Primary Progressive Multiple Sclerosis Research Articles

Understanding who benefits most from cognitive rehabilitation for multiple sclerosis: A secondary data analysis

Background: Up to 70% of people with multiple sclerosis (MS) experience cognitive difficulties. Cognitive rehabilitation is a type of therapy that helps manage cognitive problems. Objective: The Cognitive Rehabilitation for Attention and Memory in MS (CRAMMS) trial showed some evidence of effectiveness of cognitive rehabilitation in improving cognitive function, with some participants benefitting more than others. We therefore conducted a secondary analysis of the CRAMMS data to understand who benefits most. Methods: We grouped baseline data into four categories of possible predictors. We used regression models to identify specific factors/characteristics that could predict the likelihood that an individual will benefit from cognitive rehabilitation. Results: The models predicted whether a participant improved or did not improve in neuropsychological function following cognitive rehabilitation in up to 86% of participants. Results suggest that younger participants with medium to high education, diagnosed with relapsing-remitting multiple sclerosis (RRMS) and primary-progressive multiple sclerosis (PPMS) who have not experienced any recent relapses, with mild to moderate cognitive difficulties were most likely to benefit from cognitive rehabilitation. Conclusion: We can predict which participants are most likely to demonstrate significant improvements in neuropsychological function following group-based cognitive rehabilitation. Clinically, this allows us to optimise limited neuropsychology resources by offering such cognitive rehabilitation to those most likely to benefit.

The Role of Exercise on Fatigue Among Patients With Multiple Sclerosis in the King Fahad Hospital, Madinah, Saudi Arabia: An Analytical Cross-Sectional Study.

Background Multiple sclerosis (MS) is a chronic autoimmune disease caused by multiple factors. It can lead to many physical and mental symptoms. Fatigue is one of the most commonly mentioned complaints among MS patients that can affect their quality of life. Physical activityhas many benefits for the physical and mental health of patients with MS. Aim To assess the role of exercise on fatigue among patients with multiple sclerosis and identify the relationship between depression, sleep quality, sociodemographic variables, and fatigue. Methods This is an analytical cross-sectional study based on a sample size of 235patients recruited from the MS clinic at King Fahad Hospital (KFH) in Madinah. The outcome of the study was fatigue among MS patients. Data were collected through telephone calls from February to May 2022 using a structured questionnaire and scales, such as the Godin Leisure-Time Exercise Questionnaire (GLTEQ), Modified Fatigue Impact Scale (MFIS), Patient Health Questionnaire (PHQ2), and Pittsburgh Sleep Quality Index (PSQI). Data were analyzed through SPSS version 20 (IBM Corp., Armonk, NY, USA). The correlation coefficient (r), Chi-square tests, and simple and multiple logistic regression were used as found appropriate. Results Out of the total samples, 37.4% were male and 62.6% were female. The median age of patients was 36 years. The prevalence of fatigue was 37% among patients, with a reported median fatigue score of 26. It was found that 63% of the patients were physically inactive; 32.2% were overweight, 14.2% were obese; 63.8% of patients had poor sleep quality. The fatigue score was negatively correlated with the GLTEQ score, but the results were not significant (r=-0.066; P-value (level of significance)=0.335). Nonetheless, a moderately significant correlation was observed between the MFIS and PSQI and MFIS and PHQ2 (r=0.505, P=<0.001 and r=0.520, P=<0.001, respectively). The Chi-square test showed a significant association between fatigue and progressive types of MS, the primary progressive MS (PPMS), secondary progressive MS (SPMS), and relapsing-remitting MS (RRMS) (odds ratio (OR)=4.4; 95%confidence interval (CI): 2.1-8.9), P=<0.001). Depressed patients were 9.7 times more likely to develop fatigue compared to non-depressed patients (P=<0.001). Those with poor sleep quality were 4.6 times more likely to develop fatigue compared to those with good sleep quality (P=<0.001).Fifty-six percent of fatigue among MS patients were predicted by low income, progressive types, unemployment, obesity, depression, and poor sleep quality. Conclusion Fatigue is a major complaint among MS patients. Most of the patients were found to be physically inactive, depressed, and have poor sleep quality. This study found an association between physical inactivity and fatigue, but the results were not significant. There was a significant association between sociodemographic factors like low income and unemployment, poor sleep quality, obesity, progressive types of MS, depression, and fatigue. Encouraging exercise practice and implementing a regularexercise program are needed, along with weight management plans. Further studies and psychological support meetings are required, with the importance of a holistic approach to patient care.

