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.

Prevalence and Associated Clinical Characteristics of Walking-Related Motor, Cognitive, and Fatigability in Progressive Multiple Sclerosis: Baseline Results From the CogEx Study.

BACKGROUND: People with progressive multiple sclerosis (PMS) present motor (eg, walking) and cognitive impairments, and report fatigue. Fatigue encompasses fatigability which is objectively measured by the capacity to sustain a motor or cognitive task. OBJECTIVE: To investigate the prevalence of walking and cognitive fatigability (CF) and the associated clinical characteristics in a large sample of PMS patients. METHODS: PMS patients (25-65 years old) were included from 11 sites (Europe and North America), having cognitive impairment (1.28 standard deviation below normative data for the symbol digit modality test [SDMT]). Walking fatigability (WF) was assessed using the distance walk index (DWI) and CF using the SDMT (scores from the last 30 seconds compared to the first 30 seconds). Additional measures were: cognitive assessment-Brief International Cognitive Assessment for multiple sclerosis (MS), cardiorespiratory fitness, 6-minute walk, physical activity, depressive symptoms, perceived fatigue-Modified Fatigue Impact Scale (MFIS), MS impact-MSIS-29, and walking ability. RESULTS: Of 298 participants, 153 (51%) presented WF (DWI = -28.9 ± 22.1%) and 196 (66%) presented CF (-29.7 ± 15%). Clinical characteristics (EDSS, disease duration, and use of assistive device) were worse in patients with versus without WF. They also presented worse scores on MSIS-29 physical, MFIS total and physical and reduced physical capacity. CF patients scored better in the MSIS-29 physical and MFIS psychosocial, compared to non-CF group. Magnitude of CF and WF were not related. CONCLUSIONS: Half of the cognitively-impaired PMS population presented WF which was associated with higher disability, physical functions, and fatigue. There was a high prevalence of CF but without strong associations with clinical, cognitive, and physical functions. TRIAL REGISTRATION NUMBER: The "CogEx-study," www.clinicaltrial.gov identifier number: NCT03679468.

B Cells in the CNS at Postmortem Are Associated With Worse Outcome and Cell Types in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: To define the clinical and pathologic correlations of compartmentalized perivascular B cells in postmortem progressive multiple sclerosis (MS) brains. METHODS: Brain slices were acquired from 11 people with secondary progressive (SP) MS, 5 people with primary progressive (PP) MS, and 4 controls. Brain slices were immunostained for B lymphocytes (CD20), T lymphocytes (CD3), cytotoxic T lymphocytes (CD8), neuronal neurofilaments (NF200), myelin (SMI94), macrophages/microglia (CD68 and IBA1), astrocytes (glial fibrillary acidic protein [GFAP]), and mitochondria (voltage-dependent anion channel and cytochrome c oxidase subunit 4). Differences in CD20 immunostaining intensity between disease groups and associations between CD20 immunostaining intensity and both clinical variables and other immunostaining intensities were explored with linear mixed regression models and Cox regression models, as appropriate. RESULTS: CD20 immunostaining intensity was higher in PPMS (Coeff = 0.410; 95% confidence interval [CI] = 0.046, 0.774; p = 0.027) and SPMS (Coeff = 0.302; 95% CI = 0.020, 0.585; p = 0.036) compared with controls. CD20 immunostaining intensity was higher in cerebellar, spinal cord, and pyramidal onset (Coeff = 0.274; 95% CI = 0.039, 0.510; p = 0.022) compared with optic neuritis and sensory onset. Higher CD20 immunostaining intensity was associated with younger age at onset (hazard ratio [HR] = 1.033; 95% CI = 1.013, 1.053; p = 0.001), SP conversion (HR = 1.056; 95% CI = 1.022, 1.091; p = 0.001), wheelchair dependence (HR = 1.472; 95% CI = 1.108, 1.954; p = 0.008), and death (HR = 1.684; 95% CI = 1.238, 2.291; p = 0.001). Higher immunostaining intensity for CD20 was associated with higher immunostaining intensity for CD3 (Coeff = 0.114; 95% CI = 0.005, 0.224; p = 0.040), CD8 (Coeff = 0.275; 95% CI = 0.200, 0.350; p < 0.001), CD68 (Coeff = 0.084; 95% CI = 0.023, 0.144; p = 0.006), GFAP (Coeff = 0.002; 95% CI = 0.001, 0.004; p = 0.030), and damaged mitochondria (Coeff = 3.902; 95% CI = 0.891, 6.914; p = 0.011). DISCUSSION: Perivascular B cells were associated with worse clinical outcomes and CNS-compartmentalized inflammation. Our findings further support the concept of targeting compartmentalized B-cell inflammation in progressive MS.

