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Background: A subgroup of people with multiple sclerosis (pwMS) will develop severe disability. The pathophysiology underlying severe MS is unknown. The comprehensive assessment of severely affected MS (CASA-MS) was a case-controlled study that compared severely disabled in skilled nursing (SD/SN) (EDSS ≥ 7.0) to less-disabled (EDSS 3.0-6.5) community dwelling (CD) progressive pwMS, matched on age-, sex- and disease-duration (DDM)., Objectives: To identify neuroimaging and molecular biomarker characteristics that distinguish SD/SN from DDM-CD progressive pwMS., Methods: This study was carried at SN facility and at a tertiary MS center. The study collected clinical, molecular (serum neurofilament light chain, sNfL and glial acidic fibrillary protein, sGFAP) and MRI quantitative lesion-, brain volume-, and tissue integrity-derived measures. Statistical analyses were controlled for multiple comparisons., Results: 42 SD/SN and 42 DDM-CD were enrolled. SD/SN pwMS showed significantly lower cortical volume (CV) (p < 0.001, d = 1.375) and thalamic volume (p < 0.001, d = 0.972) compared to DDM-CD pwMS. In a logistic stepwise regression model, the SD/SN pwMS were best differentiated from the DDM-CD pwMS by lower CV (p < 0.001) as the only significant predictor, with the accuracy of 82.3%. No significant differences between the two groups were observed for medulla oblongata volume, a proxy for spinal cord atrophy and white matter lesion burden, while there was a statistical trend for numerically higher sGFAP in SD/SN pwMS., Conclusions: The CASA-MS study showed significantly more gray matter atrophy in severe compared to less-severe progressive MS., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Numerous studies have proposed that Helicobacter pylori infection may possess a protective effect in terms of future risk of multiple sclerosis (MS), however is poorly evidenced. We performed a systematic review and meta-analysis to obtain the pooled results regarding the prevalence of H. pylori infection in persons with multiple sclerosis (pwMS) and healthy controls. A comprehensive database search was performed in PubMed, Embase, and medRxiv for all relevant literature published from the inception of the databases until the August 1, 2022. The retrieved articles were first screened by title and abstract, followed by full-text screening based on the pre-established eligibility criteria. The risk of bias was assessed using the ROBINS-I tool. Data on the seroprevalence of H. pylori in pwMS and healthy controls was extracted, and a meta-analysis was performed in Review Manager Version 5.4.1. Sub-group analysis was performed in accordance with the geographical distribution (Eastern and Western countries) and the method of detection of H. pylori infection enzyme-linked-immunoassay (ELISA), Immunofluorescence, Immunochromatography). Furthermore, sensitivity analyses and publication bias were determined. The preliminary database search retrieved a total of 822 studies. Seventeen case-control studies with a total of 2721 pwMS and 2245 controls were included as a final sample size for the meta-analysis. The overall risk of bias was moderate. Overall, the rate of H. pylori infection in pwMS was not significantly different than in healthy controls (OR: 0.79 (95% CI = 0.58-1.08); I 2  = 79%, p = 0.14). Subgroup analysis revealed that the rate of H. pylori infection among PwMS was not significant in both Eastern and Western countries (OR: 0.75 (95% CI = 0.52-1.08); I 2  = 81%, p = 0.12). In contrast, data revealed that the prevalence of H. pylori infection in pwMS was significantly lower than that of control based on studies utilizing ELISA assays detection (OR: 0.71 (95% CI = 0.50-1.00); I 2  = 81%, p = 0.05), while no significant difference was seen on studies using other assays than ELISA (OR: 1.19 (95% CI = 0.81-1.77); I 2  = 0%, p = 0.38). Our findings of statistically indifferent prevalence of H. pylori infection as compared between pwMS and healthy controls suggested the absence of protective effect for risk of MS following H. pylori infection., (© 2024. Fondazione Società Italiana di Neurologia.)

