Evaluation of ovarian reserve and the assisted reproductive technology (ART) cycles' outcome as well as the relapse rate within one year after ART in women with multiple sclerosis: a case-control study.

OBJECTIVE: To compare the ovarian reserve and the results of infertility treatment, as well as to investigate the relapse rate in the first year after the assisted reproductive technology (ART) cycle in patients with multiple sclerosis (MS) referred to Royan Institute. MATERIALS AND METHODS: This retrospective study was carried out to evaluate all women diagnosed with MS and referred to Royan Institute for assessment and treatment of possible infertility between 2011 and 2022. The control group consisted of randomly selected healthy women with tubal factor infertility who were referred for treatment during the same time period and matched in terms of age. A comparison was made between groups in terms of ovarian reserve and infertility treatment outcomes. Additionally, patients with MS who met the criteria were monitored via telephone to evaluate the symptoms, disability and relapse rate both pre- and post-ART. RESULTS: Over the course of a decade, the database documented a total of 60 cases diagnosed with MS. Upon examination of the records, it was found that in 27 patients only admission was done without any hormonal assessment or infertility treatment cycle and 5 patients proceeded with the intrauterine insemination cycle. Eventually, 28 women with MS underwent the ART cycle and all of them were treated with interferon beta, glatiramer acetate, or some oral disease modifying therapies. No statistically significant difference in terms of the basal levels of luteinizing hormone, follicle-stimulating hormone and anti-Müllerian hormone was found between the MS and control groups (P > 0.05). Two groups were comparable in terms of menstrual status. The study revealed that both groups exhibited similarities in terms of the controlled ovarian stimulation protocol and duration, the dosage of gonadotropin administered, as well as the ovarian response type, clinical pregnancy rate, and live birth rate (P > 0.05). After follow up, only 2 patients (9.5%) reported relapse of symptoms within one year after ART. CONCLUSION: The ovarian reserve and ovarian stimulation cycle and pregnancy outcomes following the ART cycle in MS patients were similar to the age-matched control group. The relapse rate of multiple sclerosis did not show a significant increase within a year following the ART cycle.

The relationship between cognitive function and functional capacity, and cognitive reserve and reaction time in patients with multiple sclerosis.

BACKGROUND: Cognitive dysfunction is frequently seen in multiple sclerosis (MS). However, there are conflicting findings regarding the factors it is associated with. OBJECTIVE: To investigate the relationship between aerobic capacity, strength, disability, depression, fatigue, and cognitive reserve and function. METHODS: The mobile applications Trail Making Test (TMT A-B), Digit Span Test (DST), Visuospatial Memory Test (VSMT), and Tap Fast were used in the cognitive function evaluation. Functional performance was assessed with the 6-minute walk test (6MWT), 5-Time Sit-to-Sand (5STS) test, and grip strength. Cognitive Reserve Index (CRI), Beck Depression Inventory, Fatigue Severity Scale (FSS), and Nottingham Health Profile were also used. RESULTS: A significant difference was found between the MS and control groups only in the 6MWT, STS-5, grip strength, TMT, VSMT, and Tap Fast. Good correlation was found between the TMT-A and 6MWT and physical mobility. A fair correlation was shown between grip strength, energy, and pain status. A good correlation was found between TMT-B and 6MWT, and a fair relationship with disability, cognitive reserve, and pain. Good correlation was observed between the DST and 6MWT, left grip strength, pain, and energy status; fair correlations were found between right grip strength, cognitive reserve, and physical mobility. Good correlation was found between the VSMT and energy. A fair relationship between disability, cognitive reserve, and pain was demonstrated. Good correlation was observed between the Tap Fast score and disability, 5STS, FSS, energy, and physical mobility. A fair relationship was found between pain and social isolation. CONCLUSION: It has been shown that cognitive performance in MS is related to disability, functional performance, cognitive reserve, fatigue, and general health. TRIAL REGISTRATION: NCT06084182.

