Addition of quantitative MRI to the routine clinical care of patients with multiple sclerosis-Results from the MAGNON project.

BACKGROUND: The revised Lublin classification offers a framework for categorizing multiple sclerosis (MS) according to the clinical course and imaging results. Diagnosis of secondary progressive MS (SPMS) is often delayed by a period of uncertainty. Several quantitative magnetic resonance imaging (qMRI) markers are associated with progressive disease states, but they are not usually available in clinical practice. METHODS: The MAGNON project enrolled 629 patients (early relapsing-remitting MS (RRMS), n = 51; RRMS with suspected SPMS, n = 386; SPMS, n = 192) at 55 centers in Germany. Routine magnetic resonance imaging (MRI) scans at baseline and after 12 months were analyzed using a centralized automatic processing pipeline to quantify lesions and normalized brain and thalamic volume. Clinical measures included relapse activity, disability, and MS phenotyping. Neurologists completed questionnaires before and after receiving the qMRI reports. RESULTS: According to the physicians' reports, qMRI results changed their assessment of the patient in 31.8% (baseline scan) and 27.6% (follow-up scan). For ∼50% of patients with RRMS with suspected SPMS, reports provided additional information that the patient was transitioning to SPMS. In >25% of all patients, this information influenced the physicians' assessment of the patient's current phenotype. However, actual changes of treatment were reported only in a minority of these patients. CONCLUSIONS: The MAGNON results suggest that standardized qMRI reports may be integrated into the routine clinical care of MS patients and support the application of the Lublin classification as well as treatment decisions. The highest impact was reported in patients with suspected SPMS, indicating a potential to reduce diagnostic uncertainty.

Association of Cortical Lesions With Regional Glutamate, GABA, N-Acetylaspartate, and Myoinositol Levels in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Cortical lesions contribute to disability in multiple sclerosis (MS), but their impact on regional neurotransmitter levels remains to be clarified. We tested the hypothesis that cortical lesions are associated with regional glutamate and gamma-aminobutyric acid (GABA) concentrations within the affected cortical region. METHODS: In this cross-sectional study, we used structural 7T MRI to segment cortical lesions and 7T proton MR-spectroscopy of the bilateral sensorimotor hand areas to quantify regional GABA, glutamate, N-acetylaspartate, and myoinositol concentrations in patients with MS (inclusion criteria: diagnosis of relapsing-remitting [RR] or secondary progressive MS [SPMS]; age 18-80 years) and age and sex-matched healthy controls. Data were collected at a single center between August 2018 and September 2020. Linear mixed-effects models were used to test for associations between metabolite concentrations and cortical lesion volumes within the same MR-spectroscopy voxel. RESULTS: Forty-seven patients with MS (34 RRMS, 13 SPMS; 45.1 ± 12.5 years; 31 women) and 23 healthy controls (44.4 ± 13 years, 15 women) were studied. In patients, higher regional glutamate and lower regional GABA concentrations were associated with larger cortical lesion volume within the MR-spectroscopy voxel [glutamate: 0.61 (95% CI 0.19-1.03) log(mm3), p = 0.005, GABA: -0.71 (-1.24 to -0.18) log(mm3), p = 0.01]. In addition, lower N-acetylaspartate levels [-0.37 (-0.67 to -0.07) log(mm3), p = 0.016] and higher myoinositol levels [0.48 (0.03-0.93) log(mm3), p = 0.037] were associated with a larger regional cortical lesion volume. Furthermore, glutamate concentrations were reduced in patients with SPMS compared with healthy participants [-0.75 (-1.3 to -0.19) mM, p = 0.005] and patients with RRMS [-0.55 (-1.07 to -0.02) mM, p = 0.04]. N-acetylaspartate levels were lower in both patients with RRMS [-0.81 (-1.39 to -0.24) mM, p = 0.003] and SPMS [-1.31 (-2.07 to -0.54) mM, p < 0.001] when compared with healthy controls. Creatine-normalized N-acetylaspartate levels were associated with performance in the 9-hole peg test of the contralateral hand [-0.004 (-0.007 to -0.002) log(s), p = 0.002], and reduced mean creatine-normalized glutamate was associated with increased Expanded Disability Status Scale (R = -0.39, p = 0.02). DISCUSSION: Cortical lesions are associated with local increases in glutamate and a reduction in GABA concentration within the lesional or perilesional tissue. Further studies are needed to investigate the causal relationship between cortical lesions and changes in neurotransmitter concentrations.