Background: The impact of disease-modifying treatments (DMTs) on multiple sclerosis (MS) long-term outcomes is continuously evolving. Retrospective analyses of large and long-term registries could provide information regarding general disease trajectories and risk factors that are commonly not investigated in shorter clinical trial settings., Methods: Retrospective observational study of people with MS (pwMS) registered in New York State MS Consortium (NYSMSC) since 1996. Disability outcomes of reaching sustained Expanded Disability Status Scale (EDSS) scores of 4.0, 6.0 and transition to secondary-progressive MS (SPMS) were confirmed at follow-up. Four DMT categories were determined (1) continuous DMT use, (2) discontinued DMT, (3) (re)started DMT and (4) never treated with DMT. Patient-reported outcomes (PRO) were acquired using LIFEware system. Kaplan-Meier survival curves and adjusted analysis of covariance (ANCOVA) were used to determine the rate and factors related to disability progression., Results: Total of 1893 pwMS were included with baseline average age of 43.2 years (SD = 10.4), 9.6 years of disease duration (SD = 8.8), median EDSS of 3.0 (IQR 2.0-3.5) and average follow-up time of 6.9 years (SD = 4.9). In addition to being male, older, more disabled and reporting worse PROs at baseline, pwMS who discontinued DMT had more than 5.5 times greater risk of reaching sustained EDSS of 4.0 (OR = 5.56, 95% CI 2.78-11.0, p < 0.001). Similarly, pwMS who discontinued DMT during the NYSMSC follow-up had 3.8- and 4.7-times greater risk to reach sustained EDSS 6.0 (OR = 3.86, 95% CI 2.12-7.02, p < 0.001), and to transition to SPMS (OR = 4.77, 95% CI 2.9-7.87, p < 0.001). Propensity matching analysis confirmed the worse clinical outcomes., Conclusions: In addition to known predictors of long-term clinical outcomes, pwMS who discontinue DMT have worse long-term disability trajectory when compared to both early and late DMT starters. PRO-based indicators may suggest worse clinical outcomes., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: The structural changes associated with cognitive performance in older people with multiple sclerosis (PwMS; age ≥ 50 years old) remain unknown., Objective: To determine the relationship between whole-brain (WBV), thalamus as the largest deep gray matter nuclei, and cortex-specific volume measurements with both cognitive impairment and numerical performance in older PwMS. The main hypothesis is that cognitive impairment (CI) in older PwMS is explained by cortical thinning in addition to global and thalamic neurodegenerative changes., Methods: A total of 101 older PwMS underwent cognitive and neuroimaging assessment. Cognitive assessment included tests established as sensitive in MS samples (Minimal Assessment of Cognitive Function in MS; MACFIMS), as well as those tests often utilized in Alzheimer's dementia studies (Wechsler's Memory Scale, Boston Naming Test, Visual Motor Integration and language). Cognitive impairment (CI) was based on -1.5 standard deviations in at least 2 cognitive domains (executive function, learning and memory, spatial processing, processing speed and working memory and language) when compared to healthy controls. WBV and thalamic volume were calculated using SIENAX/FIRST and cortical thickness using FreeSurfer. Differences in cortical thickness between CI and cognitively preserved (CP) were determined using age, sex, education, depression and WBV-adjusted analysis of covariance (ANCOVA). The relationship between domain-specific cognitive performance and cortical thickness was analyzed by linear regression models adjusted for age, sex, education, depression, WBV and thalamic volume. Benjamini-Hochberg-adjusted p-values lower than 0.05 were considered significant., Results: The average age of the study population was 62.6 (5.9) years old. After adjustment, CI PwMS had significantly thinner left fusiform (p = 0.0003), left inferior (p = 0.0032), left transverse (p = 0.0013), and bilateral superior temporal gyri (p = 0.002 and p = 0.0011) when compared to CP PwMS. After adjusting for age, sex, education, depression WBV, and thalamic volume, CI status was additionally predicted by the thickness of the left fusiform (p = 0.001) and left cuneus gyri (p = 0.004). After the adjustment, SDMT scores were additionally associated with left fusiform gyrus (p < 0.001) whereas letter-based verbal fluency performance with left pars opercularis gyrus (p < 0.001)., Conclusion: In addition to global and thalamic neurodegenerative changes, the presence of CI in older PwMS is additionally explained by the thickness of multiple cortical regions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: People with multiple sclerosis (pwMS) have greater prevalence of comorbid cardiovascular diseases (CVD) when compared to the general population despite similar frequency of CV risk factors., Objective: Determine the impact of comorbid-onset of CVD diagnosis on long-term confirmed disability progression (CDP)., Methods: 276 pwMS (29 clinically isolated syndrome, 130 relapsing-remitting and 117 progressive) were clinically followed an average of 14.9 years, with a mean of 14.4 clinical visits. Retrospective electronic medical records (EMR) review determined CVD diagnoses (hypertension, hyperlipidemia, diabetes, and heart disease) at baseline and over the follow-up. CDP was determined with ≥1.0 point Expanded Disability Status Scale (EDSS) increase from EDSS <5.5, or ≥ 0.5-point increase from ≥5.5, and was sustained on next clinical visit., Results: A significantly shorter time to overall CDP was detected in 213 pwMS who had an existing (28 pwMS) or developed new onset (185 pwMS) of CVD, compared to 63 CVD-healthy pwMS over the follow-up (13.4 vs 15.9 years, Mantel-Cox p < 0.001), independent of baseline age and EDSS score. The CVD diagnosis preceded the CDP in 103 pwMS (55.7%), occurred after CDP in 71 pwMS (38.4%) and was concurrent in 11 pwMS (5.9%). Using mixed-effect models adjusted for significant age (F = 56.5, p < 0.001) and time effects (F = 67.8, p < 0.001), the CVD-onset diagnosis was associated with greater accrual of disability, as measured by longitudinal increase in EDSS score (F = 4.207, p = 0.04). Sex was not significant predictor of future disability in our cohort., Conclusion: PwMS with an existing or new onset of comorbid CVD diagnosis showed accelerated disability worsening over long-term. There was no temporal relationship between the onset of CVD and CDP within the group that had CVD-onset diagnosis., Competing Interests: Declaration of competing interest Taylor Wicks, Jack Reeves, Niels Bergsland and Dejan Jakimovski have nothing to disclose. Michael G. Dwyer has received personal compensation from Keystone Heart for consultant fees. He received financial support for research activities from Bristol Myers Squibb, Mapi Pharma, Keystone Heart, Protembis and V-WAVE Medical. Bianca Weinstock-Guttman received honoraria as a speaker and/or as a consultant for Biogen Idec, Sanofi &Genzyme, Genentech, Novartis, BMS, Bayer, Horizon and Janssen. Dr. Weinstock-Guttman received research funds from Biogen Idec, Genentech and Novartis. Ralph HB. Benedict has received consultation or speaking fees from Bristol Myer Squibb, Biogen, Merck, EMD Serono, Roche, Verasci, Immune Therapeutics, Novartis, and Sanofi-Genzyme. Robert Zivadinov has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Keystone Heart, Protembis and Novartis for speaking and consultant fees. He received financial support for research activities from Sanofi, Novartis, Bristol Myers Squibb, Octave, Mapi Pharma, Keystone Heart, Protembis and V-WAVE Medical., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: To investigate the frequency of dyslipidemia phenotypes in multiple sclerosis and to assess the associations with lipoprotein particle size distributions., Methods: This cross-sectional study included 203 healthy controls (HC), 221 relapsing-remitting MS (RRMS), and 126 progressive MS (PMS). A lipid profile with total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, and apolipoprotein B levels were measured. Low density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol, large buoyant LDL-C and small dense LDL-C were calculated using the Sampson-NIH equations method. Dyslipidemia phenotypes were categorized by their nonHDL-C and triglyceride values. The diameters and concentrations of triglyceride-rich lipoprotein particles (TRLP), LDL particles (LDLP), and HDL particles (HDLP) were measured with proton NMR lipoprotein profiling. Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels were obtained using immunoassay., Results: The frequencies of normolipidemia, and various dyslipidemia phenotypes were similar in HC, RRMS, and PMS. The size of the TRLP, very large TRLP, large TRLP, and small LDLP concentrations had a decreasing pattern of HC>RR>PMS. The lowest tertile of EDSS was associated with higher concentrations of HDLP and small HDLP in PMS. PCSK9 was associated with concentration of HDL particles, primarily via its effects on the concentration of small HDL particles., Conclusions: There were no differences in the frequency of dyslipidemias in MS compared to healthy controls. Higher HDLP concentrations are associated with lower disability in PMS., Competing Interests: Declaration of competing interest Taylor R. Wicks, Nasim Nehzat, Richard Browne, Anna Wolska, Dejan Jakimovski, and James D. Otvos have nothing to disclose. Irina Shalaurova is an employee of LabCorp Diagnostics. Bianca Weinstock-Guttman has participated in speaker's bureaus and/or served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen, and Horizon. Dr. Weinstock-Guttman also has received grant/research support from the agencies listed. She serves on the editorial board for BMJ Neurology, Children, CNS Drugs, MS International and Frontiers Epidemiology. Dr. Robert Zivadinov has received speaker honoraria and consultant fees from Sanofi, Bristol Myers Squibb, Sana Biotechnologies and EMD Serono. He has received research support from Mapi-Pharma, Protembis, Bristol Myers Squibb, CorEvitas, and Filterlex. Alan T. Remaley has a CRADA research agreement with Nissui Inc. Dr. Murali Ramanathan received research funding from the National Multiple Sclerosis Society, Department of Defense and National Institute of Neurological Diseases and Stroke. He receives royalty from a self-published textbook., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: The Balkan Peninsula, acting as a crossroad between central Europe and the Middle East, presents diverse ecosystems supporting various tick species capable of transmitting TBDs. This study focuses on Serbia and North Macedonia, both endemic for TBDs, aiming to investigate human-biting ticks' prevalence, TBD prevalence, and major TBPs in blood samples., Patients and Methods: This prospective observational study was conducted in 2022 at two medical centers, involving 45 patients from Novi Sad, Serbia, and 17 patients from Skopje, North Macedonia. All participants had either a tick still attached or had had one removed within the preceding 48 h. The study consisted in clinical evaluations of patients and testing of patient samples and ticks for tick-borne pathogens using a High-Throughput pathogen detection system based on microfluidic real-time PCR. In addition, the study assessed the genetic diversity of the identified pathogens., Results: Ixodes ricinus was the most prevalent tick species, with varying infestation rates across various body parts. Tick species and feeding times differed between Novi Sad and Skopje. TBPs were prevalent, with Rickettsia spp. dominant in Skopje and a mix including Rickettsia aeschlimannii, Rickettsia monacensis, Anaplasma phagocytophilum, and Borrelia afzelii in Novi Sad. Subclinical bacteremia occurred in 8.06% of cases, mostly involving Anaplasma spp. Clinical manifestations, primarily local hypersensitivity reactions, were observed in six patients. Phylogenetic analysis confirmed R. aeschlimannii and R. monacensis identity, highlighting genetic differences in gltA gene sequences., Conclusions: This study sheds light on the prevalence and diversity of TBPs in tick-infested individuals from Serbia and North Macedonia, contributing valuable insights into the epidemiology of TBDs in the Balkan region., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Background: Because secondary progressive multiple sclerosis (SPMS) is associated with worse prognosis, early predictive tools are needed. We aimed to use systematic literature review and advanced methods to create and validate a clinical tool for estimating individual patient risk of transition to SPMS over five years., Methods: Data from the Jacobs Multiple Sclerosis Center (JMSC) and the Multiple Sclerosis Center Amsterdam (MSCA) was collected between 1994 and 2022. Participants were relapsing-remitting adult patients at initial evaluation. We created the tool in four stages: (1) identification of candidate predictors from systematic literature review, (2) ordinal cutoff determination, (3) feature selection, (4) feature weighting., Results: Patients in the development/internal-validation/external-validation datasets respectively (n = 787/n = 522/n = 877) had a median age of 44.1/42.4/36.6 and disease duration of 7.7/6.2/4.4 years. From these, 12.6 %/10.2 %/15.4 % converted to SPMS (median=4.9/5.2/5.0 years). The DAAE Score was named from included predictors: Disease duration, Age at disease onset, Age, EDSS. It ranges from 0 to 12 points, with risk groups of very-low=0-2, low=3-7, medium=8-9, and high≥10. Risk of transition to SPMS increased proportionally across these groups in development (2.7 %/7.4 %/18.8 %/40.2 %), internal-validation (2.9 %/6.8 %/26.8 %/36.5 %), and external-validation (7.5 %/9.6 %/22.4 %/37.5 %)., Conclusion: The DAAE Score estimates individual patient risk of transition to SPMS consistently across datasets internationally using clinically-accessible data. With further validation, this tool could be used for clinical risk estimation., Competing Interests: Declaration of competing interest T. Pryshchepova, J.R. Jelgerhuis, and N. Bergsland have nothing to disclose T.A Fuchs received research support from the European Committee for Treatment and Research in Multiple Sclerosis, serves on the editorial board of Frontiers in Neurology, and received consulting fees for Click Therapeutics. R. Zivadinov received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Janssen, Biogen, Filterlex for speaking and consultant fees. He received financial support for research activities from Sanofi, Novartis, Bristol Myers Squibb, Octave, Mapi Pharma, CorEvitas, Protembis, Filterlex and V-WAVE Medical. B. Weinstock-Guttman received honoraria as a speaker and/or as a consultant for Biogen Idec, Viatris, Sana, Immunic, EMD Serono, Sanofi, Novartis, BMS, Labcorp, and Horizon. Dr Weinstock-Guttman received research funds from Biogen Idec, EMD Serono, Genzyme, Genentech, Sanofi, Novartis. M.G. Dwyer received research support from Novartis, Bristol Myers Squibb, Mapi Pharma, Merck Serono, Keystone Heart Ltd., Protembis GmbH, and V-Wave Ltd., and consulting fees Bristol Myers Squibb, Merck Serono, and Keystone Heart Ltd. R.H.B. Benedict received research support from Bristol Meyers Squibb, National Institutes of Health, and National Multiple Sclerosis Society, consultation or speaking fees from Bristol Meyers Squibb, Novartis, Roche, Sanofi, and EMD Serono, and royalties from Psychological Assessment Resources. D. Jakimovski received an honorarium for consulting from EMD Serono and AstraZeneca. He has received research funds from JuneBrain Inc, the Consortium of Multiple Sclerosis Centers (CMSC), NIH CTSA under award UL1TR001412 and by The Clinician-Scientists Transdisciplinary Aging Research (ClinSTAR), funded by the NIH NIA under award U24AG065204. T. Uher received financial support for conference travel from Biogen, Novartis, Sanofi, Roche and Merck and speaker honoraria from Biogen, Novartis and Roche as well as support for research activities from Biogen and Sanofi F. Barkhof serves on the steering committee or Data Safety Monitoring Board member for Biogen, Merck, ATRI/ACTC and Prothena. He consults for Roche, Celltrion, Rewind Therapeutics, Merck, IXICO, Jansen, and Combinostics. He has research agreements with Merck, Biogen, GE Healthcare, and Roche. He is a co-founder and shareholder of Queen Square Analytics LTD B.M.J. Uitdehaag received research support and/or consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Teva and Immunic Therapeutics J. Killestein received research grants for multicentre investigator initiated trials DOT-MS trial, ClinicalTrials. gov Identifier: NCT04260711 (ZonMW) and BLOOMS trial (ZonMW and Treatmeds), ClinicalTrials. gov Identifier: NCT05296161); received consulting fees for F. Hoffmann-La Roche, Biogen, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); reports speaker relationships with F. Hoffmann-La Roche, Biogen, Immunic, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); adjudication committee of MS clinical trial of Immunic (payments to institution only). E.M.M. received speaker fees from Merck and Novartis. M.M. Schoonheim serves on the editorial board of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and ZonMW (Vidi grant, project number 09150172010056) and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, EIP, Sanofi, MedDay and Merck., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is increasingly understood not only as a white matter disease but also involving both the deep and cortical gray matter (GM). GM pathology in people with MS (pwMS) includes the presence of lesions, leptomeningeal inflammation, atrophy, altered iron concentration, and microstructural changes. Studies using 7T and 3T MR imaging with optimized protocols established that GM damage is a principal driver of disease progression in pwMS. Future work is needed to incorporate the assessment of these GM imaging biomarkers into the clinical workup of pwMS and the assessment of treatment efficacy., Competing Interests: Disclosure R. Zivadinov received personal compensation from Bristol Myers Squibb, Biogen Idec, EMD Serono, Sanofi, Mapi Pharma, Filterlex, and 3D Communications for speaking and consultant fees. He received financial support for research activities from Bristol-Myers Squibb, United States, Novartis, CorEvitas, Mapi Pharma, Octave, EMD Serono, United States, and Protembis. D. Jakimovski received personal compensation from EMD Serono and AstraZeneca for consultant fees. He received financial support for research activities from ClinSTAR by NIA under award U24AG065204. M.G. Dwyer received grant support from Novartis, Bristol Myers Squibb, Mapi Pharma, Merck Serono, Keystone Heart Ltd., Protembis GmbH, V-Wave Ltd, and Filterlex Medical Ltd, and consulting fees from Bristol Myers Squibb, Merck Serono, Keystone Heart Ltd, and Mapi Pharma., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Several studies have shown the different relationships between cognitive functions and structural magnetic resonance imaging (MRI) measurements in people with multiple sclerosis (pwMS). However, there is an ongoing debate regarding the magnitude of correlation between MRI measurements and specific cognitive function tests. This systematic review and meta-analysis aimed to synthesize the most consistent correlations between MRI measurements and cognitive function in pwMS., Methods: PubMed/MEDLINE, Embase, Scopus, and Web of Science databases were systematically searched up to February 2023, to find relevant data. The search utilized syntax and medical subject headings (MeSH) relevant to cognitive performance tests and MRI measurements in pwMS. The R software version 4.3.3 with random effect models was used to estimate the pooled effect sizes., Results: 13,559 studies were reviewed, of which 136 were included. The meta-analyses showed that thalamic volume had the most significant correlations with Symbol Digit Modalities Test (SDMT) r = 0.47 (95 % CI: 0.39 to 0.56, p < 0.001, I 2 = 88 %), Brief Visual Memory Test-Revised-Total Recall (BVMT-TR) r = 0.51 (95 % CI: 0.36 to 0.66, p < 0.001, I 2 = 81 %), California Verbal Learning Test-II-Total Recall (CVLT-TR) r = 0.47 (95 % CI: 0.34 to 0.59, p < 0.001, I 2 = 69 %,), and Delis-Kaplan Executive Function System (DKEFS) r = 0.48 (95 % CI: 0.34 to 0.63, p < 0.001, I 2 = 22 %,)., Conclusion: We conclude that thalamic volume exhibits highest relationships with information processing speed (IPS), visuospatial learning-memory, verbal learning-memory, and executive function in pwMS. A comprehensive understanding of the intricacies of the mechanisms underpinning this association requires additional research., Competing Interests: Declaration of competing interest Omid Mirmosayyeb, Fardin Nabizadeh, Elham Moases Ghaffary, Mohammad Yazdan Panah, and Dejan Jakimovski have nothing to disclose. Robert Zivadinov has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Protembis, Janssen, 415 Capital, and Novartis for speaking and consultant fees. He received financial support for research activities from Sanofi, Novartis, Bristol Myers Squibb, Octave, Mapi Pharma, CorEvitas, Protembis and V-WAVE Medical. Bianca Weinstock-Guttman received honoraria as a speaker and/or as a consultant for Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme, Sanofi, Genentech, Novartis, Celgene/BMS, Janssen and Horizon Dr Weinstock-Guttman received research funds from Biogen Idec, EMD Serono, Genzyme, Genentech, Sanofi, Novartis. Ralph HB. Benedict has received consultation or speaking fees from Bristol Myer Squibb, Biogen, Merck, EMD Serono, Roche, Verasci, Immune Therapeutics, Novartis, and Sanofi- Genzyme., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Osman Ozel,1 Caila B Vaughn,1 Svetlana P Eckert,1 Dejan Jakimovski,2 Alexis A Lizarraga,1 Bianca Weinstock-Guttman1 1Jacobs MS Center for Treatment and Research, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA; 2Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USACorrespondence: Bianca Weinstock-GuttmanJacobs MS Center for Treatment and Research, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, 1010 Main Street, 2 nd Floor, Buffalo, NY 14202, USATel +1 716 829 5063Fax +1 716 829 4001Email bw8@buffalo.eduAbstract: Dimethyl fumarate (DMF) is a commonly prescribed oral medication for the treatment of relapsing forms of multiple sclerosis (MS) with a wide range of hypothesized downstream mechanisms of action. Randomized clinical trials have established its clinical efficacy by using standard objective clinical measures. However, MS is a chronic disease that, apart from physical ailments, can affect an individual’s mood, psychosocial status, and quality of life which cannot be captured by using only objective assessment tools. Given the challenge of determining the efficacy of the treatment in a real-world clinical setting, the use of patient-reported outcomes (PROs) may help us to better address these aspects of patient care and establish a more patient-centered approach to MS care. To date, a review of PubMed identified six studies which reported on PROs in patients who are taking DMF. In total, twelve different kinds of PRO measures were utilized and 6359 patients provided at least one form of PRO in these studies. Upon review of these studies, we were able to conclude that people with MS had decreased quality of life compared to the healthy population in the US. MS patients on DMF, however, had better health-related quality of life assessment scores compared to those using a placebo. Previous studies also suggested that DMF decreased work productivity impairment scores after one year of use compared to baseline. DMF was associated with less impairment in fatigue and depression scales along with improved treatment quality assessment and adherence scores. This review will present a brief synopsis of the published literature and will provide indications for future directions with respect to PROs and DMF in people with MS.Keywords: multiple sclerosis, patient-reported outcomes, outcome measures, quality of life, dimethyl fumarate