Sociodemographic and Neuroimaging Evaluation of Patients with Multiple Sclerosis and Radiologically Isolated Syndrome in Isfahan, Iran

Background: Multiple sclerosis (MS) is categorized into four subtypes, including clinically-isolated syndrome (CIS), primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), and relapsing-remitting multiple sclerosis (RRMS). On the other hand, radiologically-isolated syndrome (RIS) is characterized by the imaging manifestations of MS rather than its clinical symptoms. Objectives: This study aimed to compare the sociodemographic and neuroimaging findings of different MS phenotypes and RIS. Methods: The current cross-sectional study was conducted on 3716 patients at the Multiple Sclerosis Clinic of Kashani Hospital, Isfahan, Iran, from June 2018 to April 2019. Patients presenting with RIS, CIS, and MS were included in this study. Results: The age of disease onset was remarkably lower in patients with RRMS, while the body mass index was significantly higher in RIS (P-value &lt; 0.05). Other factors, including gender, occupation, marital status, smoking, and family history of MS, showed no significant difference (P-value &gt; 0.05). Neuroimaging assessments revealed significant differences in terms of the location of the plaques, the activity of the plaques, brain atrophy, lesion load, the number of cervical plaques, and the presence of longitudinally-extended transverse myelitis (P-value &lt; 0.05), but not regarding the activity of cervical and thoracolumbar plaques and the number of thoracolumbar lesions (P-value &gt; 0.05). Conclusions: Different MS phenotypes showed variations in terms of sociodemographic and neuroimaging characteristics. Follow-up studies are recommended to determine the risk factors predicting the conversion of RIS and CIS to other MS phenotypes.

Visual function resists early neurodegeneration in the visual system in primary progressive multiple sclerosis

BackgroundNeurodegeneration in multiple sclerosis (MS) affects the visual system but dynamics and pathomechanisms over several years especially in primary progressive MS (PPMS) are not fully understood.MethodsWe assessed longitudinal changes in...

The natural history of primary progressive multiple sclerosis: insights from the German NeuroTransData registry

BackgroundPrimary progressive multiple sclerosis (PPMS) is characterised by gradual worsening of disability from symptom onset. Knowledge about the natural course of PPMS remains limited.MethodsPPMS patients from the German NeuroTransData (NTD) MS registry with data from 56 outpatient practices were employed for retrospective cross-sectional and longitudinal analyses. The cross-sectional analysis included a contemporary PPMS cohort with a documented visit within the last 2 years before index date (1 Jan 2021). The longitudinal analysis included a disease modifying therapy (DMT)-naïve population and focused on the evolution of expanded disability status scale (EDSS) from the first available assessment at or after diagnosis within the NTD registry to index date. Outcome measures were estimated median time from first EDSS assessment to first 24-week confirmed EDSS ≥ 4 and ≥ 7. Besides EDSS change, the proportion of patients on disability pension were described over time.ResultsThe cross-sectional analysis included 481 PPMS patients (59.9% female, mean [standard deviation, SD] age 60.5 [11.5] years, mean [SD] EDSS 4.9 [2.1]). Estimated median time from first EDSS assessment after diagnosis to reach 24-week confirmed EDSS ≥ 4 for DMT-naïve patients was 6.9 years. Median time to EDSS ≥ 7 was 9.7 years for 25% of the population. Over a decade mean (SD) EDSS scores increased from 4.6 (2.1) to 5.7 (2.0); the proportion of patients on disability pension increased from 18.9% to 33.3%.ConclusionsThis study provides first insights into the German NTD real-world cohort of PPMS patients. Findings confirm the steadily deteriorating course of PPMS accompanied by increasingly limited quality of life.