CSF Levels of CXCL12 and Osteopontin as Early Markers of Primary Progressive Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: To evaluate the extent of intrathecal inflammation in patients with primary progressive MS (PPMS) at the time of diagnosis and to define markers and a specific inflammatory profile capable of distinguishing progressive from relapsing-remitting multiple sclerosis (RRMS). METHODS: Levels of 34 pro- and anti-inflammatory cytokines and chemokines in the CSF were evaluated at the diagnosis in 16 patients with PPMS and 80 with RRMS. All patients underwent clinical evaluation, including Expanded Disability Status Scale assessment and a 3T brain MRI to detect white matter and cortical lesion number and volume and global and regional cortical thickness. RESULTS: Higher levels of CXCL12 (odds ratio [OR] = 3.97, 95% CI [1.34-11.7]) and the monocyte-related osteopontin (OR = 2.24, 95% CI [1.01-4.99]) were detected in patients with PPMS, whereas levels of interleukin-10 (IL10) (OR = 0.28, 95% CI [0.09-0.96]) were significantly increased in those with RRMS. High CXCL12 levels were detected in patients with increased gray matter lesion number and volume (p = 0.001, r = 0.832 and r = 0.821, respectively). Pathway analysis confirmed the chronic inflammatory processes occurring in PPMS. CONCLUSIONS: At the time of diagnosis, a specific CSF protein profile can recognize the presence of early intrathecal inflammatory processes, possibly stratifying PPMS with respect to RRMS. Elevated CSF levels of CXCL12 and osteopontin suggested a key role of brain innate immunity and glia activity in MS. These molecules could represent useful candidate markers of MS progression, with implications for the pathogenesis and treatment of progressive MS. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CXCL12 and monocyte-related osteopontin may be correlated with PPMS, and IL-10 may be related to RRMS. It is may be correlated due to Bonferroni correction negating the statistical correlations found in the study.

CSF Chitinase 3-Like 2 Is Associated With Long-term Disability Progression in Patients With Progressive Multiple Sclerosis.

OBJECTIVE: This study aimed to identify long-term prognostic protein biomarkers associated with disease progression in patients with progressive multiple sclerosis (MS). METHODS: CSF samples were collected from a discovery cohort of 28 patients with progressive MS who participated in a clinical trial with interferon beta. Patients were classified into high and low disability progression phenotypes according to numeric progression rates (NPR) and step-based progression rates (SPR) after a mean follow-up time of 12 years. Protein abundance was measured by shotgun proteomics. Selected proteins from the discovery cohort were quantified by parallel reaction monitoring in CSF samples from an independent validation cohort of 41 patients with progressive MS classified also into high and low disability progression phenotypes after a mean follow-up time of 7 years. RESULTS: Of 2,548 CSF proteins identified in the discovery cohort, 10 were selected for validation based on their association with long-term disability progression: SPATS2-like protein, chitinase 3-like 2 (CHI3L2), plasma serine protease inhibitor, metallothionein-3, phospholipase D4, beta-hexosaminidase, neurexophilin-1, adipocyte enhancer-binding protein 1, cathepsin L1, and lipopolysaccharide-binding protein. Only CHI3L2 was validated, and patients with high disability progression exhibited significantly higher CSF protein levels compared with patients with low disability progression (p = 0.03 for NPR and p = 0.02 for SPR). CHI3L2 levels showed good performance to discriminate between high and low disability progression in patients with progressive MS (area under the curve 0.73; sensitivity 90% and specificity 63%). CONCLUSIONS: Although further confirmatory studies are needed, we propose CSF CHI3L2 as a prognostic protein biomarker associated with long-term disability progression in patients with progressive MS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that high CSF CHI3L2 levels identified higher disability progression in patients with progressive MS.

