Effect of siponimod on lymphocyte subsets in active secondary progressive multiple sclerosis and clinical implications.

BACKGROUND: Circulating immune cells play a pathogenic role in multiple sclerosis (MS). However, the role of specific lymphocyte subpopulations is not unveiled yet, especially in progressive stages. We aimed to investigate lymphocyte changes during siponimod treatment in active secondary progressive MS (aSPMS) and their associations with clinical outcomes. METHODS: We enrolled 46 aSPMS patients starting on siponimod treatment with at least 6 months of follow-up and two visits within the scheduled timeframes and 14 sex- and age-matched healthy controls (HCs). Clinical and laboratory data were collected retrospectively at baseline, 3rd, 6th, 12th, and 24th month for MS patients, and at baseline for HCs. RESULTS: At baseline SPMS patients presented with increased naïve regulatory T lymphocytes (p = 0.02) vs. HCs. Over time, SPMS patients showed decreased T CD4+ (coeff. range = -24/-17, 95% CI range = -31.60 to -10.40), B lymphocyte (coeff. range = -3.77/-2.54, 95% CI range = -6.02 to -0.35), memory regulatory B cells (coeff. range = -0.78/-0.57, 95% CI range = -1.24 to -0.17) and CD4/CD8 ratio (coeff. range = -4.44/-0.67, 95% CI range = -1.61 to -0.17) from month 3 thereafter vs. baseline, and reduced CD3+CD20+ lymphocytes from month 12 thereafter (coeff. range = -0.32/-0.24, 95% CI range = -0.59 to -0.03). Patients not experiencing disability progression while on siponimod treatment showed B lymphocyte reduction from month 3 (coeff. range = -4.23/-2.32, 95% CI range = -7.53 to -0.15) and CD3+CD20+ lymphocyte reduction from month 12 (coeff. range = -0.32/-0.24, 95% CI range = -0.59 to -0.03) vs. patients experiencing progression. CONCLUSIONS: Patients treated with siponimod showed a T and B lymphocyte reduction, especially CD4+, CD3+CD20+ and naïve regulatory T cells and memory regulatory B cells. Disability progression while on siponimod treatment was associated with a less pronounced effect on B and CD3+CD20+ lymphocytes.

Integration of the expanded disability status scale with ambulation, visual and cognitive tests.

INTRODUCTION: The Expanded Disability Status Scale (EDSS) is usually calculated through a neurological examination with self-reported performance. This may lead to incorrect assessment of Functional System scores (FSs). Aim of our study was to estimate the difference between EDSS obtained during routine visits, or after specific tests. METHODS: We enrolled 670 MS patients that underwent a regular neurology consultation, and visual evaluation using optotype tables, ambulation evaluation with a rodometer, and cognitive assessment with the Brief International Cognitive assessment for MS (BICAMS). We calculated a new integrated EDSS (iEDSS) using the refined values of the FS and compared it to the standard EDSS. RESULTS: Visual, cerebral and ambulation FSs were significantly higher compared with the self-reported counterpart [+ 1.169 (95%CI 1.077, 1.262; p < 0.001), + 0.727 (95%CI 0.653, 0.801; p < 0.001) and + 0.822 (95%CI 0.705, 0.939; p < 0.001), respectively]. Mean iEDSS was higher than EDSS (+ 0.642; p < 0.001). Visual acuity tests worsened the EDSS in 31% of cases, cognitive tests in 10%, ambulation measurement in 35%, all three measurements in 59% of cases. CONCLUSIONS: Objective measurement of FSs results in a more accurate EDSS score in almost two-thirds of cases. This could lead to a more thorough evaluation of patients in the transition or progressive phase.

Utilization of Ocrelizumab within Different Treatment Strategies for Multiple Sclerosis: A 5-Year Population-Based Study.