ANTECEDENTES: A disfunção cognitiva é frequentemente observada na esclerose múltipla (EM). No entanto, existem resultados conflitantes sobre os fatores aos quais está associada. OBJETIVO: Investigar a relação entre capacidade aeróbica, força, incapacidade, depressão, fadiga e reserva e função cognitiva. MéTODOS: Os aplicativos móveis Trail Making Test (TMT A-B), Digit Span Test (DST), Visuoespacial Memory Test (VSMT) e Tap Fast foram utilizados na avaliação da função cognitiva. O desempenho funcional foi avaliado por meio do teste de caminhada de 6 minutos (TC6), Teste de Sentar-Levantar Cinco Vezes (TSL5) e força de preensão manual. Também foram utilizados Índice de Reserva Cognitiva (IRC), Inventário de Depressão de Beck, Escala de Gravidade de Fadiga (EGF) e Perfil de Saúde de Nottingham. RESULTADOS: Foi encontrada diferença significativa entre os grupos EM e controle apenas no TC6, TSL5, força de preensão, TMT, VSMT e Tap Fast. Foi encontrada boa correlação entre o TMT-A e o TC6 e a mobilidade física. Foi demonstrada uma correlação razoável entre força de preensão, energia e estado de dor. Foi encontrada uma boa correlação entre o TMT-B e o TC6, e uma relação razoável com incapacidade, reserva cognitiva e dor. Foi observada boa correlação entre o DST e o TC6, força de preensão esquerda, dor e estado energético; correlações justas foram encontradas entre força de preensão direita, reserva cognitiva e mobilidade física. Foi encontrada boa correlação entre o VSMT e a energia. Foi demonstrada uma relação justa entre incapacidade, reserva cognitiva e dor. Foi observada boa correlação entre o escore Tap Fast e incapacidade, TLS5, EGF, energia e mobilidade física. Foi encontrada uma relação justa entre dor e isolamento social. CONCLUSãO: Foi demonstrado que o desempenho cognitivo na EM está relacionado com incapacidade, desempenho funcional, reserva cognitiva, fadiga e saúde geral. REGISTRO DE TESTE: NCT06084182.

[Research progress on the relationship between TRAF6 and neurodegenerative diseases].

Given the increasing trend of aging population in the world, neurodegenerative diseases (NDDs), a common type of diseases that mostly occur in the elderly, have attracted much more attention. It has been shown that tumor necrosis factor receptor-associated factor 6 (TRAF6) is involved in the regulation of neuroinflammation, an important pathological feature of NDDs, and affects the occurrence and development of NDDs. Most importantly, the regulatory effect of TRAF6 is related to its ubiquitination. Therefore, in the present paper, the molecular structure, biological function, and ubiquitination mechanism of TRAF6, and its relationship with some common NDDs, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, were analyzed and summarized. The possible molecular mechanisms by which TRAF6 regulates the occurrence of NDDs were also elucidated, providing a theoretical basis for exploring the etiology and treatment of NDDs.

Creating an automated tool for a consistent and repeatable evaluation of disability progression in clinical studies for multiple sclerosis.

BACKGROUND: The lack of standardized disability progression evaluation in multiple sclerosis (MS) hinders reproducibility of clinical study results, due to heterogeneous and poorly reported criteria. OBJECTIVE: To demonstrate the impact of using different parameters when evaluating MS progression, and to introduce an automated tool for reproducible outcome computation. METHODS: Re-analyzing BRAVO clinical trial data (NCT00605215), we examined the fluctuations in computed treatment effect on confirmed disability progression (CDP) and progression independent of relapse activity (PIRA) when varying different parameters. These analyses were conducted using the msprog package for R, which we developed as a tool for CDP assessment from longitudinal data, given a set of criteria that can be specified by the user. RESULTS: The BRAVO study reported a hazard ratio (HR) of 0.69 (95% confidence interval (CI): 0.46-1.02) for CDP. Using the different parameter configurations, the resulting treatment effect on CDP varied considerably, with HRs ranging from 0.59 (95% CI: 0.41-0.86) to 0.72 (95% CI: 0.48-1.07). The treatment effect on PIRA varied from an HR = 0.62 (95% CI: 0.41-0.93) to an HR = 0.65 (95% CI: 0.40-1.04). CONCLUSIONS: The adoption of an open-access tool validated by the research community, with clear parameter specification and standardized output, could greatly reduce heterogeneity in CDP estimation and promote repeatability of study results.

