Single-nucleus RNA-seq of normal-appearing brain regions in relapsing-remitting vs. secondary progressive multiple sclerosis

Multiple sclerosis (MS) is an immune-mediated demyelinating disease that alters central nervous system (CNS) functions. Relapsing-remitting MS (RRMS) is the most common form, which can transform into secondary-progressive MS (SPMS) that is associated with progressive neurodegeneration. Single-nucleus RNA sequencing (snRNA-seq) of MS lesions identified disease-related transcriptomic alterations; however, their relationship to non-lesioned MS brain regions has not been reported and which could identify prodromal or other disease susceptibility signatures. Here, snRNA-seq was used to generate high-quality RRMS vs. SPMS datasets of 33,197 nuclei from 8 normal-appearing MS brains, which revealed divergent cell type-specific changes. Notably, SPMS brains downregulated astrocytic sphingosine kinases (SPHK1/2), the enzymes required to phosphorylate and activate the MS drug, fingolimod. This reduction was modeled with astrocyte-specific Sphk1/2 null mice in which fingolimod lost activity, supporting functionality of observed transcriptomic changes. These data provide an initial resource for studies of single cells from non-lesioned RRMS and SPMS brains.

Guanidinoacetate–creatine in secondary progressive multiple sclerosis: a case report

Acute secondary progressive multiple sclerosis (SPMS) is characterized by escalating neurological disability, with limited disease-modifying therapeutic options. A 48-year-old woman with acute SPMS being treated with interferon beta-1a and oral corticosteroids presented as a clinical outpatient with no disease-modifying effects after treatment. A decision was made to treat her with a combination of guanidinoacetate and creatine for 21 days. She had made clinical progress at follow-up, with the intensity of fatigue dropping from severe to mild. Magnetic resonance spectroscopy revealed increased brain choline, creatine, N-acetylaspartate, and glutathione. Patients with SPMS may benefit from guanidinoacetate–creatine treatment in terms of patient- and clinician-reported outcomes; this requires additional study.

Impact of clinical outcomes and imaging measures on health-related quality of life in secondary progressive MS

Background: Health-related quality of life (HRQOL) outcomes are often included as secondary outcomes in clinical trials in secondary progressive MS (SPMS), but little is known about the longitudinal association of HRQOL and clinical and imaging outcome measures in SPMS. Objective: To assess the association of change in clinical and imaging outcomes with HRQOL in people with SPMS. Methods: We used data from ASCEND, a large randomized controlled trial ( n = 889), to investigate the association of significant worsening on the Expanded Disability Status Scale (EDSS), Timed 25 Foot Walk (T25FW), Nine Hole Peg Test (NHPT), Symbol Digit Modalities Test (SDMT), and change in lesional and volumetric imaging outcomes with significant worsening on the 36-Item Short Form Health Survey (SF-36) and the Multiple Sclerosis Impact Scale (MSIS-29) during 2 years of follow-up using logistic regression models. Results: HRQOL measures were most associated with EDSS and T25FW, less so with NHPT and SDMT, and not associated with lesional and volumetric imaging outcomes. Discussion: Worsening of the EDSS and T25FW was associated with two commonly used HRQOL measures. These outcomes therefore appear to be more patient relevant than either the NHPT or SDMT in the context of a 2-year clinical trial.

Density strips: visualisation of uncertainty in clinical data summaries and research findings

The disproportionate focus on statistical significance in reporting and interpreting clinical research studies contributes to publication bias and encourages selective reporting. This highlights a need for alternative approaches that clearly communicate the uncertainty in the data, enabling researchers to provide a more nuanced interpretation of clinical research findings.Our purpose in this article is to introduce the density strip method as one potential approach that might act as a bridge between data visualisation for descriptive purposes and formal statistical inference. We build on existing theory, translating it to the applied research context to illustrate its utility to clinical researchers.We achieve this by considering an exemplar clinical trial, Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART). MS-SMART was a multiarm randomised placebo-controlled trial of three potentially neuroprotective drugs in secondary progressive MS. We illustrate through MS-SMART the potential of the density strip as an effective visualisation of the distribution of clinical trial outcomes and as a complementary approach to aid the interpretation of formal, inferential, statistical analysis.We conclude by summarising the advantages and disadvantages of the density strip methodology and provide suggestions for its potential extensions and possible further uses.