BACKGROUND: We aim to provide up-to-date real-world evidence on the persistence, adherence, healthcare resource utilization, and costs of multiple sclerosis (MS) by comparing ocrelizumab to other disease-modifying treatments (DMTs) and within different DMT sequences. METHODS: We included 3371 people with MS who first received or switched DMT prescriptions from January 2018 to December 2022; they were identified through hospital discharge records, drug prescriptions, and exemption codes from the Campania Region (South Italy). We calculated persistence (time from the first prescription to discontinuation or switching to another DMT), adherence (proportion of days covered (PDC)), DMT costs, and MS hospital admissions and related costs. RESULTS: The most frequently prescribed DMT was dimethyl fumarate (n = 815; age 38.90 ± 11.91 years; 69.5% females), followed by ocrelizumab (n = 682; age 46.46 ± 11.29 years; 56.3%); 28.8% of the patients treated with ocrelizumab were naïve to DMTs. Using ocrelizumab as a statistical reference, the risk of discontinuation was higher for other highly active (HR = 6.32; 95%CI = 3.16, 12.63; p < 0.01) and low-/medium-efficacy DMTs (HR = 10.10; 95%CI = 5.10, 19.77; p < 0.01); adherence was lower for other highly active DMTs (Coeff = -0.07; 95%CI = -0.10, -0.04; p < 0.01) and low-/medium-efficacy DMTs (Coeff = -0.16; 95%CI = -0.19, -0.14; p < 0.01). monthly DMT costs were higher for other highly active DMTs (Coeff = 77.45; 95%CI = 29.36, 125.53; p < 0.01) but lower for low-/medium-efficacy DMTs (Coeff = -772.31; 95%CI = -816.95, -727.66; p < 0.01). The hospital admissions and related costs of MS were similar between ocrelizumab, other highly active DMTs, and other low-/medium-efficacy DMTs, and with ocrelizumab as the first-line DMT after other highly active DMTs and after low-/medium-efficacy DMTs, which was possibly due to the low number of observations. CONCLUSIONS: From 2018 to 2022, ocrelizumab was among the most frequently prescribed DMTs, with 28.8% prescriptions to incident MS patients, confirming its relevance in clinical practice. Ocrelizumab was associated with the highest persistence and adherence, pointing towards its favorable benefit-risk profile. The costs of ocrelizumab were lower than those of other highly active DMTs.

Assessing brain involvement in Fabry disease with deep learning and the brain-age paradigm.

While neurological manifestations are core features of Fabry disease (FD), quantitative neuroimaging biomarkers allowing to measure brain involvement are lacking. We used deep learning and the brain-age paradigm to assess whether FD patients' brains appear older than normal and to validate brain-predicted age difference (brain-PAD) as a possible disease severity biomarker. MRI scans of FD patients and healthy controls (HCs) from a single Institution were, retrospectively, studied. The Fabry stabilization index (FASTEX) was recorded as a measure of disease severity. Using minimally preprocessed 3D T1-weighted brain scans of healthy subjects from eight publicly available sources (N = 2160; mean age = 33 years [range 4-86]), we trained a model predicting chronological age based on a DenseNet architecture and used it to generate brain-age predictions in the internal cohort. Within a linear modeling framework, brain-PAD was tested for age/sex-adjusted associations with diagnostic group (FD vs. HC), FASTEX score, and both global and voxel-level neuroimaging measures. We studied 52 FD patients (40.6 ± 12.6 years; 28F) and 58 HC (38.4 ± 13.4 years; 28F). The brain-age model achieved accurate out-of-sample performance (mean absolute error = 4.01 years, R2 = .90). FD patients had significantly higher brain-PAD than HC (estimated marginal means: 3.1 vs. -0.1, p = .01). Brain-PAD was associated with FASTEX score (B = 0.10, p = .02), brain parenchymal fraction (B = -153.50, p = .001), white matter hyperintensities load (B = 0.85, p = .01), and tissue volume reduction throughout the brain. We demonstrated that FD patients' brains appear older than normal. Brain-PAD correlates with FD-related multi-organ damage and is influenced by both global brain volume and white matter hyperintensities, offering a comprehensive biomarker of (neurological) disease severity.