Classification of upper limb spasticity patterns in patients with multiple sclerosis: a pilot observational study.

OBJECTIVE: The aim of this study was to provide a classification of the upper limb patterns in patients with upper limb spasticity due to multiple sclerosis. DESIGN: Pilot observational study. PATIENTS: Twenty-five adult patients with multiple sclerosis suffering from upper limb spasticity who underwent one segmental (i.e., proximal and distal upper limb) botulinum toxin treatment cycle were recruited. METHODS: Patients remained in a sitting position during the evaluation. Upper limb spasticity postures (i.e., postural attitude of a single joint/anatomical region) were evaluated and recorded for the shoulder (adducted/internally rotated), elbow (flexed/extended), forearm (pronated/supinated/neutral), wrist (flexed/extended/neutral) and hand (fingers flexed/thumb in palm). RESULTS: On the basis of the clinical observations, 6 patterns (i.e., sets of limb postures) of upper limb spasticity have been described according to the postures of the shoulder, elbow, forearm, and wrist. CONCLUSION: The patterns of upper limb spasticity in patients with multiple sclerosis described by this pilot study do not completely overlap with those observed in patients with post-stroke spasticity. This further supports the need to consider the features of spasticity related to its aetiology in order to manage patients appropriately.

Osteopontin predicts late-time salience network-related functional connectivity in multiple sclerosis.

Resting-state functional magnetic resonance imaging (rs-fMRI) has been widely utilized to investigate plasticity mechanisms and functional reorganization in multiple sclerosis (MS). Among many resting state (RS) networks, a significant role is played by the salience network (SN, ventral attention network). Previous reports have demonstrated the involvement of osteopontin (OPN) in the pathogenesis of MS, which acts as a proinflammatory cytokine ultimately leading to neurodegeneration. Concentration of serum OPN was related to MRI findings 10.22±2.84 years later in 44 patients with MS. Local and interhemispheric correlations (LCOR, IHC), ROI-to-ROI and seed-based connectivity analyses were performed using serum OPN levels as independent variable along with age and gender as nuisance variables. We found significant associations between OPN levels and local correlation in right and left clusters encompassing the central opercular- and insular cortices (p-FDR = 0.0018 and p-FDR = 0.0205, respectively). Moreover, a significant association was identified between OPN concentration and interhemispheric correlation between central opercular- and insular cortices (p-FDR = 0.00015). Significant positive associations were found between OPN concentration and functional connectivity (FC) within the SN (FC strength between the anterior insula ventral division and 3 other insular regions, F(2,13) = 7.84, p-FDR = 0.0117). Seed-based connectivity analysis using the seven nodes of the SN resulted in several positive and inverse associations with OPN level. Serum OPN level may predict FC alterations within the SN in 10 years.

Assessing the visual afferent pathway with the multifocal visual evoked potentials in the radiologically isolated syndrome.