Background: The multi-order visual system represents an excellent testing site regarding the process of trans-synaptic degeneration. The presence and extent of global versus trans-synaptic neurodegeneration in people with multiple sclerosis (pwMS) is not clear., Objective: To explore cross-sectional and longitudinal relationships between retinal, thalamic and cortical changes in pwMS with and without MS-related optic neuritis (pwMSON and pwoMSON) using MRI and optical coherence tomography (OCT)., Methods: 162 pwMS and 47 healthy controls (HCs) underwent OCT and brain MRI at baseline and 5.5-years follow-up. Peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell inner plexiform layer (mGCIPL) thicknesses were determined. Global volume measures of brain parenchymal volume (BPV)/percent brain volume change (PBVC), thalamic volume and T2-lesion volume (LV) were derived using standard analysis protocols. Regional cortical thickness was determined using FreeSurfer. Cross-sectional and longitudinal relationship between the retinal measures, thalamic volume and cortical thickness were assessed using age, BPV/PBVC and T2-LV adjusted correlations and regressions., Results: After age, BPV and T2-LV adjustment, the thalamic volume explained additional variance in the thickness of pericalcarine (R 2 increase of 0.066, standardized β = 0.299, p = 0.039) and lateral occipital (R2 increase of 0.024, standardized β = 0.299, p = 0.039) gyrii in pwMSON. In pwoMSON, the thalamic volume was a significant predictor only of control (frontal) regions of pars opercularis. There was no relationship between thalamic atrophy and cortical thinning over the follow-up in both pwMS with and without MSON. While numerically lower in the pwMSON group, the inter-eye difference was not able to predict the presence of MSON., Conclusions: MSON can induce a measurable amount of trans-synaptic pathology on second-order cortical regions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background and Objective : Pregnancy in mothers with multiple sclerosis (MS) commonly results in significant changes in disease activity and changes in clinical care, including the discontinuation of disease modifying therapy (DMT). This study aimed at understanding the clinical and patient-reported outcomes (PROs) before, during and 1-year after delivery. Materials and Methods : A total of 30 pregnant mothers with MS were recruited as part of the study. Clinical (relapse activity and disability changes), PRO information and MRI outcomes were collected on four separate visits: one baseline visit-0-30 days post-delivery; and 3 follow-up visits at week 24, week 36 and week 52 from the baseline. PRO was assessed using a validated questionnaire called the Fatigue Scale for Motor and Cognitive Function (FSMC). The MRI scans were analyzed, and the count of new T2 lesions and/or contrast-enhancing lesions was determined. Results : The average time between delivery and the start of DMT was 142.5 days. Relapse activity before the pregnancy was numerically linked with the activity during the pregnancy, where up to 57.1% of the activity during pregnancy occurred in pwMS with previously active disease before conception (statistically trending with p = 0.073). The relapse activity after the pregnancy occurred twice as often in pwMS whose MS was clinically active before conception. All five pwMS who experienced a relapse prior to the pregnancy experienced worsening in their physical PRO domain. Conclusions : Pre-pregnancy activity is crucial in the screening of mothers with MS at risk for post-partum relapses, worsening of clinical disability and/or PRO measures. A post-partum MS period may benefit from the routine PRO utilization and screening for its worsening. The inflammatory activity during pregnancy was not associated with short-term disease progression.

Increased choroid plexus (CP) volume has been recently implicated as a potential predictor of worse multiple sclerosis (MS) outcomes. The biomarker signature of CP changes in MS are currently unknown. To determine the blood-based biomarker characteristics of the cross-sectional and longitudinal MRI-based CP changes in a heterogeneous group of people with MS (pwMS), a total of 202 pwMS (148 pwRRMS and 54 pwPMS) underwent MRI examination at baseline and at a 5-year follow-up. The CP was automatically segmented and subsequently refined manually in order to obtain a normalized CP volume. Serum samples were collected at both timepoints, and the concentration of 21 protein measures relevant to MS pathophysiology were determined using the Olink™ platform. Age-, sex-, and BMI-adjusted linear regression models explored the cross-sectional and longitudinal relationships between MRI CP outcomes and blood-based biomarkers. At baseline, there were no significant proteomic predictors of CP volume, while at follow-up, greater CP volume was significantly associated with higher neurofilament light chain levels, NfL (standardized β = 0.373, p = 0.001), and lower osteopontin levels (standardized β = -0.23, p = 0.02). Higher baseline GFAP and lower FLRT2 levels were associated with future 5-year CP % volume expansion (standardized β = 0.277, p = 0.004 and standardized β = -0.226, p = 0.014, respectively). The CP volume in pwMS is associated with inflammatory blood-based biomarkers of neuronal injury (neurofilament light chain; NfL) and glial activation such as GFAP, osteopontin, and FLRT2. The expansion of the CP may play a central role in chronic and compartmentalized inflammation and may be driven by glial changes.

Cognitive impairment is common in multiple sclerosis and negatively impacts quality of life. Cognitive status has yet to be described in people with severe progressive multiple sclerosis, in whom conventional neuropsychological testing is exceptionally difficult. The objective for the study was to characterize cognitive performance in severe progressive multiple sclerosis and compare them with age-, sex- and disease duration-matched less disabled people with multiple sclerosis using a specifically developed auditory, non-motor test of attention/cognitive processing speed-Auditory Test of Processing Speed. Also, we aimed to determine the relationship between cognitive performance and MRI-based outcomes in these matched cohorts. The Comprehensive Assessment of Severely Affected Multiple Sclerosis study was carried out at the University at Buffalo and the Boston Home, a skilled nursing facility in Dorchester, MA. Inclusion criteria were age 30-80 years and expanded disability status scale 3.0-6.5 for community-dwelling and 7.0-9.5 for skilled nursing facility people with multiple sclerosis. The cognitive assessment was performed using the Brief International Cognitive Assessment for Multiple Sclerosis consisting of Symbol Digit Modalities Test, Brief Visuospatial Memory Test-Revised, California Verbal Learning Test-2nd edition along with Auditory Test of Processing Speed, Paced Auditory Serial Addition Test-3 second and Controlled Oral Word Association Test. MRI scans were retrospectively collected and analysed for lesion and volumetric brain measurements. The rate of completion and performance of the cognitive tests was compared between the groups, and the relationship with MRI measures was determined using sex, age and years of education-adjusted linear regression models. Significantly greater percentage of the severe multiple sclerosis group completed Auditory Test of Processing Speed when compared with the current gold standard of Symbol Digit Modalities Test (93.2% versus 65.9%). Severe progressive multiple sclerosis had worse cognitive performance in all cognitive domains with greatest differences for cognitive processing speed (Symbol Digit Modalities Test > Paced Auditory Serial Addition Test-3 second > Auditory Test of Processing Speed, Cohen's d < 2.13, P < 0.001), learning and memory (Cohen's d < 1.1, P < 0.001) and language (Controlled Oral Word Association Test with Cohen's d = 0.97, P < 0.001). Multiple cognitive domains were significantly associated with lower thalamic (standardized β < 0.419, P < 0.006) and cortical (standardized β < 0.26, P < 0.031) volumes. Specially designed (auditory) cognitive processing speed tests may provide more sensitive screening of cognitive function in severe progressive multiple sclerosis. The cognitive profile of severe multiple sclerosis is proportional to their physical outcomes and best explained by decreased grey matter volume., Competing Interests: D.J., Z.W., T.R.W., C.S., T.S., N.B. and F.S. have nothing to disclose. A.B. and D.Y.-H are employees of TBH. M.G.D. has received personal compensation from Mapi Pharma for consultant fees. He received financial support for research activities from Bristol Myers Squibb, Mapi Pharma, Protembis and V-Wave Medical. S.P.E. received consultant fees from Genentech. B.W.-G. has received grant/research support from Novartis, Genentech, EMD Serono, Celgene/Bristol Myers Squibb, Sanofi and Genzyme, Janssen, Horizon, Bayer and Labcorp and has participated in speaker's bureaus for Biogen. She serves in the editorial board for BMJ Neurology, Children, CNS Drugs, MS International, Journal of Neurology and Frontiers in Epidemiology. R.Z. has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Janssen, 415 Capital, Filterlex and Mapi Pharma for speaking and consultant fees. He received financial support for research activities from Novartis, Bristol Myers Squibb, EMD Serono, Octave, Mapi Pharma, CorEvitas, Protembis and V-Wave Medical. R.H.B.B. received consultation or speaking fees from Bristol Myers Squibb, Biogen, Merck, EMD Serono, Roche, VeraSci, Immune Therapeutics, Novartis and Sanofi-Genzyme. He has received research support from Biogen, Bristol Myers Squibb, Genzyme, Genentech, Novartis, National Institutes of Health, National Multiple Sclerosis Society and VeraSci. He consults for Immunic Therapeutics, Latin American Committee for Treatment and Research in Multiple Sclerosis, Merck, Novartis, Roche and Sanofi. He is on speaker bureau for Biogen, Bristol Myers Squibb and EMD Serono. He received royalties from Psychological Assessment Resources., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: The choroid plexus (CP), located within the ventricles of the brain and the primary producer of cerebrospinal fluid, has been shown to be enlarged in patients with multiple sclerosis (MS) and linked to periventricular remyelination failure. Atrophied T2-lesion volume (aT2-LV), a promising neurodegenerative imaging marker in progressive MS (PMS), reflects the volume of periventricular lesions subsumed into cerebrospinal fluid over the follow-up., Methods: In a cohort of 143 people with relapsing-remitting MS (RRMS) and 53 with PMS, we used 3T magnetic resonance imaging (MRI) to quantify CP volume (CPV) at baseline and aT2-LV over an average of 5.4 years of follow-up. Partial correlations, adjusting for age and sex, and linear regression analyses were used to assess the relationships between imaging measures., Results: In both cohorts, CPV was associated with aT2-LV in both the RRMS group (r = 0.329, p < 0.001) as well as the PMS group (r = 0.522, p < 0.001). In regression analyses predicting aT2-LV, ventricular volume (final adjusted R2 = 0.407, p < 0.001) explained additional variance beyond age, sex, and T2-lesion volume in the RRMS group while CPV (final adjusted R2 = 0.446, p = 0.009) was retained in the PMS group., Conclusion: Findings from this study suggest that the CP enlargement is associated with future neurodegeneration, with a particularly relevant role in PMS., Competing Interests: Declaration of competing interest Niels Bergsland has nothing to disclose. Michael G. Dwyer received grant support from Novartis, Bristol Myers Squibb, Mapi Pharma, Merck Serono, Keystone Heart Ltd., Protembis GmbH, and V-Wave Ltd., and consulting fees Bristol Myers Squibb, Merck Serono, and Keystone Heart Ltd. Dejan Jakimovski has nothing to disclose. Eleonora Tavazzi has nothing to disclose. Bianca Weinstock-Guttman has participated in speaker's bureaus and/or served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen, Labcorp and Horizon. Dr. Weinstock-Guttman also has received grant/research support from the agencies listed in the previous sentence. She serves in the editorial board for BMJ Neurology, Children, CNS Drugs, MS International and Frontiers Epidemiology. Robert Zivadinov has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Janssen, Sanofi, Biogen, Filterlex and Mapi Pharma for speaking and consultant fees. He received financial support for research activities from Novartis, Bristol Myers Squibb, EMD Serono, Octave, Mapi Pharma, CorEvitas, Protembis and V-WAVE Medical., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Expanded Disability Status Scale (EDSS) is limited when utilized in highly disabled people with multiple sclerosis (pwMS)., Objetive: To explore the relationship between disability measures and MRI outcomes in severely-affected pwMS., Methods: PwMS recruited from The Boston Home (TBH), a specialized residential facility for severly-affected pwMS and University at Buffalo (UB) MS Center were assessed using EDSS, MS Severity Scale, age-related MSS, Scripps Neurological Rating Scale (SNRS) and Combinatorial Weight-Adjusted Disability Score (CombiWISE). In all scores except SNRS, higher score indicates greater disability. MRI measures of T1, T2-lesion volume (LV), whole brain, gray matter, medulla oblongata and thalamic volumes (WBV, GMV, MOV, TV) and thalamic dysconnectivity were obtained., Results: Greatest disability differences between the TBH and UB pwMS were in SNRS (24.4 vs 71.9, p < 0.001, Cohen's d = 4.05) and CombiWISE (82.3 vs. 38.9, p < 0.001, Cohen's d = 4.02). In combined analysis of all pwMS, worse SNRS scores were correlated with worse MRI pathology in 8 out of 9 outcomes. EDSS only with 3 measures (GMV, MOV and TV). In severely-affected pwMS, SNRS was associated with T1-LV, T2-LV and WBV (not surviving false discovery rate (FDR) correction for multiple comparisons) whereas EDSS did not., Conclusion: Granular and dynamic disability measures may bridge the clinico-radiologcal gap present in severely affected pwMS., Competing Interests: Declaration of competing interest Dejan Jakimovski, Zachary Weinstock, Taylor Wicks, Christopher Suchan, Tommaso Sciortino, Niels Bergsland, Ferdinand Schweser, Cheryl Kennedy have nothing to disclose. Alex Burnham, Mark Ostrem, Jessica Reilly and David Young-Hong are employees of the Boston Home. Murali Ramanathan received research funding from the Department of Defense, National Science Foundation, and the National Institutes of Health. Michael G. Dwyer has received personal compensation from Mapi Pharma for consultant fees. He received financial support for research activities from Bristol Myers Squibb, Mapi Pharma, Protembis and V-WAVE Medical. Svetlana Eckert received consultant fees from Genentech. David Hojnacki received speaking and consulting from Biogen Idec and Bristol Myers Squibb. Ralph HB. Benedict has received consultation or speaking fees from Bristol Myer Squibb, Biogen, Merck, EMD Serono, Roche, Verasci, Immune Therapeutics, Novartis, and Sanofi-Genzyme. Bianca Weinstock-Guttman has received grant/research support Novartis, Genentech, EMD Serono, Celgene/Bristol Meyers Squibb, Sanofi &Genzyme, Janssen, Horizon, Bayer, Labcorp and has participated in speaker's bureaus for Biogen. She serves in the editorial board for BMJ Neurology, Children, CNS Drugs, MS International, Journal of Neurology and Frontiers Epidemiology. Robert Zivadinov has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Janssen, Sanofi, 415 Capital, Filterlex and Mapi Pharma for speaking and consultant fees. He received financial support for research activities from Novartis, Bristol Myers Squibb, EMD Serono, Octave, Mapi Pharma, CorEvitas, Protembis and V-WAVE Medical., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: The etiology of multiple sclerosis (MS) remains unknown. Pathogenesis likely relies on a complex interaction between multiple environmental, genetic, and behavioral risk factors. However, a growing body of literature supports the role of a preceding Epstein-Barr virus (EBV) infection in the majority of cases., Areas Covered: In this narrative review, we summarize the latest findings regarding the potential role of EBV as a predisposing event inducing new onset of MS. EBV interactions with the genetic background and other infectious agents such as human endogenous retrovirus are explored. Additional data regarding the role of EBV regarding the rate of mid- and long-term disease progression is also discussed. Lastly, the effect of currently approved disease-modifying therapies (DMT) for MS treatment on the EBV-based molecular mechanisms and the development of new EBV-specific therapies are further reviewed., Expert Opinion: Recent strong epidemiological findings support that EBV may be the primary inducing event in certain individuals that shortly thereafter develop MS. More studies are needed in order to better understand the significant variability in susceptibility based on environmental factors such as EBV exposure. Future investigations should focus on determining the specific EBV-related risk antigen(s) and phenotyping people with likely EBV-induced MS. Targeting EBV via several different avenues, including development of an EBV vaccine, may become the mainstay of MS treatment in the future.

