Sex differences in proteomic response to ischemic stroke

Abstract Background Women often experience greater disability after ischemic stroke than men, but the biological mechanisms underlying these differences remain unclear. Proteomic analysis may identify sex-specific molecular pathways that contribute to stroke rehabilitation and recovery. Methods We analyzed plasma samples from 141 patients enrolled in the Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC). Expression of 184 inflammatory and cardiometabolic proteins, measured proximal and distal to the clot, was quantified using Olink panels. Associations between protein expression and discharge outcomes – including the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS), and Montreal Cognitive Assessment (MoCA) – were evaluated with models including a sex by protein interaction term, adjusting for clinical and demographic covariates. Results The median age was 69 years, and 55% were women. After controlling the false discovery rate, systemic TGFBI was expressed at higher levels in men. Multiple proteins demonstrated sex-specific associations with discharge outcomes. For NIHSS, systemic PCOLCE and NT3, as well as intracranial FGF5, NT3, TNFSF14, and TWEAK, were differentially associated by sex, with higher expression generally linked to worse outcomes in women and protective trends in men. For mRS, systemic ICAM3 and TGFBI were associated with higher odds of poor mRS scores in women, while SELL showed a potential protective effect in men. Intracranial CD6 and LAP TGF-β1 also demonstrated sex-specific associations with mRS scores. No sex-specific associations were observed for MoCA. Conclusions Several sex dependent proteins were associated with post-stroke discharge outcomes. These findings suggest that sex-specific molecular responses could contribute to disparities in post-stroke recovery and highlight the importance of incorporating sex as a biological variable in biomarker studies as well as stratifying clinical trials based on sex.