The early identification of individuals with radiologically isolated syndrome (RIS) who are at an elevated risk of progressing to multiple sclerosis (MS) is essential for making informed treatment decisions. This study aimed to evaluate the predictive potential of multifocal Visual Evoked Potentials (mfVEP) measures in individuals with RIS with respect to their conversion to MS. A prospective observational cohort study was conducted, involving 21 individuals with RIS recruited from a MS center. Baseline assessments, including mfVEP, magnetic resonance imaging (MRI), and clinical examinations, were performed, and participants were longitudinally followed for up to 24 months. The primary outcome measures were the conversion to MS. Over a clinical follow-up period of 24 months, five individuals (5/21) with RIS progressed to MS. MfVEP amplitude responses (interocular and monocular probability analysis) demonstrated abnormal cluster visual field defects in 47.6% of RIS eyes at baseline, whereas multifocal VEP latency analysis showed significant delays in 38.4%. A reduction in interocular amplitude [OR = 0.036, (95% CI 0.003-0.503); P = 0.014], monocular amplitude [OR = 0.083, (95% CI 0.007-0.982); P = 0.048], and a prolonged interocular latency [OR = 0.095, (95% CI 0.009-0.972); P = 0.047] were associated with a higher relative risk of clinical conversion at the 2-year follow-up. Multifocal VEP may serve as a novel and independent risk factor for predicting the conversion to MS in individuals with Radiologically Isolated Syndrome.

Influence of virtual reality and task complexity on digital health metrics assessing upper limb function.

BACKGROUND: Technology-based assessments using 2D virtual reality (VR) environments and goal-directed instrumented tasks can deliver digital health metrics describing upper limb sensorimotor function that are expected to provide sensitive endpoints for clinical studies. Open questions remain about the influence of the VR environment and task complexity on such metrics and their clinimetric properties. METHODS: We aim to investigate the influence of VR and task complexity on the clinimetric properties of digital health metrics describing upper limb function. We relied on the Virtual Peg Insertion Test (VPIT), a haptic VR-based assessment with a virtual manipulation task. To evaluate the influence of VR and task complexity, we designed two novel tasks derived from the VPIT, the VPIT-2H (VR environment with reduced task complexity) and the PPIT (physical task with reduced task complexity). These were administered in an observational longitudinal study with 27 able-bodied participants and 31 participants with multiple sclerosis (pwMS, VPIT and PPIT only) and the value of kinematic and kinetic metrics, their clinimetric properties, and the usability of the assessment tasks were compared. RESULTS: Intra-participant variability strongly increased with increasing task complexity (coefficient of variation + 56%) and was higher in the VR compared to the physical environment (+ 27%). Surprisingly, this did not translate into significant differences in the metrics' measurement error and test-retest reliability across task conditions (p > 0.05). Responsiveness to longitudinal changes in pwMS was even significantly higher (effect size + 0.35, p < 0.05) for the VR task with high task complexity compared to the physical instrumented task with low task complexity. Increased inter-participant variability might have compensated for the increased intra-participant variability to maintain good clinimetric properties. No significant influence of task condition on concurrent validity was present in pwMS. Lastly, pwMS rated the PPIT with higher usability than the VPIT (System Usability Scale + 7.5, p < 0.05). CONCLUSION: The metrics of both the VR haptic- and physical task-based instrumented assessments showed adequate clinimetric properties. The VR haptic-based assessment may be superior when longitudinally assessing pwMS due to its increased responsiveness. The physical instrumented task may be advantageous for regular clinical use due to its higher usability. These findings highlight that both assessments should be further validated for their ideal use-cases.

[Questionnaires for arm function assessment in patients with multiple sclerosis]. / Oprosniki dlya otsenki funktsii ruki u patsientov s rasseyannym sklerozom.

Arm dysfunction is one of the disabling manifestations of multiple sclerosis (MS), especially in later stages of the disease. Assessment of the functioning of the upper limbs is necessary to objectify the course of MS, determine the effectiveness of therapy, and individualize rehabilitation measures. The tools that assess the upper extremity dysfunction include tests and questionnaires. Questionnaires (patient-reported outcome measures) represent the special importance, since the opinions and preferences of patients themselves help to implement a patient-centered approach to treatment. The article presents a brief description of three multidimensional MS-specific and four unidimensional MS-nonspecific questionnaires that used in assessment of upper limb function in MS patients. The disease-specific unidimensional Arm Function in Multiple Sclerosis Questionnaire (AMSQ), specifically designed to assess the arm use in patients with MS, is discussed in more detail. The use of AMSQ in the Russian population is possible only after the procedure of cultural adaptation and validation of the Russian version.

