Plasma Lipid Profiling Identifies Biomarkers of Cerebral Microvascular Disease

Brain-specific sphingolipids (SLs) may serve as effective biomarkers of white matter hyperintensities (WMH). Here, we investigate the efficacy of SLs as a novel fluid-based biomarker to identify WMH reflective of chronic ischemia. Patients presenting to our stroke center for evaluation of acute neurological deficits were enrolled in the Advanced Serum Profiling in Recent Stroke (ASPIRE) study. From this cohort of 202 individuals, 58 patients who underwent an MRI and did not have a clinical stroke event were included in this study. Plasma samples were collected at the time of MRI, and targeted SL profiling was performed by HPLC/tandem mass spectrometry. T₂ FLAIR imaging was evaluated for WMH and scored according to the Fazekas scoring (FS) method and manually quantified. Twenty two SLs were definitively identified, consisting of ceramide (Cer) and sphingomyelin (SM) species. Of these, two sphingolipids, SM 38:1 and Cer 34:1, significantly correlated with high FS (r = 0.287, p = 0.029, and r = 0.356, p = 0.006, respectively) and were used in subsequent analysis. SM 38:1 (OR 1.129, 95% CI 1.032, 1.236, p = 0.008) and Cer 34:1 (OR 1.118, 95% CI 1.031, 1.212, p = 0.007), accurately differentiated between FS 0-2 vs. 2.5-6 in regression analysis. A combined lipid score demonstrated fair discrimination in ROC analysis (AUC = 0.729, p = 0.003) and was cross-validated using leave-one-out analysis. Plasma levels of brain-specific SLs may serve as effective biomarkers of subacute white matter disease.