Background: Brain hypoperfusion is linked with worse physical, cognitive and MRI outcomes in multiple sclerosis (MS). Understanding the proteomic signatures related to hypoperfusion could provide insights into the pathophysiological mechanism., Methods: 140 people with MS (pwMS; 86 clinically isolated syndrome (CIS)/relapsing-remitting (RRMS) and 54 progressive (PMS)) were included. Cerebral arterial blood flow (CABF) was determined using ultrasound Doppler measurement as the sum of blood flow in the bilateral common carotid arteries and vertebral arteries. Proteomic analysis was performed using the Multiple Sclerosis Disease Activity (MSDA) test assay panel performed on the Olink™ platform. The MSDA test measures the concentrations of 18 proteins that are age and sex-adjusted. It utilizes a stacked classifier logistic regression model to determine 4 disease pathway scores (immunomodulation, neuroinflammation, myelin biology, and neuroaxonal integrity) as well as an overall disease activity score (1 to 10). MRI measures of T2 lesion volume (LV) and whole brain volume (WBV) were derived., Results: The pwMS were on average 54 years old and had an average CABF of 951 mL/min. There were no differences in CABF between CIS/RRMS vs. PMS groups. Lower CABF levels were correlated with the overall disease activity score (r = -0.26, p = 0.003) and with the neuroinflammation (r = -0.29, p = 0.001), immunomodulation (r = -0.26, p = 0.003) and neuroaxonal integrity (r = -0.23, p = 0.007) pathway scores. After age and body mass index (BMI)-adjustment, lower CABF remained associated with the neuroinflammatory (r = -0.23, p = 0.011) and immunomodulation (r = -0.20, p = 0.024) pathway scores. The relationship between CABF and the neuroinflammation pathway score remained significant after adjusting for T2-LV and WBV (p = 0.038). Individual analyses identified neurofilament light chain, CCL-20 and TNFSF13B as contributors. When compared to the highest quartile (>1133.5 mL/min), the pwMS in the lowest CABF quartile (<764 mL/min) had greater overall disease activity score (p = 0.003), neuroinflammation (p = 0.001), immunomodulation (p = 0.004) and neuroaxonal integrity pathway scores (p = 0.007)., Conclusion: Lower cerebral arterial perfusion in MS is associated with changes in neuroinflammatory/immunomodulation pathways and their respective proteomic biomarkers. These findings may suggest a relationship between the hypoperfusion and pro-inflammatory MS changes rather than being merely an epiphenomenon subsequent to lower energy demands., Competing Interests: Declaration of competing interest Dejan Jakimovski, Karen Marr and Niels Bergsland have nothing to disclose. Ferhan Qureshi, Anisha Keshavan, Ati Ghoreyshi, Kian Jalaleddini and Kelly Leyden are employees of Octave Bioscience. Murali Ramanathan received research funding from the Department of Defense and National Institute of Neurological Diseases and Stroke. Michael G. Dwyer received compensation from Keystone Heart for consultant fees. He received financial support for research activities from Bristol Myers Squibb, Mapi Pharma, Keystone Heart, Protembis and V-WAVE Medical. Bianca Weinstock-Guttman received honoraria for serving in advisory boards and educational programs from Biogen Idec, Novartis, Genentech, Genzyme and Sanofi, Janssen, Abbvie and Bayer. She also received support for research activities from the National Institutes of Health, National Multiple Sclerosis Society, Department of Defense, and Biogen Idec, Novartis, Genentech, Genzyme and Sanofi. Robert Zivadinov has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Keystone Heart, Protembis and Novartis for speaking and consultant fees. He received financial support for research activities from Sanofi, Novartis, Bristol Myers Squibb, Octave, Mapi Pharma, Keystone Heart, Protembis and V-WAVE Medical., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Atrophied lesion volume (aLV), a proposed biomarker of disability progression in multiple sclerosis (MS) and transition into progressive MS (PMS), depicts chronic periventricular white matter (WM) pathology. Meningeal infiltrates, imaged as leptomeningeal contrast enhancement (LMCE), are linked with greater cortical pathology., Objectives: To determine the relationship between serum-derived proteomic data with the development of aLV and LMCE in a heterogeneous group of people with MS (pwMS)., Methods: Proteomic and MRI data for 202 pwMS (148 clinically isolated syndrome /relapsing-remitting MS and 54 progressive MS (PMS)) were acquired at baseline and at 5.4-year follow-up. The concentrations of 21 proteins related to multiple MS pathophysiology pathways were derived using a custom-developed Proximity Extension Assay on the Olink™ platform. The accrual of aLV was determined as the volume of baseline T2-weighted lesions that were replaced by cerebrospinal fluid over the follow-up. Regression models and age-adjusted analysis of covariance (ANCOVA) were used., Results: Older age (standardized beta = 0.176, p = 0.022), higher glial fibrillary acidic protein (standardized beta = 0.312, p = 0.001), and lower myelin oligodendrocyte glycoprotein levels (standardized beta = -0.271, p = 0.002) were associated with accrual of aLV over follow-up. This relationship was driven by the pwPMS population. The presence of LMCE at the follow-up visit was not predicted by any baseline proteomic biomarker nor cross-sectionally associated with any protein concentration., Conclusion: Proteomic markers of glial activation are associated with chronic lesional WM pathology (measured as aLV) and may be specific to the progressive MS phenotype. LMCE presence in MS does not appear to relate to proteomic measures., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Several studies report mixed associations between the retinal nerve fiber layer (RNFL) thickness with cognitive and physical disability in persons with multiple sclerosis (PwMS). Systematic synthesis of these findings is crucial in deriving credible conclusions., Methods: Five databases were searched from their inception to March 2022. The inclusion criteria for studies were MS-specific and required RNFL and cognitive performance data in order to be analyzed. The selection processes followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines., Results: The systematic review yielded 31 studies that investigated the association between RNFL thickness and cognitive performance. Twenty-two studies reported positive associations, and nine did not. The meta-analysis included 11 studies with a total of 782 PwMS with mean age of 40.5 years, mean Expanded Disability Status Scale (EDSS) of 2.7, and disease duration of 11.3 years. RNFL thickness was significantly associated Symbol Digit Modalities Test (pooled r = 0.306, p < 0.001), Paced Auditory Serial Addition Test (pooled r = 0.374, p < 0.001) and Word List Generation (WLG, pooled r = 0.177, p < 0.001). RNFL was also significantly correlated with visuospatial learning and memory tests (pooled r = 0.148, p = 0.042) and verbal learning and memory tests (pooled r = 0.245, p = 0.005). Within three eligible studies, no significant association between ganglion cell inner-plexiform layer and SDMT 0.083 (95% CI - 0.186, 0.352) was noted. The heterogeneity was high in all correlation studies (I 2  > 63% and p < 0.008) except for the WLG and visuospatial memory findings., Conclusion: RNFL thickness is associated with cognitive processing speed, verbal learning and memory, visual learning and memory, as well as verbal fluency in PwMS. The number of studies included in the meta-analyses were limited due to non-standardized reporting., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: CHRFAM7A , a uniquely human fusion gene, has been associated with neuropsychiatric disorders including Alzheimer's disease, schizophrenia, anxiety, and attention deficit disorder. Understanding the physiological function of CHRFAM7A in the human brain is the first step to uncovering its role in disease. CHRFAM7A was identified as a potent modulator of intracellular calcium and an upstream regulator of Rac1 leading to actin cytoskeleton reorganization and a switch from filopodia to lamellipodia implicating a more efficient neuronal structure. We performed a neurocognitive-MRI correlation exploratory study on 46 normal human subjects to explore the effect of CHRFAM7A on human brain., Methods: Dual locus specific genotyping of CHRFAM7A was performed on genomic DNA to determine copy number (TaqMan assay) and orientation (capillary sequencing) of the CHRFAM7A alleles. As only the direct allele is expressed at the protein level and affects α7 nAChR function, direct allele carriers and non-carriers are compared for neuropsychological and MRI measures. Subjects underwent neuropsychological testing to measure motor (Timed 25-foot walk test, 9-hole peg test), cognitive processing speed (Symbol Digit Modalities Test), Learning and memory (California Verbal Learning Test immediate and delayed recall, Brief Visuospatial Memory Test-Revised immediate and delayed recall) and Beck Depression Inventory-Fast Screen, Fatigue Severity Scale. All subjects underwent MRI scanning on the same 3 T GE scanner using the same protocol. Global and tissue-specific volumes were determined using validated cross-sectional algorithms including FSL's Structural Image Evaluation, using Normalization, of Atrophy (SIENAX) and FSL's Integrated Registration and Segmentation Tool (FIRST) on lesion-inpainted images. The cognitive tests were age and years of education-adjusted using analysis of covariance (ANCOVA). Age-adjusted analysis of covariance (ANCOVA) was performed on the MRI data., Results: CHRFAM7A direct allele carrier and non-carrier groups included 33 and 13 individuals, respectively. Demographic variables (age and years of education) were comparable. CHRFAM7A direct allele carriers demonstrated an upward shift in cognitive performance including cognitive processing speed, learning and memory, reaching statistical significance in visual immediate recall (FDR corrected p  = 0.018). The shift in cognitive performance was associated with smaller whole brain volume (uncorrected p  = 0.046) and lower connectivity by resting state functional MRI in the visual network (FDR corrected p  = 0.027) accentuating the cognitive findings., Conclusion: These data suggest that direct allele carriers harbor a more efficient brain consistent with the cellular biology of actin cytoskeleton and synaptic gain of function. Further larger human studies of cognitive measures correlated with MRI and functional imaging are needed to decipher the impact of CHRFAM7A on brain function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Jakimovski, Dorn, Regno, Bartnik, Bergsland, Ramanathan, Dwyer, Benedict, Zivadinov and Szigeti.)