Glial cell injury and atrophied lesion volume as measures of chronic multiple sclerosis inflammation.

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.

Continuous diffuse brain atrophy independent of relapse as a hallmark of multiple sclerosis beginning from relapsing-remitting stage.

BACKGROUND: Neurodegenerative changes are observed in relapsing-remitting multiple sclerosis (RRMS) and are prominent in secondary progressive MS (SPMS). However, whether neurodegenerative changes accelerate and are altered after the transition into SPMS or in the presence of relapses remains uncertain. METHODS: In this study, 73 patients with MS (seven with relapsing RRMS, 56 with relapse-free RRMS, and 10 with relapse-free SPMS) were evaluated for brain segmental volume changes over a 2-year follow-up period. Volume change was calculated using a within-subject unbiased longitudinal image analysis model. RESULTS: The rates of brain volume change in the 11 brain regions evaluated were relatively similar among different brain regions. Moreover, they were similar among the relapsing RRMS, relapse-free RRMS, and SPMS groups, even after adjusting for age. CONCLUSIONS: The relatively constant brain segmental atrophy rate throughout the disease course, regardless of relapse episodes, suggests that RRMS and SPMS are continuous, uniform, and silent progressing brain atrophy diseases on a spectrum.

Analysis of potential microRNA biomarkers for multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating autoimmune neurodegenerative disorder for which no specific blood biomarker is available. MicroRNAs (miRNAs) have been investigated for their diagnostic potential in MS. However, MS-associated miRNAs are rarely replicated in different MS populations, thus impeding their use in clinical testing. Here, we evaluated the fold expression of seven reported MS miRNAs associated with MS incidence and clinical characteristics in 76 MS patients and 75 healthy control plasma samples. We found miR-23a-3p to be upregulated in relapsing-remitting MS (RRMS), while miR-326 was downregulated. MiR-150-5p and -320a-3p were significantly downregulated in secondary progressive MS (SPMS) patients compared to RRMS. High disability was associated with low miR-320a-3p, whereas low BDNF levels were associated with upregulation of miR-150-5p and downregulation of miR-326 expression in the total cohort. MiR-23a-3p and miR-326 showed significant diagnostic sensitivity, specificity, and accuracy for RRMS diagnosis. In addition, miR-150-5p and miR-320a-3p had comparable significant diagnostic test performance metrics distinguishing SPMS from RRMS. Therefore, there is potential for including miR-23a-3p and miR-326 in an RRMS diagnostic miRNA panel. Moreover, we have shown that miR-150-5p and miR-320a-3p could be novel RRMS conversion to SPMS biomarkers. The use of these miRNAs in MS diagnosis and prognosis warrants further investigation.

The multidimensional assessment of body representation and interoception in multiple sclerosis.

BACKGROUND: The mental representation of the body (or body representation, BR) derives from the processing of multiple sensory and motor inputs and plays a crucial role in guiding our actions and in how we perceive our body. Fundamental inputs for BR construction come also from the interoceptive systems which refer to the whole bidirectional processes between the brain and the body. People with Multiple sclerosis (MS) show an abnormal multisensory integration which may compromise BR and interoception integrity. However, no study has evaluated possible deficits on distinct and dissociable dimensions of body representation (i.e., action-oriented, aBR; and a nonaction-oriented body representation, NaBR) and interoception (i.e., interoceptive accuracy, interoceptive sensibility, and interoceptive awareness) in MS. OBJECTIVE: In the present study, we aimed to determine whether participants with MS present changes in BR and interoceptive dimensions. METHODS: We performed comparison analyses on tasks and questionnaires tapping all BR and interoceptive dimensions between 36 people with relapsing-remitting MS (RRMS) and 42 healthy controls, and between 23 people with progressive MS (PMS) and 33 healthy controls. RESULTS: Overall, patients with MS exhibited lower interoceptive accuracy than matched controls. The RRMS group also showed higher visceral interoceptive sensibility levels. No differences were found in BR accuracy measures, but the PMS reported longer response times when performing the aBR task. CONCLUSION: These findings open a new issue on the role of inner-signal monitoring in the body symptomatology of MS and highlight the need for an accurate BR and interoceptive assessment in a clinical setting.

Choroid plexus enlargement is associated with future periventricular neurodegeneration in multiple sclerosis.

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.

