Abstract WP374: Alterations in Sphingolipid Pathway Associate with Clinical Outcomes after Intracerebral Hemorrhage

Introduction: Intracerebral hemorrhage (ICH) is a disabling stroke, with only ~25% of survivors regaining independence. Secondary injury mechanisms such as inflammation, blood–brain barrier disruption, and perihematomal edema contribute to poor outcomes. Sphingolipids regulate membrane integrity, signaling, and cell survival; among them, sphingosine-1-phosphate (S1P) influences endothelial function, vascular permeability, and immune trafficking. S1P receptor modulators (fingolimod, Siponimod) reduced edema and improved recovery in preclinical and early-phase trials. The role of S1P dysregulation in ICH remains unclear. We hypothesized that altered sphingolipid metabolism, particularly involving S1P, is associated with poor ICH outcomes. Methods: Plasma samples were collected from 48 ICH patients within 72 hours of symptom onset, dichotomized by good (modified Rankin Scale (mRS) 0-2, n = 24) or poor (mRS 4-6, n = 24) outcome 90 days post ICH, and assessed for metabolites in the sphingolipid pathway using untargeted metabolomics with Ultra-Performance Liquid Chromatography–Mass Spectrometry. Samples were matched for ICH volume and age. Missing values were imputed with the minimum observed value, log transformed and analyzed using ANCOVA to assess differences by outcome and ICH location (lobar vs deep). Results: Among patients with good outcomes, no significant sphingolipid differences were observed between deep and lobar ICH, although deep ICH showed trend-level reductions in two sphingomyelin species. In contrast, among patients with poor outcomes, sphinganine, sphinganine-1-phosphate, sphingadienine, sphingosine, and S1P were significantly elevated in deep compared with lobar ICH (p < 0.05), with one additional sphingomyelin showing a non-significant trend toward increase. In lobar ICH, poor outcome was associated with reduced sphinganine-1-phosphate and three sphingomyelin species (p < 0.05), along with trend-level reductions in S1P and three other sphingomyelins. In deep ICH, poor outcome was associated with reduced levels of a single sphingomyelin subtype (p < 0.05). Conclusions: These novel exploratory findings suggest that dysregulation of sphingolipid metabolism may contribute to ICH outcomes. Reduced S1P in poor-outcome lobar ICH, appearing as relatively higher levels in deep ICH, suggests a role for S1P signaling in secondary injury and recovery and highlights the need for validation in larger cohorts.