Background: Paramagnetic rim lesions (PRLs) have been linked to higher clinical disease severity and relapse frequency. However, it remains unclear whether PRLs predict future, long-term disease progression., Objectives: The study aimed to assess whether baseline PRLs were associated with subsequent long-term (10 years) Expanded Disability Status Scale (EDSS) increase and relapse frequency and, if so, whether PRL-associated EDSS increase was mediated by relapse., Methods: This retrospective analysis included 172 people with multiple sclerosis (pwMS) with 1868 yearly clinical visits over a mean follow-up time of 10.2 years. 3T magnetic resonance imaging (MRI) was acquired at baseline and PRLs were assessed on quantitative susceptibility mapping (QSM) images. The associations between PRLs, relapse, and rate of EDSS change were assessed using linear models., Results: PRL+ pwMS had greater overall annual relapse rate (β = 0.068; p = 0.010), three times greater overall odds of relapse (exp(β) = 3.472; p = 0.009), and greater rate of yearly EDSS change (β = 0.045; p = 0.010) than PRL- pwMS. Greater PRL number was associated with greater odds of at least one progression independent of relapse activity (PIRA) episode over follow-up (exp(β) = 1.171, p = 0.009). Mediation analysis showed that the association between PRL presence (yes/no) and EDSS increase was 96.7% independent of relapse number., Conclusion: PRLs are a marker of aggressive ongoing disease inflammatory activity, including more frequent future clinical relapses and greater long-term, relapse-independent disability progression., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.A.R., M.M., T.W., F.Sa., A.B., D.J., N.B., and F.Sc. have no conflicts of interest to disclose. M.G.D. has received personal compensation from Bristol Myers Squibb, Novartis, EMD Serono, and Keystone Heart, and financial support for research activities from Bristol Myers Squibb, Novartis, Mapi Pharma, Keystone Heart, Protembis, and V-WAVE Medical. B.W.G. has participated in speakers’ bureaus for, served as a consultant for, and has received research support from Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Myers Squibb, Sanofi & Genzyme, Janssen, Horizon, Bayer, and Labcorp. Dr. B.W.G. also serves on the editorial board for BMJ Neurology, Children, CNS Drugs, MS International, and Frontiers Epidemiology. R.Z. has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, and Novartis for speaking and consultant fees; he received financial support for research activities from Sanofi, Novartis, Bristol Myers Squibb, Mapi Pharma, Keystone Heart, Protembis, and V-WAVE Medical.

Background: A quantitative measurement of serum proteome biomarkers that would associate with disease progression endpoints can provide risk stratification for persons with multiple sclerosis (PwMS) and supplement the clinical decision-making process., Materials and Methods: In total, 202 PwMS were enrolled in a longitudinal study with measurements at two time points with an average follow-up time of 5.4 years. Clinical measures included the Expanded Disability Status Scale, Timed 25-foot Walk, 9-Hole Peg, and Symbol Digit Modalities Tests. Subjects underwent magnetic resonance imaging to determine the volumetric measures of the whole brain, gray matter, deep gray matter, and lateral ventricles. Serum samples were analyzed using a custom immunoassay panel on the Olink™ platform, and concentrations of 18 protein biomarkers were measured. Linear mixed-effects models and adjustment for multiple comparisons were performed., Results: Subjects had a significant 55.6% increase in chemokine ligand 20 (9.7 pg/mL vs. 15.1 pg/mL, p < 0.001) and neurofilament light polypeptide (10.5 pg/mL vs. 11.5 pg/mL, p = 0.003) at the follow-up time point. Additional changes in CUB domain-containing protein 1, Contactin 2, Glial fibrillary acidic protein, Myelin oligodendrocyte glycoprotein, and Osteopontin were noted but did not survive multiple comparison correction. Worse clinical performance in the 9-HPT was associated with neurofilament light polypeptide (p = 0.001). Increases in several biomarker candidates were correlated with greater neurodegenerative changes as measured by different brain volumes., Conclusion: Multiple proteins, selected from a disease activity test that represent diverse biological pathways, are associated with physical, cognitive, and radiographic outcomes. Future studies should determine the utility of multiple protein assays in routine clinical care., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objectives: To determine the relationship between systemic arterial blood flow (SABF) and cerebral perfusion measures in multiple sclerosis (MS) patients., Methods: Cerebral perfusion and SABF were assessed in 118 patients (75 clinically isolated syndrome (CIS)/relapsing-remitting MS and 43 progressive MS) through MRI examination with dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) and Doppler ultrasound, respectively. Measures of mean transit time (MTT) and time-to-peak (TTP), measured in seconds, of the normal-appearing whole brain (NAWB) and gray matter (GM) were calculated. Blood flow through the bilateral common carotid and vertebral arteries (in mL/min) represents the SABF. Whole brain volume (WBV) and body mass index (BMI) were used as additional covariates., Results: Higher systolic blood pressure was associated with lower SABF (-0.256, p = 0.006). In the total MS sample, higher SABF was associated with shorter MTT and TTP of the NAWB (r = -0.256, p = 0.007 and r = -0.307, p = 0.001) and GM (r = -0.239, p = 0.012 and r = -0.3, p = 0.001). The SABF and TTP associations were driven by the PMS patients (r = -0.451, p = 0.004 and r = -0.451, p = 0.011). Only in PMS, SABF remained a significant predictor of NAWB (standardized β = -0.394, p = 0.022) and GM TTP (standardized β = -0.351, p = 0.037). MTT and TTP were significantly lower in patients within lower SABF quartiles when compared to the higher quartiles (age-, sex-, BMI-, and WBV-adjusted ANCOVA p < 0.025)., Conclusions: The direct relationship between systemic and cerebral blood flow seen in PMS patients may suggest failure in cerebrovascular reactivity mechanisms and insufficient perfusion control. Cerebral blood flow in PMS may be increasingly dependent on the SABF., Key Points: • In progressive multiple sclerosis (MS) patients, the systemic arterial blood flow (SABF) is associated with perfusion-based measure of time-to-peak (TTP) of the normal-appearing whole brain (r = -0.451, p = 0.004) and gray matter (r = -0.451, p = 0.004). • Cerebral blood flow in progressive MS is directly dependent on systemic arterial blood flow and may be influenced by blood pressure changes. • Neurovascular unit impairment may play an important role in MS pathophysiology and contribute towards greater clinical disability., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Background and Purpose: Hypoperfusion, vascular pathology, and cardiovascular risk factors are associated with disease severity in multiple sclerosis (MS). We aimed to assess relationships between cerebral arterial blood flow (CABF) and serum neurofilament light chain (sNfL) as neuronal damage biomarkers., Methods and Materials: Total CABF was measured in 137 patients (86 with clinically isolated syndrome/relapsing-remitting (RR) MS and 51 with progressive MS [PMS]) and 48 healthy controls using Doppler ultrasonography. sNfL was quantitated using a single-molecule assay (Simoa). Examination using 3.0-T magnetic resonance imaging (MRI) allowed quantification of T2 lesions and whole-brain volume (WBV). Multiple linear regression models determined the sNfL association with CABF after correction for demographic and MRI-derived variables., Results: After adjustment for age, sex and body mass index (BMI), total CABF remained statistically significant and model comparisons showed that CABF explained an additional 2.6% of the sNfL variance (β = -0.167, p = 0.044). CABF also remained significant in a stepwise regression model (β = 0.18, p = 0.034) upon the inclusion of T2 lesion burden and WBV effects. Patients in the lowest CABF quartile (CABF ≤ 761 ml/min) had significantly higher sNfL levels (34.6 vs. 23.9 pg/ml, age and BMI-adjusted-p = 0.042) when compared to the highest quartile (CABF ≥ 1130 ml/min)., Conclusion: Lower CABF is associated with increased sNfL in MS patients, highlighting the relationship between cerebral hypoperfusion and axonal pathology., (© 2022 European Academy of Neurology.)