Patient-reported outcomes in multiple sclerosis: a prospective registry cohort study.

Registries have the potential to tackle some of the current limitations in determining the long-term impact of multiple sclerosis. Online assessments using patient-reported outcomes can streamline follow-up enabling large-scale, long-term, cost-effective, home-based, and patient-focused data collection. However, registry data are sparsely sampled and the sensitivity of patient-reported outcomes relative to clinician-reported scales is unknown, making it hard to fully leverage their unique scope and scale to derive insights. This retrospective and prospective cohort study over 11 years involved 15 976 patients with multiple sclerosis from the United Kingdom Multiples Sclerosis Register. Primary outcomes were changes in two patient-reported outcomes: Multiple Sclerosis Impact Scale motor component, and Multiple Sclerosis Walking Scale. First, we investigated their validity in measuring the impact of physical disability in multiple sclerosis, by looking at their sensitivity to disease subtype and duration. We grouped the available records (91 351 for Multiple Sclerosis Impact Scale motor and 68 092 for Multiple Sclerosis Walking Scale) by these two factors, and statistically compared the resulting groups using a novel approach based on Monte Carlo permutation analysis that was designed to cope with the intrinsic sparsity of registry data. Next, we used the patient-reported outcomes to draw novel insights into the developmental time course of subtypes; in particular, the period preceding the transition from relapsing to progressive forms. We report a robust main effect of disease subtype on the patient-reported outcomes and interactions of disease subtype with duration (all P < 0.0001). Specifically, patient-reported outcomes worsen with disease duration for all subtypes (all P < 0.0001) apart from benign multiple sclerosis (Multiple Sclerosis Impact Scale motor: P = 0.796; Multiple Sclerosis Walking Scale: P = 0.983). Furthermore, the patient-reported outcomes of each subtype are statistically different from those of the other subtypes at all time bins (Multiple Sclerosis Impact Scale motor: all P < 0.05; Multiple Sclerosis Walking Scale: all P < 0.01) except when comparing relapsing-remitting multiple sclerosis with benign multiple sclerosis and primary progressive multiple sclerosis with secondary progressive multiple sclerosis. Notably, there were statistically significant differences between relapsing-remitting and progressive subtypes at disease onset. Critically, the patient-reported outcomes are sensitive to future transitions to progressive subtypes, with individuals who transition presenting with higher patient-reported outcomes in their relapsing-remitting phase compared to individuals who don't transition since onset (all P < 0.0001). Patient-reported outcomes capture different patterns of physical worsening over disease length and across subtypes; therefore, they are a valid tool to measure the physical impact of multiple sclerosis over the long-term and cost-effectively. Furthermore, more advanced physical disability manifests years before clinical detection of progressive subtypes, adding evidence to the presence of a multiple sclerosis prodrome.

Restoring Control: Bladder and Bowel Function Assessment in Multiple Sclerosis Rehabilitation

Aims: This study aim was to evaluate the impact of multiple sclerosis on bowel and bladder function and its consequences for socialization and sexual function in MS patients. Additionally, it sought to investigate potential variations in these effects among different MS subtypes. Methodology: A total of 780 participants were internationally recruited, with a predominant representation from the United States. Participants completed self-reported surveys assessing bowel and bladder function, and their MS subtype (relapsing-remitting, primary progressive, or secondary progressive) was documented. Results: Findings indicated that most respondents reported occasional issues with bowel and bladder function. Notably, individuals with primary progressive and secondary progressive MS demonstrated a higher prevalence of bowel and bladder difficulties compared to those with relapsing-remitting MS. Scientific Novelty: This study offers new insights by highlighting the distinct impact of MS subtypes on bowel and bladder function. It underscores the importance of understanding how MS affects various functions of the organism, beyond the central nervous system, and its repercussions for patients' quality of life. Practical Significance of the Results Obtained: The practical significance of this research lies in its potential to inform clinical practice and enhance the QoL for MS patients. Recognizing the unique challenge faced by individuals with primary progressive and secondary progressive MS in terms of bowel and bladder function enables the healthcare providers tailoring interventions and accordingly supporting services. Conclusion: The Multiple sclerosis exerts a multifaceted impact on patients. This study underscored that the type of MS a patient has can significantly affect their bowel and bladder function, potentially leading to difficulties in socialization and sexual function. Acknowledging the study's limitations, including the self-reported data, these findings emphasized the importance of comprehensive care strategies for MS patients.