The Role of Glial Fibrillary Acidic Protein as a Biomarker in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder: A Systematic Review and Meta-Analysis.

There is debate on the role of glial fibrillary acidic protein (GFAP) as a reliable biomarker in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), and its potential to reflect disease progression. This review aimed to investigate the role of GFAP in MS and NMOSD. A systematic search of electronic databases, including PubMed, Embase, Scopus, and Web of Sciences, was conducted up to 20 December 2023 to identify studies that measured GFAP levels in people with MS (PwMS) and people with NMOSD (PwNMOSD). R software version 4.3.3. with the random-effect model was used to pool the effect size with its 95% confidence interval (CI). Of 4109 studies, 49 studies met our inclusion criteria encompassing 3491 PwMS, 849 PwNMOSD, and 1046 healthy controls (HCs). The analyses indicated that the cerebrospinal fluid level of GFAP (cGFAP) and serum level of GFAP (sGFAP) were significantly higher in PwMS than HCs (SMD = 0.7, 95% CI: 0.54 to 0.86, p < 0.001, I2 = 29%, and SMD = 0.54, 95% CI: 0.1 to 0.99, p = 0.02, I2 = 90%, respectively). The sGFAP was significantly higher in PwNMOSD than in HCs (SMD = 0.9, 95% CI: 0.73 to 1.07, p < 0.001, I2 = 10%). Among PwMS, the Expanded Disability Status Scale (EDSS) exhibited significant correlations with cGFAP (r = 0.43, 95% CI: 0.26 to 0.59, p < 0.001, I2 = 91%) and sGFAP (r = 0.36, 95% CI: 0.23 to 0.49, p < 0.001, I2 = 78%). Regarding that GFAP is increased in MS and NMOSD and has correlations with disease features, it can be a potential biomarker in MS and NMOSD and indicate the disease progression and disability in these disorders.

Post-Partum Clinical and Patient-Reported Outcome Changes in Mothers with Multiple Sclerosis: Findings from the NAPPREMS Study.

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.

Portable multi-focal visual evoked potential diagnostics for multiple sclerosis/optic neuritis patients.

PURPOSE: Multiple sclerosis (MS) is a neuro-inflammatory disease affecting the central nervous system (CNS), where the immune system targets and damages the protective myelin sheath surrounding nerve fibers, inhibiting axonal signal transmission. Demyelinating optic neuritis (ON), a common MS symptom, involves optic nerve damage. We've developed NeuroVEP, a portable, wireless diagnostic system that delivers visual stimuli through a smartphone in a headset and measures evoked potentials at the visual cortex from the scalp using custom electroencephalography electrodes. METHODS: Subject vision is evaluated using a short 2.5-min full-field visual evoked potentials (ffVEP) test, followed by a 12.5-min multifocal VEP (mfVEP) test. The ffVEP evaluates the integrity of the visual pathway by analyzing the P100 component from each eye, while the mfVEP evaluates 36 individual regions of the visual field for abnormalities. Extensive signal processing, feature extraction methods, and machine learning algorithms were explored for analyzing the mfVEPs. Key metrics from patients' ffVEP results were statistically evaluated against data collected from a group of subjects with normal vision. Custom visual stimuli with simulated defects were used to validate the mfVEP results which yielded 91% accuracy of classification. RESULTS: 20 subjects, 10 controls and 10 with MS and/or ON were tested with the NeuroVEP device and a standard-of-care (SOC) VEP testing device which delivers only ffVEP stimuli. In 91% of the cases, the ffVEP results agreed between NeuroVEP and SOC device. Where available, the NeuroVEP mfVEP results were in good agreement with Humphrey Automated Perimetry visual field analysis. The lesion locations deduced from the mfVEP data were consistent with Magnetic Resonance Imaging and Optical Coherence Tomography findings. CONCLUSION: This pilot study indicates that NeuroVEP has the potential to be a reliable, portable, and objective diagnostic device for electrophysiology and visual field analysis for neuro-visual disorders.