Secondary Progressive Multiple Sclerosis: New Insights.

In most cases, multiple sclerosis (MS) begins with a relapsing-remitting course followed by insidious disability worsening that is independent from clinically apparent relapses and is termed secondary progressive MS (SMPS). Major differences exist between relapsing-remitting MS (RRMS) and SPMS, especially regarding therapeutic response to treatment. This review provides an overview of the pathology, differentiation, and challenges in the diagnosis and treatment of SPMS. We emphasize the criticality of conversion from a relapsing-remitting to a secondary progressive disease course not only because such conversion is evidence of disability progression, but also because, until recently, treatments that effectively reduced disability progression in relapsing MS were not proven to be effective in SPMS. Clear clinical, imaging, immunologic, or pathologic criteria marking the transition from RRMS to SPMS have not yet been established. Early identification of SPMS will require tools that, together with the use of appropriate treatments, may result in better long-term outcomes for the population of patients with SPMS.

Diroximel Fumarate in Relapsing Forms of Multiple Sclerosis: A Profile of Its Use.

Diroximel fumarate (Vumerity®), an orally administered disease-modifying drug (DMD), expands the available treatment options for adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS (RRMS), and active secondary progressive MS. It demonstrates bioequivalence to dimethyl fumarate and was developed to provide similar clinical benefits, but with an improved gastrointestinal (GI) tolerability profile. In RRMS patients who are treatment-naïve or were previously treated with interferon-ß or glatiramer acetate, diroximel fumarate reduces annualized relapse rates, with most patients experiencing no relapses during treatment, and reduces the formation of new MS-associated brain lesions. Diroximel fumarate has an acceptable tolerability profile that is consistent with that of dimethyl fumarate, albeit with a significantly lower rate of GI adverse events.

Pain Intensity and Pain Interference in People With Progressive Multiple Sclerosis Compared With People With Relapsing-Remitting Multiple Sclerosis.

OBJECTIVE: To describe pain intensity and interference in people with progressive multiple sclerosis (MS), compare these with people with relapsing-remitting multiple sclerosis (RRMS), and identify common and unique factors associated with pain intensity in people with progressive MS and RRMS. DESIGN: Observational, cross-sectional analysis using baseline data from a longitudinal survey on quality of life in participants with MS. SETTING: Community. PARTICIPANTS: A total of 573 adults with MS (N=573; progressive MS, n=142; RRMS, n=431). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Average pain intensity was measured by an 11-point numeric rating scale, and pain interference was measured by the Patient-Reported Outcomes Measurement Information System Pain Interference Short Form. RESULTS: Participants with progressive MS reported moderate average pain intensity (3.22±2.50) and elevated pain interference (T score of 55.55±9.13). They did not differ significantly from those with RRMS in average pain intensity or pain interference. Common factors associated with higher average pain intensity were more severe disability, lower education level, unemployment, and current smoking. In those with progressive MS, older age was associated with lower average pain intensity. CONCLUSIONS: Pain intensity and interference are similar across MS types. In addition to assessing and treating pain, it is important to screen for modifiable pain-related factors, such as smoking cessation, in this population.

Network Damage Predicts Clinical Worsening in Multiple Sclerosis: A 6.4-Year Study.