Multiple sclerosis remains one of the most common causes of neurological disability in the young adult population (aged 18-40 years). Novel pathophysiological findings underline the importance of the interaction between genetics and environment. Improvements in diagnostic criteria, harmonised guidelines for MRI, and globalised treatment recommendations have led to more accurate diagnosis and an earlier start of effective immunomodulatory treatment than previously. Understanding and capturing the long prodromal multiple sclerosis period would further improve diagnostic abilities and thus treatment initiation, eventually improving long-term disease outcomes. The large portfolio of currently available medications paved the way for personalised therapeutic strategies that will balance safety and effectiveness. Incorporation of cognitive interventions, lifestyle recommendations, and management of non-neurological comorbidities could further improve quality of life and outcomes. Future challenges include the development of medications that successfully target the neurodegenerative aspect of the disease and creation of sensitive imaging and fluid biomarkers that can effectively predict and monitor disease changes., Competing Interests: Declaration of interests DJ has received consulting fees from AstraZeneca; and serves as an Associate Editor for Clinical Neurology and Neurosurgery and is compensated by Elsevier. SB has received funding support for this manuscript by the German Research Foundation (CRC-TR-128 and CRC-TR-355) and the Hermann and Lilly Schilling Foundation; and consulting fees, payments, or honoraria from Merck Healthcare, Sanofi, Novartis, Roche, Biogen, TEVA, and Bristol Myers Squibb. RZ has received funding support from Mapi Pharma, EMD Serono, Novartis, Bristol Myers Squibb, Octave, V-VAWE Medical, and Protembis; and consulting fees, payments, or honoraria from EMD Serono, 415 Capital, Sanofi, Novartis, Janssen, and Bristol Myers Squibb. RHBB has received funding support from Biogen, Bristol Myers Squibb, Celgene, Genzyme, Genentech, Latin American Committee for Treatment and Research in Multiple Sclerosis, Novartis, and Verasci; royalties from the Psychological Assessment Resources; and consulting fees, payments, or honoraria from Biogen, Accorda, EMD Serono, Novartis, Bristol Myers Squibb, Immunic Therapeutics, Merck, Roche, and Sanofi. SAM has received funding support from the Multiple Sclerosis Society of Canada, Canadian Institutes of Health Research, EMD Serono, Roche, Novartis, Sanofi, Biogen, and Bristol Myers Squibb; and consulting fees, payments, or honoraria from Biogen, Bristol Myers Squibb, EMD Serono, Novartis, Roche, and Sanofi. FZ has received funding support by the German Research Foundation, German Federal Ministry of Education and Research, Novartis Cyprus, and Progressive Multiple Sclerosis Alliance; consulting fees from Actelion, Biogen, Bristol Meyers Squibb, Celgene, Janssen, Max Planck Society, Merck Serono, Novartis, Roche, Sanofi, Genzyme, and Sandoz. BW-G has received funding from Biogen, Bristol Myers Squibb, Celgene, Genentech, and Novartis; and consulting fees from Biogen, Bayer, Bristol Myers Squibb, Janssen, Horizon Therapeutics, Genzyme, and Sanofi; and payment or honoraria as a speaker from Biogen and Janssen., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Prior research has established a link between thalamic pathology and cognitive impairment (CI) in people with multiple sclerosis (pwMS). However, the translation of these findings to pwMS in everyday clinical settings has been insufficient., Objective: To assess which global and/or thalamic imaging biomarkers can be used to identify pwMS at risk for CI and cognitive worsening (CW) in a real-world setting., Methods: This was an international, multi-center (11 centers), longitudinal, retrospective, real-word study of people with relapsing-remitting MS (pwRRMS). Brain MRI exams acquired at baseline and follow-up were collected. Cognitive status was evaluated using the Symbol Digit Modalities Test (SDMT). Thalamic volume (TV) measurement was performed on T2-FLAIR, as well as on T1-WI, when available. Thalamic dysconnectivity, T2-lesion volume (T2-LV), and volumes of gray matter (GM), whole brain (WB) and lateral ventricles (LVV) were also assessed., Results: 332 pwMS were followed for an average of 2.8 years. At baseline, T2-LV, LVV, TV and thalamic dysconnectivity on T2-FLAIR (p < 0.016), and WB, GM and TV volumes on T1-WI (p < 0.039) were significantly worse in 90 (27.1 %) CI vs. 242 (62.9 %) non-CI pwRRMS. Greater SDMT decline over the follow-up was associated with lower baseline TV on T2-FLAIR (standardized β = 0.203, p = 0.002) and greater thalamic dysconnectivity (standardized β = -0.14, p = 0.028) in a linear regression model., Conclusions: PwRRMS with thalamic atrophy and worse thalamic dysconnectivity present more frequently with CI and experience greater CW over mid-term follow-up in a real-world setting., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Robert Zivadinov has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Janssen, Protembis, Filterlex and Novartis for speaking and consultant fees. He received financial support for research activities from Novartis, Bristol Myers Squibb, Octave, Mapi Pharma, Protembis, CorEvitas and V-WAVE Medical. Niels Bergsland and Dejan Jakimovski have nothing to disclose. Myassar Zarif, Samuel Hunter, Stephen Newman, Tom Fuchs and Mary Ann Picone have not declared any conflict of interest. Bianca Weinstock-Guttman received honoraria as a speaker and/or as a consultant for Biogen Idec, Sanofi &Genzyme, Genentech, Novartis, BMS, Bayer, Horizon and Janssen. Dr Weinstock-Guttman received research funds from Biogen Idec, Genentech and Novartis. Lorena Lorefice received honoraria for consultancy and speaking from Biogen, Novartis, Sanofi, Genzyme, Merck and Bristol Myers Squibb. Menno Schoonheim: Serves on the editorial board of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and ZonMW (Vidi grant, project number 09150172010056) and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, EIP, Sanofi, MedDay and Merck. Sarah A. Morrow, in the last 3 years, has served as an advisory board member or received consulting fees from Biogen Idec; BMS/Celgene; EMDSerono; Novartis; Roche; Sanofi. She has participated in a speaker’s bureau for Biogen Idec; BMS/Celgene; EMDSerono; Novartis; Roche; Sanofi. She has received research support from Biogen Idec; EMDSerono, Novartis, Roche; Sanofi Genzyme. She has participated as a site investigator in clinical trials sponsored by Bristol Myers Squibb/Celgene; EMDSerono; Novartis; Roche; Sanofi. Gabriel Pardo received grants (to the institution) from Biogen, EMD Serono, Roche/Genentech, Sanofi Genzyme, Novartis, Abbvie, and BMS; consultant and/or speaker bureau for Biogen, EMD Serono, Roche/Genentech, Sanofi Genzyme, Novartis, Janssen, BMS, TG Therapeutics, PRIME Education, and MSAA. Mark Gudesblatt received honoraria from Biogen and Genentech. Jacqueline Nicholas received research grants from Biogen, Novartis, PCORI, Genentech, University of Buffalo, EMD Serono; Consulting for EMD Serono, Genentech, Greenwich Biosciences, Novartis, TG Therapeutics and Sanofi; Speaking honoraria for BMS, EMD Serono, Horizon, TG Therapeutics. Andrew Smith received honorariums from EMD Serono and Sanofi Genzyme for speaking bureau and combination for Genzyme for an advisory board. Mahmoud A. AbdelRazek received consultant fees from Bristol Myers Squibb. Wachy Vongchucherd, Jon Riolo and Diego Silva are employees of Bristol Myers Squibb. Michael G. Dwyer has received personal compensation from Bristol Myers Squibb and Filterlex for consultant fees. He received financial support for research activities from Novartis, Bristol Myers Squibb, Octave, Mapi Pharma, Protembis, CorEvitas and V-WAVE Medical. Ralph HB. Benedict has received consultation or speaking fees from Bristol Myer Squibb, Biogen, Merck, EMD Serono, Roche, Immune Therapeutics, Novartis, and Sanofi-Genzyme., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Retinol, tocopherols, and carotenoids (RTC) have physiological roles as vitamins, pro-vitamins, and antioxidants, and provide biomarkers of dietary vegetable and fruit intake. The goal was to investigate RTC in multiple sclerosis (MS)., Methods: This exploratory study included 106 people with MS (71 relapsing-remitting MS or RR-MS; and 35 progressive MS or PMS) and 31 healthy controls (HC) at baseline and 5-year follow-up (5YFU). Serum retinol, α-carotene, β-carotene, α-tocopherol, δ-tocopherol, γ-tocopherol, β-cryptoxanthin, lutein/zeaxanthin, and lycopene were measured using high performance liquid chromatography. Serum neurofilament light chain (sNfL) levels were measured using the single molecule array method. Expanded Disability Status Scale (EDSS) and low contrast letter acuity (LCLA) were used as disability measures., Results: Retinol in MS was positively correlated with α-carotene, β-carotene, β-cryptoxanthin, lutein/zeaxanthin, and α-tocopherol but negatively correlated with δ-tocopherol. EDSS was associated with α-tocopherol, δ-tocopherol, and lycopene. Greater retinol levels were associated with greater LCLA in RR-MS and PMS; high contrast visual acuity was not associated. Greater γ-tocopherol levels were associated with lower LCLA and high contrast visual acuity in PMS., Conclusions: RTC exhibit distinctive associations with LCLA and EDSS in MS., Competing Interests: Declaration of Competing Interest Ms. Nasim Nehzat and Dr. Richard Browne have nothing to disclose. Dr. Dejan Jakimovski is an Associate Editor for Clinical Neurology and Neurosurgery, and Frontiers in Cardiovascular Medicine. Bianca Weinstock-Guttman participated in speaker's bureaus and/or served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen, and Horizon. Dr. Weinstock-Guttman also received grant/research support from the agencies listed. She serves on the editorial board for BMJ Neurology, Children, CNS Drugs, MS International and Frontiers Epidemiology. Dr. Robert Zivadinov received speaker honoraria and consultant fees from Sanofi, Bristol Myers Squibb, Janssen, Mapi Pharma, CorEvitas, 415 Capital, and EMD Serono. He has received research support from Mapi-Pharma, Protembis, Bristol Myers Squibb, CorEvitas, Octave and Novartis. Dr. Murali Ramanathan received research funding from the National Multiple Sclerosis Society, Department of Defense and National Institute of Neurological Diseases and Stroke. He receives royalty from a self-published textbook., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Patient-reported outcomes (PRO) are increasingly utilized as part of the routine clinical assessment in people with multiple sclerosis (pwMS). The long-term effect of disease modifying therapies (DMTs) and their discontinuation on PRO measures remains largely unknown., Methods: Two pwMS groups treated with natalizumab were selected from the New York State MS Consortium (NYSMSC) database. The first group utilized long-term follow-up data of pwMS that either still continue natalizumab treatment or discontinued. Minimal requirement of three visits (before natalizumab initiation, during treatment and after discontinuation/latest follow-up) was implemented. The second group consisted of pwMS that completed PRO questionnaire on the day of the infusion and 7 days later PROs were assessed using the LIFEware System™ that assesses limitations in multiple physical and psychosocial domains. Additional physical disability was assessed using Expanded Disability Status Scale (EDSS) and Timed 25-ft walk test (T25FWT). PRO reports were Rasch-transformed, ranging from 0 to 100, with higher scores indicating a better outcome. Linear mixed-effect models and paired analyses were utilized., Results: Within the prospective cohort, 242 pwMS were followed on average of 6.5 years. Greater number of PRO domains worsened in the 141 pwMS that discontinued natalizumab when compared to 101 pwMS that remained on the drug (10 vs. 2 PRO domains). PwMS that discontinued natalizumab had significant decline in PROs regarding lower extremities, bladder and bower control and psychosocial aspects (feeling lonesome). Contrarily, pwMS that continued natalizumab had significant improvement in bladder and bowel PRO measures. Seven days after the natalizumab infusion, the 67 pwMS from the prospective cohort reported improvement in PRO measures of fatigue (62.8 vs. 66.4, p = 0.019), bladder limitations (80.3 vs. 85.0, p = 0.012), and feelings of lonesomeness (81.2 vs. 88.0, p = 0.009)., Conclusion: Continuous natalizumab treatment provides long-term stability or improvement in PRO measures. Natalizumab also provides short term improvements recorded after the infusion., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Studies have demonstrated that people with multiple sclerosis (pwMS) experience visual impairments and neurodegenerative retinal processes. The disability progression in pwMS may be associated with retinal changes assessed with optical coherence tomography (OCT). This meta-analysis aims at synthesizing the correlations between OCT measurements of disability in pwMS., Methods: We systematically searched four databases (PubMed/MEDLINE, Embase, Scopus, and Web of Science) from inception to November 2022, then conducted a meta-analysis using a random effects model to determine the pooled correlation coefficient(r) between OCT measurements and disability scales by R version 4.2.3 with the meta version 6.2-1 package., Results: From 3129 studies, 100 studies were included. Among 9051 pwMS, the female-to-male ratio was 3.15:1, with a mean age of 39.57 ± 6.07 years. The mean disease duration and Expanded Disability Status Scale (EDSS) were 8.5 ± 3.7 and 2.7 ± 1.1, respectively. Among the pooled subgroup analyses, macular ganglion cell inner plexiform layer (mGCIPL) in patients with relapsing-remitting (pwRRMS) and peripapillary retinal nerve fiber layer (pRNFL) in patients with progressive MS (pwPMS) had strong correlations with EDSS, r = -0.33 (95% CI: -0.45 to -0.20, I 2  = 45%, z-score = -4.86, p < 0.001) and r = -0.20 (95% CI:-0.58 to 0.26, I 2  = 76%, z-score = -0.85, p = 0.395), respectively. According to subgroup analysis on pwMS without optic neuritis (ON) history, the largest correlation was seen between EDSS and macular ganglion cell complex (mGCC): r = -0.39 (95% CI: -0.70 to 0.04, I 2  = 79%, z-score = -1.79, p = 0.073)., Conclusion: OCT measurements are correlated with disability in pwMS, and they can complement the comprehensive neurological visit as an additional paraclinical test., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest regarding the publication of this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Plasmodium falciparum is the leading cause of imported malaria and the most common cause of death in returning travellers., Aim: To identify the main epidemiological and clinical characteristics of patients with imported falciparum malaria in the Republic of North Macedonia., Material and Methods: Retrospectively analyzed were the epidemiological and clinical features of 34 patients with imported falciparum malaria who were diagnosed and treated at the university clinic for infectious diseases and febrile conditions in Skopje from 2010 to 2022. Malaria diagnosis was based on the microscopic detection of parasites in thick and thin blood smears., Results: All patients were male, with a median age of 36 years and a range of 22-60 years. Of the patients 33 (97.1%) acquired the disease in Sub-Saharan Africa. All patients except one stayed in endemic regions for work/business purposes. Chemoprophylaxis was completely applied in 4 (11.8%) patients. The median time of onset between the symptoms and diagnosis was 4 days, with a range of 1-12 days. Prevailing clinical manifestations were fever, chills, and splenomegaly in 100%, 94%, and 68% of patients, respectively. Severe malaria was noticed in 8 (23.5%) patients. In 5 (14.7%) patients the initial parasitemia was higher than 5%. On admission, thrombocytopenia, hyperbilirubinemia, and elevated alanine aminotransferase were registered in 94%, 58%, and 62% of patients, respectively. Out of the 33 patients with adequate follow-up, the outcome was favorable in 31 (93.9%)., Conclusion: In every febrile traveller returned from Africa, imported falciparum malaria should be an essential part of differential diagnostic considerations., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: The Symbol Digit Modalities Test (SDMT) is a gold-standard measure of cognitive efficiency and processing speed for people with multiple sclerosis (PwMS) but relies on vision and oculomotor function., Objectives: To develop and validate a new processing speed test with minimal memory involvement and no eye function requirements., Methods: We created an Auditory Test of Processing Speed (ATOPS). A total of 122 PwMS, of whom 33 were severely disabled (median Expanded Disability Status Scale 8.0) and 37 healthy volunteers (HVs), were enrolled. We assessed sensitivity to discriminate MS participants from HVs, convergent validity between ATOPS and SDMT, sensitivity to discriminate between cognitively impaired (CI) and cognitively preserved (CP) MS participants, and correlations with MS pathology (overall brain lesion burden). Acceptability was examined with completion rates and participant ratings of ATOPS., Results: ATOPS discriminated PwMS from HVs ( d = 0.739-0.856), correlated with SDMT (| r | = 0.528-0.587), discriminated between CI and CP PwMS ( d = 0.623-0.776), and correlated with lesion burden ( r = 0.332-0.436). All groups indicated high favorability of ATOPS and severely disabled MS patients could be assessed by ATOPS more frequently than by SDMT (100% vs. 72.4% completion)., Conclusions: ATOPS is a novel, accessible, and acceptable cognitive processing speed test that may be useful in clinical and/or research settings., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: ZLW, MJ III, AB, TRW, MY, Celeste S, SC, JG, Christopher S, NB, and TJC have nothing to disclose. MGD received personal compensation from Bristol Myers Squibb, Novartis, EMD Serono, and Keystone Heart, and financial support for research activities from Bristol Myers Squibb, Novartis, Mapi Pharma, Keystone Heart, Protembis, and V-WAVE Medical. DJ received honoraria for serving on the advisory board of AstraZeneca. He also serves as Associate Editor for Clinical Neurology and Neurosurgery and is compensated by Elsevier B.V. BWG served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen, Labcorp, and Horizon. She served in the speaker bureau for Biogen. She has also received grant/research support from the agencies listed in the previous sentence. She serves on the editorial board for BMJ Neurology, Children, CNS Drugs, MS International, and Frontiers Epidemiology. RZ has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Protembis, Janssen, 415 Capital, and Novartis for speaking and consultant fees. He received financial support for research activities from Sanofi, Novartis, Bristol Myers Squibb, Octave, Mapi Pharma, CorEvitas, Protembis, and V-WAVE Medical. RHBB received honoraria, speaking, or consulting fees from Biogen, BMS, Celgene, EMD Serono, Merck, Novartis, Roche, and Sanofi and has received research support from Biogen, BMS, Genzyme, NIH, NMSS, and Novartis. He has also received royalties from Psychological Assessment Resources, Inc.

