Soluble Epoxide Hydrolase Derived Linoleic Acid Oxylipins, Small Vessel Disease Markers, and Neurodegeneration in Stroke
Authors: Yu Di , Liang Nuanyi , Zebarth Julia , Shen Qing , Ozzoude Miracle , Goubran Maged , Rabin Jennifer S. , Ramirez Joel , Scott Christopher J. M. , Gao Fuqiang , Bartha Robert , Symons Sean , Haddad Seyyed Mohammad Hassan , Berezuk Courtney , Tan Brian , Kwan Donna , Hegele Robert A. , Dilliott Allison A. , Nanayakkara Nuwan D. , Binns Malcolm A. , Beaton Derek , Arnott Stephen R. , Lawrence‐Dewar Jane M. , Hassan Ayman , Dowlatshahi Dar , Mandzia Jennifer , Sahlas Demetrios , Casaubon Leanne , Saposnik Gustavo , Otoki Yurika , Lanctôt Krista L. , Masellis Mario , Black Sandra E. , Swartz Richard H. , Taha Ameer Y. , Swardfager Walter , Rashkovan Natalie , Black Sandra E. , Abrahao Agessandro , Zinman Lorne , Bonnick Alisia , Swartz Richard H. , Masellis Mario , Ramirez Joel , Scott Christopher , Symons Sean , Berezuk Courtney , Holmes Melissa , Adamo Sabrina , Ozzoude Miracle , Freedman Morris , Tan Brian , Zamyadi Mojdeh , Arnott Stephen , Beaton Derek , Binns Malcolm , Raamana Pradeep , Strother Stephen , Sunderland Kelly , Theyers Athena , Uthirakumaran Abiramy , Levine Brian , Troyer Angela , Strong Michael , Kleinstiver Peter , Borrie Michael , Finger Elizabeth , Shoesmith Christen , Faria Frederico , Montero‐Odasso Manuel , Sarquis‐Adamson Yanina , Black Alanna , Mandzia Jennifer , Dilliott Allison Ann , Hegele Rob , Robinson John , Farhan Sali , Bartha Rob , Haddad Hassan , Nanayakkara Nuwan , Zou Guangyong , Pasternak Stephen , Orange JB , Roberts Angela , Jog Mandar , Seitz Dallas , Brien Don , Chen Ying , Coe Brian , Munoz Doug , McLaughlin Paula , Peltsch Alicia , Kwan Donna , Bronskill Susan , Lou Wendy , Kumar Sanjeev , Pollock Bruce , Rajji Tarek , Tang‐Wai David , Tartaglia Carmela , Varriano Brenda , Chum Marvin , Turnbull John , Lawrence‐Dewar Jane , Hassan Ayman , Fraser Julia , McIlroy Bill , Cornish Ben , Van Ooteghem Karen , Hudson Chris , Leontieva Elena , Hatch Wendy , Tayyari Faryan , Defrawy Sherif , Margolin Edward , Mandelcorn Efrem , Greenberg Barry , Casaubon Leanne , Lang Anthony , Marras Connie , Frank Andrew , Dowlatshahi Dar , Grimes David , Bulman Dennis , Woulfe John , Ghani Mahdi , Sahlas Demetrios , Saposnik Gustavo , Steeves Tom , Munoz David , Fischer Corinne , Rogaeva Ekaterina , Sujanthan Sujeevini , Breen David , Dixon Roger A. 
Published: December 2022

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.