OBJECTIVE: In multiple sclerosis (MS), clinical impairment is likely due to both structural damage and abnormal brain function. We assessed the added value of integrating structural and functional network MRI measures to predict 6.4-year MS clinical disability deterioration. METHODS: Baseline 3D T1-weighted and resting-state functional MRI scans were obtained from 233 patients with MS and 77 healthy controls. Patients underwent a neurologic evaluation at baseline and at 6.4-year median follow-up (interquartile range = 5.06-7.51 years). At follow-up, patients were classified as clinically stable/worsened according to disability changes. In relapsing-remitting (RR) MS, secondary progressive (SP) MS conversion was evaluated. Global brain volumetry was obtained. Furthermore, independent component analysis identified the main functional connectivity (FC) and gray matter (GM) network patterns. RESULTS: At follow-up, 105/233 (45%) patients were clinically worsened; 26/157 (16%) patients with RRMS evolved to SPMS. The treatment-adjusted random forest model identified normalized GM and brain volumes, decreased FC between default-mode networks, increased FC of the left precentral gyrus in the sensorimotor network (SMN), and GM atrophy in the fronto-parietal network (false discovery rate [FDR]-corrected p = range 0.01-0.09) as predictors of clinical worsening (out-of-bag [OOB] accuracy = 0.74). An expected contribution of baseline disability was also present (FDR-p = 0.01). Baseline disability, normalized GM volume, and GM atrophy in the SMN (FDR-p = range 0.01-0.09) were independently associated with SPMS conversion (OOB accuracy = 0.84). At receiver operating characteristic analysis, including network MRI variables improved disability worsening (p = 0.05) and SPMS conversion (p = 0.02) prediction. CONCLUSIONS: Integration of MRI network measures helped determining the relative contributions of global/local GM damage and functional reorganization to clinical deterioration in MS.

Tissue Transglutaminase Expression Associates With Progression of Multiple Sclerosis.

OBJECTIVE: The clinical course of multiple sclerosis (MS) is variable and largely unpredictable pointing to an urgent need for markers to monitor disease activity and progression. Recent evidence revealed that tissue transglutaminase (TG2) is altered in patient-derived monocytes. We hypothesize that blood cell-derived TG2 messenger RNA (mRNA) can potentially be used as biomarker in patients with MS. METHODS: In peripheral blood mononuclear cells (PBMCs) from 151 healthy controls and 161 patients with MS, TG2 mRNA was measured and correlated with clinical and MRI parameters of disease activity (annualized relapse rate, gadolinium-enhanced lesions, and T2 lesion volume) and disease progression (Expanded Disability Status Scale [EDSS], normalized brain volume, and hypointense T1 lesion volume). RESULTS: PBMC-derived TG2 mRNA levels were significantly associated with disease progression, i.e., worsening of the EDSS over 2 years of follow-up, normalized brain volume, and normalized gray and white matter volume in the total MS patient group at baseline. Of these, in patients with relapsing-remitting MS, TG2 expression was significantly associated with worsening of the EDSS scores over 2 years of follow-up. In the patients with primary progressive (PP) MS, TG2 mRNA levels were significantly associated with EDSS, normalized brain volume, and normalized gray and white matter volume at baseline. In addition, TG2 mRNA associated with T1 hypointense lesion volume in the patients with PP MS at baseline. CONCLUSION: PBMC-derived TG2 mRNA levels hold promise as biomarker for disease progression in patients with MS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with MS, PBMC-derived TG2 mRNA levels are associated with disease progression.

Motor Sequence Learning across Multiple Sessions Is Not Facilitated by Targeting Consolidation with Posttraining tDCS in Patients with Progressive Multiple Sclerosis.

Compared to relapsing-remitting multiple sclerosis (MS), progressive MS is characterized by a lack of spontaneous recovery and a poor response to pharmaceutical immunomodulatory treatment. These patients may, therefore, particularly benefit from interventions that augment training-induced plasticity of the central nervous system. In this cross-sectional double-blind cross-over pilot study, effects of transcranial direct current stimulation (tDCS) on motor sequence learning were examined across four sessions on days 1, 3, 5, and 8 in 16 patients with progressive MS. Active or sham anodal tDCS of the primary motor cortex was applied immediately after each training session. Participants took part in two experiments separated by at least four weeks, which differed with respect to the type of posttraining tDCS (active or sham). While task performance across blocks of training and across sessions improved significantly in both the active and sham tDCS experiment, neither online nor offline motor learning was modulated by the type of tDCS. Accordingly, the primary endpoint (task performance on day 8) did not differ between stimulation conditions. In sum, patients with progressive MS are able to improve performance in an ecologically valid motor sequence learning task through training. However, even multisession posttraining tDCS fails to promote motor learning in progressive MS.