Efficacy of intrathecal mesenchymal stem cell-neural progenitor therapy in progressive MS: results from a phase II, randomized, placebo-controlled clinical trial.

BACKGROUND: Mesenchymal stem cell-neural progenitors (MSC-NPs) are a bone marrow mesenchymal stem cell (MSC)-derived ex vivo manipulated cell product with therapeutic potential in multiple sclerosis (MS). The objective of this study was to determine efficacy of intrathecal (IT) MSC-NP treatment in patients with progressive MS. METHODS: The study is a phase II randomized, double-blind, placebo-controlled clinical trial with a compassionate crossover design conducted at a single site. Subjects were stratified according to baseline Expanded Disability Status Scale (EDSS) (3.0-6.5) and disease subtype (secondary or primary progressive MS) and randomized into either treatment or placebo group to receive six IT injections of autologous MSC-NPs or saline every two months. The primary outcome was EDSS Plus, defined by improvement in EDSS, timed 25-foot walk (T25FW) or nine-hole peg test. Secondary outcomes included the individual components of EDSS Plus, the six-minute walk test (6MWT), urodynamics testing, and brain atrophy measurement. RESULTS: Subjects were randomized into MSC-NP (n = 27) or saline (n = 27) groups. There was no difference in EDSS Plus improvement between the MSC-NP (33%) and saline (37%) groups. Exploratory subgroup analysis demonstrated that in subjects who require assistance for ambulation (EDSS 6.0-6.5) there was a significantly higher percentage of improvement in T25FW and 6MWT in the MSC-NP group (3.7% ± 23.1% and - 9.2% ± 18.2%) compared to the saline group (-54.4% ± 70.5% and - 32.1% ± 30.0%), (p = 0.030 and p = 0.036, respectively). IT-MSC-NP treatment was also associated with improved bladder function and reduced rate of grey matter atrophy on brain MRI. Biomarker analysis demonstrated increased MMP9 and decreased CCL2 levels in the cerebrospinal fluid following treatment. CONCLUSION: Results from exploratory outcomes suggest that IT-MSC-NP treatment may be associated with a therapeutic response in a subgroup of MS patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03355365, registered November 14, 2017, https://clinicaltrials.gov/study/NCT03355365?term=NCT03355365&rank=1 .

Assessment of serum inflammatory parameters in RRMS and SPMS patients.

OBJECTIVES: Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease. Patients with relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) differ in their responses to treatment; therefore, the correct diagnosis of the particular type of MS is crucial, and biomarkers that can differentiate between the forms of MS need to be identified. The aim of this study was to compare the levels of inflammatory parameters in serum samples from patients with RRMS and SPMS. METHODS: The study group consisted of 60 patients with diagnosed MS. The patients were divided into RRMS and SPMS groups. In the RRMS patients, the usage of disease-modifying treatment was included in our analysis. The serum levels of inflammatory parameters were evaluated. RESULTS: The serum levels of BAFF, gp130 and osteopontin were significantly higher in SPMS patients than in RRMS patients. The serum levels of BAFF correlated with age in both RRMS and SPMS patients. The serum levels of MMP-2 were significantly higher in RRMS patients than in SPMS patients and correlated with the number of past relapses. The serum levels of IL-32 were significantly higher in RRMS treatment-naïve patients than in RRMS patients treated with disease-modifying therapy. DISCUSSION: Significant differences were found in BAFF, gp130, MMP-2 and osteopontin levels between RRMS and SPMS patients. Serum IL-32 levels were statistically lower in RRMS patients treated with disease-modifying therapy than in treatment-naïve patients.

Mapping brain volume change across time in primary-progressive multiple sclerosis.

PURPOSE: Detection and prediction of the rate of brain volume loss with age is a significant unmet need in patients with primary progressive multiple sclerosis (PPMS). In this study we construct detailed brain volume maps for PPMS patients. These maps compare age-related changes in both cortical and sub-cortical regions with those in healthy individuals. METHODS: We conducted retrospective analyses of brain volume using T1-weighted Magnetic Resonance Imaging (MRI) scans of a large cohort of PPMS patients and healthy subjects. The volume of brain parenchyma (BP), cortex, white matter (WM), deep gray matter, thalamus, and cerebellum were measured using the robust SynthSeg segmentation tool. Age- and gender-related regression curves were constructed based on data from healthy subjects, with the 95% prediction interval adopted as the normality threshold for each brain region. RESULTS: We analyzed 495 MRI scans from 169 PPMS patients, aged 20-79 years, alongside 563 exams from healthy subjects aged 20-86. Compared to healthy subjects, a higher proportion of PPMS patients showed lower than expected brain volumes in all regions except the cerebellum. The most affected areas were BP, WM, and thalamus. Lower brain volumes correlated with longer disease duration for BP and WM, and higher disability for BP, WM, cortex, and thalamus. CONCLUSIONS: Constructing age- and gender-related brain volume maps enabled identifying PPMS patients at a higher risk of brain volume loss. Monitoring these high-risk patients may lead to better treatment decisions and improve patient outcomes.