Threshold definitions for significant change on the timed 25-foot walk and nine-hole peg test in primary progressive multiple sclerosis.

The timed 25-foot walk (T25FW) and nine-hole peg test (NHPT) exhibit random variability in the short term. A threshold of ≥20% change from baseline has been used to indicate true disability change, but other threshold definitions may be better suited to exclude false and include true change events. The aim of this study was to use patient-level original trial data to investigate the short-term variation in T25FW and NHPT, and to compare its extent with disability change at 12-month follow-up in people with primary progressive multiple sclerosis (PPMS). We used original patient-level data from PROMISE, a large PPMS trial. In this trial, three separate T25FW and NHPT measurements were performed 1 week apart during screening. We used these repeated measures to describe the extent of short-term variation. We used binary logistic regression models to investigate the association between screening characteristics and unacceptable short-term variation. The traditional 20% threshold excluded a reasonable number of false change events, while also yielding a large number of change events at follow-up. Increasing index values on the T25FW and NHPT were associated with higher short-term variation. The traditional ≥20% change threshold for the T25FW and NHPT represents a reasonable compromise between reducing the number of false change events and achieving the largest number of change events in people with PPMS. Our analyses inform the design of clinical trials in PPMS.

Role of the immune system in amyotrophic lateral sclerosis. Analysis of the natural killer cells and other circulating lymphocytes in a cohort of ALS patients

AimsNeuroinflammation might be involved in the degeneration and progression of Amyotrophic Lateral Sclerosis (ALS). Here, we studied the role of the circulating lymphocytes in ALS, in particular the NK cells. We focused on the relationship between blood lymphocytes, ALS clinical subtype and disease severity.Subjects and MethodsBlood samples were collected from 92 patients with sporadic ALS, 21 patients with Primary Lateral Sclerosis (PLS) and 37 patients affected by primary progressive multiple sclerosis (PPMS) with inactive plaques. Blood was taken from ALS and controls at the time of diagnosis/referral. Circulating lymphocytes were analyzed by flow cytometry with specific antibodies. Values were expressed as absolute number (n°/µl) of viable lymphocytes subpopulations in ALS were compared with controls. Multivariable analysis was made using site of onset, gender changes in ALSFRS-R and disease progression rate (calculated as ΔFS score).ResultsAge at onset was 65y (58–71) in ALS (spinal 67.4%; bulbar, 32.6%), 57y (48–78) in PLS and 56y (44–68) PPMS. Absolute blood levels of the lymphocytes in the different cohorts were within normal range. Furthermore, while levels of lymphocytes T and B were not different between disease groups, NK cells were increased in the ALS cohort (ALS = 236 [158–360] vs. Controls = 174[113–240], p < 0.001). In ALS, blood levels of NK cells were not related with the main clinical-demographic variables, including the rate of disease progression. Multivariable analysis suggested that male gender and bulbar onset were independently associated with a risk of high blood NK cells levels.ConclusionsWe show that blood NK cells are selectively increased in ALS, though their level appear unaffected in patients with an estimated rapidly progressing disease. Being of a male gender and with a bulbar onset seems to confer higher susceptibility to have increased NK lymphocytes levels at diagnosis/referral. Our experiments provides a further clear-cut evidence of the role of the NK lymphocytes as a significant player in ALS pathogenesis.

Cognitive function in primary and secondary progressive multiple sclerosis: a multiparametric MRI study.