Immune Soluble Factors in the Cerebrospinal Fluid of Progressive Multiple Sclerosis Patients Segregate Into Two Groups.

Primary-progressive (PP) and secondary-progressive (SP) multiple sclerosis (MS) are characterized by neurological deficits caused by a permanent neuronal damage, clinically quantified by the expanded disability status scale (EDSS). Neuronal tissue damage is also mediated by immune infiltrates producing soluble factors, such as cytokines and chemokines, which are released in the cerebrospinal fluid (CSF). The mechanisms regulating the production of a soluble factor are not completely defined. Using multiplex bead-based assays, we simultaneously measured 27 immune soluble factors in the CSF collected from 38 patients, 26 with PP-MS and 12 with SP-MS. Then, we performed a correlation matrix of all soluble factors expressed in the CSF. The CSF from patients with PP-MS and SP-MS had similar levels of cytokines and chemokines; however, the stratification of patients according to active or inactive magnetic resonance imaging (MRI) unveils some differences. Correlative studies between soluble factors in the CSF of patients with PP-MS and SP-MS revealed two clusters of immune mediators with pro-inflammatory functions, namely IFN-γ, MCP-1, MIP-1α, MIP-1ß, IL-8, IP-10, and TNF-α (group 1), and anti-inflammatory functions, namely IL-9, IL-15, VEGF, and IL-1ra (group 2). However, most of the significant correlations between cytokines of group 1 and of group 2 were lost in patients with more severe disability (EDSS ≥ 4) compared to patients with mild to moderate disability (EDSS < 4). These results suggest a common regulation of cytokines and chemokines belonging to the same group and indicate that, in patients with more severe disability, the production of those factors is less coordinated, possibly due to advanced neurodegenerative mechanisms that interfere with the immune response.

A pilot study of oxidative pathways in MS fatigue: randomized trial of N-acetyl cysteine.

OBJECTIVE: To assess feasibility, tolerability, and safety of N-acetyl cysteine (NAC) for fatigue in progressive MS. Secondary objectives evaluated changes in fatigue and oxidative pathway biomarkers on NAC versus placebo. METHODS: Individuals with progressive MS with Modified Fatigue Impact Scale (MFIS) > t38 were randomized 2:1 to NAC 1250mg TID or placebo for 4 weeks. The primary outcome was tolerability and safety. The secondary outcome to evaluate efficacy was MFIS change from baseline to week 4 between groups. Exploratory biomarker outcomes included change in blood GSH/GSSG ratio (reduced-to-oxidized glutathione (GSH)) and in vivo relative GSH using 7T MR spectroscopy (MRS) between groups. Fisher exact test was used for categorical and rank sum for continuous outcomes. RESULTS: Fifiteen were randomized (10 NAC, 5 placebo; mean age 56.1 years, 80% female, median EDSS 6.0). At least one adverse event (AE) occurred in 60% on NAC versus 80% on placebo (p = 0.75). There were two AEs attributed to NAC in one patient (abdominal pain and constipation), with 94% adherence to NAC. MFIS decreased in both groups at week 4, with the mean improvement of 11-points on NAC versus 18-points on placebo (p = 0.33). GSH/GSSG ratio decreased on placebo (-0.6) and NAC (-0.1) (p = 0.18). Change in GSH levels to total creatine in anterior and posterior cingulate cortex, insula, caudate, putamen, and thalamus did not differ between groups. INTERPRETATION: NAC was well-tolerated in progressive MS, although reduction in fatigue on NAC was similar to placebo. Antioxidant blood and MRS biomarkers were not significantly altered by NAC, which could be due to dose, route of administration, time of sample collection, short half-life, or lack of effect. REGISTERED: clinicaltrials.gov NCT02804594.

