponsored by the University College London. This independent research is awarded by and funded by the Medical Research Council, the UK MS Society and the National MS Society and is managed by the National Institute for Health Research on behalf of the Medical Research Council–National Institute for Health partnership. Additional support came from the University of Edinburgh, the National Institute for Health Research University College London Hospitals Biomedical Research Centre and University College London and the National Institute for Health Research Leeds Clinical Research Facility (Dental Translational and Clinical Research Unit). Riluzole was provided without charge by Sanofi-Genzyme who was not involved in either the trial design, running of the trial or analysis. F.D.A. received speaker honoraria from Neurology Academy, Janssen, Merck, Novartis and Sanofi; is on the advisory board for Novartis and Coloplast; has received congress fees from Janssen, Merck, Novartis and Roche; and is a regional coordinator for the Oratorio Hand Trial (Hoffmann-La Roche). The rest of the authors declared no conflicting interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Low serum levels of 25-hydroxyvitamin D [25(OH)D] and low sunlight exposure are known risk factors for the development of multiple sclerosis. Add-on vitamin D supplementation trials in established multiple sclerosis have been inconclusive. The effects of vitamin D supplementation to prevent multiple sclerosis is unknown. We aimed to test the hypothesis that oral vitamin D3 supplementation in high-risk clinically isolated syndrome (abnormal MRI, at least three T2 brain and/or spinal cord lesions), delays time to conversion to definite multiple sclerosis, that the therapeutic effect is dose-dependent, and that all doses are safe and well tolerated. We conducted a double-blind trial in Australia and New Zealand. Eligible participants were randomized 1:1:1:1 to placebo, 1000, 5000 or 10 000 international units (IU) of oral vitamin D3 daily within each study centre (n = 23) and followed for up to 48 weeks. Between 2013 and 2021, we enrolled 204 participants. Brain MRI scans were performed at baseline, 24 and 48 weeks. The main study outcome was conversion to clinically definite multiple sclerosis based on the 2010 McDonald criteria defined as either a clinical relapse or new brain MRI T2 lesion development. We included 199 cases in the intention-to-treat analysis based on assigned dose. Of these, 116 converted to multiple sclerosis by 48 weeks (58%). Compared to placebo, the hazard ratios (95% confidence interval) for conversion were 1000 IU 0.87 (0.50, 1.50); 5000 IU 1.37 (0.82, 2.29); and 10 000 IU 1.28 (0.76, 2.14). In an adjusted model including age, sex, latitude, study centre and baseline symptom number, clinically isolated syndrome onset site, presence of infratentorial lesions and use of steroids, the hazard ratios (versus placebo) were 1000 IU 0.80 (0.45, 1.44); 5000 IU 1.36 (0.78, 2.38); and 10 000 IU 1.07 (0.62, 1.85). Vitamin D3 supplementation was safe and well tolerated. We did not demonstrate reduction in multiple sclerosis disease activity by vitamin D3 supplementation after a high-risk clinically isolated syndrome., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Cortical myelin loss and repair in multiple sclerosis (MS) have been explored in neuropathological studies, but the impact of these processes on neurodegeneration and the irreversible clinical progression of the disease remains unknown. Here, we evaluated in vivo cortical demyelination and remyelination in a large cohort of people with all clinical phenotypes of MS followed up for 5 years using magnetization transfer imaging (MTI), a technique that has been shown to be sensitive to myelin content changes in the cortex. We investigated 140 people with MS (37 clinically isolated syndrome, 71 relapsing-MS, 32 progressive-MS), who were clinically assessed at baseline and after 5 years and, along with 84 healthy controls, underwent a 3 T-MRI protocol including MTI at baseline and after 1 year. Changes in cortical volume over the radiological follow-up were computed with a Jacobian integration method. Magnetization transfer ratio was employed to calculate for each patient an index of cortical demyelination at baseline and of dynamic cortical demyelination and remyelination over the follow-up period. The three indices of cortical myelin content change were heterogeneous across patients but did not significantly differ across clinical phenotypes or treatment groups. Cortical remyelination, which tended to fail in the regions closer to CSF (-11%, P < 0.001), was extensive in half of the cohort and occurred independently of age, disease duration and clinical phenotype. Higher indices of cortical dynamic demyelination (β = 0.23, P = 0.024) and lower indices of cortical remyelination (β = -0.18, P = 0.03) were significantly associated with greater cortical atrophy after 1 year, independently of age and MS phenotype. While the extent of cortical demyelination predicted a higher probability of clinical progression after 5 years in the entire cohort [odds ratio (OR) = 1.2; P = 0.043], the impact of cortical remyelination in reducing the risk of accumulating clinical disability after 5 years was significant only in the subgroup of patients with shorter disease duration and limited extent of demyelination in cortical regions (OR = 0.86, P = 0.015, area under the curve = 0.93). In this subgroup, a 30% increase in cortical remyelination nearly halved the risk of clinical progression at 5 years, independently of clinical relapses. Overall, our results highlight the critical role of cortical myelin dynamics in the cascade of events leading to neurodegeneration and to the subsequent accumulation of irreversible disability in MS. Our findings suggest that early-stage myelin repair compensating for cortical myelin loss has the potential to prevent neuro-axonal loss and its long-term irreversible clinical consequences in people with MS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Traumatic spinal cord injury (SCI) is a leading cause of lifelong disabilities. Permanent sensory, motor and autonomic impairments after SCI are substantially attributed to degeneration of spinal cord neurons and axons, and disintegration of neural network. To date, minimal regenerative treatments are available for SCI with an unmet need for new therapies to reconstruct the damaged spinal cord neuron-glia network and restore connectivity with the supraspinal pathways. Multipotent neural precursor cells (NPCs) have a unique capacity to generate neurons, oligodendrocytes and astrocytes. Due to this capacity, NPCs have been an attractive cell source for cellular therapies for SCI. Transplantation of NPCs has been extensively tested in preclinical models of SCI in the past two decades. These studies have identified opportunities and challenges associated with NPC therapies. While NPCs have the potential to promote neuroregeneration through various mechanisms, their low long-term survival and integration within the host injured spinal cord limit the functional benefits of NPC-based therapies for SCI. To address this challenge, combinatorial strategies have been developed to optimize the outcomes of NPC therapies by enriching SCI microenvironment through biomaterials, genetic and pharmacological therapies. In this review, we will provide an in-depth discussion on recent advances in preclinical NPC-based therapies for SCI. We will discuss modes of actions and mechanism by which engrafted NPCs contribute to the repair process and functional recovery. We will also provide an update on current clinical trials and new technologies that have facilitated preparation of medical-grade human NPCs suitable for transplantation in clinical studies., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Multiple sclerosis (MS) is a debilitating inflammatory and neurodegenerative disease which commonly involves cognitive dysfunction. Magnetic resonance imaging (MRI) studies have shown that patients with MS (pwMS) have diffuse patterns of brain atrophy, however, the relationship between the presentation of cognitive dysfunction and brain tissue loss remains understudied. Given the integral function of thalamus as a central nervous