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Complement activation in cerebrospinal fluid in clinically isolated syndrome and early stages of relapsing remitting multiple sclerosis
Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping.
Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.ORCID iD: 0000-0001-9456-2044
Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping.
Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
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2020 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 340, article id 577147Article in journal (Refereed) Published
Abstract [en]

To assess if markers of complement activation are associated with disease activity, C1q, C3, C3a and sC5b-9 levels in plasma and cerebrospinal fluid (CSF) were determined in 41 patients with clinically isolated syndrome (CIS) or remitting multiple sclerosis (RRMS), in a prospective longitudinal four-year cohort study. C1q in CSF (CSF-C1q) was significantly higher in patients than in controls. Baseline CSF-C1q and CSF-C3a correlated with several neuroinflammatory markers and neurofilament light chain levels. Baseline CSF-C3a correlated with the number of T2 lesions at baseline and new T2 lesions during follow-up. Baseline CSF-C3a was also significantly higher in patients with (n = 21) than in patients without (n = 20) signs of disease activity according to the NEDA-3 concept during one year of follow-up (p ≀ .01) Study results support that complement activation is involved in MS pathophysiology and that CSF-C3a carries prognostic information.

Place, publisher, year, edition, pages
Elsevier, 2020. Vol. 340, article id 577147
Keywords [en]
Complement system, C1q, C3a, Multiple sclerosis, Clinically isolated syndrome, Disease activity
National Category
Neurology Rheumatology and Autoimmunity Clinical Laboratory Medicine
Identifiers
URN: urn:nbn:se:liu:diva-163143DOI: 10.1016/j.jneuroim.2020.577147ISI: 000514757300005OAI: oai:DiVA.org:liu-163143DiVA, id: diva2:1386037
Note

Funding agencies:  Medical Research Council of Southeast Sweden (FORSS); NEURO Sweden; Swedish Research CouncilSwedish Research Council [K2013-61X-22310-01-4, 2016-2075-5.1]; ALF grants, Region Ostergotland; Linnaeus University

Available from: 2020-01-16 Created: 2020-01-16 Last updated: 2020-03-09Bibliographically approved
In thesis
1. Biomarkers and Disease Activity in Multiple Sclerosis: A cohort study on patients with clinically isolated syndrome and relapsing remitting multiple sclerosis
Open this publication in new window or tab >>Biomarkers and Disease Activity in Multiple Sclerosis: A cohort study on patients with clinically isolated syndrome and relapsing remitting multiple sclerosis
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2019. p. 78
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1697
National Category
Neurology
Identifiers
urn:nbn:se:liu:diva-160762 (URN)10.3384/diss.diva-160762 (DOI)9789176850121 (ISBN)
Public defence
2019-10-18, Berzeliussalen, Hus 463, Campus US, Linköping, 13:00 (Swedish)
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Supervisors
Available from: 2019-10-07 Created: 2019-10-07 Last updated: 2020-01-16Bibliographically approved

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Håkansson, IreneErnerudh, JanVrethem, MagnusDahle, Charlotte

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Division of Inflammation and InfectionFaculty of Medicine and Health SciencesDepartment of Neurology in LinköpingDepartment of Clinical Immunology and Transfusion MedicineDivision of Neurobiology
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