Treatment modifiers across different regimens of natalizumab treatment in MS: An Italian real-world experience.

Despite its widespread use in clinical practice, the effectiveness of natalizumab extended interval dosing (EID) adopted from treatment start across different treatment intervals and individual modifiers (body mass index - BMI) is still under-investigated. Here, seven-hundred and forty-five multiple sclerosis (MS) patients, exposed to natalizumab for 3.30 â€‹± â€‹1.34 years, were retrospectively enrolled in an observational multicenter study. After stratifying patients in EID or standard interval dosing (SID), we assessed differences in time to relapse, MRI activity and Expanded Disability Status Scale (EDSS) progression. The primary analysis was conducted on patients exposed to EID interval from 5 weeks and 1 day to 7 weeks, while a secondary analysis included also EID periods up to 8 weeks. An additional analysis explored the impact of BMI. No differences in time to first relapse, time to radiological activity, time to EDSS progression or time to EDA (evidence of disease activity) were detected between SID and EID group (EID interval from 5 weeks to 1 day to 7 weeks). When including EID periods from 7 weeks and 1 day to 8 weeks, the EID group showed a trend towards higher risk of experience clinical relapses than the SID group. A higher EDA risk was also identified in EID patients with BMI above median. In conclusion, a higher risk of relapses seems to occur for EID above 7 weeks. Independently from the EID scheme adopted, higher BMI increases the risk of EDA in these patients.

The impact of image contrast, resolution and reader expertise on black hole identification in Multiple Sclerosis.

OBJECTIVES: In the neuroradiological work-up of Multiple Sclerosis (MS), the detection of "black holes" (BH) represent an information of undeniable importance. Nevertheless, different sequences can be used in clinical practice to evaluate BH in MS. Aim of this study was to investigate the possible impact of different sequences, resolutions, and levels of expertise on the intra- and inter-rater reliability identification of BH in MS. METHODS: Brain MRI scans of 85 MS patients (M/F = 22/63; mean age = 36.0 ± 10.2 years) were evaluated in this prospective single-center study. The acquisition protocol included a 3 mm SE-T1w sequence, a 1 mm 3D-GrE-T1w sequence from which a resliced 3 mm sequence was also obtained. Images were evaluated independently by two readers of different expertise at baseline and after a wash-out period of 30 days. The intraclass correlation coefficient (ICC) was calculated as an index of intra and inter-reader reliability. RESULTS: For both readers, the intra-reader ICC analysis showed that the 3 mm SE-T1w and 3 mm resliced GrE-T1w images achieved an excellent performance (both with an ICC ≥ 0.95), while 1 mm 3D-GrE-T1w scans achieved a moderate one (ICC < 0.90). The inter-reader analysis showed that each of the three sequences achieved a moderate performance (all ICCs < 0.90). CONCLUSIONS: The 1 mm 3D-GrE-T1w sequence seems to be prone to a greater intra-reader variability compared to the 3 mm SE-T1w, with this effect being driven by the higher spatial resolution of the first sequence. To ensure reliability levels comparable with the standard SE-T1w in BH count, an assessment on a 3 mm resliced GrE-T1w sequence should be recommended.

Switching to ozanimod as a strategy to adjust fingolimod-related lymphopenia.