system relay center and its involvement in various brain circuits, thalamic atrophy may play a key role in the development and progression of cognitive dysfunction. The purpose of this study is to examine the relationship between cognitive impairment in pwMS and thalamic atrophy., Methods: A total of 121 pwMS who had neuropsychological testing and quantitative MRI within 1 year of each were retrospectively identified. Grouped LASSO linear regression with 10-fold cross validation was used to estimate each neuropsychological test score with thalamic volume as the focal predictor and all other demographic and MRI metrics as covariates., Results: Rates of impairment ranged from 19% to 44%. Results showed notable associations between thalamic volume and Symbol Digit Modalities Test (β = 0.11), Brief Visuospatial Memory Test, delayed (β = 0.12), California Verbal Learning Test, delayed and total (β = 0.24 and β = 0.15 respectively), and Trail Making Test Part A (β = -0.01), after adjusting for covariates., Conclusions: These findings demonstrate an independent association between thalamic volumes and processing speed and memory performance, after accounting for demographic, clinical, and other MRI variables, among pwMS., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

The identification of prognostic markers in early multiple sclerosis (MS) is challenging and requires reliable measures that robustly predict future disease trajectories. Ideally, such measures should make inferences at the individual level to inform clinical decisions. This study investigated the prognostic value of longitudinal structural networks to predict 5-year Expanded Disability Status Scale (EDSS) progression in patients with relapsing-remitting MS (RRMS). We hypothesized that network measures, derived from MRI, outperform conventional MRI measurements at identifying patients at risk of developing disability progression. This longitudinal, multicentre study within the Magnetic Resonance Imaging in MS (MAGNIMS) network included 406 patients with RRMS (mean age = 35.7 ± 9.1 years) followed up for 5 years (mean follow-up = 5.0 ± 0.6 years). EDSS was determined to track disability accumulation. A group of 153 healthy subjects (mean age = 35.0 ± 10.1 years) with longitudinal MRI served as controls. All subjects underwent MRI at baseline and again 1 year after baseline. Grey matter atrophy over 1 year and white matter lesion load were determined. A single-subject brain network was reconstructed from T1-weighted scans based on grey matter atrophy measures derived from a statistical parameter mapping-based segmentation pipeline. Key topological measures, including network degree, global efficiency and transitivity, were calculated at single-subject level to quantify network properties related to EDSS progression. Areas under receiver operator characteristic (ROC) curves were constructed for grey matter atrophy and white matter lesion load, and the network measures and comparisons between ROC curves were conducted. The applied network analyses differentiated patients with RRMS who experience EDSS progression over 5 years through lower values for network degree [H(2) = 30.0, P < 0.001] and global efficiency [H(2) = 31.3, P < 0.001] from healthy controls but also from patients without progression. For transitivity, the comparisons showed no difference between the groups [H(2) = 1.5, P = 0.474]. Most notably, changes in network degree and global efficiency were detected independent of disease activity in the first year. The described network reorganization in patients experiencing EDSS progression was evident in the absence of grey matter atrophy. Network degree and global efficiency measurements demonstrated superiority of network measures in the ROC analyses over grey matter atrophy and white matter lesion load in predicting EDSS worsening (all P-values < 0.05). Our findings provide evidence that grey matter network reorganization over 1 year discloses relevant information about subsequent clinical worsening in RRMS. Early grey matter restructuring towards lower network efficiency predicts disability accumulation and outperforms conventional MRI predictors., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Fingolimod is a frequently used disease-modifying therapy in relapsing-remitting multiple sclerosis. However, case reports and small observational studies indicate a highly increased risk of disease reactivation after discontinuation. We aimed to investigate the risk of radiological disease reactivation in patients discontinuing fingolimod. We performed a nationwide cohort study in Denmark, including patients who discontinued fingolimod between January 2014 and January 2023. Eligibility was a diagnosis with relapsing-remitting multiple sclerosis and two MRIs performed respectively within 1 year before and after discontinuing fingolimod. The included patients were compared with those discontinuing dimethyl fumarate with the same eligibility criteria in an unadjusted and matched propensity score analysis. Matching was done on age, sex, Expanded Disability Status Scale, MRI data, cause for treatment discontinuation, treatment duration and relapse rate. The main outcome was the presence of new T 2 lesions on the first MRI after treatment discontinuation. To identify high-risk patients among those discontinuing fingolimod, we made a predictive model assessing risk factors for obtaining new T 2 lesions. Of 1324 patients discontinuing fingolimod in the study period, 752 were eligible for inclusion [mean age (standard deviation), years, 41 (10); 552 females (73%); median Expanded Disability Status Scale (Q1-Q3), 2.5 (2.0-3.5); mean disease duration (standard deviation), years, 12 (8)]. Of 2044 patients discontinuing dimethyl fumarate in the study period, 957 were eligible for inclusion, presenting similar baseline characteristics. Among patients discontinuing fingolimod, 127 (17%) had 1-2 new T 2 lesions, and 124 (17%) had ≥3 new T 2 lesions compared with 114 (12%) and 45 (5%), respectively, for those discontinuing dimethyl fumarate, corresponding to odds ratios (95% confidence interval) of 1.8 (1.3-2.3) and 4.4 (3.1-6.3). The predictive model, including 509 of the 752 patients discontinuing fingolimod, showed a highly increased risk of new T 2 lesions among those with disease activity during fingolimod treatment and among females under 40 years. This nationwide study suggests that discontinuing fingolimod in some cases carries a risk of developing new T 2 lesions, emphasizing the importance of clinical awareness. If feasible, clinicians should prioritize the prompt initiation of new disease-modifying therapies, particularly among young females., Competing Interests: M.F.W.-H. has served on the scientific advisory board for Sanofi and has received honoraria for lecturing for Novartis and Sanofi. R.P.H. has served on the scientific advisory board for Novartis and received honoraria for lecturing for Novartis and Sanofi. A.H. has served on the scientific advisory board for Merck and received honoraria for lecturing for Biogen and Merck. A.R.L. reports no competing interests. M.M. has served on the scientific advisory board for Biogen, Sanofi, Roche, Novartis, Merck and AbbVie, has received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi and Genzyme and has received research support and support for congress participation from Biogen, Genzyme, Teva, Roche, Merck and Novartis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Speech and language processing involve complex interactions between cortical areas necessary for articulatory movements and auditory perception and a range of areas through which these are connected and interact. Despite their fundamental importance, the precise mechanisms underlying these processes are not fully elucidated. We measured BOLD signals from normal hearing participants using high-field 7 Tesla fMRI with 1-mm isotropic voxel resolution. The subjects performed 2 speech perception tasks (discrimination and classification) and a speech production task during the scan. By employing univariate and multivariate pattern analyses, we identified the neural signatures associated with speech production and perception. The left precentral, premotor, and inferior frontal cortex regions showed significant activations