Clinical variables influencing the perception of fatigue in people with multiple sclerosis: a cross-sectional study using FSIQ-RMS.

BACKGROUND: Physical fatigue is one of the most disabling symptoms in people with Multiple Sclerosis (PwMS). Several factors might influence the development of fatigue, such as gender, education, body mass index (BMI), Expanded Disability Status Scale (EDSS), disease duration, working status (Ws), physiotherapy (Ph), and disease-modifying therapies (DMTs). Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) is a patient-reported outcome (PRO) that allows one to define the impact of fatigue in PwMS clearly. This study aimed to assess fatigue impact on PwMS by using FSIQ-RMS. METHODS: The participants were enrolled from May to July 2021 in MS Centers of Sant'Andrea Hospital and Policlinico Umberto I Hospital in Rome. Fatigue was evaluated using the FSIQ-RMS, validated, and culturally adapted in Italian. Clinical and demographic data were collected at the same time. RESULTS: We enrolled 178 PwMS [Female 74.16%; RMS 82.58%, SPMS 17.52%]. FSIQ-RMS scores were significantly correlated with EDSS (p-value < 0.01). Analysis of variance between means showed a statistically significant difference between the BMI groups at the 24hours_FSIQ-RMS score and the 7days_FSIQ-RMS score (p < 0.01), with the lower BMI group having the highest scores. Furthermore, perceived fatigue significantly improved both in subjects performing Ph (p < 0.05) and in those who actively work (p < 0.01). CONCLUSIONS: The use of FSIQ-RMS in a real-world setting confirmed that underweight and high levels of disability are closely related to fatigue. In addition, Ph and active Ws are strongly correlated with fatigue in PwMS.

Single-Cell Multi-Omics Map of Cell Type-Specific Mechanistic Drivers of Multiple Sclerosis Lesions.

BACKGROUND AND OBJECTIVES: In progressive multiple sclerosis (MS), compartmentalized inflammation plays a pivotal role in the complex pathology of tissue damage. The interplay between epigenetic regulation, transcriptional modifications, and location-specific alterations within white matter (WM) lesions at the single-cell level remains underexplored. METHODS: We examined intracellular and intercellular pathways in the MS brain WM using a novel dataset obtained by integrated single-cell multi-omics techniques from 3 active lesions, 3 chronic active lesions, 3 remyelinating lesions, and 3 control WM of 6 patients with progressive MS and 3 non-neurologic controls. Single-nucleus RNA-seq and ATAC-seq were combined and additionally enriched with newly conducted spatial transcriptomics from 1 chronic active lesion. Functional gene modules were then validated in our previously published bulk tissue transcriptome data obtained from 73 WM lesions of patients with progressive MS and 25 WM of non-neurologic disease controls. RESULTS: Our analysis uncovered an MS-specific oligodendrocyte genetic signature influenced by the KLF/SP gene family. This modulation has potential associations with the autocrine iron uptake signaling observed in transcripts of transferrin and its receptor LRP2. In addition, an inflammatory profile emerged within these oligodendrocytes. We observed unique cellular endophenotypes both at the periphery and within the chronic active lesion. These include a distinct metabolic astrocyte phenotype, the importance of FGF signaling among astrocytes and neurons, and a notable enrichment of mitochondrial genes at the lesion edge populated predominantly by astrocytes. Our study also identified B-cell coexpression networks indicating different functional B-cell subsets with differential location and specific tendencies toward certain lesion types. DISCUSSION: The use of single-cell multi-omics has offered a detailed perspective into the cellular dynamics and interactions in MS. These nuanced findings might pave the way for deeper insights into lesion pathogenesis in progressive MS.

Therapeutic lag: Is treatment effect delayed in progressive MS?

