Association of Arachidonic Acid-Derived Lipid Mediators With Disease Severity in Patients With Relapsing and Progressive Multiple Sclerosis

Abstract

Background and objectives: Excessive activation of certain lipid mediator (LM) pathways plays a role in the complex pathogenesis of multiple sclerosis (MS). However, the relationship between bioactive LMs and different aspects of CNS-related pathophysiologic processes remains largely unknown. Therefore, in this study, we assessed the association of bioactive LMs belonging to the ω-3/ω-6 lipid classes with clinical and biochemical (serum neurofilament light [sNfL] and serum glial fibrillary acidic protein [sGFAP]) parameters and MRI-based brain volumes in patients with MS (PwMS) and healthy controls (HCs).

Methods: A targeted high-performance liquid chromatography-tandem mass spectrometry approach was used on plasma samples of PwMS and HCs of the Project Y cohort, a cross-sectional population-based cohort that contains PwMS all born in 1966 in the Netherlands and age-matched HCs. LMs were compared between PwMS and HCs and were correlated with levels of sNfL, sGFAP, disability (Expanded Disability Status Scale [EDSS]), and brain volumes. Finally, significant correlates were included in a backward multivariate regression model to identify which LMs best related to disability.

Results: The study sample consisted of 170 patients with relapsing remitting MS (RRMS), 115 patients with progressive MS (PMS), and 125 HCs. LM profiles of patients with PMS significantly differed from those of patients with RRMS and HCs, particularly patients with PMS showed elevated levels of several arachidonic acid (AA) derivatives. In particular, 15-hydroxyeicosatetraenoic acid (HETE) (r = 0.24, p < 0.001) correlated (average r = 0.2, p < 0.05) with clinical and biochemical parameters such as EDSS and sNfL. In addition, higher 15-HETE levels were related to lower total brain (r = -0.24, p = 0.04) and deep gray matter volumes (r = -0.27, p = 0.02) in patients with PMS and higher lesion volume (r = 0.15, p = 0.03) in all PwMS.

Discussion: In PwMS of the same birth year, we show that ω-3 and ω-6 LMs are associated with disability, biochemical parameters (sNfL, GFAP), and MRI measures. Furthermore, our findings indicate that, particularly, in patients with PMS, elevated levels of specific products of the AA pathway, such as 15-HETE, associate with neurodegenerative processes. Our findings highlight the potential relevance of ω-6 LMs in the pathogenesis of MS.

Figure 1. Two-Way Hierarchical Clustered Heatmap Shows Differences in LM Profiles Related to the ω-3/ω-6 Lipid Pathways

Heatmap with hierarchical cluster analysis (Euclidean distance) showing the distribution of Project Y cohort participants (x-axis) over the 3 sample clusters that are based on the ω-3/ω-6 lipid mediator plasma levels (y-axis). Table indicates the cohort group distribution over the sample clusters (χ² test = 0.0008). AA = arachidonic acid; AdA = adrenic acid; DGLA = dihomo-γ-linolenic acid; DHA = docosahexaenoic acid; DiHDPA = dihydroxydocosapentaenoic acid; DiHET = dihydroxyeicosatrienoic acid; DiHETE = dihydroxyeicosatetraenoic acid; DPA = docosapentaenoic acid; HETE = hydroxyeicosatetraenoic acid; HODE = hydroxyoctadecadienoic acid; LM = lipid mediator; HC = healthy control; MS = multiple sclerosis; PMS = progressive MS; RRMS = relapsing-remitting MS; SC = sample cluster.

Figure 2. Volcano Plots Displaying Significant Differences of ω-3/ω-6 LMs Between HC and MS Groups

Volcano plots showing the log2 fold change of LMs between the HCs and (A) patients with RRMS and (B) patients with PMS. (C) Log2 fold change of LMs between patients with RRMS and PMS. Level of significance is indicated on the y-axis as –log10(p value). AA = arachidonic acid; AdA = adrenic acid; DGLA = dihomo-γ-linolenic acid; DHA = docosahexaenoic acid; DiHDPA = dihydroxydocosapentaenoic acid; DiHET = dihydroxyeicosatrienoic acid; DiHETE = dihydroxyeicosatetraenoic acid; DPA = docosapentaenoic acid; HETE = hydroxyeicosatetraenoic acid; HODE = hydroxyoctadecadienoic acid; LM = lipid mediator; HC = healthy control; MS = multiple sclerosis; PMS = progressive MS; RRMS = relapsing-remitting MS.

Figure 3. Schematic Overview of ω-3/ω-6 LM Pathways and Correlations With Clinical Parameters

This figure represents all significant correlations between lipid mediators, clinical and biochemical parameters (EDSS, NfL, and GFAP) in both patients with progressive MS and in the whole MS group. Symbols and colors are indicative of the direction of the correlation (orange/hexagonal = positive correlation, blue/square = negative correlation), and numbers are indicative for the clinical/biochemical correlate (1 = EDSS, 2 = sNFL, 3 = sGFAP). AdA = adrenic acid; DGLA = dihomo-γ-linolenic acid; DHA = docosahexaenoic acid; DiHDPA = dihydroxydocosapentaenoic acid; DiHET = dihydroxyeicosatrienoic acid; DiHETE = dihydroxyeicosatetraenoic acid; DPA = docosapentaenoic acid; EDSS = Expanded Disability Status Scale; EPA = eicosapentaenoic acid; HETE = hydroxyeicosatetraenoic acid; HODE = hydroxyoctadecadienoic acid; LA = linoleic acid; LM = lipid mediator; GFAP = glial fibrillary acidic protein; LM = lipid mediator; NfL = neurofilament light; PLS-DA = partial least squares discriminant analysis; sGFAP = serum GFAP; sNfL = serum NfL.