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This thesis focuses on disease activity in clinically isolated syndrome (CIS) and newly diagnosed relapsing remitting multiple sclerosis (RRMS). The papers are based on data from 41 patients in a prospective longitudinal cohort study. All patients were untreated at baseline. Age- and sex-matched healthy controls (n=22) for blood and cerebrospinal fluid (CSF) samples were recruited from blood donors. Paper I evaluated the prognostic value of baseline levels of CXCL1, CXCL8, CXCL10, CXCL13, CCL22, neurofilament light chain (NFL), neurofilament heavy chain, glial fibrillary acidic protein, chitinase-3-like-1 (CHI3L1), matrix metalloproteinase-9 (MMP-9) and osteopontin in CSF in relation to disease activity during the first two years of follow-up. Disease activity was defined as clinical relapses, new T2 lesions in brain magnetic resonance imaging (MRI) and/or sustained Expanded Disability Status Scale (EDSS) progression. Absence of these three signs of disease activity was called no evidence of disease activity (NEDA-3). Logistic regression analysis showed that NFL in CSF was the best predictive marker of disease activity and correctly classified 93% of the patients with evidence of disease activity during two years of follow-up and 67% of those without. Paper II presented four year follow-up data from the cohort and also included brain volume data as well as serum levels of NFL. The correlation between NFL in CSF and serum was fairly strong (r=0.74, p<0.001). NFL in CSF was associated with new T2 lesions as well as with brain volume loss, whereas CHI3L1 in CSF was associated mainly with brain volume loss and CXCL1, CXCL10, CXCL13, CCL22 and MMP-9 in CSF were mainly associated with new T2 lesions. Taken together, paper I and II confirm and extend the knowledge of NFL as a useful biomarker in CIS and RRMS and suggests that NFL, rather than total brain volume loss, could be included in an expanded NEDA concept and used in clinical monitoring of disease activity/treatment effect. Although serum levels of NFL were correlated with the corresponding CSF levels, CSF-NFL showed a stronger association to subsequent disease activity (NEDA-3). Paper III addressed the patients´ self-reported Modified Fatigue Impact Scale (MFIS) scores in relation to other cohort study data. MFIS scores correlated with other self-assessment questionnaire data (Hospital Anxiety and Depression scale (HAD), Multiple Sclerosis Impact Scale 29 (MSIS-29) and Short Form 36 (SF-36) scores (Spearman´s rho 0.45-0.78, all p?0.01)) but not with EDSS ratings, number of T2 lesions, total brain volume or NFL levels, indicating that subjective fatigue scores are not well reflected by some commonly used and objectively measurable disease parameters. Paper IV focused on the complement factors C1q, C3, C3a and sC5b-9 in CSF and plasma. CSFC1q was significantly higher in patients than in controls at baseline. The subgroup of patients with ongoing relapse at baseline also had higher levels of CSF-C3a than controls. Baseline levels of CSF-C1q and CSF-C3a correlated significantly with several pro-inflammatory chemokines as well as with MMP-9, CHI3L1 and NFL in CSF. Baseline CSF-C3a also correlated significantly with the number of T2 lesions and Gadolinium enhancing lesions in brain MRI at baseline, as well as with the number of new T2 lesions during follow-up. This study indicates that the complement system is involved already at early stages of MS. It also suggests that especially CSF-C1q and CSF-C3a levels are associated with other neuroinflammatory and neurodegenerative markers and that CSF-C3a levels may carry some prognostic information.
Several processes are presumed to sequentially or simultaneously contribute to the pathophysiology of multiple sclerosis (MS). This work examines the potential of biomarkers in the context of MS. It explores the state of biomarker research for MS, barriers to progress and possible solutions and priorities.
Clinical, biological, and radiological evidence are currently needed to diagnose MS, but lack of preclinical biomarkers hinders the earliest possible diagnosis and treatment. Conventional biomarkers target immunity, blood-brain barrier disruption, demyelination, and neuronal and axonal damage, as well as mitochondrial activity. An increase of specific brain metabolites with 30,Äì40% is registered before detection of MRI lesions in MS. Potential lipid biomarkers are fatty acids, phospholipids, and oxysterols. The role of proteoforms in the pathogenesis of MS was confirmed. Serum neurofilament light chains (sNfL) are currently being studied as a readily available biomarker for prognosis and response to treatment in MS. The sNfL levels reflect ongoing neuroaxonal damage caused by inflammation, and the sNfL levels predict disease activity over the next few years. The retinal nerve fiber layer (RNFL) thinning is reliable as a biomarker of disability worsening. The neutrophil-to-lymphocyte ratio and CRP are also MS biomarkers. The development of rationally targeted therapeutic agents that allow preventive treatment to stop the disease is also delayed without definite biomarkers.