The differences in cognitive function between primary progressive (PP) and secondary progressive (SP) multiple sclerosis (MS) remain unclear. We compared cognitive performance between PPMS and SPMS, and explored the structural and functional MRI correlates of their cognitive functions. Seventy-five healthy controls and 183 MS patients (60 PPMS and 123 SPMS) underwent 3.0T MRI. MS patients were administered the Brief Repeatable Battery of Neuropsychological Tests; cognitive domain z-scores were calculated and then averaged to obtain a measure of global cognition. Using hierarchical linear regression analysis, the contribution of lesion volumes, normalized brain volumes, white matter fractional anisotropy (FA) and mean diffusivity abnormalities, and resting state (RS) functional connectivity (FC) alterations to global cognition in PPMS and SPMS was investigated. PPMS and SPMS had similar z-scores in all investigated cognitive domains. Poor global cognitive function resulted associated with decreased FA of the medial lemniscus (ΔR2 =0.11; p=0.011) and lower normalized gray matter volume (ΔR2 =0.29; p<0.001) in PPMS, and with decreased FA of the fornix (ΔR2 =0.35; p<0.001) and lower normalized white matter volume (ΔR2 =0.05; p=0.034) in SPMS. PPMS and SPMS had similar neuropsychological performance. Cognitive dysfunction in PPMS and SPMS was related to distinct patterns of structural MRI abnormalities and involvement of different white matter tracts, while RS FC alterations did not contribute to explain their global cognitive functioning.

Processing speed and memory test performance are associated with different brain region volumes in Veterans and others with progressive multiple sclerosis.

Cognitive dysfunction and brain atrophy are both common in progressive multiple sclerosis (MS) but are seldom examined comprehensively in clinical trials. Antioxidant treatment may affect the neurodegeneration characteristic of progressive MS and slow its symptomatic and radiographic correlates. This study aims to evaluate cross-sectional associations between cognitive battery components of the Brief International Cognitive Assessment for Multiple Sclerosis with whole and segmented brain volumes and to determine if associations differ between secondary progressive (SPMS) and primary progressive (PPMS) MS subtypes. The study was based on a baseline analysis from a multi-site randomized controlled trial of the antioxidant lipoic acid in veterans and other people with progressive MS (NCT03161028). Cognitive batteries were conducted by trained research personnel. MRIs were processed at a central processing site for maximum harmonization. Semi-partial Pearson's adjustments evaluated associations between cognitive tests and MRI volumes. Regression analyses evaluated differences in association patterns between SPMS and PPMS cohorts. Of the 114 participants, 70% had SPMS. Veterans with MS made up 26% (n = 30) of the total sample and 73% had SPMS. Participants had a mean age of 59.2 and sd 8.5 years, and 54% of them were women, had a disease duration of 22.4 (sd 11.3) years, and had a median Expanded Disability Status Scale of 6.0 (with an interquartile range of 4.0-6.0, moderate disability). The Symbol Digit Modalities Test (processing speed) correlated with whole brain volume (R = 0.29, p = 0.01) and total white matter volume (R = 0.33, p < 0.01). Both the California Verbal Learning Test (verbal memory) and Brief Visuospatial Memory Test-Revised (visual memory) correlated with mean cortical thickness (R = 0.27, p = 0.02 and R = 0.35, p < 0.01, respectively). Correlation patterns were similar in subgroup analyses. Brain volumes showed differing patterns of correlation across cognitive tasks in progressive MS. Similar results between SPMS and PPMS cohorts suggest combining progressive MS subtypes in studies involving cognition and brain atrophy in these populations. Longitudinal assessment will determine the therapeutic effects of lipoic acid on cognitive tasks, brain atrophy, and their associations.

Ocrelizumab extended-interval dosing in multiple sclerosis during SARS-CoV-2 pandemic: a real-world experience.

