Soluble Epoxide Hydrolase Derived Linoleic Acid Oxylipins, Small Vessel Disease Markers, and Neurodegeneration in Stroke
Di Yu, Nuanyi Liang, Julia Zebarth, Qing Shen, Miracle Ozzoude, Maged Goubran, Jennifer S. Rabin, Joel Ramirez, Christopher J.M. Scott, Fuqiang Gao, Robert Bartha, Sean Symons, Seyyed Mohammad Hassan Haddad, Courtney Berezuk, Brian Tan, Donna Kwan, Robert A. Hegele, Allison A. Dilliott, Nuwan D. Nanayakkara, Malcolm A. Binns, Derek Beaton, Stephen R. Arnott, Jane M. Lawrence‐Dewar, Ayman Hassan, Dar Dowlatshahi, Jennifer Mandzia, Demetrios J. Sahlas, Leanne K. Casaubon, Gustavo Saposnik, Yurika Otoki, Krista L. Lanctôt, Mario Masellis, Sandra E. Black, Richard H. Swartz, Ameer Y. Taha, Walter Swardfager, Natalie Rashkovan, Sandra E. Black, Agessandro Abrahão, Lorne Zinman, Alisia Bonnick, Richard H. Swartz, Mario Masellis, Joel Ramirez, Christopher J.M. Scott, Sean Symons, Courtney Berezuk, Melissa F. Holmes, Sabrina Adamo, Miracle Ozzoude, Morris Freedman, Brian Tan, Mojdeh Zamyadi, Stephen R. Arnott, Derek Beaton, Malcolm A. Binns, Pradeep Reddy Raamana, Stephen C. Strother, Kelly M. Sunderland, Athena Theyers, Abiramy Uthirakumaran, Brian Levine, Angela K. Troyer, Michael J. Strong, Peter Kleinstiver, Michael Borrie, Elizabeth Finger, Christen Shoesmith, Frederico Faria, Manuel Montero‐Odasso, Yanina Sarquis‐Adamson, Alanna Black, Jennifer Mandzia, Allison A. Dilliott, Rob Hegele, John F. Robinson, Sali M.K. Farhan, Robert Bartha, Hassan Haddad, Nuwan D. Nanayakkara, Guangyong Zou, Stephen Pasternak, J. B. Orange, Angela Roberts, Mandar Jog, Dallas Seitz, Don Brien, Ying Chen, Brian C. Coe, Doug Munoz, Paula McLaughlin, Alicia Peltsch, Donna Kwan, Susan E. Bronskill, Wendy Lou, Sanjeev Kumar, Bruce G. Pollock, Tarek K. Rajji, David F. Tang‐Wai, Carmela Tartaglia
Abstract
Background Cerebral small vessel disease is associated with higher ratios of soluble‐epoxide hydrolase derived linoleic acid diols (12,13‐dihydroxyoctadecenoic acid [DiHOME] and 9,10‐DiHOME) to their parent epoxides (12(13)‐epoxyoctadecenoic acid [EpOME] and 9(10)‐EpOME); however, the relationship has not yet been examined in stroke. Methods and Results Participants with mild to moderate small vessel stroke or large vessel stroke were selected based on clinical and imaging criteria. Metabolites were quantified by ultra‐high‐performance liquid chromatography–mass spectrometry. Volumes of stroke, lacunes, white matter hyperintensities, magnetic resonance imaging visible perivascular spaces, and free water diffusion were quantified from structural and diffusion magnetic resonance imaging (3 Tesla). Adjusted linear regression models were used for analysis. Compared with participants with large vessel stroke (n=30), participants with small vessel stroke (n=50) had a higher 12,13‐DiHOME/12(13)‐EpOME ratio (β=0.251, P =0.023). The 12,13‐DiHOME/12(13)‐EpOME ratio was associated with more lacunes (β=0.266, P =0.028) but not with large vessel stroke volumes. Ratios of 12,13‐DiHOME/12(13)‐EpOME and 9,10‐DiHOME/9(10)‐EpOME were associated with greater volumes of white matter hyperintensities (β=0.364, P <0.001; β=0.362, P <0.001) and white matter MRI‐visible perivascular spaces (β=0.302, P =0.011; β=0.314, P =0.006). In small vessel stroke, the 12,13‐DiHOME/12(13)‐EpOME ratio was associated with higher white matter free water diffusion (β=0.439, P =0.016), which was specific to the temporal lobe in exploratory regional analyses. The 9,10‐DiHOME/9(10)‐EpOME ratio was associated with temporal lobe atrophy (β=−0.277, P =0.031). Conclusions Linoleic acid markers of cytochrome P450/soluble‐epoxide hydrolase activity were associated with small versus large vessel stroke, with small vessel disease markers consistent with blood brain barrier and neurovascular‐glial disruption, and temporal lobe atrophy. The findings may indicate a novel modifiable risk factor for small vessel disease and related neurodegeneration.