Background: Recent developments in iron-sensitive MRI techniques have enabled visualization of chronic active lesions as paramagnetic rim lesions (PRLs) in vivo. Although PRLs have potential as a diagnostic and prognostic tool for multiple sclerosis (MS), limited studies have reported the reliability of PRL assessment. Further evaluation of PRL reliability, through original investigations and review of PRL literature, are warranted., Methods: A single-center cohort study was conducted to evaluate the inter-rater reliability of PRL identification on quantitative susceptibiltiy mapping (QSM) in 10 people with MS, 5 people with clinically isolated syndrome, and 5 healthy controls. An additional systematic literature search was then conducted of published PRL reliability data, and these results were synthesized., Results: In the single-center study, both inter-rater and intra-rater reliability of per-subject PRL number were at an "Excellent" (intraclass correlation coefficient (ICC) of 0.901 for both) level with only 2-years lesion classification experience. Across the reported literature values, reliability of per-lesion rim presence was on average "Near perfect" (for intra-rater; Cohen's κ = 0.833) and "Substantial" (for inter-rater; Cohens κ = 0.687), whereas inter-rater reliability of per-subject PRL number was "Good" (ICC = 0.874). Only 4/22 studies reported complete information on rater experience, rater level of training, detailed PRL classification criteria, and reliability cohort size and disease subtypes., Conclusion: PRLs can be reliably detected both at per-lesion and per-subject level. We recommend that future PRL studies report detailed reliability results, including rater experience level, and use a standardized set of reliability metrics (Cohen's κ or ICC) for improved comparability between studies., Competing Interests: Declaration of Competing Interest R.Z. has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, and Novartis for speaking and consultant fees. He received financial support for research activities from Sanofi, Novartis, Bristol Myers Squibb, Mapi Pharma, Keystone Heart, Protembis, and V-WAVE Medical. M.D. received personal compensation from Bristol Myers Squibb, Novartis, EMD Serono and Keystone Heart, and financial support for research activities from Bristol Myers Squibb, Novartis, Mapi Pharma, Keystone Heart, Protembis, and V-WAVE Medical., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction and Objectives: Multiple sclerosis (MS) is a disease of the central nervous system associated with immune dysfunction, demyelination, and neurodegeneration. The disease has heterogeneous clinical phenotypes such as relapsing-remitting MS (RRMS) and progressive multiple sclerosis (PMS), each with unique pathogenesis. Metabolomics research has shown promise in understanding the etiologies of MS disease. However, there is a paucity of clinical studies with follow-up metabolomics analyses. This 5-year follow-up (5YFU) cohort study aimed to investigate the metabolomics alterations over time between different courses of MS patients and healthy controls and provide insights into metabolic and physiological mechanisms of MS disease progression., Methods: A cohort containing 108 MS patients (37 PMS and 71 RRMS) and 42 controls were followed up for a median of 5 years. Liquid chromatography-mass spectrometry (LC-MS) was applied for untargeted metabolomics profiling of serum samples of the cohort at both baseline and 5YFU. Univariate analyses with mixed-effect ANCOVA models, clustering, and pathway enrichment analyses were performed to identify patterns of metabolites and pathway changes across the time effects and patient groups., Results and Conclusions: Out of 592 identified metabolites, the PMS group exhibited the most changes, with 219 (37%) metabolites changed over time and 132 (22%) changed within the RRMS group (Bonferroni adjusted P < 0.05). Compared to the baseline, there were more significant metabolite differences detected between PMS and RRMS classes at 5YFU. Pathway enrichment analysis detected seven pathways perturbed significantly during 5YFU in MS groups compared to controls. PMS showed more pathway changes compared to the RRMS group., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Central nervous system (CNS) atrophy provides valuable additional evidence of an ongoing neurodegeneration independent of lesion accrual in persons with multiple sclerosis (PwMS). However, there are limitations for interpretation of CNS volume changes at individual patient-level. Patients are receiving information on the topic of atrophy through various sources, including media, patient support groups and conferences, and discussions with their providers. Whether or not the topic of CNS atrophy should be proactively discussed with PwMS during office appointments is currently controversial. This commentary/perspective article represents perspectives of PwMS, providers and researchers with recommendations for minimizing confusion and anxiety, and facilitating proactive discussion about brain atrophy, as an upcoming routine measure in evaluating disease progression and treatment response monitoring. The following recommendations were created based on application of patient's and provider's surveys, and various workshops held over a period of 2 years: (1) PwMS should receive basic information on understanding of brain functional anatomy, and explanation of inflammation and neurodegeneration; (2) the expertise for atrophy measurements should be characterized as evolving; (3) quality patient education materials on these topics should be provided; (4) the need for standardization of MRI exams has to be explained and communicated; (5) providers should discuss background on volumetric changes, including references to normal aging; (6) the limitations of brain volume assessments at an individual-level should be explained; (7) the timing and language used to convey this information should be individualized based on the patient's background and disease status; (8) a discussion guide may be a very helpful resource for use by providers/staff to support these discussions; (9) understanding the role of brain atrophy and other MRI metrics may elicit greater patient satisfaction and acceptance of the value of therapies that have proven efficacy around these outcomes; (10) the areas that represent possibilities for positive self-management of MS symptoms that foster hope for improvement should be emphasized, and in particular regarding use of physical and mental exercise that build or maintain brain reserve through increased network efficiency, and (11) an additional time during clinical visits should be allotted to discuss these topics, including creation of specific educational programs., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Employment deterioration is common in people with multiple sclerosis (PwMS). Clinicians often learn of job loss after its occurrence, leaving no opportunity for preventive measures., Objectives: Identify which neuropsychological measures discriminate between healthy volunteers (HVs) and employed/disabled PwMS at baseline and predict work deterioration over 2 years., Methods: We examined 198 PwMS with computerized tests such as the Processing Speed Test (PST) and conventional tests such as the Symbol-Digit Modalities Test (SDMT), administered at baseline. Employment was assessed via Buffalo Vocational Monitoring Survey. Univariate and regression analyses identified significant predictors of PwMS categorized as work-stable versus work-deteriorated status., Results: PwMS were impaired on all baseline assessments relative to HVs ( p 's < 0.001). Post hoc analyses showed that employed PwMS and HVs performed similarly and better than work-disabled PwMS. At the univariate level, both PST and SDMT discriminated between work-deteriorated and work-stable PwMS ( p 's < 0.01). The logistic regression model accounting for all measures retained PST and the computerized Walking Speed Test. PwMS with increased negative work events had lower PST ( p < 0.001), SDMT ( p < 0.001), and BVMT- R ( p < 0.01) scores than stable PwMS. The related regression model retained PST and BVMT- R ( p < 0.001)., Conclusion: Cognition, as measured by the PST and BVMT-R, are predictive of job deterioration in PwMS and may be a useful screening tool to identify those at high risk of unemployment.

The last report of Crimean-Congo haemorrhagic fever (CCHF) in North Macedonia was more than 50 years ago in the northwest. We report on a fatal CCHF case following a Hyalomma tick bite in the east of the country in July 2023. Tracing of 67 contacts identified CCHF in one healthcare worker (HCW) providing care for the patient. Monitoring of contacts is concluded (including further 11 HCW contacts), thus far 28 days after the death of the case no additional cases were identified.

Background and Purpose: Oxidative stress biomarkers are increased in multiple sclerosis (MS) lesions. Antioxidant defense enzymes regulate reactive oxygen species that can cause tissue injury in MS., Methods: The study of 91 subjects included 64 relapsing-remitting MS (RR-MS; 72% female, baseline age ± SD = 44.6 ± 11 years, disease duration = 13.3 ± 8.8 years, median Expanded Disability Status Scale [EDSS] = 2.0, interquartile range = 1.8) and 27 healthy controls (HC) at baseline and 5-year follow-up (5YFU). Serum glutathione peroxidase (GPX), glutathione-S-transferase (GST), glutathione reductase (GSHR), superoxide dismutase, and paraoxonase-1 (PON1) arylesterase and paraoxonase activities were measured using kinetic enzyme assays. Total cholesterol (TC), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), and an apolipoprotein (Apo) panel with ApoA-I, ApoA-II, ApoB, ApoC-II, and ApoE were obtained. Serum neurofilament (sNfL) was used to assess axonal injury. Disability was measured on the EDSS., Results: GSHR activity was lower in HC compared to RR-MS at baseline and 5YFU. GPX (p = 0.008) and PON1 arylesterase and paraoxonase activities (both p = 0.05) increased between baseline and 5YFU in HC but did not increase in RR-MS. At baseline and 5YFU, GPX and GST were associated with TC, LDL-C, and ApoA-II; GSHR was associated with ApoA-II and ApoC-II. Antioxidant enzymes were not associated with sNfL or EDSS in RR-MS., Conclusions: RR-MS patients did not exhibit the changes in antioxidant enzyme activities over 5YFU found in HC; however, the differences were modest. Antioxidant enzyme activities are not associated with disability., (© 2023 European Academy of Neurology.)