BACKGROUND: Randomized clinical trials (RCTs) in progressive multiple sclerosis (MS) often revealed non-significant treatment effects on disability progression. OBJECTIVES: To investigate whether the failure to detect a significant benefit from treatment may be motivated by a delay in treatment effect, possibly related to baseline characteristics. METHODS: We re-analyzed data from two RCTs testing interferon-beta and glatiramer-acetate versus placebo in progressive MS with no significant effect on EDSS progression. We first designed a time-dependent Cox model with no treatment effect up to time = t0, and constant hazard ratio (HR) after time = t0. We selected the best-fitting t0 from 0 (standard Cox model) to 2.5 years. Furthermore, we modeled the delay as a function of baseline EDSS and fitted the resulting Cox model to the merged dataset. RESULTS: The time-dependent Cox model revealed a significant benefit of treatment delayed by t0 = 2.5 years for the SPECTRIMS study (HR = 0.65 (0.43-0.98), p = 0.041), and delayed by t0 = 2 years for the PROMISE study (HR = 0.65, (0.42-0.99), p = 0.044). In the merged dataset, the HR for the EDSS-dependent delayed effect was 0.68 (0.56, 0.82), p < 0.001. CONCLUSION: The assumption of a delayed treatment effect improved the fit to the data of the two examined RCTs, uncovering a significant, although shifted, benefit of treatment.

A metformin add-on clinical study in multiple sclerosis to evaluate brain remyelination and neurodegeneration (MACSiMiSE-BRAIN): study protocol for a multi-center randomized placebo controlled clinical trial.

Introduction: Despite advances in immunomodulatory treatments of multiple sclerosis (MS), patients with non-active progressive multiple sclerosis (PMS) continue to face a significant unmet need. Demyelination, smoldering inflammation and neurodegeneration are important drivers of disability progression that are insufficiently targeted by current treatment approaches. Promising preclinical data support repurposing of metformin for treatment of PMS. The objective of this clinical trial is to evaluate whether metformin, as add-on treatment, is superior to placebo in delaying disease progression in patients with non-active PMS. Methods and analysis: MACSiMiSE-BRAIN is a multi-center two-arm, 1:1 randomized, triple-blind, placebo-controlled clinical trial, conducted at five sites in Belgium. Enrollment of 120 patients with non-active PMS is planned. Each participant will undergo a screening visit with assessment of baseline magnetic resonance imaging (MRI), clinical tests, questionnaires, and a safety laboratory assessment. Following randomization, participants will be assigned to either the treatment (metformin) or placebo group. Subsequently, they will undergo a 96-week follow-up period. The primary outcome is change in walking speed, as measured by the Timed 25-Foot Walk Test, from baseline to 96 weeks. Secondary outcome measures include change in neurological disability (Expanded Disability Status Score), information processing speed (Symbol Digit Modalities Test) and hand function (9-Hole Peg test). Annual brain MRI will be performed to assess evolution in brain volumetry and diffusion metrics. As patients may not progress in all domains, a composite outcome, the Overall Disability Response Score will be additionally evaluated as an exploratory outcome. Other exploratory outcomes will consist of paramagnetic rim lesions, the 2-minute walking test and health economic analyses as well as both patient- and caregiver-reported outcomes like the EQ-5D-5L, the Multiple Sclerosis Impact Scale and the Caregiver Strain Index. Ethics and dissemination: Clinical trial authorization from regulatory agencies [Ethical Committee and Federal Agency for Medicines and Health Products (FAMHP)] was obtained after submission to the centralized European Clinical Trial Information System. The results of this clinical trial will be disseminated at scientific conferences, in peer-reviewed publications, to patient associations and the general public. Trial registration: ClinicalTrials.gov Identifier: NCT05893225, EUCT number: 2023-503190-38-00.

Passive assessment of tapping speed through smartphone is useful for monitoring multiple sclerosis.