INTRODUCTION: Fingolimod is a disease-modifying therapy for multiple sclerosis (MS) that modulates sphingosine 1-phospate receptors, impeding the egress of lymphocytes from lymphnodes and thus causing lymphopenia. Severe lymphopenia should lead to fingolimod discontinuation. We aim to evaluate whether switching from fingolimod to ozanimod can adjust fingolimod-related lymphopenia while maintaining clinical efficacy. METHODS: In this real-world observational study, we included 18 people with MS (47.7 ± 7.6 years of age, 77.8 % of women, 13.9 ± 6.9 years of disease duration, median EDSS 3.0) at the time of fingolimod discontinuation due to lymphopenia. We collected laboratory (lymphocyte absolute count on the same hematological counter) and clinical variables at fingolimod discontinuation, at ozanimod prescription, and 6 months after ozanimod prescription. RESULTS: From 13 cases of grade 3 and 4 lymphopenia at the time of fingolimod discontinuation, we observed only 2 cases of grade 3 and no cases of grade 4 lymphopenia after 6 months of ozanimod treatment. On paired t-tests, absolute lymphocyte count at fingolimod discontinuation were lower than ozanimod prescription (p<0.001), and after 6 months (p<0.001). We observed no clinical changes. DISCUSSION: People with MS who have severe fingolimod-related lymphopenia and are clinically stable, can exhibit increased absolute lymphocyte counts when switched to ozanimod, while preserving clinical stability.

Low serum 25­hydroxy-vitamin D levels are associated with cognitive impairment in multiple sclerosis.

BACKGROUND: Cognitive impairment frequently affects people with multiple sclerosis (MS). Low vitamin D has been associated with cognitive dysfunction in different neurodegenerative diseases, and, in MS, with motor disability and disease activity. We aim to investigate associations between vitamin D and cognitive status in MS. METHODS: In this cross-sectional study, we included 181 MS patients, recruited consecutively at the MS Unit of the Policlinico Federico II University Hospital of Naples, Italy, between January and April 2022, with serum 25­hydroxy (25-OH) vitamin D measurements using Chemiluminescence-ImmunoAssay, and cognitive assessment using the Brief International Cognitive Assessment for MS (BICAMS), which includes Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-II (CVLT-II) and Brief Visuospatial Memory Test-Revised (BVMT-R). We collected demographics (age, sex, education), and clinical variables (disease duration, disease subtype, expanded disability status scale (EDSS), disease modifying treatment, relapses in previous 12 months, vitamin D supplementation, comorbidities). For a subset of patients (n = 41, 23.2% of the total sample), we collected Beck Depression Inventory-II, Beck Anxiety Inventory, and Modified Fatigue Impact Scale. RESULTS: At univariable linear regression models, serum 25-OH-vitamin D levels were 0.9 ng/mL higher for each unit increase of SDMT adjusted scores (Coeff=0.93; 95%CI=0.81, 1.04; p<0.01), 0.7 ng/mL higher for each unit increase of CVLT-II adjusted scores (Coeff=0.68; 95%CI=0.53, 0.83; p<0. 01), 0.6 ng/mL higher for each unit increase of BVMT-R adjusted scores (Coeff=0.58; 95%CI=0.43, 0.73; p<0.01), -9.63 ng/mL lower for each impaired BICAMS test (Coeff=-9.63; 95%CI=-11.48, -7.79; p<0.01), and -2.2 ng/mL lower for each unit increase of EDSS (Coeff=-2.16; 95%CI=-3.57, -0.75; p<0.01). At multivariable linear regression models, we confirmed associations between 25-OH-vitamin D and EDSS (Coeff=-2.09; 95%CI=-4.45, -0.43; p<0.01), SDMT (Coeff=0.75; 95%CI=0.60, 0.90; p<0.01), and CVLT-II (Coeff=0.14; 95%CI=0.01, 0.28; p = 0. 04). Results remained unchanged when including depression, anxiety and fatigue scores. CONCLUSIONS: Lower serum 25-OH-vitamin D was associated with worse cognitive function in MS. Future studies should consider longitudinal variations in cognitive function in relation to vitamin D supplementation.

Google Maps Timeline: An open-access digital tool to monitor walking abilities in people with multiple sclerosis.

