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Introduction: Silent infarcts are associated with increased risk for symptomatic stroke, hemorrhagic transformation after thrombolysis, and global cognitive decline. Currently, there are no methods for detecting these lesions without imaging studies. We previously showed brain-specific sphingolipids (SLs) may serve as effective biomarkers of brain injury. Here, we evaluate the potential for these primarily white matter based molecules to identify clinically silent white matter injury.Methods: From our prospectively maintained institutional bio-bank, patients who underwent an MRI without acute stroke were identified. Plasma samples were collected at the time of MRI, and targeted SL profiling was performed by HPLC/tandem mass spectrometry. SLs were identified by exact mass. T2 Flair imaging was evaluated and scored according to the Fazekas scoring (FS) method. Data were analyzed with a dichotomized endpoint (FS 0-2 vs 3-6) with logistic regression.Results: Among 58 patients that met inclusion criteria, 28 (48%) were male, mean age was 66±17 and mean FS was 2.5 [IQR 2.5]. On MRI imaging, 46.5% scored FS 3-6 and 53.4% FS 0-2. Higher FS was associated with advanced age (29% vs 70% over 70yo, FS 0-2 vs. 3-6, p=0.002). 22 SLs could be definitively identified, consisting of ceramide (Cer) and sphingomyelin (SM) species. In univariate analysis, two species, SM 38:1 (OR 1.129, p=0.008) and Cer 34:1 (OR 1.118, p=0.007), accurately differentiated between FS 0-2 vs 3-6. The sum of these two SL intensities demonstrated excellent discrimination in ROC analysis (AUC= 0.729, p=0.003).Conclusion: Plasma levels of brain-specific SLs may serve as effective biomarkers of “clinically silent” white matter disease.