This book provides cutting-edge information on the epidemiology, etiopathogenesis, clinical manifestations, diagnostic procedures and treatment approaches for the main white matter (WM) disorders of the central nervous system (CNS). WM lesions are associated with many neurological conditions, and with aging. The diagnostic work-up of neurological diseases characterized by the presence of these lesions has changed dramatically over the past few years. This is mainly due on the one hand to the discovery of specific pathogenetic factors in some of these conditions, and on the order to the optimized use of diagnostic tools. All of this has resulted in new diagnostic algorithms, and in the identification of new neurological conditions. The book offers neurologists essential guidance in the diagnosis and treatment of the most frequent WM conditions, promoting their correct and cost-saving diagnosis and management. By integrating neurological, laboratory and imaging concepts with the demands of accurate diagnosis, this reference guide provides a state-of-the-art overview of the current state of knowledge on these conditions, as well as practical guidelines for their diagnosis and treatment.
Multiple sclerosis (MS) is a lifelong neurological condition that has no known cure. This book provides an extensive exploration of current and future directions for understanding immunology, neuroscience, and the development of potent treatment modalities. It presents an in-depth analysis and expert commentary on the role of genetics, lifestyle factors, biomarkers, neuroimaging, cognitive domains, artificial intelligence, and innate immunity in MS pathogenesis. We hope that the book is helpful to readers of all spheres of life, including those who want to understand more about MS, those who are keen to improve their understanding of MS disease pathogenesis, those who are enthusiastic to know more about treatment modalities, and those who want to be informed about state-of-the-art clinical developments in MS.
In this issue of Neurologic Clinics, guest editor Dr. Carrie M. Hersh brings her considerable expertise to the topic of Multiple Sclerosis. Top experts in the field discuss diagnosis and pathophysiology concepts, treatment, special populations in MS, and contemporary issues related to MS. Contains 18 relevant, practice-oriented topics including recent advances in diagnostic, prognostic, and disease monitoring biomarkers in MS; the growing problem of MS misdiagnosis; highly effective therapy versus escalation approaches in early MS; clinical considerations in the diagnosis, management, and treatment of MS in Black and Latinx populations; women’s health and pregnancy in MS; the era of COVID-19 in MS care; and more. Provides in-depth clinical reviews on multiple sclerosis, offering actionable insights for clinical practice. Presents the latest information on this timely, focused topic under the leadership of experienced editors in the field. Authors synthesize and distill the latest research and practice guidelines to create clinically significant, topic-based reviews.
Multiple sclerosis (MS) is characterized by a dysregulated immune system leading to chronic inflammation in the central nervous system. Despite increasing number of treatments, many patients continue to deteriorate. A better understanding of the underlying disease mechanisms involved in driving disease is a pre-requisite for finding new biomarkers and new treatment targets. The improvement of MS during pregnancy, comparable to the beneficial effects of the most effective treatment, suggests that the transient and physiological immune tolerance established during pregnancy could serve as a model for successful immune regulation. Most likely the immune-endocrine alterations that take place during pregnancy to accommodate the presence of the semi-allogenic fetus contribute to the observed disease improvement. The aim of this thesis was to characterize the dysregulated immune system in MS and define potential factors and mechanisms established during pregnancy that could be involved in the pregnancy-induced effects in MS, focusing on CD4+ T cells as one of the main drivers in immunity and in the MS pathogenesis. Using a network-based modular approach based on gene expression profiling, we could show that CD4+ T cells from patients with MS displayed an altered dynamic gene response to activation, in line with a dysregulated immune system in MS. The resulting gene module disclosed cell activation and chemotaxis as central components in the deviating response, results that form a basis for further studies on its modulation during pregnancy. Moreover, a combination of secreted proteins (OPN+CXCL1-3+CXCL10-CCL2), identified from the module, could be used to separate patients and controls, predict disease activity after 2 years and discriminate between high and low responders to treatment, highlighting their potential use as biomarkers for predicting disease activity and response to treatment. The pregnancy hormone progesterone (P4), a potential factor involved in the pregnancy-induced amelioration of MS, was found to significantly dampen CD4+ T cell activation. Further detailed transcriptomic profiling revealed that P4 almost exclusively down-regulated immune-related pathways in activated T cells, several related to or downstream of T cell activation such as JAKSTAT signaling, T cell receptor signaling and cytokine-cytokine receptor interaction. In particular, P4 significantly affected genes of relevance to diseases known to be modulated during pregnancy, where genes associated to MS were most significantly affected, supporting a role for P4 in the pregnancy-induced immunomodulation. By using another approach, the role of thymus in T cell regulation during pregnancy was assessed. Two established measures of thymic output, CD31 expression and TREC content, were used and showed that thymic output of T cells is maintained during human pregnancy, or even possibly increased in terms of regulatory T cells. This thesis further supports a pivotal role for CD4+ T cells and T cell activation in the MS pathogenesis and adds to the knowledge of how they could be involved in driving disease. We identified a novel strategy for capturing central aspects of the deviating response to T cell activation that could be translated into potentially clinically relevant biomarkers. Further, P4 is emerging as a promising candidate for the pregnancy-induced immunomodulation that could be of importance as a future treatment option. Lastly, maintained thymic output of T cells during human pregnancy challenges the rodent-based dogma of an inactive thymus during pregnancy. Thymic dysfunction has been reported not only in MS but also in rheumatoid arthritis, another inflammatory disease that improves during pregnancy, which highlights a potential role for thymus in immune regulation that could be involved in the pregnancy-induced amelioration.