INTRODUCTION: Continuously acquired smartphone keyboard interactions may be useful to monitor progression in multiple sclerosis (MS). We aimed to study the correlation between tapping speed (TS), measured as keys/s, and baseline disability scales in patients with MS. METHODS: Single-center prospective study in patients with MS. We passively assessed TS during first week, measured by an "in house" smartphone application. Reliability was assessed by intraclass correlation coefficient (ICC). Correlations between median and maximum keys/s of first week of assessment and baseline disability measures were explored. RESULTS: One-hundred three patients were included: 62.1 % women, with a median (IQR) age of 47 (40.4-54.8) years-old and an EDSS score of 3.0 (2.0-4.0). Distribution by MS subtypes was: 77.7 % relapsing-remitting MS (RRMS), 17.5 % secondary-progressive MS (SPMS) and 4.9 % primary-progressive MS (PPMS). ICC during first week was 0.714 (p < 0.00001). Both median and maximum keys/s showed a negative correlation with Expanded Disability Status Score, 9-hole peg test and timed 25-foot walk and a positive correlation with Processing Speed Test CogEval® raw and Z-score. Median and maximum keys/s were lower in patients diagnosed with SPMS than in RRMS. Both measures of tapping speed were associated with MS phenotype independently of age. CONCLUSION: TS measured through our application is reliable and correlates with baseline disability scales.

Recent advances in the treatment of primary and secondary progressive Multiple Sclerosis.

BACKGROUND: The article highlights upcoming potential treatments, which target different phases of inflammation and offer remyelinating strategies as well as direct and indirect neuroprotective and oligodendrocyte protective effects, providing a hopeful outlook for patients with primary and secondary progressive multiple sclerosis (PPMS and SPMS). OBJECTIVES: The review aims to identify potential treatments and ongoing clinical trials for PPMS and SPMS, and compare their mechanisms of action, efficacy, and side effects with current treatments. METHODS: We reviewed ongoing clinical trials for PPMS and SPMS on the NIH website, as well as articles from PubMed, Embase, and clinicaltrails.gov since 2010. RESULTS: BTKIs like, tolebrutinib, and fenebrutinib are being explored as potential PMS treatments. Vidofludimus calcium, an orally available treatment, has shown a reduction of active and new MRI lesions. Other treatments like simvastatin, N-acetylcysteine (NAC), and alpha-lipoic acid are being explored for their antioxidant properties. AHSCT and mesenchymal stem cell therapy are experimental options for younger patients with high inflammatory activity. CONCLUSIONS: SPMS and PPMS are being studied for new treatments and future trials should consider combination therapies targeting inflammation, demyelination, and neuronal death, as the pathogenesis of PMS involves complex factors.

Plasma Lipidomic Profiling Using Mass Spectrometry for Multiple Sclerosis Diagnosis and Disease Activity Stratification (LipidMS).

This investigation explores the potential of plasma lipidomic signatures for aiding in the diagnosis of Multiple Sclerosis (MS) and evaluating the clinical course and disease activity of diseased patients. Plasma samples from 60 patients with MS (PwMS) were clinically stratified to either a relapsing-remitting (RRMS) or a chronic progressive MS course and 60 age-matched controls were analyzed using state-of-the-art direct infusion quantitative shotgun lipidomics. To account for potential confounders, data were filtered for age and BMI correlations. The statistical analysis employed supervised and unsupervised multivariate data analysis techniques, including a principal component analysis (PCA), a partial least squares discriminant analysis (oPLS-DA) and a random forest (RF). To determine whether the significant absolute differences in the lipid subspecies have a relevant effect on the overall composition of the respective lipid classes, we introduce a class composition visualization (CCV). We identified 670 lipids across 16 classes. PwMS showed a significant increase in diacylglycerols (DAG), with DAG 16:0;0_18:1;0 being proven to be the lipid with the highest predictive ability for MS as determined by RF. The alterations in the phosphatidylethanolamines (PE) were mainly linked to RRMS while the alterations in the ether-bound PEs (PE O-) were found in chronic progressive MS. The amount of CE species was reduced in the CPMS cohort whereas TAG species were reduced in the RRMS patients, both lipid classes being relevant in lipid storage. Combining the above mentioned data analyses, distinct lipidomic signatures were isolated and shown to be correlated with clinical phenotypes. Our study suggests that specific plasma lipid profiles are not merely associated with the diagnosis of MS but instead point toward distinct clinical features in the individual patient paving the way for personalized therapy and an enhanced understanding of MS pathology.

The prevalence and topography of spinal cord demyelination in multiple sclerosis: a retrospective study.

