Soluble Epoxide Hydrolase-Derived Linoleic Acid Oxylipins in Serum Are Associated with Periventricular White Matter Hype
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ORIGINAL ARTICLE
Soluble Epoxide Hydrolase-Derived Linoleic Acid Oxylipins in Serum Are Associated with Periventricular White Matter Hyperintensities and Vascular Cognitive Impairment Di Yu 1,2,3,4 & Marie Hennebelle 5 & Demetrios J. Sahlas 6 & Joel Ramirez 1 & Fuqiang Gao 1 & Mario Masellis 1,7 & Hugo Cogo-Moreira 8,9 & Richard H. Swartz 1,7 & Nathan Herrmann 1 & Pak Cheung Chan 10,11 & Jacqueline A. Pettersen 12 & Donald T. Stuss 1,7,13 & Sandra E. Black 1,3,4,7 & Ameer Y. Taha 5 & Walter Swardfager 1,2,3,4,14 Received: 23 May 2018 / Revised: 15 October 2018 / Accepted: 18 October 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract White matter hyperintensities (WMH) are presumed to indicate subcortical ischemic vascular disease but their underlying pathobiology remains incompletely understood. The soluble epoxide hydrolase (sEH) enzyme converts anti-inflammatory and vasoactive cytochrome p450-derived polyunsaturated fatty acid epoxides into their less active corresponding diol species. Under the hypothesis that the activity of sEH might be associated with subcortical ischemic vascular disease and vascular cognitive impairment, this study aimed to compare the relative abundance of sEH substrates and products in peripheral blood between patients with extensive WMH (discovered due to transient ischemic attack; n = 29) and healthy elderly with minimal WMH (n = 25). The concentration of 12,13-DiHOME (a sEHderived linoleic acid metabolite), and the ratio of 12,13-DiHOME to its sEH substrate, 12,13-EpOME, were elevated in the extensive WMH group (F1,53 = 5.9, p = 0.019), as was the 9,10-DiHOME/9,10-EpOME ratio (F1,53 = 5.4, p = 0.024). The 12,13-DiHOME/ 12,13-EpOME ratio was associated with poorer performance on a composite score derived from tests of psychomotor processing speed, attention, and executive function (β = − 0.473, p = 0.001, adjusted r2 = 0.213), but not with a composite verbal memory score. In a mediation model, periventricular WMH (but not deep WMH), explained 37% of the effect of the 12,13-DiHOME/12,13-EpOME ratio on the speed/attention/executive function composite score (indirect effect = − 0.50, 95% bootstrap confidence interval [− 0.99, − 0.17] Zscore units). Serum oxylipin changes consistent with higher sEH activity were markers of vascular cognitive impairment, and this association was partly explained by injury to the periventricular subcortical white matter. Keywords Small vessel disease . Vascular cognitive impairment . Oxylipins . Soluble epoxide hydrolase . Linoleic acid
Ameer Y. Taha and Walter Swardfager contributed equally to this work. * Walter Swardfager [email protected]
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Department of Medicine (Neurology Division), University of Toronto, Toronto, Canada
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Departamento Psiquiatria, Universidade Federal de São Paulo, São Paulo, Brazil
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Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Canada
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Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada
Department of Education and Psychology:
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