Background and Purpose: Atrophied T2 lesion volume (LV), reflecting the complete transformation of lesions into cerebrospinal fluid (CSF), has been associated with disease progression in multiple sclerosis (MS). The underlying damage leading to lesion destruction remains poorly understood. The objective of this study was to use diffusion tensor imaging (DTI) to investigate the extent of microstructural tissue damage at baseline in lesions that subsequently transform into CSF., Methods: Ninety-nine MS patients (67 relapsing-remitting MS [RRMS] and 32 progressive PMS [PMS]) were imaged at baseline and after an average of 5.3 ± 0.6 years of follow-up. Assessments included T2 LV and DTI at baseline and atrophied T2 LV over follow-up. Lesioned areas that became atrophied T2 LV were compared to those that did not. Baseline lesional DTI metrics were compared between RRMS versus PMS patients and between patients with disability progression (DP, n = 35) versus non-DP (n = 64), using ANCOVA models., Results: Lesion tissue that developed into atrophied T2 LV had significantly different baseline DTI parameters compared to nonatrophied T2-LV tissue (p<0.001), with the largest effect for free-water (d = 2.739). Baseline tissue characteristics of future atrophied T2 LV were not significantly different between groups. However, DP patients developed greater atrophied T2 LV (377 vs. 83 mm 3 , p < 0.001)., Conclusions: Extensive microstructural damage characterizes lesions replaced by CSF, independently of disease phenotype or future DP. Greater atrophied T2 LV predicts DP., (© 2021 American Society of Neuroimaging.)

Lyme borreliosis (LB) and tick-borne encephalitis (TBE) are important tick-borne diseases in Europe. This study aimed to investigate the seroreactivity against Borrelia burgdorferi and TBE virus (TBEV) in tick-infested individuals in North Macedonia and Serbia. Serum samples were collected from tick-infested individuals and from healthy individuals in the same regions. Samples were tested for anti- Borrelia IgG reactivity and TBEV-neutralizing antibodies. Results showed higher seroreactivity against Borrelia antigens in patients and healthy donors from Novi Sad compared to those from the Skopje region. However, there was no statistically significant difference between tick-infested patients and healthy donors within each region. No TBEV-neutralizing antibodies were detected in participants from Novi Sad or in the control groups, except for one person from North Macedonia who had a moderate TBEV-neutralizing reaction. The study highlights the need for improved surveillance and diagnostic capabilities for LB and TBE in these regions. It also suggests the potential existence of TBEV foci in North Macedonia. The findings provide a complementary understanding of the LB and TBE epidemiology in the studied regions; however, further research is needed to investigate the presence and distribution of Borrelia spp. and TBEV in ticks to assess the significance of detected seroreactivity.

Introduction: B cell depletion has been established as an efficacious anti-inflammatory therapy in people with relapsing forms of multiple sclerosis (MS). Ublituximab (ublituximab-xiiy) is the latest approved chimeric glycoengineered anti-CD20 monoclonal antibody (mAb) for the treatment of relapsing forms of MS., Areas Covered: In this narrative review, the authors explore the safety and effectiveness of data derived from the Phase 2 and Phase 3 ublituximab trials and from their respective post-hoc analyses. Moreover, they consider the similarities and differences between the currently available anti-CD20 antibodies for treatment of relapsing MS. Lastly, the authors discuss the role and place of ublituximab in the current disease modifying therapy landscape., Expert Opinion: Ublituximab is a rapid-acting and effective anti-inflammatory option as a treatment in people with relapsing MS that significantly reduced the annualized relapse rate and MRI-based disease activity. When compared to the Phase III trials of the other two anti-CD20 mAbs (ocrelizumab and ofatumumab), ublituximab did not result with reduction of 3 or 6-month confirmed disability progression. These differences may be attributed to the overall low rate of progression in both the ublituximab and the active comparator teriflunomide arm. Future data from open-label extensions are warranted. There was no significant reduction of ublituximab on whole-brain atrophy compared to teriflunomide.

Background: Paramagnetic rim lesions (PRL) may be linked to relapse risk of people with relapsing-remitting multiple sclerosis (pwRRMS)., Objective: To determine the relationship between presence of PRL lesions and cognitive recovery after relapse., Methods: PRL load was compared between acutely relapsing pwRRMS and matched stable pwRRMS controls (each group n  = 21). In addition, cognitive recovery was compared between acutely relapsing pwRRMS with at least one PRL (PRL+) and those without any PRL (PRL-)., Results: Acutely relapsing pwRRMS had significantly greater prevalence and number of PRL ( p  = 0.004 and p  = 0.003) compared with stable controls. These findings remained significant after adjusting for global neuroinflammatory burden (enhancing and non-enhancing lesions). In addition, acutely relapsing PRL + pwRRMS ( n  = 10) had worse recovery of verbal memory following relapse compared with acutely relapsing PRL - pwRRMS ( n  = 7; p  = 0.027)., Conclusion: These findings may partially explain previously suggested associations between presence of PRL with more severe disease course.

Blood-based biomarkers can be economic and easily accessible tools for monitoring and predicting disease activity in multiple sclerosis. The objective of this study was to determine the predictive value of a multivariate proteomic assay for concurrent and future microstructural/axonal brain pathology in a longitudinal study of a heterogeneous group of people with multiple sclerosis. A proteomic analysis was obtained on serum samples from 202 people with multiple sclerosis (148 relapsing-remitting and 54 progressive) at baseline and 5-year follow-up. The concentration of 21 proteins related to multiple pathways of multiple sclerosis pathophysiology was derived using Proximity Extension Assay on the Olink platform. Patients were imaged on the same 3T MRI scanner at both timepoints. Тhe rate of whole brain, white matter and grey matter atrophy over the 5-year follow-up was determined using the multi-timepoint Structural Image Evaluation, using Normalisation, of Atrophy algorithms. Lesion burden measures were also assessed. The severity of microstructural axonal brain pathology was quantified using diffusion tensor imaging. Fractional anisotropy and mean diffusivity of normal-appearing brain tissue, normal-appearing white matter, grey matter, T2 and T1 lesions were calculated. Age, sex and body mass index-adjusted step-wise regression models were used. Glial fibrillary acidic protein was the most common and highest-ranked proteomic biomarker associated with greater concurrent microstructural central nervous system alterations ( P < 0.001). The rate of whole brain atrophy was associated with baseline levels of glial fibrillary acidic protein, protogenin precursor, neurofilament light chain and myelin oligodendrocyte ( P < 0.009), whereas grey matter atrophy was associated with higher baseline neurofilament light chain, higher osteopontin and lower protogenin precursor levels ( P < 0.016). Higher baseline glial fibrillary acidic protein level was a significant predictor of future severity of the microstructural CNS alterations as measured by normal-appearing brain tissue fractional anisotropy and mean diffusivity (standardized β = -0.397/0.327, P < 0.001), normal-appearing white matter fractional anisotropy (standardized β = -0.466, P < 0.0012), grey matter mean diffusivity (standardized β = 0.346, P < 0.011) and T2 lesion mean diffusivity (standardized β = 0.416, P < 0.001) at the 5-year follow-up. Serum levels of myelin-oligodendrocyte glycoprotein, neurofilament light chain, contactin-2 and osteopontin proteins were additionally and independently associated with worse concomitant and future axonal pathology. Higher glial fibrillary acidic protein levels were associated with future disability progression (Exp(B) = 8.65, P = 0.004). Multiple proteomic biomarkers are independently associated with greater severity of axonal brain pathology as measured by diffusion tensor imaging in multiple sclerosis. Baseline serum glial fibrillary acidic protein levels can predict future disability progression., Competing Interests: D.J. and N.B. have nothing to disclose. F.Q., V.G., A.K. and K.L. are employees of Octave Bioscience. M.R. received research funding from the National Multiple Sclerosis Society, Department of Defense and National Institute of Neurological Diseases and Stroke. M.G.D. received compensation from Keystone Heart for consultant fees. He received financial support for research activities from Bristol Myers Squibb, Mapi Pharma, Keystone Heart, Protembis and V-WAVE Medical. B.W.-G. received honoraria for serving in advisory boards and educational programmes from Biogen Idec, Novartis, Genentech, Genzyme and Sanofi, Janssen, Abbvie and Bayer. She also received support for research activities from the National Institutes of Health, National Multiple Sclerosis Society, Department of Defense, Biogen Idec, Novartis, Genentech, Genzyme and Sanofi. R.Z. has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Keystone Heart, Protembis and Novartis for speaking and consultant fees. He received financial support for research activities from Sanofi, Novartis, Bristol Myers Squibb, Octave, Mapi Pharma, Keystone Heart, Protembis and V-WAVE Medical., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Patient-reported outcomes (PROs) are valuable measures for routine clinical care of people with multiple sclerosis (pwMS). Materials: 646 pwMS treated with interferon-β-1a (IFN-β-1a) were retrospectively included from the New York State Multiple Sclerosis Consortium. Clinical and PRO data at enrollment and 3 year follow-up were collected. PwMS with stable disease and disability worsening were matched (1:1) based on age, Expanded Disability Status Scale (EDSS) scores and disease duration. Disability worsening was determined based on trial criteria. Results: PwMS with future EDSS worsening had higher baseline and follow-up timed-25-foot walk (6.6 vs 5.5 s; 9.1 vs 5.5 s; p < 0.001) when compared with stable pwMS. Worsening pwMS reported higher baseline difficulties in getting up (odds ratio [OR] = 2.4; p = 0.009), climbing stairs (OR = 1.6; p = 0.024) and standing (OR = 2.2; p < 0.001). Worsening pwMS reported greater lower limb limitations (OR = 2.3; p = 0.004) and fatigue (OR = 1.8; p = 0.002). Conclusion: Higher fatigue and lower limb functional limitations are significant predictors of future disability worsening in pwMS.

Background: The effect of disease modifying therapies (DMTs) on brain atrophy in persons with multiple sclerosis (pwMS) is typically investigated in highly standardized clinical trial settings or single-center academic institutions. We aimed at utilizing artificial intelligence (AI)-based volumetric analysis on routine unstandardized T2-FLAIR scans in determining the effect of DMTs on lateral ventricular volume (LVV) and thalamic volume (TV) changes in pwMS., Methods: The DeepGRAI (Deep Gray Rating via Artificial Intelligence) registry is a multi-center, longitudinal, observational, real-word study with a convenience sample of 1002 relapsing-remitting (RR) pwMS from 30 United States sites. Brain MRI exams acquired as part of the routine clinical management were collected at baseline and on average at 2.6-years follow-up. The MRI scans were acquired either on 1.5T or 3T scanners with no prior harmonization. TV was determined using the DeepGRAI tool and lateral ventricular volume LVV was measured using NeuroSTREAM software., Results: After propensity matching based on baseline age, disability and time of follow-up, untreated pwRRMS had significantly greater TV change when compared to treated pwRRMS (-1.2% vs. -0.3%, p = 0.044). PwRRMS treated with high-efficacy DMTs had significant and two-fold lower% LVV change when compared to pwRRMS treated on moderate-efficacy DMTs (3.5% vs. 7.0%, p = 0.001). PwRRMS who stopped DMT during the follow-up had significantly greater annualized% TV change compared to pwRRMS who remained on their DMT (-0.73% vs. -0.14%, p = 0.012) and significantly greater annualized% LVV change (3.4% vs. 1.7%, p = 0.047). These findings were also observed in a propensity analysis that additionally incorporated matching for scanner model at both baseline and follow-up visits., Conclusions: LVV and TV measured on T2-FLAIR scans can detect treatment-induced short-term neurodegenerative changes measured in a real-word unstandardized, multicenter, clinical routine setting., (Copyright © 2023. Published by Elsevier B.V.)