Introduction: Gait impairment is common in multiple sclerosis (MS), but difficult to evaluate in clinical practice. In this proof-of-concept observational study, we compared walking ability recorded by Google Maps Timeline to conventional clinical measures in people with MS. Methods: We used open-access Google Maps Timeline to record the total number of days with walking activity, walking distance, walking time, and walking speed. Each Google Maps Timeline variable was included in a different stepwise linear regression model including all conventional clinical variables. Results: We included nine people with MS (age 43.1 ± 6.6 years; females 55.6%; disease duration 12.7 ± 3.1 years; median Expanded Disability Status Scale 3.0 (range 1.0-5.5)). Higher percentage of days with recorded walking was associated with lower Fatigue Severity Scale (p = 0.01), and higher MS Walking Scale (p = 0.04). Longer average daily walking distance was associated with shorter Timed-25 Foot Walking Test (p = 0.02), lower Expanded Disability Status Scale (p = 0.01), and higher Euro-Quality of Life (p = 0.04). Longer average daily walking time was associated with shorter Timed-25 Foot Walking Test (p = 0.03). Higher walking speed was associated with lower Fatigue Severity Scale (p = 0.04). Conclusion: Google Maps Timeline parameters provide actual estimates of daily walking activities in MS.

Exploring the relation between reserve and fatigue in multiple sclerosis.

INTRODUCTION: Intellectual enrichment and brain reserve modulate the expression of cognitive and motor disability in multiple sclerosis (MS). Their association with fatigue, one of the most debilitating and common symptoms of MS, has never been explored. MATERIALS AND METHODS: Forty-eight MS patients underwent clinical and MRI examination at baseline and after 1 year. Physical and cognitive MS-related fatigue were evaluated via Modified Fatigue Impact subscales (MFIS-P and MFIS-C). Differences in reserve indexes between fatigued and non-fatigued patients were tested. The relationship between clinico-demographic features, global brain structural damage, indexes of reserve (age-adjusted intracranial volume and cognitive reserve index) and fatigue were tested via correlations and hierarchical linear/binary logistic regression, to predict MFIS-P and MFIS-C (at baseline) or new-onset fatigue and meaningful worsening in MFIS (at follow-up). RESULTS: At baseline, although a significant difference was identified for cognitive reserve questionnaire between fatigued and non-fatigued patients (18.19 ± 4.76 versus 15.15 ± 3.56, p = 0.015), only depression accounted for significant variance in MFIS-P and MFIS-C (R2=0.248, p = 0.002; R2=0.252, p<0.001). MFIS-T, MFIS-P and MFIS-C changes over time were associated to depression changes over time (r = 0.56, r = 0.55, and r = 0.57, respectively; all p<0.001). Indexes of reserve did not differ between non-fatigued patients and patients developing new-onset fatigue at follow-up. None of the baseline features was able to predict the new-onset fatigue or meaningful worsening in MFIS at follow-up. CONCLUSIONS: Among the explored features, only depression was strongly associated to both physical and cognitive fatigue. Intellectual enrichment and brain reserve did not seem to affect fatigue symptoms in MS patients.

The added value of spinal cord lesions to disability accrual in multiple sclerosis.

Spinal cord MRI is not routinely performed for multiple sclerosis (MS) monitoring. Here, we explored whether spinal cord MRI activity offers any added value over brain MRI activity for clinical outcomes prediction in MS. This is a retrospective, monocentric study including 830 MS patients who underwent longitudinal brain and spinal cord MRI [median follow-up 7 years (range: < 1-26)]. According to the presence (or absence) of MRI activity defined as at least one new T2 lesion and/or gadolinium (Gd) enhancing lesion, each scan was classified as: (i) brain MRI negative/spinal cord MRI negative; (ii) brain MRI positive/spinal cord MRI negative; (iii) brain MRI negative/spinal cord MRI positive; (iv) brain MRI positive/spinal cord MRI positive. The relationship between such patterns and clinical outcomes was explored by multivariable regression models. When compared with the presence of brain MRI activity alone: (i) Gd + lesions in the spine alone and both in the brain and in the spinal cord were associated with an increased risk of concomitant relapses (OR = 4.1, 95% CI 2.4-7.1, p < 0.001 and OR = 4.9, 95% CI 4.6-9.1, p < 0.001, respectively); (ii) new T2 lesions at both locations were associated with an increased risk of disability worsening (HR = 1.4, 95% CI = 1.0-2.1, p = 0.05). Beyond the presence of brain MRI activity, new spinal cord lesions are associated with increased risk of both relapses and disability worsening. In addition, 16.1% of patients presented asymptomatic, isolated spinal cord activity (Gd + lesions). Monitoring MS with spinal cord MRI may allow a more accurate risk stratification and treatment optimization.