Consenso sobre la identificación y seguimiento de la esclerosis múltiple secundaria progresiva en Argentina / Argentinean consensus guidelines on the identification and clinical care of secondary progressive multiple sclerosis

INTRODUCCIÓN: Existen diferencias significativas en el diagnóstico, la identificación y el seguimiento de pacientes con esclerosis múltiple secundaria progresiva (EMSP) entre los profesionales de la salud a cargo de su tratamiento. OBJETIVO: Proveer recomendaciones sobre el tratamiento de los pacientes con EMSP en Argentina con el fin de optimizar su cuidado. DESARROLLO: Un grupo de neurólogos expertos en esclerosis múltiple de Argentina elaboró un consenso para el tratamiento de pacientes con EMSP en la región mediante metodología de ronda de encuestas a distancia y reuniones presenciales. Se establecieron 33 recomendaciones basadas en la evidencia publicada y en el criterio de los expertos que participaron. Las recomendaciones se enfocaron en el diagnóstico y el seguimiento de los pacientes con EMSP. CONCLUSIÓN: Las recomendaciones establecidas en el presente consenso permitirían optimizar el cuidado y el seguimiento de los pacientes con EMSP en Argentina

INTRODUCTION: The identification, diagnosis, follow-up, and treatment of patients with secondary progressive multiple sclerosis (SPMS) show significant differences between health care professionals in Argentina. AIM: To provide consensus recommendations on the management of patients with SPMS in Argentina to optimize patient care. DEVELOPMENT: A panel of expert neurologists from Argentina dedicated to the diagnosis and care of multiple sclerosis patients gathered during 2019 and 2020 to carry out a consensus recommendation on the diagnosis and treatment of SPMS patients in Argentina. To achieve consensus, the methodology of formal consensus-RAND/UCLA method was used. Recommendations were established based on published evidence and the expert opinion. Recommendations focused on how to define SPMS and how to follow SPMS patients. CONCLUSION: The recommendations of this consensus guidelines attempt to optimize the care of SPMS patients in Argentina

Real-world experience of ocrelizumab in multiple sclerosis in a Spanish population.

OBJECTIVE: Pivotal trial have shown that patients with multiple sclerosis (MS) receiving ocrelizumab had better outcomes. However, data on ocrelizumab in clinical practice are limited. The aim of this study was to evaluate the preliminary safety profile and effectiveness of ocrelizumab treatment for multiple sclerosis (MS) in a real-world clinical setting. METHODS: We conducted a retrospective study including consecutive patients from nine public hospitals in south-eastern Spain who received ocrelizumab after it was approved. RESULTS: A total of 228 MS patients were included (144 with relapsing-remitting MS [RRMS], 25 secondary progressive MS [SPMS], and 59 primary progressive MS [PPMS]). Median follow-up period was 12 months (range, 1-32). No evidence of disease activity (NEDA) status at year 1 was achieved in 91.2% of the relapsing MS (RMS) population, while disability progression was detected in 37.5% of the PPMS patients (median follow-up period, 19 months). The most common adverse events reported were infusion-related reactions and infections, with the most common infections being urinary tract infections followed by upper respiratory infections and COVID-19. INTERPRETATION: The preliminary results in our real-world setting show that ocrelizumab presented excellent results in suppressing disease activity with a favorable and consistent safety profile.

Increasing Progenitor Cell Proliferation in the Sub-Ventricular Zone: A Therapeutic Treatment for Progressive Multiple Sclerosis?