that correlated with phoneme category variability during perceptual discrimination tasks. In addition, the perceived sound categories could be decoded from signals in a region of interest defined based on activation related to production task. The results support the hypothesis that articulatory motor networks in the left hemisphere, typically associated with speech production, may also play a critical role in the perceptual categorization of syllables. The study provides valuable insights into the intricate neural mechanisms that underlie speech processing., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Few studies examined blood biomarkers informative of patient-reported outcome (PRO) of disability in people with multiple sclerosis (MS). We examined the associations between serum multi-protein biomarker profiles and patient-reported MS disability. In this cross-sectional study (2017-2020), adults with diagnosis of MS (or precursors) from two independent clinic-based cohorts were divided into a training and test set. For predictors, we examined seven clinical factors (age at sample collection, sex, race/ethnicity, disease subtype, disease duration, disease-modifying therapy [DMT], and time interval between sample collection and closest PRO assessment) and 19 serum protein biomarkers potentially associated with MS disease activity endpoints identified from prior studies. We trained machine learning (ML) models (Least Absolute Shrinkage and Selection Operator regression [LASSO], Random Forest, Extreme Gradient Boosting, Support Vector Machines, stacking ensemble learning, and stacking classification) for predicting Patient Determined Disease Steps (PDDS) score as the primary endpoint and reported model performance using the held-out test set. The study included 431 participants (mean age 49 years, 81% women, 94% non-Hispanic White). For binary PDDS score, combined feature input of routine clinical factors and the 19 proteins consistently outperformed base models (comprising clinical features alone or clinical features plus one single protein at a time) in predicting severe (PDDS ≥ 4) versus mild/moderate (PDDS < 4) disability across multiple machine learning approaches, with LASSO achieving the best area under the curve (AUC PDDS = 0.91) and other metrics. For ordinal PDDS score, LASSO model comprising combined clinical factors and 19 proteins as feature input ( R 2 , binary and ordinal PDDS score) shared six clinical features (age, sex, race/ethnicity, disease subtype, disease duration, DMT efficacy) and nine proteins (cluster of differentiation 6, CUB-domain-containing protein 1, contactin-2, interleukin-12 subunit-beta, neurofilament light chain [NfL], protogenin, serpin family A member 9, tumor necrosis factor superfamily member 13B, versican). By comparison, LASSO models with clinical features plus one single protein at a time as feature input did not select either NfL or glial fibrillary acidic protein (GFAP) as a final feature. Forcing either NfL or GFAP as a single protein feature into models did not improve performance beyond clinical features alone. Stacking classification model using five functional pathways to represent multiple proteins as meta-features implicated those involved in neuroaxonal integrity as significant contributors to predictive performance. Thus, serum multi-protein biomarker profiles improve the prediction of real-world MS disability status beyond clinical profile alone or clinical profile plus single protein biomarker, reaching clinically actionable performance.PDDS = 0.31) again outperformed base models. The two best-performing LASSO models ( i.e. , binary and ordinal PDDS score) shared six clinical features (age, sex, race/ethnicity, disease subtype, disease duration, DMT efficacy) and nine proteins (cluster of differentiation 6, CUB-domain-containing protein 1, contactin-2, interleukin-12 subunit-beta, neurofilament light chain [NfL], protogenin, serpin family A member 9, tumor necrosis factor superfamily member 13B, versican). By comparison, LASSO models with clinical features plus one single protein at a time as feature input did not select either NfL or glial fibrillary acidic protein (GFAP) as a final feature. Forcing either NfL or GFAP as a single protein feature into models did not improve performance beyond clinical features alone. Stacking classification model using five functional pathways to represent multiple proteins as meta-features implicated those involved in neuroaxonal integrity as significant contributors to predictive performance. Thus, serum multi-protein biomarker profiles improve the prediction of real-world MS disability status beyond clinical profile alone or clinical profile plus single protein biomarker, reaching clinically actionable performance., Competing Interests: Sample collection and biomarker assay were funded in part by Octave Bioscience. Z.X. serves on the scientific advisory board of Roche/Genentech and has a research agreement with Octave Biosciences. W,Z. serves on the scientific advisory board of Roche/Genentech. J.F.F. has received research support from Biogen, Novartis, Adamas, Octave and Genentech. He received speakers’ honoraria from Biogen. He has participated in advisory boards with TG Therapeutics, Sandoz, Biogen and Octave. He has equity interest in Octave. He is the founder of InterPro Bioscience. F.Q. is an employee of Octave Bioscience Inc. F.Z. was an employee of Octave Bioscience Inc, when the study analysis was performed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Multiple sclerosis risk has a well-established polygenic component, yet the genetic contribution to disease course and severity remains unclear and difficult to examine. Accurately measuring disease progression requires long-term study of clinical and radiological outcomes with sufficient follow-up duration to confidently confirm disability accrual and multiple sclerosis phenotypes. In this retrospective study, we explore genetic influences on long-term disease course and severity; in a unique cohort of clinically isolated syndrome patients with homogenous 30-year disease duration, deep clinical phenotyping and advanced MRI metrics. Sixty-one clinically isolated syndrome patients [41 female (67%): 20 male (33%)] underwent clinical and MRI assessment at baseline, 1-, 5-, 10-, 14-, 20- and 30-year follow-up (mean age ± standard deviation: 60.9 ± 6.5 years). After 30 years, 29 patients developed relapsing-remitting multiple sclerosis, 15 developed secondary progressive multiple sclerosis and 17 still had a clinically isolated syndrome. Twenty-seven genes were investigated for associations with clinical outcomes [including disease course and Expanded Disability Status Scale (EDSS)] and brain MRI (including white matter lesions, cortical lesions, and brain tissue volumes) at the 30-year follow-up. Genetic associations with changes in EDSS, relapses, white matter lesions and brain atrophy (third ventricular and medullary measurements) over 30 years were assessed using mixed-effects models. HLA-DRB1*1501 -positive ( n = 26) patients showed faster white matter lesion accrual [+1.96 lesions/year (0.64-3.29), P = 3.8 × 10 -3 ], greater 30-year white matter lesion volumes [+11.60 ml, (5.49-18.29), P = 1.27 × 10 -3 ] and higher annualized relapse rates [+0.06 relapses/year (0.005-0.11), P = 0.031] compared with HLA-DRB1*1501 -negative patients ( n = 35). PVRL2 -positive patients ( n = 41) had more cortical lesions (+0.83 [0.08-1.66], P = 0.042), faster EDSS worsening [+0.06 points/year (0.02-0.11), P = 0.010], greater 30-year EDSS [+1.72 (0.49-2.93), P = 0.013; multiple sclerosis cases: +2.60 (1.30-3.87), P = 2.02 × 10 -3 ], and greater risk of secondary progressive multiple sclerosis [odds ratio (OR) = 12.25 (1.15-23.10), P = 0.031] than PVRL2 -negative patients ( n = 18). In contrast, IRX1 -positive ( n = 30) patients had preserved 30-year grey matter fraction [+0.76% (0.28-1.29), P = 8.4 × 10 -3 ], lower risk of cortical lesions [OR = 0.22 (0.05-0.99), P = 0.049] and lower 30-year EDSS [-1.35 (-0.87,-3.44), P = 0.026; multiple sclerosis cases: -2.12 (-0.87, -3.44), P = 5.02 × 10 -3 ] than IRX1 -negative patients ( n = 30). In multiple sclerosis cases, IRX1 -positive patients also had slower EDSS worsening [-0.07 points/year (-0.01,-0.13), P = 0.015] and