Fertility, pregnancy and childbirth in women with multiple sclerosis: a population-based study from 2018 to 2020.

BACKGROUND: We aim to evaluate whether fertility, pregnancy, delivery and breastfeeding have been actually improving in women with multiple sclerosis (MS), compared with general population, and in relation to treatment features. METHODS: We included 2018-2020 population-level healthcare data on women with MS living in the Campania region (Italy). Fertility, pregnancy and delivery outcomes were obtained from Certificate of Delivery Assistance; breastfeeding was collected up to 6 months after delivery by trained personnel. RESULTS: Out of 2748 women with MS in childbearing age, 151 women delivered 156 babies. Fertility rate was 0.58 live births per woman with MS, compared with 1.29 in Campania region and 1.25 in Italy. Disease-modifying treatment (DMT) continuation during pregnancy was associated with lower birth weight (coeff -107.09; 95% CI -207.91 to -6.26; p=0.03). Exposure to DMTs with unknown/negative effects on pregnancy was associated with birth defects (OR 8.88; 95% CI 1.35 to 58.41; p=0.02). Birth defects occurred in pregnancies exposed to dimethyl fumarate (2/21 exposed pregnancies), fingolimod (1/11 exposed pregnancies) and natalizumab (2/30 exposed pregnancies). After delivery, 18.8% of women with MS were escalated of DMT efficacy, while 50.7% started on same/similar-efficacy DMTs, and 30.5% did not receive DMT. The probability of breastfeeding was higher in women who were treated with breastfeeding-safe DMTs (OR 5.57; 95% CI 1.09 to 28.55; p=0.03). CONCLUSIONS: Fertility rate in women with MS remains below the general population. Family planning and subsequent DMT decisions should aim to achieve successful pregnancy, delivery and breastfeeding outcomes, while controlling disease activity.

Sexual Dysfunction in People with Multiple Sclerosis: The Role of Disease Severity, Illness Perception, and Depression.

Despite being a common issue in people with multiple sclerosis (pwMS), sexual dysfunction is still underinvestigated. This work aims to assess the potential determinants of sexual dysfunction in pwMS by considering its relationship with disease severity (in terms of global disability), illness perception, and depressive symptoms. In this multicenter study, 1010 pwMS responded to an online survey. A serial mediation model considering negative illness perception and depressive symptoms as mediators of the relationship between disease severity and sexual dysfunction was conducted using the SPSS PROCESS Macro with bias-corrected bootstrapping (5000 samples). Disease severity exerts an indirect effect on sexual dysfunction via illness perception, both independently and through depressive symptoms. However, the results indicated that illness perception plays a more crucial role in sexual dysfunction in pwMS with mild disability than in pwMS with moderate-severe disability. This study suggests that higher disability increases its magnitude by enhancing negative illness perception, that, in turn, affects sexual dysfunction both directly and through depressive symptoms, especially in pwMS with mild disability. Modulating the effect of illness perception by favoring adaptive coping strategies might represent a valid approach to mitigate sexual dysfunction symptoms in MS.

Using The Virtual Brain to study the relationship between structural and functional connectivity in patients with multiple sclerosis: a multicenter study.

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

The independent contribution of brain, spinal cord and gadolinium MRI in treatment decision in multiple sclerosis: A population-based retrospective study.

