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Biomarkers and Disease Activity in Multiple Sclerosis: A cohort study on patients with clinically isolated syndrome and relapsing remitting multiple sclerosis
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology in Linköping.
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: urn:nbn:se:liu:diva-160762DOI: 10.3384/diss.diva-160762ISBN: 9789176850121 (print)OAI: oai:DiVA.org:liu-160762DiVA, id: diva2:1358189
Public defence
2019-10-18, Berzeliussalen, Hus 463, Campus US, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2019-10-07 Created: 2019-10-07 Last updated: 2019-10-08Bibliographically approved
List of papers
1. Neurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing-remitting multiple sclerosis
Open this publication in new window or tab >>Neurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing-remitting multiple sclerosis
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2017 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 24, no 5, p. 703-712Article in journal (Refereed) Published
Abstract [en]

Background and purpose: Improved biomarkers are needed to facilitate clinical decision-making and as surrogate endpoints in clinical trials in multiple sclerosis (MS). We assessed whether neurodegenerative and neuroinflammatory markers in cerebrospinal fluid (CSF) at initial sampling could predict disease activity during 2 years of follow-up in patients with clinically isolated syndrome (CIS) and relapsing-remitting MS. Methods: Using multiplex bead array and enzyme-linked immunosorbent assay, CXCL1, CXCL8, CXCL10, CXCL13, CCL20, CCL22, neurofilament light chain (NFL), neurofilament heavy chain, glial fibrillary acidic protein, chitinase-3-like-1, matrix metalloproteinase-9 and osteopontin were analysed in CSF from 41 patients with CIS or relapsing-remitting MS and 22 healthy controls. Disease activity (relapses, magnetic resonance imaging activity or disability worsening) in patients was recorded during 2 years of follow-up in this prospective longitudinal cohort study. Results: In a logistic regression analysis model, NFL in CSF at baseline emerged as the best predictive marker, correctly classifying 93% of patients who showed evidence of disease activity during 2 years of follow-up and 67% of patients who did not, with an overall proportion of 85% (33 of 39 patients) correctly classified. Combining NFL with either neurofilament heavy chain or osteopontin resulted in 87% overall correctly classified patients, whereas combining NFL with a chemokine did not improve results. Conclusions: This study demonstrates the potential prognostic value of NFL in baseline CSF in CIS and relapsing-remitting MS and supports its use as a predictive biomarker of disease activity.

Place, publisher, year, edition, pages
WILEY, 2017
Keywords
biomarker; clinically isolated syndrome; disease activity; multiple sclerosis; neurofilament light chain
National Category
Neurology
Identifiers
urn:nbn:se:liu:diva-137379 (URN)10.1111/ene.13274 (DOI)000399704400010 ()28261960 (PubMedID)
Note

Funding Agencies|Swedish Research Council [K2013-61X-22310-01-4]; Linkoping University, Sweden; University Hospital Linkoping, Sweden; Novartis; Torsten Soderberg foundation; Royal Academy of Sciences, Sweden

Available from: 2017-05-18 Created: 2017-05-18 Last updated: 2019-10-07
2. Neurofilament levels, disease activity and brain volume during follow-up in multiple sclerosis
Open this publication in new window or tab >>Neurofilament levels, disease activity and brain volume during follow-up in multiple sclerosis
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2018 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 15, article id 209Article in journal (Refereed) Published
Abstract [en]

Background: There is a need for clinically useful biomarkers of disease activity in clinically isolated syndrome (CIS) and relapsing remitting MS (RRMS). The aim of this study was to assess the correlation between neurofilament light chain (NFL) in cerebrospinal fluid (CSF) and serum and the relationship between NFL and other biomarkers, subsequent disease activity, and brain volume loss in CIS and RRMS. Methods: A panel of neurodegenerative and neuroinflammatory markers were analyzed in repeated CSF samples from 41 patients with CIS or RRMS in a prospective longitudinal cohort study and from 22 healthy controls. NFL in serum was analyzed using a single-molecule array (Simoa) method. "No evidence of disease activity-3" (NEDA-3) status and brain volume (brain parenchymal fraction calculated using SyMRI (R)) were recorded during 4 years of follow-up. Results: NFL levels in CSF and serum correlated significantly (all samples, n = 63, r 0.74, p amp;lt; 0.001), but CSF-NFL showed an overall stronger association profile with NEDA-3 status, new T2 lesions, and brain volume loss. CSF-NFL was associated with both new T2 lesions and brain volume loss during follow-up, whereas CSF-CHI3L1 was associated mainly with brain volume loss and CXCL1, CXCL10, CXCL13, CCL22, and MMP-9 were associated mainly with new T2 lesions. Conclusions: Serum and CSF levels of NFL correlate, but CSF-NFL predicts and reflects disease activity better than S-NFL. CSF-NFL levels are associated with both new T2 lesions and brain volume loss. Our findings further add to the accumulating evidence that CSF-NFL is a clinically useful biomarker in CIS and RRMS and should be considered in the expanding NEDA concept. CSF-CXCL10 and CSF-CSF-CHI3L1 are potential markers of disease activity and brain volume loss, respectively.

Place, publisher, year, edition, pages
BMC, 2018
Keywords
Multiple sclerosis; Clinically isolated syndrome; Disease activity; Neurofilament light chain; CHI3L1; CXCL10; Brain volume
National Category
Neurology
Identifiers
urn:nbn:se:liu:diva-150263 (URN)10.1186/s12974-018-1249-7 (DOI)000439133500001 ()30021640 (PubMedID)
Note

Funding Agencies|Swedish Research Council [K2013-61X-22310-01-4]; Linkoping University; University Hospital of Linkoping, Sweden; Novartis; Torsten Soderberg Foundation; Royal Academy of Sciences, Sweden

Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2019-10-07

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