INTRODUCTION: The purpose of this study was to determine if pharmacological treatment could increase progenitor cell proliferation in the Sub-ventricular Zone of aged rats. Previous work had shown that increasing progenitor cell proliferation in this region correlated well (R2=0.78; p= 0.0007) with functional recovery in a damaged corpus callosum (white matter tract), suggesting that progenitor cell proliferation results in oligodendrocytes in this region. METHODS: 10 month old male and female Sprague Dawley rats were fed the drugs for 30 days in cookie dough, then immunocytochemistry was performed on coronal brain sections, using Ki67 labeling to determine progenitor cell proliferation. RESULTS: Female rats showed low endogenous (control) progenitor cell proliferation, significantly different from male rats (P<0.0001), at this age. Ascorbic Acid (20 mg/kg, daily for 30 days) increased progenitor cell proliferation overall, but maintained the innate gender difference in stem cell proliferation (P=0.001). Prozac (5 mg/kg, daily for 30 days) increased progenitor cell proliferation for females but decreased stem cell proliferation for males, again showing a gender difference (P<0.0001). Simvastatin (1 mg/kg for 30 days) also increased progenitor cell proliferation in females and decreased progenitor cell proliferation in males, leading to a significant gender difference. DISCUSSION: The three drug combinations (fluoxetine, simvastatin, and ascorbic acid, patent # 9,254,281) led to ~ 4 fold increase in progenitor cell proliferation in females, while male progenitor cell proliferation was highest with 50 mg/kg ascorbic acid. However, the ascorbic acid increase in proliferation appears to be only on the sides of the ventricles, which is not the region that normally gives rise to oligodendrocytes. CONCLUSION: There are innate gender differences in progenitor cell proliferation at the Sub-Ventricular Zone at middle age in rats, possibly due to the loss of estrogen in females. We also see notable gender differences in progenitor cell proliferation in the Sub ventricular Zone in response to common drugs, such as fluoxetine, simvastatin and Vitamin C (ascorbic acid).

Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort. METHODS: SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29). FINDINGS: From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (<1%) person died in the MD1003 group and there were no deaths in the placebo group. Despite use of mitigation strategies, MD1003 led to inaccurate laboratory results for tests using biotinylated antibodies. INTERPRETATION: This study showed that MD1003 did not significantly improve disability or walking speed in patients with progressive multiple sclerosis and thus, in addition to the potential of MD1003 for deleterious health consequences from interference of laboratory tests, MD1003 cannot be recommended for treatment of progressive multiple sclerosis. FUNDING: MedDay Pharmaceuticals.

Siponimod: A Review in Secondary Progressive Multiple Sclerosis.

Oral siponimod (Mayzent®), a next-generation, selective sphingosine 1-phosphate receptor (S1PR) 1 and 5 modulator, is approved in several countries for the treatment of secondary progressive multiple sclerosis (SPMS), with specific indications varying between individual countries. In the pivotal EXPAND trial (median duration double-blind treatment 18 months) in a broad spectrum of patients with SPMS, once-daily oral siponimod 2 mg (initial dose titration over 6 days) was significantly more effective than placebo in reducing clinical and MRI-defined outcomes of disease activity and disability progression, including 3-month confirmed disability progression on the Expanded Disability Status Scale (EDSS), and was generally well tolerated in the core phase of the study. These beneficial effects of siponimod appeared to be sustained during up to 5 years of treatment in the ongoing open-label extension phase of EXPAND. The safety profile of siponimod is similar to that of other agents in its class, including adverse events of special interest (i.e. those known to be associated with S1PR modulators). No new safety signals were identified during up to 5 years' treatment in the open-label extension phase. Albeit further long-term efficacy and safety data from the real-world setting are required to fully define its role, given the paucity of current treatment options and its convenient dosage regimen, siponimod represents an important emerging option for the treatment of adult patients with SPMS with active disease evidenced by relapses or imaging-features of inflammatory activity.

Rituximab versus natalizumab, fingolimod, and dimethyl fumarate in multiple sclerosis treatment.

