Oxylipins in cerebrospinal fluid in clinically isolated syndrome and relapsing remitting multiple sclerosis
Introduction
Relapsing remitting multiple sclerosis (RRMS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). Pathology, clinical presentation and disease progression in RRMS is highly variable. Clinically isolated syndrome (CIS) denotes a first episode of neurological symptoms consistent with demyelinating inflammation in the CNS, but where the criteria for multiple sclerosis (MS) diagnosis, which require dissemination in time and space, are not fulfilled. Many patients with CIS later convert to MS, but some do not.
Oxylipins is an umbrella term for fatty acid metabolites involved in maintaining homeostasis. Prostaglandins belong to the eicosanoids, a sub-category of oxylipins derived from arachidonic acid (AA). Other oxylipins are derived from linoleic acid or various other polyunsaturated fatty acids by non-enzymatic oxidation, or cyclooxygenase, lipoxygenase and cytochrome P450 catalyzed reactions. The vast network of bioactive lipid mediators covered by the oxylipin metabolome includes molecules with both pro- and anti-inflammatory properties and several of them have been extensively studied in relation to disease states with an inflammatory component [1]. Mapping this network in a physiological context is challenging, but a better understanding of how altered levels associate with disease may facilitate novel preventive and therapeutic strategies and reveal potential disease biomarkers.
The structural similarities and low abundance of most of the constituents in the oxylipin metabolome have previously been obstacles for quantification in complex human body fluids and tissues. However, recent technological and laboratory advances in lipidomics now enable accurate quantification of these compounds with liquid chromatography combined with tandem mass spectrometry (LCMS/MS) methods [2,3]. The physiological roles, including pro-inflammatory and anti-inflammatory functions, of all the constituents in the oxylipin metabolome have not yet been fully elucidated. Regarding oxylipins in MS patients, there are reports of increased levels of 13-hydroxyoctadecadienoic acid (HODE) in plasma [4] and increased levels of prostaglandin E2 (PGE2) and 15-hydroxyeicosatetraenoic acid (HETE) in cerebrospinal fluid (CSF) from MS patients compared to controls [5]. Increased levels of PGE2 and 15-HETE in CSF were also reported in active MS in a study comparing more active MS patients to less active MS patients [6], whereas CSF levels of 4-, 7-, 14- and 17-hydroxydocosahexaenoic acid (HDHA), 5- and 12-HETE, PGD2, PGF2, lipoxin A4 and B4 (LXA4, LXB4), leukotriene B4 (LTB4), thromboxane B2 (TXB2), AA, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) did not differ significantly between these groups [6].
The aim of this study was to compare levels of a panel of constituents in the CSF oxylipin metabolome in treatment free patients with CIS or RRMS and healthy controls. Furthermore, we explored whether levels of these metabolites correlated to clinical parameters, magnetic resonance imaging (MRI) parameters and a panel of protein markers of neuroinflammation and neurodegeneration. Finally, to assess prognostic biomarker potential, we investigated whether baseline metabolite levels differed between patients that showed signs of disease activity during follow-up and patients that did not.
Section snippets
Patients and controls
41 patients with CIS or RRMS were consecutively enrolled in a prospective longitudinal cohort study of CIS and newly diagnosed MS at the Department of Neurology, University Hospital of Linköping, Sweden. All patients fulfilled the revised McDonald criteria from 2010 [7] for CIS or MS. Patients underwent clinical neurological examination including expanded disability status scale (EDSS), peripheral blood and CSF sampling and MRI at baseline and at one, two and four years of follow-up. Only CSF
Oxylipins in patients and healthy controls
9-HODE and 13-HODE levels were significantly higher in patients than in healthy controls, both p < 0.001 (Table 2 and Fig. 1). Excluding the two patients with chronic pain did not change this finding (both p still <0.001). Samples from patients had longer storage times than samples from healthy controls, but ANCOVA analysis showed that there was a significant difference between HODE levels in patients and healthy controls also when storage time was controlled for. 9-HODE and 13-HODE levels
Discussion
We report that CSF levels of 9-HODE and 13-HODE were significantly higher in patients with CIS and RRMS than in healthy controls. Patients in relapse had significantly higher levels of 11,12-DHET than patients not in relapse at the time of sample collection and this lipid was also significantly higher in men compared to women in the patient group. 9-HODE and 13-HODE performed well at separating patients and healthy controls and also correlated with several protein markers of neuroinflammation
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These authors contributed equally to this work.