Plasma Sphingolipids Mediate a Relationship between Type 2 Diabetes and Memory Outcomes in Patients with Coronary Artery Disease Undertaking Exercise

Background: Exercise prevents recurrent cardiovascular events and it may combat cognitive decline in coronary artery disease (CAD); however, evidence in type 2 diabetes (T2DM) has been mixed. T2DM and memory decline have been associated with differences in the plasma sphingolipidome. Objective: Here, we will investigate whether T2DM-related sphingolipids predict less memory improvement over an exercise intervention for CAD. Methods: Among participants with CAD entering a 6-month exercise intervention, we matched 20 with T2DM to 40 without T2DM for age, sex, and body mass index. We assessed 45 sphingolipid species using high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometry with multiple reaction monitoring. We assessed memory using the California Verbal Learning Test, 2nd Ed, and the revised Brief Visuospatial Learning Test. Results: Partial least squares discriminant analysis identified 8 species that distinguished T2DM from non-T2DM groups with 83% (95% confidence interval [70%, 95%]) accuracy in a receiver operator characteristic curve (validated by internal resampling, 1000 permutations, p=0.01). At baseline, T2DM-associated sphingolipids (ceramide C22:0, monohexylceramide C16:1, and lactosylceramide C24:0) were associated with poorer memory, attention, and psychomotor processing speed performance. Among 50 completers, an indirect effect of T2DM on less improvement in verbal memory was mediated by monohexylceramide C16:1 (0.86 fewer words recalled, 95% bootstrap confidence interval [-2.32, -0.24]), and an indirect effect of T2DM on less visuospatial memory improvement was mediated by ceramide C22:0 concentrations (0.42 fewer points, 95% bootstrap confidence interval [-1.17, -0.05]). Conclusions: Ceramide species associated with T2DM predicted poorer cognitive responses to exercise in patients with CAD.