BACKGROUND: Spinal cord and gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) can provide additional information to brain MRI to determine prognosis of multiple sclerosis (MS). However, the real-world impact of routine use of brain MRI with spinal cord and/or Gd sequences is unknown. Our aim was to evaluate the effect of brain, spinal cord and Gd MRI on treatment decisions in MS. METHODS: In this 2015-2020 population-based study, we performed a retrospective analysis on MS patients resident in the Campania Region (South Italy), with disease modifying treatment (DMT) prescription (n = 6,161). DMTs were classified as platform (dimethyl fumarate, glatiramer acetate, interferon-beta, peg-interferon-beta, teriflunomide), or high-efficacy (alemtuzumab, cladribine, fingolimod, natalizumab, ocrelizumab). We evaluated the association between binary MRI variables and switch from platform to high-efficacy DMT using multivariable logistic regression. RESULTS: The likelihood of switch from platform to high-efficacy DMT was 47% higher when including post-Gd acquisitions to brain and/or spinal cord MRI, 59% higher when including spinal cord acquisitions to brain MRI, and 132% higher when including any MRI compared with no MRI (all p < 0.05). The likelihood of switch to high-efficacy DMT decreased over time from treatment start. CONCLUSION: Our results show that spinal cord and Gd MRI acquisitions can provide relevant information to influence subsequent treatment decisions, especially in early treatment phases, compared with stand-alone brain MRI.

Disability outcomes in early-stage African American and White people with multiple sclerosis.

BACKGROUND: Factors driving differences in disease burden between African American and White people with multiple sclerosis (pwMS) remain unclear. Here, we explored whether differences in disability outcomes could be observed after controlling for major sociodemographic factors and comorbidities, and assessed the presence of a possible interaction between MS and race. METHODS: In this cross-sectional study, 120 pwMS within 6 years from disease onset and 82 healthy controls between 18 and 70 years of age, self-identified as either African American or White, were prospectively enrolled. Inclusion criteria for pwMS were: diagnosis of MS according to the revised McDonald criteria, relapsing-remitting phenotype and Expanded Disability Status Scale (EDSS) < 6.5. Study outcomes included: (i) global disability (EDSS); (ii) quantitative mobility and leg function (Timed 25 Foot Walk Test-T25FWT); (iii) quantitative finger dexterity (9-Hole Peg Test-9HPT); (iv) cognitive efficiency and speed performance (Symbol Digit Modalities Test-SDMT). Differences in disability outcomes were assessed employing multivariable linear regression models. Based on their association with MS or disability, covariates included age, gender, race, years of education, total income, body mass index, comorbidities. The interaction between MS and race on disability outcomes was estimated via relative excess risk of interaction and attributable proportion. RESULTS: Accounting for age, gender, total income, education, body mass index and comorbidities, African American pwMS showed significantly worse performances in manual dexterity and cognition than White pwMS (White pwMS coeff. 3.24, 95% CI 1.55, 4.92 vs African American pwMS coeff. 5.52, 95% CI 3.55, 7.48 and White pwMS coeff. -5.87, 95% CI -8.86, -2.87 vs African American pwMS coeff. -7.99, 95% CI -11.58,-4.38). MS and race independently contributed to the observed gradient in disability severity. CONCLUSIONS: Complex social disparities and systemic racism might contribute to clinical heterogeneity in MS.

Clinical correlates of R1 relaxometry and magnetic susceptibility changes in multiple sclerosis: a multi-parameter quantitative MRI study of brain iron and myelin.

