Total plasma cytochrome P450‐soluble epoxide hydrolase oxylipins, apolipoprotein E ε4 carrier status, and white matter hyperintensities in cerebrovascular disease
Bibliographic record
Abstract
BACKGROUND: The cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) pathway has been implicated in cerebral small vessel disease (cSVD) due to the anti-inflammatory and vasoactive effects of epoxide species produced by CYP450, which are converted into diols by sEH. However, the associations between total oxylipins and cSVD markers and the interactions with other risk factors (e.g., apolipoprotein E ε4 or APOE ε4 allele) remain unclear. METHOD: Participants diagnosed with cerebrovascular disease were identified from the Ontario Neurodegenerative Disease Research Initiative study. Periventricular and deep white matter hyperintensity (pWMH/dWMH) volumes at baseline were quantified using MRI images processed using a semi-automated pipeline. 24 arachidonic, linoleic, eicosapentaenoic, and docosahexaenoic acid-derived oxylipins were extracted from plasma with Folch extraction followed by hydrolysis, solid-phase extraction, and quantification with LC-MS/MS. Diol to epoxide ratios were calculated as a proxy for sEH activity. Cross-sectional associations were examined using linear regression models between log-transformed WMH volumes and log-transformed oxylipin concentrations, including age, sex, diabetes, hypertension, creatinine, cholesterol, triglycerides, and presence of the APOE ε4 allele as covariates. Stratified analyses were performed within APOE ε4 carrier and non-carrier subgroups. RESULT: Across 159 participants (67.9% male, mean age = 69.2 years), the eicosapentaenoic acid-derived 11(12)-epoxyeicosatetraenoic acid (EpETE) (β = 0.157, p = 0.034) and 14(15)-EpETE (β = 0.155, p = 0.039) were positively associated with pWMH volumes. The 11,12-dihydroxyeicosatetraenoic acid was also positively associated with pWMH volumes (β = 0.157, p = 0.031). The 9(10)-linoleic acid diol/epoxide ratio was associated with greater dWMH volumes (β = 0.186, p = 0.031). In subgroup analyses, all omega-3-derived epoxides and diols were associated with greater pWMH volumes in APOE ε4 non-carriers (β = 0.191 to 0.257, p = 0.027 to 0.002), whereas these effects were attenuated in APOE ε4 carriers. The 9(10)- and 12(13)-linoleic acid diol/epoxide ratios were positively associated with dWMH volumes only in APOE ε4 non-carriers. CONCLUSION: In individuals with cerebrovascular disease, APOE ε4 carrier status may moderate associations between CYP-sEH oxylipins and WMH volumes. Studies of interventions targeting this pathway should consider stratification based on APOE genotype.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".