Association of retinal microvascular curve tortuosity and multiple sclerosis: A cross-section analysis from the UK Biobank.

BACKGROUND: There is growing evidence supporting that vascular abnormalities contribute to multiple sclerosis (MS), and retinal microvasculature functions as a visible window to observe vessels. We hypothesized that retinal vascular curve tortuosity is associated with MS, which this study aims to address. METHODS: Participants from the UK Biobank with complete clinical records and gradable fundus photos were included in the study. Arteriolar and venular curve tortuosity and vessel area density are quantified automatically using a deep learning system. Individuals with MS were matched to healthy controls using propensity score matching (PSM). Conditional logistic regression was used to investigate the association between retinal vascular characteristics and MS. We also used a receiver operating characteristic (ROC) curve to assess the diagnostic performance of MS. RESULTS: Venular curve tortuosity (VCT) was found to be significantly associated with MS. And patients with multiple sclerosis were probable to have lower VCT than the non-MS group (OR = 0.22 [95 % CI, 0.05 to 0.92], P < 0.05). CONCLUSIONS: Our study reveals a significant association between vessel curve tortuosity and MS. The lower curve tortuosity of the retinal venular network may indicate a higher risk of incident multiple sclerosis.

Investigating the relationship between multiple sclerosis disability and driving performance: A comparative study of the multiple sclerosis functional composite and expanded disability status scale.

INTRODUCTION: Multiple Sclerosis (MS) can affect the ability to perform complex tasks such as driving. The Expanded Disability Status Scale (EDSS) overlooks cognitive deficits crucial for driving. We investigated the relationship between the Multiple Sclerosis Functional Composite (MSFC), which includes cognitive assessment, and EDSS in relation to driving performance. METHODS:  This exploratory study involved 30 MS patients (mean EDSS 2.4 ± 2.0) and 15 healthy controls. We correlated the results of the EDSS, MSFC, and driving performance tests, namely the Two-Hand Coordination Test (2HAND) and the Speed Anticipation Reaction Test (SART). RESULTS: Patients did not differ from the healthy controls regarding age, sex, and driving experience. However, they exhibited lower mean Z-scores in MSFC, particularly in motor domains, but not in cognitive function. The mean Z-score for the 25-foot Walk test was -0.42 in patients compared to -0.04 in controls. For the 9-hole Peg Test, it was 0.17 in patients versus 1.47 in controls. Patients had a mean total error time of 19.7 seconds for both hands in the 2HAND test, compared to 7.7 seconds in controls. In MS patients, the MSFC and EDSS significantly correlated with SART and 2HAND components. While upper limb function (9-HPT) did not correlate with 2HAND, cognitive function (PASAT) did correlate with the number of 2HAND errors, indicating that cognitive dysfunction impacts driving performance more than physical dysfunction. CONCLUSION: The MSFC may provide valuable insights into the driving abilities of MS patients, potentially offering advantages over the EDSS in predicting driving performance. Further research with larger, more diverse populations across various driving environments is necessary to validate these findings.

Insight into motor fatigue mechanisms in natalizumab treated multiple sclerosis patients with wearing off.