lower risk of secondary progressive multiple sclerosis [OR = 0.19 (0.04-0.92), P = 0.042]. These exploratory findings support diverse genetic influences on pathological mechanisms associated with multiple sclerosis disease course. HLA-DRB1*1501 influenced white matter inflammation and relapses, while IRX1 (protective) and PVRL2 (adverse) were associated with grey matter pathology (cortical lesions and atrophy), long-term disability worsening and the risk of developing secondary progressive multiple sclerosis., Competing Interests: N.S. has been a clinical research fellow in a post supported by Merck (supervised by S.A.T. and D.C.) and subsequently by MRC (MR/W019906/1). K.C has received honoraria for participation and attendance of educational events from Novartis, Roche, Biogen and Merck; she has received honoraria for consultancy work from Novartis, Roche, Biogen, Merck and Viatris. F.P.C. received a Guarantors of Brain fellowship 2017–2020. F.P.C. and B.K. are supported by the National Institute for Health Research (NIHR), Biomedical Research Centre initiative at University College London Hospitals (UCLH). A.J.T. reports personal fees paid to his institution from Eisai Ltd; is an editorial board member for The Lancet Neurology receiving a free subscription; is Editor-in-Chief for MS Journal receiving an honorarium from SAGE Publications; receives support for travel as member, Clinical Trials Committee, International PPMS Alliance, and from the National MS Society (NMSS) (USA) as member, NMSS Research Programs Advisory Committee. S.A.T. receives support from the UCLH Biomedical Research Centre; has received honoraria from Roche, Merck, Novartis, Sanofi-Genzyme and Biogen in the last 3 years and co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck. W.B. has received speaker honoraria for educational activities and/or acted as a consultant for Biogen, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme and Viatris. O.C. is a member of independent data and safety monitoring board for Novartis, gave a teaching talk on McDonald criteria in a Merck local symposium, and contributed to an Advisory Board for Biogen; she is Deputy Editor of Neurology, for which she receives an honorarium. C.T. is currently being funded by a Junior Leader La Caixa Fellowship (The project that gave rise to these results received the support of a fellowship from ‘la Caixa’ Foundation (ID 100010434); fellowship code is LCF/BQ/PI20/117600080; She has also received the 2021 Merck’s Award for the Investigation in MS (Spain) and a grant from Instituto de Salud Carlos III (ISCIII), Spain (grant ID: PI21/01860); In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK Multiple Sclerosis Society (grant number 77); She has also received speaker honoraria from Roche and Novartis; She serves on the Editorial Board of Neurology and Multiple Sclerosis Journal. F.B. is supported by the UCLH biomedical research centre; He is a steering committee or iDMC member for Biogen, Merck, Roche, EISAI and Prothena; He is a consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics; He has research agreements with Merck, Biogen, GE Healthcare, Roche; He is co-founder and shareholder of Queen Square Analytics LTD. D.C. is a consultant for Hoffmann-La Roche; In the last three years he has been a consultant for Biogen, received research funding from Hoffmann-La Roche, the International Progressive Multiple Sclerosis Alliance, the Multiple Sclerosis Society, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, and speaker’s honorarium from Novartis; He co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck. The remaining authors, L.H., R.S., C.A.M.G.W.K. and H.H.: nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The spectrum of MOG-IgG-associated disease (MOGAD) includes optic neuritis (ON), myelitis (MY), acute disseminated encephalomyelitis (ADEM), brainstem encephalitis, cerebral cortical encephalitis (CE) and AQP4-IgG-negative neuromyelitis optica spectrum disorder (NMOSD). In MOGAD, MOG-IgG are usually detected in sera (MOG-IgGSERUM), but there have been some seronegative MOGAD cases with MOG-IgG in CSF (MOG-IgGCSF), and its diagnostic implications remains unclear. In this cross-sectional study, we identified patients with paired serum and CSF sent from all over Japan for testing MOG-IgG. Two investigators blinded to MOG-IgG status classified them into suspected MOGAD (ADEM, CE, NMOSD, ON, MY and Others) or not based on the current recommendations. The MOG-IgGSERUM and MOG-IgGCSF titres were assessed with serial 2-fold dilutions to determine end point titres [≥1:128 in serum and ≥1:1 (no dilution) in CSF were considered positive]. We analysed the relationship between MOG-IgGSERUM, MOG-IgGCSF and the phenotypes with multivariable regression. A total of 671 patients were tested [405 with suspected MOGAD, 99 with multiple sclerosis, 48 with AQP4-IgG-positive NMOSD and 119 with other neurological diseases (OND)] before treatment. In suspected MOGAD, 133 patients (33%) tested MOG-IgG-positive in serum and/or CSF; 94 (23%) double-positive (ADEM 36, CE 15, MY 8, NMOSD 9, ON 15 and Others 11); 17 (4.2%) serum-restricted-positive (ADEM 2, CE 0, MY 3, NMOSD 3, ON 5 and Others 4); and 22 (5.4%) CSF-restricted-positive (ADEM 3, CE 4, MY 6, NMOSD 2, ON 0 and Others 7). None of AQP4-IgG-positive NMOSD, multiple sclerosis or OND cases tested positive for MOG-IgGSERUM, but two with multiple sclerosis cases were MOG-IgGCSF-positive; the specificities of MOG-IgGSERUM and MOG-IgGCSF in suspected MOGAD were 100% [95% confidence interval (CI) 99-100%] and 99% (95% CI 97-100%), respectively. Unlike AQP4-IgG-positive NMOSD, the correlation between MOG-IgGSERUM and MOG-IgGCSF titres in MOGAD was weak. Multivariable regression analyses revealed MOG-IgGSERUM was associated with ON and ADEM, whereas MOG-IgGCSF was associated with ADEM and CE. The number needed to test for MOG-IgGCSF to diagnose one additional MOGAD case was 13.3 (14.3 for ADEM, 2 for CE, 19.5 for NMOSD, infinite for ON, 18.5 for MY and 6.1 for Others). In terms of MOG-IgGSERUM/CSF status, most cases were double-positive while including either serum-restricted (13%) or CSF-restricted (17%) cases. These statuses were independently associated with clinical phenotypes, especially in those with ON in serum and CE in CSF, suggesting pathophysiologic implications and the utility of preferential diagnostic testing. Further studies are warranted to deduce the clinical and pathological significance of compartmentalized MOG-IgG., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Multiple sclerosis is a complex autoimmune disease, and several therapies for multiple sclerosis have been developed and widely used. However, existing medications for multiple sclerosis were far from satisfactory due to their failure to suppress relapses and alleviate disease progression. Novel drug targets for multiple sclerosis prevention are still needed. We performed Mendelian randomization to explore potential drug targets for multiple sclerosis using summary statistics from the International Multiple Sclerosis Genetics Consortium (nCase = 47 429, nControl = 68 374) and further replicated in UK Biobank (nCase = 1356, nControl = 395 209) and FinnGen cohorts (nCase = 1326, nControl = 359 815). Genetic instruments for 734 plasma and 154 CSF proteins were obtained from recently published genome-wide association studies. The reverse causality detection using bidirectional Mendelian randomization analysis and Steiger filtering, Bayesian co-localization, and phenotype scanning that searched previously reported genetic variant-trait associations were implemented to consolidate the Mendelian randomization findings further. In addition, the protein-protein interaction network was performed to reveal potential associations among proteins and/or present multiple sclerosis medications. At Bonferroni significance (P < 5.63 × 10-5), Mendelian randomization analysis revealed six protein-multiple sclerosis pairs. In plasma, per standard deviation increase in FCRL3, TYMP and AHSG had a protective effect. Odds ratios for the proteins above were 0.83 (95% CI, 0.79-0.89), 0.59 (95% CI, 0.48-0.71) and 0.88 (95% CI, 0.83-0.94), respectively. In CSF, per 10-fold increase in MMEL1 (OR, 5.03; 95% CI, 3.42-7.41) increased the risk of multiple