During the COVID-19 pandemic, ocrelizumab administration was frequently postponed because of a lack of safety information and to favour vaccination. The clinical implications of ocrelizumab administration delay in multiple sclerosis (MS) patients were assessed. Relapsing (RMS) and primary progressive (PPMS) MS patients receiving ocrelizumab for at least 6 months at our centre were retrospectively classified, according to the possible occurrence of a delay (≥4 weeks) in treatment administration. Patients were categorized in the extended-interval dosing (EID) group in the presence of at least one delayed infusion; otherwise they were considered as part of the standard interval dosing (SID) cohort. MS history, magnetic resonance imaging examinations and B-cell counts were also retrospectively collected and analysed. A total of 213 RMS and 61 PPMS patients were enrolled; 115 RMS and 29 PPMS patients had been treated according to the SID regimen, whilst 98 RMS and 32 PPMS patients were included in the EID cohort. Average follow-up after delay was 1.28 ± 0.7 years in the EID cohort. In RMS, comparing SID and EID patients, no differences were found considering the occurrence of clinical relapses (9.6% vs. 16.3%, p = 0.338), magnetic resonance imaging activity (9.8% vs. 14.1%, p = 0.374) or disability progression (11.3% vs. 18.4%, p = 0.103). Similar findings were observed in PPMS patients. In the pooled EID group, treatment delay correlated with CD19-positive relative (r = 0.530, p < 0.001) and absolute (r = 0.491, p < 0.001) cell counts, without implications on disease activity. Sporadic ocrelizumab administration delay granted sustained treatment efficacy in our cohort. Prospective data should be obtained to confirm these observations and set up systematic extended-interval regimens.

Trigeminal neuralgia in multiple sclerosis: Association with demyelination and progression.

Trigeminal neuralgia (TN) is a well-recognized symptom of multiple sclerosis (MS), yet its clinical characteristics related to MS subtype is poorly studied. Our aim was to evaluate whether development and clinical outcome of TN are influenced by MS phenotype. In this retrospective cohort study, our database from 2007 to 2022 was reviewed to identify patients who had both the diagnosis of MS and TN, whether TN was an initial symptom of MS or developed later in diagnosis. A detailed medical history and treatment outcome was obtained. Pain status was assessed retrospectively using the Barrow Neurological Institute Pain Scale (BNI-PS), with BNI-PS I-III considered as good pain control and BNI-PS IV-V as poor pain control. 58 patients had MS-related TN. 44 patients had relapsing remitting multiple sclerosis (RRMS) at the time of TN diagnosis, 11 had secondary progressive multiple sclerosis (SPMS) at the time of TN diagnosis, and type of MS was not clear in 3 patients at the time of TN diagnosis (either RRMS or SPMS). Over a mean follow up of 18.8 (SD=10.9) years, 30 transitioned to SPMS. TN was refractory to medical management in 9 RRMS and 22 SPMS patients (p=0.001). TN patients with RRMS required lower median number of pain medications compared to SPMS (p=0.014). Brain MRI was available in 41 of the entire cohort. Of these, 27 patients had demyelinating lesions in the trigeminal sensory pathway and 14 did not. Patients with existing lesions had a higher chance of failure of medical management (74% versus 36%, p=0.017) and required surgical intervention (55% versus 7%, p=0.003). TN was not seen in primary progressive multiple sclerosis (PPMS). In patients who transitioned to SPMS, TN was more likely to be refractory to medical management. TN was more refractory in the presence of demyelinating plaque involving trigeminal sensory pathway.

PCR163 Work Productivity Impairment Among Individuals with Progressive Multiple Sclerosis

To describe and characterize the impact of multiple sclerosis (MS) on work productivity and activity impairment of individuals with active and nonactive primary and secondary progressive MS (PPMS and SPMS).

