Abstract DP366: Sex-Specific Metabolomic Signatures of Social Isolation After Ischemic Stroke

Introduction: Acute ischemic stroke (AIS) is a leading cause of mortality and disability worldwide. Social isolation (SI) is an established and modifiable risk factor for stroke and is strongly linked to worse functional recovery, potentially more so in women. The detrimental effects of SI differ between males and females in pre-clinical studies, driven by interactions across metabolic, neuroendocrine, and immune systems. Yet, the sex-specific mechanisms by which SI influences stroke pathophysiology remain largely unexplored, representing a critical barrier to developing targeted interventions. Hypothesis: We hypothesize that SI differentially disrupts metabolic pathways in males and females after stroke, that may contribute to disparities in outcomes. Methods: We analyzed untargeted serum metabolic profiles of AIS patients (N=144; 64± 14 y, 91 males, 53 females) 24 hours after last known well, to assess metabolic differences between socially isolated and socially interactive individuals. Potential confounding from medications affecting metabolomic profiles was controlled in the analysis. Social isolation was assessed using the Lubben Social Network Scale, and loneliness was measured with the UCLA Loneliness Scale, both administered during the index hospitalization. Results: In social isolated females, pathway enrichment analysis showed uniquely significant overrepresentation of primary bile acid biosynthesis, steroid hormone biosynthesis, and glycerophospholipid metabolism. These hormones are known to regulate affect, reward circuits, and social behaviors, suggesting a potential mechanistic link between steroid metabolism and loneliness, In males, dopaminergic metabolites such as dopamine 3-O-sulfate and dopamine 4-sulfate were positively associated with loneliness, possibly reflecting compensatory changes in monoaminergic tone. Neuroactive ligand receptor interaction was uniquely enriched in males, implicating dysregulation of central receptor pathways involved in social behavior, reward processing, and mood regulation, including serotonergic, GABAergic, and dopaminergic systems. Conclusions: These findings reveal that loneliness drives sex-specific biological alterations after stroke. Targeting these pathways holds promise for developing precision therapies to improve functional outcomes.