sclerosis, while SLAMF7 (OR, 0.42; 95% CI, 0.29-0.60) and CD5L (OR, 0.30; 95%CI, 0.18-0.52) decreased the risk. None of the six proteins had reverse causality. Bayesian co-localization suggested that FCRL3 [coloc.abf-posterior probability of hypothesis 4 (PPH4) = 0.889], TYMP (coloc.susie-PPH4 = 0.896), AHSG (coloc.abf-PPH4 = 0.957, coloc.susie-PPH4 = 0.973), MMEL1 (coloc.abf-PPH4 = 0.930) and SLAMF7 (coloc.abf-PPH4 = 0.947) shared the same variant with multiple sclerosis. FCRL3, TYMP and SLAMF7 interacted with target proteins of current multiple sclerosis medications. MMEL1 was replicated in both UK Biobank and FinnGen cohorts. Our integrative analysis suggested that genetically determined levels of circulating FCRL3, TYMP, AHSG, CSF MMEL1 and SLAMF7 had causal effects on multiple sclerosis risk. These findings suggested those five proteins might be promising drug targets for multiple sclerosis and warrant further clinical investigation, especially FCRL3 and SLAMF7., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in the CNS within individuals lacking symptoms typical of multiple sclerosis (MS). The RIS criteria have been validated and predict the transition to symptomatic MS reliably. The performance of RIS criteria that require fewer MRI lesions is unknown. 2009-RIS subjects, by definition, fulfil three to four of four criteria for 2005 dissemination in space (DIS) and subjects fulfilling only one or two lesions in at least one 2017 DIS location were identified within 37 prospective databases. Univariate and multivariate Cox regression models were used to identify predictors of a first clinical event. Performances of different groups were calculated. Seven hundred and forty-seven subjects (72.2% female, mean age 37.7 ± 12.3 years at the index MRI) were included. The mean clinical follow-up time was 46.8 ± 45.4 months. All subjects had focal T2 hyperintensities suggestive of inflammatory demyelination on MRI; 251 (33.6%) fulfilled one or two 2017 DIS criteria (designated as Groups 1 and 2, respectively), and 496 (66.4%) fulfilled three or four 2005 DIS criteria representing 2009-RIS subjects. Group 1 and 2 subjects were younger than the 2009-RIS group and were more likely to develop new T2 lesions over time (P < 0.001). Groups 1 and 2 were similar regarding survival distribution and risk factors for transition to MS. At 5 years, the cumulative probability for a clinical event was 29.0% for Groups 1 and 2 compared to 38.7% for 2009-RIS (P = 0.0241). The presence of spinal cord lesions on the index scan and CSF-restricted oligoclonal bands in Groups 1-2 increased the risk of symptomatic MS evolution at 5 years to 38%, comparable to the risk of development in the 2009-RIS group. The presence of new T2 or gadolinium-enhancing lesions on follow-up scans independently increased the risk of presenting with a clinical event (P < 0.001). The 2009-RIS subjects or Groups 1 and 2 with at least two of the risk factors for a clinical event demonstrated better sensitivity (86.0%), negative predictive value (73.1%), accuracy (59.8%) and area under the curve (60.7%) compared to other criteria studied. This large prospective cohort brings Class I evidence that subjects with fewer lesions than required in the 2009 RIS criteria evolve directly to a first clinical event at a similar rate when additional risk factors are present. Our results provide a rationale for revisions to existing RIS diagnostic criteria., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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

Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international multiple sclerosis registry, MSBase. We assembled a cohort of deeply phenotyped individuals of European ancestry with relapse-onset multiple sclerosis. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined multiple sclerosis severity phenotypes in 1813 individuals. Our primary analyses did not identify any genetic variants of moderate to large effect sizes that met genome-wide significance thresholds. The strongest signal was associated with rs7289446 (β = -0.4882, P = 2.73 × 10-7), intronic to SEZ6L on chromosome 22. However, we demonstrate that clinical outcomes in relapse-onset multiple sclerosis are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62 000 variants together with clinical and demographic variables available at multiple sclerosis disease onset, we could predict severity with an area under the receiver operator curve of 0.84 (95% CI 0.79-0.88). Our machine learning algorithm achieved positive predictive value for outcome assignation of 80% and negative predictive value of 88%. This outperformed our machine learning algorithm that contained clinical and demographic variables alone (area under the receiver operator curve 0.54, 95% CI 0.48-0.60). Secondary, sex-stratified analyses identified two genetic loci that met genome-wide significance thresholds. One in females (rs10967273; βfemale = 0.8289, P = 3.52 × 10-8), the other in males (rs698805; βmale = -1.5395, P = 4.35 × 10-8), providing some evidence for sex dimorphism in multiple sclerosis severity. Tissue enrichment and pathway analyses identified an overrepresentation of genes expressed in CNS compartments generally, and specifically in the cerebellum (P = 0.023). These involved mitochondrial function, synaptic plasticity, oligodendroglial biology, cellular senescence, calcium and G-protein receptor signalling pathways. We further identified six variants with strong evidence for regulating clinical outcomes, the strongest signal again intronic to SEZ6L (adjusted hazard ratio 0.72, P = 4.85 × 10-4). Here we report a milestone in our progress towards understanding the clinical heterogeneity of multiple sclerosis outcomes, implicating functionally distinct mechanisms to multiple sclerosis risk. Importantly, we demonstrate that machine learning using common single nucleotide variant clusters, together with clinical variables readily available at diagnosis can improve prognostic capabilities at diagnosis, and with further validation has the potential to translate to meaningful clinical practice change., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: High emotional demands at work require sustained emotional effort and are associated with adverse health outcomes. We tested whether individuals in occupations with high emotional demands, compared with low demands, had a higher future risk of all-cause long-term sickness absence (LTSA). We further explored whether the risk of LTSA associated with high emotional demands differed by LTSA diagnoses., Methods: We conducted a prospective, nationwide cohort study on the association between emotional demands and LTSA (>30 days) in the workforce in Sweden (n = 3 905 685) during a 7-year follow-up. Using Cox regression, we analyzed sex-stratified risks of all-cause and diagnosis-specific LTSA due to common mental disorders (CMD), musculoskeletal disorders (MSD) and all other diagnoses. Multivariable adjusted models included age, birth country, education, living area, family situation and physical work demands., Results: Working in emotionally demanding occupations was associated with a higher risk of all-cause LTSA in women [hazard ratio (HR) = 1.92, 95% confidence interval (CI): 1.88-1.96] and men (HR = 1.23, 95% CI: 1.21-1.25). In women, the higher risk was similar for LTSA due to CMD, MSD and all other diagnoses (HR of 1.82, 1.92 and 1.93, respectively). In men, risk of LTSA due to CMD was pronounced (HR = 2.01, 95% CI: 1.92-2.11), whereas risk of LTSA due to MSD and all other diagnoses was only slightly elevated (HR of 1.13, both outcomes)., Conclusions: Workers in occupations with high emotional demands had a higher risk of all-cause LTSA. In women, risk of all-cause and diagnosis-specific LTSA were similar. In men, the risk was more pronounced for LTSA due to CMD., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Public Health Association.)