Motor fatigue in Multiple Sclerosis (MS) is due to reduced motor cortex (M1) output and altered sensorimotor network (SMN) modulation. Natalizumab, a disease-modifying therapy, reduces neuroinflammation and improves fatigue. However, some patients treated with natalizumab experience fatigue recurrence ('wearing-off') before subsequent infusions. Wearing-off provides a valuable window into MS-related motor fatigue mechanisms in a controlled, clinically stable, setting. This study investigates whether wearing-off is associated with worsening motor fatigue and its neurophysiological mechanisms and assesses natalizumab's effect on MS-related fatigue. Forty-five relapsing-remitting MS patients with wearing-off symptoms were evaluated pre- and post-natalizumab infusion. Assessments included evaluating disability levels, depressive symptoms, and the impact of fatigue symptoms on cognitive, physical, and psychosocial functioning. The motor fatigue index was computed through the number of blocks completed during a fatiguing task and peripheral, central, and supraspinal fatigue (M1 output) were evaluated by measuring the superimposed twitches evoked by peripheral nerve and transcranial magnetic stimulation of M1. Transcranial magnetic stimulation-electroencephalography assessed M1 effective connectivity by measuring TMS-evoked potentials (TEPs) within the SMN before- and after the task. We found that wearing-off was associated with increased motor fatigue index, increased central and supraspinal fatigue, and diminished task-related modulation of TEPs compared to post-natalizumab infusion. Wearing-off was also associated with worsened fatigue impact and depression symptom scores. We conclude that the wearing-off phenomenon is associated with worsening motor fatigue due to altered M1 output and modulation of the SMN. Motor fatigue in MS may reflect reversible, inflammation-related changes in the SMN that natalizumab can modulate. Our findings apply primarily to MS patients receiving natalizumab, emphasizing the need for further research on other treatments with wearing-off.

Frontal-striatal glucose metabolism and fatigue in patients with multiple sclerosis, long COVID, and COVID-19 recovered controls.

This study compared brain glucose metabolism using FDG-PET in the caudate nucleus, putamen, globus pallidus, thalamus, and dorsolateral prefrontal cortex (DLPFC) among patients with Long COVID, patients with fatigue, people with multiple sclerosis (PwMS) patients with fatigue, and COVID recovered controls. PwMS exhibited greater hypometabolism compared to long COVID patients with fatigue and the COVID recovered control group in all studied brain areas except the globus pallidus (effect size range 0.7-1.5). The results showed no significant differences in glucose metabolism between patients with Long COVID and the COVID recovered control group in these regions. These findings suggest that long COVID fatigue may involve non-CNS systems, neurotransmitter imbalances, or psychological factors not captured by FDG-PET, while MS-related fatigue is associated with more severe frontal-striatal circuit dysfunction due to demyelination and neurodegeneration. Symmetrical standardized uptake values (SUVs) between hemispheres in all groups imply that fatigue in these conditions may be related to global or network-level alterations rather than hemisphere-specific changes. Future studies should employ fine-grained analysis methods, explore other brain regions, and control for confounding factors to better understand the pathophysiology of fatigue in MS and long COVID. Longitudinal studies tracking brain glucose metabolism in patients with Long COVID could provide insights into the evolution of metabolic patterns as the condition progresses.

Cognitive-motor dual task to reveal gait impairments in multiple sclerosis patients at an early stage: A systematic review.

BACKGROUND: Multiple sclerosis can cause locomotor and cognitive impairments even at lower levels of disability, which can impact daily life. The cognitive-motor dual task is commonly used to assess everyday locomotion. Thus, this study aimed to examine the effect of cognitive-motor dual tasks on gait parameters among patients with multiple sclerosis in the early disease stages and to determine whether dual tasks could be used as a clinical test to detect locomotion impairments. METHODS: A systematic search of five databases was conducted in May 2024. The population of interest was patients with multiple sclerosis with an Expanded Disability Status Scale score of 4 or less. The following outcome measures were examined: spatiotemporal and kinematic parameters. The Newcastle-Ottawa Scale was used to assess the quality of the studies. FINDINGS: Eleven studies including 270 patients with multiple sclerosis and 221 healthy controls. Three spatiotemporal parameters were modified both in patients with multiple sclerosis and healthy controls during dual-task performance: gait speed, stride length and the double support phase. No spatiotemporal parameter was affected during dual-task performance in patients with multiple sclerosis alone. INTERPRETATION: Dual-task performance could be useful for assessing gait impairments in patients with multiple sclerosis provided that assessments and protocols are standardized. Nevertheless, the spatiotemporal parameters did not allow discrimination between patients with multiple sclerosis at an early stage and healthy controls. Three-dimensional gait analysis during dual-task performance could be a useful approach for detecting early gait impairments in patients with multiple sclerosis, assessing their progression and adjusting rehabilitation programs.