INTRODUCTION: Limited comparative effectiveness data for rituximab (RTX) versus natalizumab (NTZ), fingolimod (FTY), and dimethyl fumarate (DMF) for the treatment of multiple sclerosis (MS) exist. METHODS: Clinician-reported data on patients prescribed RTX, NTZ, FTY, or DMF for the treatment of MS at the Rocky Mountain MS Center at the University of Colorado were retrospectively collected. Outcomes included a composite effectiveness measure consisting of clinical relapse, contrast-enhancing lesions, and/or new T2 lesions, individual effectiveness outcomes, and discontinuation. Logistic regression was used on patients matched by propensity scores and using average treatment effect on treated doubly robust weighting estimator. RESULTS: A total of 182, 451, 271, and 342 patients initiated RTX, NTZ, FTY, and DMF and were followed for 2 years. Before and after adjustment, the odds of experiencing disease activity was significantly higher for FTY [adjusted OR (aOR) = 3.17 (95% CI: 1.81-5.55), P < 0.001].and DMF [aOR = 2.68 (95% CI:1.67-4.29), P < 0.001], and similar for NTZ [aOR = 1.36 (95% CI:0.83-2.23), P = 0.216] versus RTX. When examining months 6-24, NTZ demonstrated higher odds of disease activity compared to RTX [aOR = 2.21 (95% CI: 1.20-4.06), P = 0.007]. Similar odds of discontinuation were seen between NTZ and RTX [aOR = 1.39 (95% CI: 0.88-2.20), P = 0.157]; however, FTY [aOR = 2.02 (95% CI: 1.24-3.30), P = 0.005] and DMF [aOR = 3.27 (95% CI: 2.15-4.97), P < 0.001] had greater odds of discontinuation than RTX. INTERPRETATION: RTX demonstrated superior effectiveness and discontinuation outcomes compared to FTY and DMF. Although RTX demonstrated similar effectiveness and discontinuation compared to NTZ, RTX had superior effectiveness during months 6-24 and fewer discontinuations when excluding discontinuations due to insurance issues. Results suggest superiority of RTX in reducing disease activity and maintaining long-term treatment in a real-world MS cohort.

Conduction delays in the visual pathways of progressive multiple sclerosis patients covary with brain structure.

In developed countries, multiple sclerosis (MS) is the leading cause of non-traumatic neurological disability in young adults. MS is a chronic demyelinating disease of the central nervous system, in which myelin is attacked, changing white matter structure and leaving lesions. The demyelination has a direct effect on white matter conductivity. This effect can be examined in the visual system, where damage is highly prevalent in MS, leading to substantial delays in conduction, commonly measured with visual evoked potentials (VEPs). The structural damage to the visual system in MS is often estimated with MRI measurements in the white matter. Recent developments in quantitative MRI (qMRI) provide improved sensitivity to myelin content and new structural methods allow better modeling of the axonal structure, leading researchers to link white matter microstructure to conduction properties of action potentials along fiber tracts. This study attempts to explain the variance in conduction latencies down the visual pathway using structural measurements of both the retina and the optic radiation (OR). Forty-eight progressive MS patients, participants in a longitudinal stem-cell therapy clinical trial, were included in this study, three and six months post final treatment. Twenty-seven patients had no history of optic neuritis, and were the main focus of this study. All participants underwent conventional MRI scans, as well as diffusion MRI and qMRI sequences to account for white matter microstructure. Optical coherence tomography scans were also obtained, and peripapillary retinal nerve fiber layer (pRNFL) thickness and macular volume measurements were extracted. Finally, latencies of recorded VEPs were estimated. Our results show that in non-optic neuritis progressive MS patients there is a relationship between the VEP latency and both retinal damage and OR lesion load. In addition, we find that qMRI values, sampled along the OR, are also correlated with VEP latency. Finally, we show that combining these parameters using PCA we can explain more than 40% of the inter-subject variance in VEP latency. In conclusion, this study contributes to understanding the relationship between the structural properties and conduction in the visual system in disease. We focus on the visual system, where the conduction latencies can be estimated, but the conclusions could be generalized to other brain systems where the white matter structure can be measured. It also highlights the importance of having multiple parameters when assessing the clinical stages of MS patients, which could have major implications for future studies of other white matter diseases.