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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.
Multiple sclerosis is a chronic and often disabling disease of the nervous system, affecting about 1 million people worldwide. Even though it has been known for over a hundred years, no cause or cure has yet been discovered-but now there is hope. New therapies have been shown to slow the disease progress in some patients, and the pace of discoveries about the cellular machinery of the brain and spinal cord has accelerated. This book presents a comprehensive overview of multiple sclerosis today, as researchers seek to understand its processes, develop therapies that will slow or halt the disease and perhaps repair damage, offer relief for specific symptoms, and improve the abilities of MS patients to function in their daily lives. The panel reviews existing knowledge and identifies key research questions, focusing on: Research strategies that have the greatest potential to understand the biological mechanisms of recovery and to translate findings into specific strategies for therapy. How people adapt to MS and the research needed to improve the lives of people with MS. Management of disease symptoms (cognitive impairment, depression, spasticity, vision problems, and others). The committee also discusses ways to build and financially support the MS research enterprise, including a look at challenges inherent in designing clinical trials. This book will be important to MS researchers, research funders, health care advocates for MS research and treatment, and interested patients and their families.
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.
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.
Over the past decade, we have made great advances in the field of multiple sclerosis (MS) research, and this book focuses on those advances in MS pathogenesis and treatment. While some of these advances have been through new approaches and ideas that have emerged in the last decade such as the newly identified protective role that amyloid proteins may play in MS or the use of helminths to treat autoimmune diseases, others have evolved from previous theories and ideas that have only now gained momentum and a deeper understanding such as the role of HLA or gender in MS susceptibility. This book covers these emerging and evolving topics and highlights the substantial advancements made in elucidation of the factors regulating susceptibility or disease progression, identification of new ways to monitor or predict MS pathology, and development of new strategies for treating MS.
This is the latest edition of the classic book on the subject of multiple sclerosis. An international group of authors has been involved in updating this edition which features more information on imaging and investigations, and a new chapter on neurobiology and glial development.
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 revised, updated second edition draws together the basic science, pathology, epidemiology and treatment possibilities in progressive multiple sclerosis. Each chapter addresses specific aspects of progressive multiple sclerosis providing an extensive review of the current literature and a discussion of the likely mechanisms of tissue injury relevant to the disease. New additions to the second edition include a description of clinical scales used to determine levels of disability; recent trials specifically directed at reducing disease progression; rehabilitation; and an in depth discussion of the similarities and differences between primary and secondary multiple sclerosis. The biological processes underlying disease progression are elucidated as are specific pathophysiological mechanisms. The basic science of axonal degeneration and the clinical understanding of progressive multiple sclerosis are discussed in the context of emerging and future therapies for disease progression as are trials which have been and will be conducted for progressive multiple sclerosis. An overview of biomarkers for the disease is included and existing symptomatic therapies for progressive multiple sclerosis are covered in detail. Progressive Multiple Sclerosis, Second Edition is ideal for both general neurologists and those with a specialist interest in multiple sclerosis. It will also be of interest to neurologists in training and other medical professionals treating this common disease.