Objective: The purpose of this study was to examine the association between frailty and the quantity and quality of free-living walking and the mediating effect of frailty on the relationship between disability and walking performance in people with multiple sclerosis (MS)., Methods: Ninety-nine people with relapsing-remitting MS (mean age = 49.3 [SD = 9.8] years; 73.7% women; Expanded Disability Status Scale [EDSS] score range = 2.0-6.0) wore a triaxial accelerometer for 7 days. Recorded measures reflected the quantity (daily step counts, number of 30-second walking bouts, and signal vector magnitude [SVM]) and quality (gait speed, step cadence, step and stride regularity, and sample entropy) of walking. For each walking quality measure, the typical (median), best (90th percentile), and worst (10th percentile) values were calculated. Frailty was evaluated through a 38-item frailty index., Results: Participants were classified as not frail (n = 31), moderately frail (n = 34), and severely frail (n = 34) on the basis of established procedures. Patients who were moderately and severely frail exhibited poorer performance in all measures of walking quantity and quality, except for sample entropy, than individuals who were not frail. No differences in free-living walking performance were observed between the moderately and severely frail groups. Frailty did not mediate the relationship between disability (EDSS) and measures of walking quality. Conversely, frailty had a significant mediating effect on the relationship between disability and measures of walking quantity, such as daily step counts (indirect effect: b = -220.42, 95% CI = -452.03 to -19.65) and SVM (indirect effect: b = -1.00, 95% CI = -1.86 to -0.30)., Conclusion: Frailty is associated with poorer free-living walking performance in people with MS. The study findings suggest that frailty, rather than disability, may be primarily responsible for the lower amount of physical activity performed by people with MS in the real world., Impact: The observation that frailty and disability are differently related to measures of walking quality and quantity underscores the importance of a targeted approach to rehabilitation in people with MS., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Multiple sclerosis is clinically characterized by relapses and remissions (relapsing-remitting multiple sclerosis) that over time may evolve to a progressive course (secondary progressive multiple sclerosis) or as having a progressive course from disease onset (primary progressive multiple sclerosis). At present, it is not definitively known whether these clinical entities constitute a single pathological disease or whether these manifestations represent two distinct disease entities sharing inflammatory demyelination as a pathological feature. Here we show using a novel mouse model that CSF of primary progressive multiple sclerosis patients is unique in its capacity to induce motor disability and spinal cord pathology including demyelination, impaired remyelination, reactive astrogliosis and axonal damage. Notably, removal of immunoglobulin G from primary progressive multiple sclerosis CSF via filtration or immunodepletion attenuates its pathogenic capacity. Furthermore, injection of recombinant antibodies derived from primary progressive multiple sclerosis CSF recapitulates the pathology. Our findings suggest that the clinical and pathological features of primary progressive multiple sclerosis are antibody-mediated and pathogenically distinct from relapsing-remitting and secondary progressive multiple sclerosis. Our study has potentially important implications for the development of specific therapies for patients with primary progressive multiple sclerosis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The trafficking of autoreactive leucocytes across the blood-brain barrier endothelium is a hallmark of multiple sclerosis pathogenesis. Although the blood-brain barrier endothelium represents one of the main CNS borders to interact with the infiltrating leucocytes, its exact contribution to neuroinflammation remains understudied. Here, we show that Mcam identifies inflammatory brain endothelial cells with pro-migratory transcriptomic signature during experimental autoimmune encephalomyelitis. In addition, MCAM was preferentially upregulated on blood-brain barrier endothelial cells in multiple sclerosis lesions in situ and at experimental autoimmune encephalomyelitis disease onset by molecular MRI. In vitro and in vivo, we demonstrate that MCAM on blood-brain barrier endothelial cells contributes to experimental autoimmune encephalomyelitis development by promoting the cellular trafficking of TH1 and TH17 lymphocytes across the blood-brain barrier. Last, we showcase ST14 as an immune ligand to brain endothelial MCAM, enriched on CD4+ T lymphocytes that cross the blood-brain barrier in vitro, in vivo and in multiple sclerosis lesions as detected by flow cytometry on rapid autopsy derived brain tissue from multiple sclerosis patients. Collectively, our findings reveal that MCAM is at the centre of a pathological pathway used by brain endothelial cells to recruit pathogenic CD4+ T lymphocyte from circulation early during neuroinflammation. The therapeutic targeting of this mechanism is a promising avenue to treat multiple sclerosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Multiple sclerosis is a tissue-specific autoimmune disease of the central nervous system in which the antigen(s) remains elusive. Antibodies targeting the flotillin-1/2 complex have been described in 1-2% of the patients in a recent study. Other candidate antigens as anoctamin-2 or neurofascin-155 have been previously described in multiple sclerosis patients, although their clinical relevance remains uncertain. Our study aims to analyse the frequency and clinical relevance of antibodies against neurofascin-155, anoctamin-2 and flotillin-1/2 complex in multiple sclerosis. Serum ( n = 252) and CSF ( n = 50) samples from 282 multiple sclerosis patients were included in the study. The control group was composed of 260 serum samples (71 healthy donors and 189 with other neuroinflammatory disorders). Anti-flotillin-1/2, anti-anoctamin-2 and anti-neurofascin-155 antibodies were tested by cell-based assays using transfected cells. We identified six multiple sclerosis patients with antibodies against the flotillin-1/2 complex (2.1%) and one multiple sclerosis patient with antibodies against anoctamin-2 (0.35%). All multiple sclerosis patients were negative for anti-neurofascin-155 antibodies. Three of the anti-flotillin-1/2 positive patients showed anti-flotillin-1/2 positivity in other serum samples extracted at different moments of their disease. Immunoglobulin G subclasses of anti-flotillin-1/2 antibodies were predominantly one and three. We confirm that antibodies targeting the flotillin-1/2 complex are present in a subgroup of patients with multiple sclerosis. Further studies are needed to understand the clinical and pathological relevance of anti-flotillin-1/2 autoantibodies in multiple sclerosis., Competing Interests: L.Q. received research grants from Instituto de Salud Carlos III—Ministry of Economy and Innovation (Spain), CIBERER, Fundació La Marató, GBS-CIDP Foundation International, UCB and Grifols, received speaker or expert testimony honoraria from CSL Behring, Novartis, Sanofi-Genzyme, Merck, Annexon, Alnylam, Biogen, Janssen, Lundbeck, ArgenX, UCB, LFB, Octapharma and Roche, serves at Clinical Trial Steering Committee for Sanofi-Genzyme and Roche and is Principal Investigator for UCB’s CIDP01 trial., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Persistent somatic and neuropsychiatric symptoms have been frequently described in patients after infection with severe acute respiratory syndrome coronavirus 2 even after a benign clinical course of the acute infection during the early phases of the coronavirus severe acute respiratory syndrome coronavirus 2 pandemic and are part of Long COVID. The Omicron variant emerged in November 2021 and has rapidly become predominant due to its high infectivity and suboptimal vaccine cross-protection. The frequency of neuropsychiatric post-acute sequelae after infection with the severe acute respiratory syndrome coronavirus 2 Omicron and adequate vaccination status is not known. Here, we aimed to characterize post-acute symptoms in individuals with asymptomatic or mildly symptomatic breakthrough infection with severe acute respiratory syndrome coronavirus 2. These individuals had either proven infection with the Omicron variant ( n = 157) or their infection occurred in 2022 where Omicron was the predominant variant