The significance of time stages in different types of multiple sclerosis course for the formation of prognosis

Background. The purpose was to develop a prognosis assessment system based on clinical and mathematical analysis of indicators at different stages in various types of the course of multiple sclerosis. Materials and methods. Clinical (clinical neurological method and survey using a questionnaire developed at the Department of Autoimmune and Degenerative Pathology of the Nervous System of the State Institution “Institute of Neurology, Psychiatry and Narcology of the National Academy of Medical Sciences of Ukraine”) and mathematical and statistical (permutation test) methods were applied. Using the method of permutation (permutation test) in groups of patients with different types of multiple sclerosis, the differences in the mean values of clinical indicators were evaluated characterizing the type of multiple sclerosis course at different time stages: preclinical stage, the onset, recurrent stage for relapsing-remitting and secondary progressive multiple sclerosis, stage of progression — for secondary and primary progressive multiple sclerosis. On this basis, clinical indicators were identified, which with a high probability (confidence interval of 0.95) at each time stage of multiple sclerosis determine the final prognosis of the disease. Results. We have examined 280 patients: 80 (50 women and 30 men) with a relapsing-remitting course, 140 (80 women and 60 men) with a secondary progressive course and 60 (30 women and 30 men) with a primary progressive course of multiple sclerosis. The nature of prognosis (good and uncertain with a relapsing-remitting course, uncertain and poor with progressive types) was assessed on the basis of clinical and diagnostic criteria developed taking into account the features of the disease course as a whole. The studies have shown that a good prognosis is highly probable with a combination of clinical indicators such as mild onset, complete remission after onset, mild relapses developing rapidly, and long-term remission between relapses at a relapsing-remitting stage; uncertain prognosis — in the presence of moderate onset, stem symptoms at the onset, severe and moderate relapses, and a tendency to aggravate and lengthen relapses at a relapsing-remitting stage. A poor prognosis in a secondary progressive course is reliably associated with the chickenpox at the preclinical stage in a premorbid history, lightning-fast onset development, steady progression proceeding without clinically outlined periods of stabilization; uncertain prognosis — with a fast development of the onset. A poor prognosis in a primary progressive course was closely associated with severe traumatic brain injury at the preclinical stage in a premorbid history, cerebellar symptoms at the onset, formation of the progression stage immediately after the onset, without the stabilization period, steady type of progression at the stage of progression; uncertain prognosis — with herpetic infections at the preclinical stage in a premorbid history, mild onset, the formation of a progression stage after a stabilization period that occurred after the onset, incremental progression at the progression stage proceeding in the form of alternating periods of slow accumulation of neurological deficit, which, as a rule, has a local focus, and stages of stabilization with different duration. Conclusions. Thus, with the help of clinical and mathematical analysis, it was shown that the formation of alternative prognosis variants for different types of multiple sclerosis occurs through a selective involvement in a single pattern of clinical indicators that have diagnostic significance at different time stages of the course of the disease.

Charting a global research strategy for progressive MS—An international progressive MS Alliance proposal

Background: Progressive forms of multiple sclerosis (MS) affect more than 1 million individuals globally. Recent approvals of ocrelizumab for primary progressive MS and siponimod for active secondary progressive MS have opened the therapeutic door, though results from early trials of neuroprotective agents have been mixed. The recent introduction of the term ‘active’ secondary progressive MS into the therapeutic lexicon has introduced potential confusion to disease description and thereby clinical management. Objective: This paper reviews recent progress, highlights continued knowledge and proposes, on behalf of the International Progressive MS Alliance, a global research strategy for progressive MS. Methods: Literature searches of PubMed between 2015 and May, 2021 were conducted using the search terms “progressive multiple sclerosis”, “primary progressive multiple sclerosis”, “secondary progressive MS”. Proposed strategies were developed through a series of in-person and virtual meetings of the International Progressive MS Alliance Scientific Steering Committee. Results: Sustaining and accelerating progress will require greater understanding of underlying mechanisms, identification of potential therapeutic targets, biomarker discovery and validation, and conduct of clinical trials with improved trial design. Encouraging developments in symptomatic and rehabilitative interventions are starting to address ongoing challenges experienced by people with progressive MS. Conclusion: We need to manage these challenges and realise the opportunities in the context of a global research strategy, which will improve quality of life for people with progressive MS.