Phenotype-Aligned Metabolomics Identifies Plasma Arginine as a Candidate Predictor of Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage.

Delayed cerebral ischemia (DCI) affects approximately 30% of aneurysmal subarachnoid hemorrhage (aSAH) survivors and is a leading cause of morbidity and mortality post-aSAH. Current risk assessment relies on radiographic severity scores that stratify populations based on hemorrhage characteristics but cannot predict DCI onset for individual patients. No plasma-based biomarkers for DCI prediction currently exist. We used liquid chromatography – mass spectrometry to perform plasma metabolomics in 60 aSAH patients (50% female, 30 DCI, 30 No-DCI) with longitudinal sampling until 7 days post-aSAH. Samples were retrospectively aligned to individual DCI onset times per patient, isolating 24–48 h and 48–72 h pre-event windows. Arginine emerged as the sole FDR-significant metabolite 24–48 h before DCI (q = 0.022, 39% depletion) and ranked #1 of 2,022 metabolites across three statistical methods (Student’s t-test, Welch’s t-test, Mann-Whitney U test, p = 10⁻⁵ to 10⁻⁴). Zero metabolites achieved FDR significance at 48–72 h, confirming temporal specificity. Independent logistic regression validated predictive performance (odds ratio 0.22, p = 0.001, AUC 0.808, 95% CI: 0.647–0.945), outperforming modified Fisher radiographic score (AUC 0.718, 95% CI: 0.593–0.830). The combination model of arginine and modified Fisher score performed best with AUC 0.856 (95% CI: 0.733–0.955), with arginine as the dominant factor. Mechanistic investigation revealed FDR-significant depletion of arginine/ornithine (q = 0.011) and glutamine/glutamate ratios (q = 0.011), consistent with increased arginase activity competing with nitric oxide synthesis. Plasma arginine represents a candidate single-molecule biomarker for DCI with a clinically actionable pre-event detection window, pending prospective validation. Temporal alignment to individual DCI onsets enabled detection of pre-event metabolic changes 24–48 h before symptom onset.