of severe acute respiratory syndrome coronavirus 2 in Germany ( n = 107). This monocentric cross-sectional study was conducted at the University Medical Center Hamburg-Eppendorf between 11 February 2022 and 11 April 2022. We employed questionnaires addressing self-reported somatic symptom burden (Somatic Symptom Scale 8) and neuropsychiatric symptoms including mood (Patient Health Questionnaire 2), anxiety (Generalized Anxiety Disorder 7), attention (Mindful Attention Awareness Scale) and fatigue (Fatigue Assessment Scale) in a cohort of hospital workers. Scores were compared between 175 individuals less than 4 weeks after positive testing for severe acute respiratory syndrome coronavirus 2, 88 individuals more than 4 weeks after positive testing and 87 severe acute respiratory syndrome coronavirus 2 uninfected controls. The majority ( n = 313; 89.5%) of included individuals were vaccinated at least three times. After recovery from infection, no significant differences in scores assessing neuropsychiatric and somatic symptoms were detected between the three groups (severe acute respiratory syndrome coronavirus 2 uninfected controls, individuals less and more than 4 weeks after positive testing) independent of age, sex, preconditions and vaccination status. In addition, self-reported symptom burden did not significantly correlate with the number of vaccinations against severe acute respiratory syndrome coronavirus 2, time from recovery or the number of infections. Notably, in all three groups, the mean scores for each item of our questionnaire lay below the pathological threshold. Our data show that persistent neuropsychiatric and somatic symptoms after recovery from severe acute respiratory syndrome coronavirus 2 infection in fully vaccinated hospital workers do not occur more frequently than that in uninfected individuals. This will guide healthcare professionals in the clinical management of patients after recovery from breakthrough infections with severe acute respiratory syndrome coronavirus 2., Competing Interests: The authors declare no competing interests and no conflict of interest. MAF received honoraria for consultation and travel expenses from Biogen, Merck KGaA, Novartis and Roche unrelated to this work., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Maternal viral infection and immune response are known to increase the risk of altered development of the foetal brain. Given the ongoing global pandemic of coronavirus disease 2019 (COVID-19), investigating the impact of SARS-CoV-2 on foetal brain health is of critical importance. Here, we report the presence of SARS-CoV-2 in first and second trimester foetal brain tissue in association with cortical haemorrhages. SARS-CoV-2 spike protein was sparsely detected within progenitors and neurons of the cortex itself, but was abundant in the choroid plexus of haemorrhagic samples. SARS-CoV-2 was also sparsely detected in placenta, amnion and umbilical cord tissues. Cortical haemorrhages were linked to a reduction in blood vessel integrity and an increase in immune cell infiltration into the foetal brain. Our findings indicate that SARS-CoV-2 infection may affect the foetal brain during early gestation and highlight the need for further study of its impact on subsequent neurological development., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The anterior optic pathway is one of the preferential sites of involvement in CNS inflammatory demyelinating diseases, such as multiple sclerosis and neuromyelitis optica, with optic neuritis being a common presenting symptom. What is more, optic nerve involvement in these diseases is often subclinical, with optical coherence tomography demonstrating progressive neuroretinal thinning in the absence of optic neuritis. The pathological substrate for these findings is poorly understood and requires investigation. We had access to post-mortem tissue samples of optic nerves, chiasms and tracts from 29 multiple sclerosis (mean age 59.5, range 25-84 years; 73 samples), six neuromyelitis optica spectrum disorders (mean age 56, range 18-84 years; 22 samples), six acute disseminated encephalomyelitis (mean age 25, range 10-39 years; 12 samples) cases and five non-neurological controls (mean age 55.2, range 44-64 years; 16 samples). Formalin-fixed paraffin-embedded samples were immunolabelled for myelin, inflammation (microglial/macrophage, T- and B-cells, complement), acute axonal injury and astrocytes. We assessed the extent and distribution of these markers along the anterior optic pathway for each case in all compartments (i.e. parenchymal, perivascular and meningeal), where relevant. Demyelinated plaques were classified as active based on established criteria. In multiple sclerosis, demyelination was present in 82.8% of cases, of which 75% showed activity. Microglia/macrophage and lymphocyte inflammation were frequently found both in the parenchymal and meningeal compartments in non-demyelinated regions. Acute axonal injury affected 41.4% of cases and correlated with extent of inflammatory activity in each compartment, even in cases that died at advanced age with over 20 years of disease duration. An antero-posterior gradient of anterior optic pathway involvement was observed with optic nerves being most severely affected by inflammation and acute axonal injury compared with the optic tract, where a higher proportion of remyelinated plaques were seen. In neuromyelitis optica spectrum disorder, cases with a history of optic neuritis had extensive demyelination and lost aquaporin-4 reactivity. In contrast, those without prior optic neuritis did not have demyelination but rather diffuse microglial/macrophage, T- and B-lymphocyte inflammation in both parenchymal and meningeal compartments, and acute axonal injury was present in 75% of cases. Acute demyelinating encephalomyelitis featured intense inflammation, and perivenular demyelination in 33% of cases. Our findings suggest that chronic inflammation is frequent and leads to neurodegeneration in multiple sclerosis and neuromyelitis optica, regardless of disease stage. The chronic inflammation and subsequent neurodegeneration occurring along the optic pathway broadens the plaque-centred view of these diseases and partly explains the progressive neuroretinal changes observed in optic coherence tomography studies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Genetic frontotemporal lobar degeneration caused by autosomal dominant gene mutations provides an opportunity for targeted drug development in a highly complex and clinically heterogeneous dementia. These neurodegenerative disorders can affect adults in their middle years, progress quickly relative to other dementias, are uniformly fatal and have no approved disease-modifying treatments. Frontotemporal dementia, caused by mutations in the GRN gene which encodes the protein progranulin, is an active area of interventional drug trials that are testing multiple strategies to restore progranulin protein deficiency. These and other trials are also examining neurofilament light as a potential biomarker of disease activity and disease progression and as a therapeutic endpoint based on the assumption that cerebrospinal fluid and blood neurofilament light levels are a surrogate for neuroaxonal damage. Reports from genetic frontotemporal dementia longitudinal studies indicate that elevated concentrations of blood neurofilament light reflect disease severity and are associated with faster brain atrophy. To better inform patient stratification and treatment response in current and upcoming clinical trials, a more nuanced interpretation of neurofilament light as a biomarker of neurodegeneration is now required, one that takes into account its relationship to other pathophysiological and topographic biomarkers of disease progression from early presymptomatic to later clinically symptomatic stages., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Intrathecal production of kappa free light chains occurs in multiple sclerosis and can be measured using the kappa free light chain index. Kappa free light chain index values can be determined more easily than oligoclonal bands detection and seem more sensitive than the immunoglobulin (Ig)G index to diagnose multiple sclerosis. We assessed the value of oligoclonal