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Soluble Epoxide Hydrolase-Derived Linoleic Acid Oxylipins in Serum Are Associated with Periventricular White Matter Hyperintensities and Vascular Cognitive Impairment

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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 sEH-derived 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] Z-score 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.

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Acknowledgements

WS gratefully acknowledges support from the Alzheimer’s Association (US) & Brain Canada, The Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre Department of Psychiatry, Sunnybrook Research Institute Hurvitz Brain Sciences Program, the University of Toronto Department of Pharmacology & Toxicology, and the Centre for Collaborative Drug Research. RHS is grateful to acknowledge support from the Heart and Stroke Foundation New Investigator Award, the Ontario Brain Institute’s Ontario Neurodegenerative Disease Research Initiative (ONDRI), the Departments of Medicine at the University of Toronto and Sunnybrook Health Sciences Centre, the Canadian Partnership for Stroke Recovery, and partial support from the Brill Chair in Neurology at Sunnybrook (Chair holder SEB).

The authors would like to thank Dr. Alan Moody for his contributions to the study, including data collection. The authors would also like to thank Maisha Khan for her contributions to the study, including helping with the samples.

Dr. Yurika Otoki is thanked for her contributions to the oxylipin method development.

Funding

This study is funded by the Alzheimer’s Association (US) and Brain Canada (AARG501466). JR & SEB received financial and salary support from the Fondation Leducq, Canadian Institutes of Health Research (#125740 & #13129), Heart & Stroke Foundation Canadian Partnership for Stroke Recovery, Hurvitz Brain Sciences Research program at Sunnybrook Research Institute and the Linda C. Campbell Foundation. JR additionally received partial funding from the Canadian Vascular Network and the ONDRI. SEB received financial and salary support from the Sunnybrook Research Institute, Sunnybrook Health Sciences Centre Department of Medicine and the Brill Chair Neurology, University of Toronto.

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Author notes

  1. Ameer Y. Taha and Walter Swardfager contributed equally to this work.

Authors and Affiliations

  1. Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Canada

    Di Yu, Joel Ramirez, Fuqiang Gao, Mario Masellis, Richard H. Swartz, Nathan Herrmann, Donald T. Stuss, Sandra E. Black & Walter Swardfager

  2. Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada

    Di Yu & Walter Swardfager

  3. Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, Toronto, Canada

    Di Yu, Sandra E. Black & Walter Swardfager

  4. LC Campbell Cognitive Neurology Unit, Sunnybrook Research Institute, Toronto, Canada

    Di Yu, Sandra E. Black & Walter Swardfager

  5. Department of Food Science and Technology, College of Agriculture and Environmental Sciences, University of California, Davis, CA, USA

    Marie Hennebelle & Ameer Y. Taha

  6. Department of Medicine (Neurology Division), McMaster University, Hamilton, Canada

    Demetrios J. Sahlas

  7. Department of Medicine (Neurology Division), University of Toronto, Toronto, Canada

    Mario Masellis, Richard H. Swartz, Donald T. Stuss & Sandra E. Black

  8. Departamento Psiquiatria, Universidade Federal de São Paulo, São Paulo, Brazil

    Hugo Cogo-Moreira

  9. Department of Education and Psychology: Division of Methods and Evaluation, Freie Universität Berlin, Berlin, Germany

    Hugo Cogo-Moreira

  10. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

    Pak Cheung Chan

  11. Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, Canada

    Pak Cheung Chan

  12. Department of Medicine (Neurology Division) and the Northern Medical Program, University of British Columbia, Vancouver, Canada

    Jacqueline A. Pettersen

  13. Department of Psychology, University of Toronto, Toronto, Canada

    Donald T. Stuss

  14. University Health Network Toronto Rehabilitation Institute, Toronto, Canada

    Walter Swardfager

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  1. Di Yu
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Correspondence to Walter Swardfager.

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Conflict of Interest

DY declares that she has no conflict of interest.

HCM declares that he has no conflict of interest.

RHS declares grant and personnel funding from the Heart and Stroke Foundation, CIHR, Ontario Brain Institute, Sunnybrook Health Sciences Centre and the University of Toronto, Department of Medicine.

NH declares research support from Lundbeck and consultant fees from Astellas, Merck & Lilly.

PCC declares that he has no conflict of interest.

JP declares that she has no conflict of interest.

DTS declares that he has no conflict of interest. .

SEB declares institutional grants from Pfizer, GE Healthcare, Eli Lilly, Cognoptix, Biogen Idec, and personal honoraria from Novartis, Merck, Pfizer, Eli Lilly, and Medscape/Biogen.

AT declares that he has no conflict of interest.

WS declares that he has no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Yu, D., Hennebelle, M., Sahlas, D.J. et al. Soluble Epoxide Hydrolase-Derived Linoleic Acid Oxylipins in Serum Are Associated with Periventricular White Matter Hyperintensities and Vascular Cognitive Impairment. Transl. Stroke Res. 10, 522–533 (2019). https://doi.org/10.1007/s12975-018-0672-5

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