Japanese translation and validation of the 12-item Multiple Sclerosis Walking Scale version 2.

BACKGROUND: Disability in ambulation has a critical impact on activities of daily living in patients with multiple sclerosis (MS). The 12-item Multiple Sclerosis Walking Scale (MSWS-12) is a self-reported instrument developed to assess the impact of MS on walking. The scale's 12 items assess various aspects of walking-related tasks during the past 2 weeks. MSWS-12 has been used in multiple clinical studies and translated into several languages. In the present study, we translated the MSWS-12 into Japanese and evaluated its psychometric properties in a cross-sectional study. METHODS: The original English MSWS-12 version 2 (v2) was translated into Japanese through a standard procedure. Sixty consecutive Japanese MS patients completed the newly prepared Japanese MSWS-12v2 questionnaire and repeated the test 14 days later. Physical disability was assessed by the Expanded Disability Status Scale (EDSS), Timed 25-foot Walk (T25FW), and 9-hole Peg Test (9HPT). Cognitive performance was evaluated using the Processing Speed Test (PST). Fatigue and health-related quality of life were assessed using the Japanese versions of the Fatigue Severity Scale (FSS) and the Functional Assessment of MS (FAMS). RESULTS: The mean age of the patients was 42.5 years, with median disease duration of 10 years, and median EDSS of 2.0 (range 0, 6.5). Forty-seven patients (78.3 %) had relapsing-remitting, 9 (15.0 %) had secondary-progressive, and 4 (6.7 %) had primary-progressive phenotypes. The median score of the MSWS-12v2 was 5.95 (interquartile range 0, 50.6). Twenty-seven patients (45 %) scored the lowest possible score (0 points), while one (1.7 %) scored the highest possible score (100 points). Cronbach's alpha was 0.98 (95 % confidence interval [CI] 0.97, 0.98), and the test-retest intraclass correlation was 0.95 (95%CI 0.94, 0.96). MSWS-12v2 score was strongly correlated with EDSS (Spearman's ρ = 0.73 [95%CI 0.58, 0.83]), T25FW (ρ = 0.70 [95%CI 0.55, 0.81]), and total FAMS score (ρ = -0.80 [95%CI -0.88, -0.69]), and moderately correlated with 9HPT (ρ = 0.65 [95%CI 0.47, 0.77] for the dominant hand; ρ = 0.62 [95%CI 0.43, 0.75] for the non-dominant hand), PST (ρ = -0.65 [95%CI -0.78, -0.47]), and FSS (ρ = 0.68 [95%CI 0.52, 0.80]). Among the subcomponents of FAMS, the mobility subcomponent showed the most robust correlation with MSWS-12v2 score (ρ = -0.91 [95%CI -0.94, -0.81]). In patients with minimal or no objective disability (EDSS < 3.0, n = 40), only the mobility subcomponent of FAMS was strongly correlated with MSWS-12v2 score (ρ = -0.76 [95% CI -0.87, -0.58]). In contrast, correlations of MSWS-12v2 score with EDSS and T25FW were weak in this subgroup (ρ = 0.28 [95%CI -0.03, 0.55] for EDSS; ρ = 0.25 [95%CI -0.06, 0.52] for T25FW). Response patterns for the single items showed that 32.5 % of the patients with EDSS below 3.0 reported having problems with balance, followed by climbing stairs and standing while doing things (both 25 %). CONCLUSION: The Japanese version of the MSWS-12v2 developed in this study is reliable, valid, and helpful for screening walking disability in Japanese MS patients, including those with minimal objective disability.