bands, kappa free light chain index cut-offs 5.9, 6.6 and 10.61, and IgG index to diagnose multiple sclerosis with prospectively acquired data from a clinically isolated syndrome inception cohort. We selected patients with sufficient data to determine oligoclonal bands positivity, MRI dissemination in space and time, IgG index and sufficient quantities of paired CSF and blood samples to determine kappa free light chain indexes (n = 214). We used Kendall's Tau coefficient to estimate concordance, calculated the number of additional diagnoses when adding each positive index to dissemination in space and positive oligoclonal bands, performed survival analyses for oligoclonal bands and each index with the outcomes second attack and 2017 MRI dissemination in space and time and estimated the diagnostic properties of oligoclonal bands and the different indexes for the previously mentioned outcomes at 5 years. Oligoclonal bands were positive in 138 patients (64.5%), kappa free light chain-5.9 in 136 (63.6%), kappa free light chain-6.6 in 135 (63.1%), kappa free light chain-10.61 in 126 (58.9%) and IgG index in 101 (47.2%). The highest concordance was between oligoclonal bands and kappa free light chain-6.6 (τ = 0.727) followed by oligoclonal bands and kappa free light chain-5.9 (τ = 0.716). Combining dissemination in space plus oligoclonal bands or kappa free light chain-5.9 increased the number of diagnosed patients by 11 (5.1%), with kappa free light chain-6.6 by 10 (4.7%), with kappa free light chain-10.61 by 9 (4.2%) and with IgG index by 3 (1.4%). Patients with positive oligoclonal bands or indexes reached second attack and MRI dissemination in space and time faster than patients with negative results (P < 0.0001 except IgG index in second attack: P = 0.016). In multivariable Cox models [adjusted hazard ratio (95% confidence interval)], the risk for second attack was very similar between kappa free light chain-5.9 [2.0 (0.9-4.3), P = 0.068] and kappa free light chain-6.6 [2.1 (1.1-4.2), P = 0.035]. The highest risk for MRI dissemination in space and time was demonstrated with kappa free light chain-5.9 [4.9 (2.5-9.6), P < 0.0001], followed by kappa free light chain-6.6 [3.4 (1.9-6.3), P < 0.0001]. Kappa free light chains-5.9 and -6.6 had a slightly higher diagnostic accuracy than oligoclonal bands for second attack (70.5, 71.1 and 67.8) and MRI dissemination in space and time (85.7, 85.1 and 81.0). Kappa free light chain indexes 5.9 and 6.6 performed slightly better than oligoclonal bands to assess multiple sclerosis risk and in terms of diagnostic accuracy. Given the concordance between oligoclonal bands and these indexes, we suggest using dissemination in space plus positive oligoclonal bands or positive kappa free light chain index as a modified criterion to diagnose multiple sclerosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dysregulation of microRNA gene expression has been implicated in many neurodegenerative diseases, including Parkinson's disease. However, the individual dysregulated microRNAs remain largely unknown. Previous meta-analyses have highlighted several microRNAs being differentially expressed in post-mortem Parkinson's disease and Alzheimer's disease brains versus controls, but they were based on small sample sizes. In this study, we quantified the expression of the most compelling Parkinson's and Alzheimer's disease microRNAs from these meta-analyses ('candidate miRNAs') in one of the largest Parkinson's/Alzheimer's disease case-control post-mortem brain collections available ( n = 451), thereby quadruplicating previously investigated sample sizes. Parkinson's disease candidate microRNA hsa-miR-132-3p was differentially expressed in our Parkinson's ( P = 4.89E-06) and Alzheimer's disease samples ( P = 3.20E-24) compared with controls. Alzheimer's disease candidate microRNAs hsa-miR-132-5p ( P = 4.52E-06) and hsa-miR-129-5p ( P = 0.0379) were differentially expressed in our Parkinson's disease samples. Combining these novel data with previously published data substantially improved the statistical support (α = 3.85E-03) of the corresponding meta-analyses, clearly implicating these microRNAs in both Parkinson's and Alzheimer's disease. Furthermore, hsa-miR-132-3p/-5p (but not hsa-miR-129-5p) showed association with α-synuclein neuropathological Braak staging ( P = 3.51E-03/ P = 0.0117), suggesting that hsa-miR-132-3p/-5p play a role in α-synuclein aggregation beyond the early disease phase. Our study represents the largest independent assessment of recently highlighted candidate microRNAs in Parkinson's and Alzheimer's disease brains, to date. Our results implicate hsa-miR-132-3p/-5p and hsa-miR-129-5p to be differentially expressed in both Parkinson's and Alzheimer's disease, pinpointing shared pathogenic mechanisms across these neurodegenerative diseases. Intriguingly, based on publicly available high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation data, hsa-miR-132 may interact with SNCA messenger RNA in the human brain, possibly pinpointing novel therapeutic approaches in fighting Parkinson's disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Cortical lesions constitute a key manifestation of multiple sclerosis and contribute to clinical disability and cognitive impairment. Yet it is unknown whether local cortical lesions and cortical lesion subtypes contribute to domain-specific impairments attributable to the function of the lesioned cortex. In this cross-sectional study, we assessed how cortical lesions in the primary sensorimotor hand area relate to corticomotor physiology and sensorimotor function of the contralateral hand. Fifty relapse-free patients with relapsing-remitting or secondary-progressive multiple sclerosis and 28 healthy age- and sex-matched participants underwent whole-brain 7 T MRI to map cortical lesions. Brain scans were also used to estimate normalized brain volume, pericentral cortical thickness, white matter lesion fraction of the corticospinal tract, infratentorial lesion volume and the cross-sectional area of the upper cervical spinal cord. We tested sensorimotor hand function and calculated a motor and sensory composite score for each hand. In 37 patients and 20 healthy controls, we measured maximal motor-evoked potential amplitude, resting motor threshold and corticomotor conduction time with transcranial magnetic stimulation and the N20 latency from somatosensory-evoked potentials. Patients showed at least one cortical lesion in the primary sensorimotor hand area in 47 of 100 hemispheres. The presence of a lesion was associated with worse contralateral sensory (P = 0.014) and motor (P = 0.009) composite scores. Transcranial magnetic stimulation of a lesion-positive primary sensorimotor hand area revealed a decreased maximal motor-evoked potential amplitude (P < 0.001) and delayed corticomotor conduction (P = 0.002) relative to a lesion-negative primary sensorimotor hand area. Stepwise mixed linear regressions showed that the presence of a primary sensorimotor hand area lesion, higher white-matter lesion fraction of the corticospinal tract, reduced spinal cord cross-sectional area and higher infratentorial lesion volume were associated with reduced contralateral motor hand function. Cortical lesions in the primary sensorimotor hand area, spinal cord cross-sectional area and normalized brain volume were also associated with smaller maximal motor-evoked potential amplitude and longer corticomotor conduction times. The effect of cortical lesions on sensory function was no longer significant when controlling for MRI-based covariates. Lastly, we found that intracortical and subpial lesions had the largest effect on reduced motor hand function, intracortical lesions on reduced motor-evoked potential amplitude and leucocortical lesions on delayed corticomotor conduction. Together, this comprehensive multilevel assessment of sensorimotor brain damage shows that the presence of a cortical lesion in the primary sensorimotor hand area is associated with impaired corticomotor function of the hand, after accounting for damage at the subcortical level. The results also provide preliminary evidence that cortical lesion types may affect the various facets of corticomotor function differentially., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)