OBJECTIVES: The clinical impact of brain microstructural abnormalities in multiple sclerosis (MS) remains elusive. We aimed to characterize the topography of longitudinal relaxation rate (R1) and quantitative susceptibility (χ) changes, as indices of iron and myelin, together with brain atrophy, and to clarify their contribution to cognitive and motor disability in MS. METHODS: In this cross-sectional study, voxel-based morphometry, and voxel-based quantification analyses of R1 and χ maps were conducted in gray matter (GM) and white matter (WM) of 117 MS patients and 53 healthy controls. Voxel-wise between-group differences were assessed with nonparametric permutation tests, while correlations between MRI metrics and clinical variables (global disability, cognitive and motor performance) were assessed both globally and voxel-wise within clusters emerging from the between-group comparisons. RESULTS: MS patients showed widespread R1 decrease associated with more limited modifications of χ, with atrophy mainly involving deep GM, posterior and infratentorial regions (p < 0.02). While R1 and χ showed a parallel reduction in several WM tracts (p < 0.001), reduced GM R1 values (p < 0.001) were associated with decreased thalamic χ (p < 0.001) and small clusters of increased χ in the caudate nucleus and prefrontal cortex (p < 0.02). In addition to the atrophy, χ values in the cingulum and corona radiata correlated with global disability and motor performance, while focal demyelination correlated with cognitive performance (p < 0.04). CONCLUSIONS: We confirmed the presence of widespread R1 changes, involving both GM and WM, and atrophy in MS, with less extensive modifications of tissue χ. While atrophy and χ changes are related to global and motor disability, R1 changes are meaningful correlates of cognition. KEY POINTS: • Compared to healthy controls, multiple sclerosis patients showed R1 and χ changes suggestive of iron increase within the basal ganglia and reduced iron and myelin content within (subnuclei of) the thalamus. • Thalamic volume and χ changes significantly predicted clinical disability, as well as pulvinar R1 and χ changes, independently from atrophy. • Atrophy-independent R1 and χ changes, suggestive of thalamic iron and myelin depletion, may represent a sensitive marker of subclinical inflammation.

Consensus Paper: Ataxic Gait.

The aim of this consensus paper is to discuss the roles of the cerebellum in human gait, as well as its assessment and therapy. Cerebellar vermis is critical for postural control. The cerebellum ensures the mapping of sensory information into temporally relevant motor commands. Mental imagery of gait involves intrinsically connected fronto-parietal networks comprising the cerebellum. Muscular activities in cerebellar patients show impaired timing of discharges, affecting the patterning of the synergies subserving locomotion. Ataxia of stance/gait is amongst the first cerebellar deficits in cerebellar disorders such as degenerative ataxias and is a disabling symptom with a high risk of falls. Prolonged discharges and increased muscle coactivation may be related to compensatory mechanisms and enhanced body sway, respectively. Essential tremor is frequently associated with mild gait ataxia. There is growing evidence for an important role of the cerebellar cortex in the pathogenesis of essential tremor. In multiple sclerosis, balance and gait are affected due to cerebellar and spinal cord involvement, as a result of disseminated demyelination and neurodegeneration impairing proprioception. In orthostatic tremor, patients often show mild-to-moderate limb and gait ataxia. The tremor generator is likely located in the posterior fossa. Tandem gait is impaired in the early stages of cerebellar disorders and may be particularly useful in the evaluation of pre-ataxic stages of progressive ataxias. Impaired inter-joint coordination and enhanced variability of gait temporal and kinetic parameters can be grasped by wearable devices such as accelerometers. Kinect is a promising low cost technology to obtain reliable measurements and remote assessments of gait. Deep learning methods are being developed in order to help clinicians in the diagnosis and decision-making process. Locomotor adaptation is impaired in cerebellar patients. Coordinative training aims to improve the coordinative strategy and foot placements across strides, cerebellar patients benefiting from intense rehabilitation therapies. Robotic training is a promising approach to complement conventional rehabilitation and neuromodulation of the cerebellum. Wearable dynamic orthoses represent a potential aid to assist gait. The panel of experts agree that the understanding of the cerebellar contribution to gait control will lead to a better management of cerebellar ataxias in general and will likely contribute to use gait parameters as robust biomarkers of future clinical trials.