Spinal cord pathology is a major determinant of irreversible disability in progressive multiple sclerosis. The demyelinated lesion is a cardinal feature. The well-characterised anatomy of the spinal cord and new analytic approaches allows the systematic study of lesion topography and its extent of inflammatory activity unveiling new insights into disease pathogenesis. We studied cervical, thoracic, and lumbar spinal cord tissue from 119 pathologically confirmed multiple sclerosis cases. Immunohistochemistry was used to detect demyelination (PLP) and classify lesional inflammatory activity (CD68). Prevalence and distribution of demyelination, staged by lesion activity, was determined and topographical maps were created to identify patterns of lesion prevalence and distribution using mixed models and permutation-based voxelwise analysis. 460 lesions were observed throughout the spinal cord with 76.5% of cases demonstrating at least 1 lesion. The cervical level was preferentially affected by lesions. 58.3% of lesions were inflammatory with 87.9% of cases harbouring at least 1 inflammatory lesion. Topographically, lesions consistently affected the dorsal and lateral columns with relative sparing of subpial areas in a distribution mirroring the vascular network. The presence of spinal cord lesions and the proportion of active lesions related strongly with clinical disease milestones, including time from onset to wheelchair and onset to death. We demonstrate that spinal cord demyelination is common, highly inflammatory, has a predilection for the cervical level, and relates to clinical disability. The topography of lesions in the dorsal and lateral columns and relative sparing of subpial areas points to a role of the vasculature in lesion pathogenesis, suggesting short-range cell infiltration from the blood and signaling molecules circulating in the perivascular space incite lesion development. These findings challenge the notion that end-stage progressive multiple sclerosis is 'burnt out' and an outside-in lesional gradient predominates in the spinal cord. Taken together, this study provides support for long-term targeting of inflammatory demyelination in the spinal cord and nominates vascular dysfunction as a potential target for new therapeutic approaches to limit irreversible disability.

The Impact of Sample Storage on Blood Methylation: Towards Assessing Myelin Gene Methylation as a Biomarker for Progressive Multiple Sclerosis.

One of the major challenges in multiple sclerosis (MS) is to accurately monitor and quantify disability over time. Thus, there is a pressing need to identify new biomarkers for disease progression. Peripheral blood DNA methylation has been demonstrated to be an easily accessible and quantifiable marker in many neurodegenerative diseases. In this study, we aimed to investigate whether methylation patterns that were previously determined in chronic inactive white matter lesions of patients with progressive MS are also reflected in the blood, and whether the latter can serve as a biomarker for disease progression in MS. While our initial analysis revealed differences in the blood methylation state of important myelin-related genes between patients with progressive MS and controls, these findings could not be validated in other independent patient cohorts. Subsequent investigation suggests that sample storage can selectively influence DNA methylation patterns, potentially hindering accurate epigenetic analysis. Therefore, sample storage time should be taken into consideration during the initial sample selection stage in biomarker studies.

Siponimod Attenuates Neuronal Cell Death Triggered by Neuroinflammation via NFκB and Mitochondrial Pathways.

Multiple sclerosis (MS) is the most common autoimmune demyelinating disease of the central nervous system (CNS), consisting of heterogeneous clinical courses varying from relapsing-remitting MS (RRMS), in which disability is linked to bouts of inflammation, to progressive disease such as primary progressive MS (PPMS) and secondary progressive MS (SPMS), in which neurological disability is thought to be linked to neurodegeneration. As a result, successful therapeutics for progressive MS likely need to have both anti-inflammatory and direct neuroprotective properties. The modulation of sphingosine-1-phosphate (S1P) receptors has been implicated in neuroprotection in preclinical animal models. Siponimod/BAF312, the first oral treatment approved for SPMS, may have direct neuroprotective benefits mediated by its activity as a selective (S1P receptor 1) S1P1 and (S1P receptor 5) S1P5 modulator. We showed that S1P1 was mainly present in cortical neurons in lesioned areas of the MS brain. To gain a better understanding of the neuroprotective effects of siponimod in MS, we used both rat neurons and human-induced pluripotent stem cell (iPSC)-derived neurons treated with the neuroinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Cell survival/apoptotic assays using flow cytometry and IncuCyte live cell analyses showed that siponimod decreased TNF-α induced neuronal cell apoptosis in both rat and human iPSCs. Importantly, a transcriptomic analysis revealed that mitochondrial oxidative phosphorylation, NFκB and cytokine signaling pathways contributed to siponimod's neuroprotective effects. Our data suggest that the neuroprotection of siponimod/BAF312 likely involves the relief of oxidative stress in neuronal cells. Further studies are needed to explore the molecular mechanisms of such interactions to determine the relationship between mitochondrial dysfunction and neuroinflammation/neurodegeneration.