Central and peripheral myeloid-derived suppressor cell-like cells are closely related to the clinical severity of multiple sclerosis

Multiple sclerosis (MS) is a highly heterogeneous demyelinating disease of the central nervous system (CNS) that needs for reliable biomarkers to foresee disease severity. Recently, myeloid-derived suppressor cells (MDSCs) have emerged as an immune cell population with an important role in MS. The monocytic-MDSCs (M-MDSCs) share the phenotype with Ly-6Chi-cells in the MS animal model, experimental autoimmune encephalomyelitis (EAE), and have been retrospectively related to the severity of the clinical course in the EAE. However, no data are available about the presence of M-MDSCs in the CNS of MS patients or its relation with the future disease aggressiveness. In this work, we show for the first time cells exhibiting all the bona-fide phenotypical markers of M-MDSCs associated with MS lesions, whose abundance in these areas appears to be directly correlated with longer disease duration in primary progressive MS patients. Moreover, we show that blood immunosuppressive Ly-6Chi-cells are strongly related to the future severity of EAE disease course. We found that a higher abundance of Ly-6Chi-cells at the onset of the EAE clinical course is associated with a milder disease course and less tissue damage. In parallel, we determined that the abundance of M-MDSCs in blood samples from untreated MS patients at their first relapse is inversely correlated with the Expanded Disability Status Scale (EDSS) at baseline and after a 1-year follow-up. In summary, our data point to M-MDSC load as a factor to be considered for future studies focused on the prediction of disease severity in EAE and MS.

Long non-coding RNAs BACE1-AS and BC200 in multiple sclerosis and their relation to cognitive function: A gene expression analysis

Cognitive impairment is a common and debilitating feature of multiple sclerosis (MS), and the dysregulation of synaptic plasticity is one of its direct causes. Long non-coding RNAs (lncRNAs) have been shown to play a role in synaptic plasticity, but their role in cognitive impairment in MS has not been fully explored. In this study, using quantitative real-time PCR, we examined the relative expression of two specific lncRNAs, BACE1-AS and BC200, in the serum of two cohorts of MS patients with and without cognitive impairment. Both lncRNAs were overexpressed in both cognitively impaired and non-cognitively impaired MS patients, with consistently higher levels in the cohort with cognitive impairment. We also found a strong positive correlation between the expression levels of these two lncRNAs. Notably, BACE1-AS was consistently higher in the remitting cases of both relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) groups than in the respective relapse cases of the same subtype, with the SPMS-Remitting group of cognitively impaired MS patients showing the highest expression of BACE1-AS among all MS groups. Additionally, we observed that the primary progressive MS (PPMS) group had the highest expression of BC200 in both cohorts of MS. Furthermore, we developed a model called Neuro_Lnc-2, which showed better diagnostic performance than either BACE1-AS or BC200 alone in predicting MS. Our findings suggest that these two lncRNAs may have a significant impact on the pathogenesis of the progressive types of MS and on the cognitive function of the patients. Future research is required to confirm these findings.

Central Versus Peripheral Drug Exposure Ratio, a Key Differentiator for Siponimod Over Fingolimod?

Siponimod, a potent and selective sphingosine-1-phosphate (S1P1,5) agonist, is the only therapeutic agent that has shown efficacy against disability progression, decline in cognitive processing speed, total brain volume loss, gray matter atrophy and signs of demyelination in patients with secondary progressive multiple sclerosis (SPMS). Although the pathophysiology of progression in SPMS and primary progressive MS (PPMS) is thought to be similar, fingolimod, the prototype S1P1,3,45 agonist, failed to show efficacy against disability progression in PPMS. Differentiating siponimod from fingolimod at the level of their central effects is believed to be the key to a better understanding of the underlying characteristics that could make siponimod uniquely efficacious in progressive MS (PMS). Here, we compared the central vs. peripheral dose-dependent drug exposures for siponimod and fingolimod in healthy mice and mice with experimental autoimmune encephalomyelitis (EAE). Siponimod treatment achieved dose-dependent efficacy and dose-proportional increases in steady-state drug blood levels, with a central nervous system (CNS)/blood drug-exposure ratio (CNS/bloodDER) of ~ 6 in both healthy and EAE mice. In contrast, fingolimod treatments achieved dose-proportional increases in fingolimod and fingolimod-phosphate blood levels, with respective CNS/bloodDER that were markedly increased (≥ threefold) in EAE vs. healthy mice. If proven to have translational value, these observations would suggest that CNS/bloodDER may be a key differentiator for siponimod over fingolimod for clinical efficacy in PMS.

Features of Steven L. Hauser's professional activity regarding the application of rehabilitation tools for patients with multiple sclerosis

The article, based on the study and synthesis of scientific literature, establishes that the incidence of multiple sclerosis in the world is high, and treatment is long and not always effective. The professional activities of Dr. Stephen L. Hauser are analyzed. The main topic of his research concerns multiple sclerosis. A multicomponent model is used to rehabilitate patients with this disease, including physical therapy to maintain the individual's motor activity and occupational therapy to improve patient performance and safety.&#x0D; Dr. Gauser's research has expanded the understanding of the genetic determinants, immune mechanisms, and treatment of multiple sclerosis. His work has led to the development of B-cell therapy for patients with the disease, representing a new approach to treating all forms of the disease and the first therapy with proven efficacy for advanced multiple sclerosis. Dr. Steven Gauser was instrumental in the research and clinical trials that ultimately led to Ocrevus (ocrelizumab), the first drug approved by the Food and Drug Administration for both relapsing-remitting and primary progressive multiple sclerosis patients.&#x0D; The development of B-cell therapy for patients with multiple sclerosis in combination with physical rehabilitation has significant benefits and proven efficiency.

Quantitative comparison of the efficacy of clinical drug treatments for primary progressive multiple sclerosis

ObjectiveThis study proposes a comprehensive quantitative evaluation of the efficacy of drugs and placebo in clinical trials for primary progressive multiple sclerosis (PPMS). MethodsA literature search was conducted using the PubMed, EMBASE, and Cochrane library databases and the clinical studies reporting drug efficacy in the treatment of PPMS were included in the analyses. The cumulative proportion of patients without confirmed disability progression (wCDP%) was used as the main efficacy endpoint. The model-based meta-analysis method was used to describe the time course of each drug (as well as placebo) in order to rank the drug efficacy for the treatment of PPMS. ResultsFifteen studies involving 3779 patients were included, of which, nine were placebo-controlled and six were single-arm trials. Twelve drugs were included in the study. The results showed that, except for biotin, interferon β-1a, and interferon β-1b, whose efficacy was comparable to the placebo, the efficacy of the other 9 drugs were significantly better than placebo. Among these, ocrelizumab showed outstanding performance, with wCDP% of 72.6 at 96 weeks, while the proportions of rest of the drugs ranged between approximately 55–70%. ConclusionThe results of this study provide the necessary quantitative information for both the rational clinical use of drugs and future clinical trials in primary progressive multiple sclerosis.

The prevalence and incidence of multiple sclerosis over the past 20 years in northern Japan

The prevalence of multiple sclerosis (MS) in East Asia is thought to be lower than in Western countries. Globally, there is a trend of increasing MS prevalence. We investigated the changes in the prevalence and clinical phenotype of MS in the Tokachi province of Hokkaido in northern Japan, from 2001 to 2021. Data processing sheets were sent to all related institutions inside and outside the Tokachi area of Hokkaido island in Japan and were collected from April to May 2021. The prevalence according to the Poser's diagnostic criteria for MS was determined on March 31, 2021. In 2021, the crude MS prevalence in northern Japan was 22.4/100,000 (95% confidence interval, 17.6-28.0). The prevalences of MS standardized by the Japanese national population in 2001, 2006, 2011, 2016, and 2021 were 6.9, 11.5, 15.3, 18.5, and 23.3, respectively. The female/male ratio was 4.0 in 2021, increased from 2.6 in 2001. We checked the prevalence using the 2017 revised McDonald criteria, and found only additional male patient who had not fulfilled Poser's criteria. The age- and sex-adjusted incidence of MS per 100,000 individuals increased from 0.09 in 1980-1984 to 0.99 in 2005-2009; since then, it has remained stable. The proportions of primary-progressive, relapsing-remitting, and secondary-progressive MS types in 2021 were 3%, 82%, and 15%, respectively. Our results demonstrated a consistent increase in the prevalence of MS among the northern Japanese over 20 years, particularly in females, and consistently lower rates of progressive MS in northern Japan than elsewhere in the world.