A LIPIDOMICS APPROACH TO ASSESS PLASMA SPHINGOLIPIDS AS PREDICTORS OF VERBAL MEMORY PERFORMANCE IN CORONARY ARTERY DISEASE PATIENTS UNDERTAKING CARDIAC REHABILITATION: A C18:0 SIGNATURE FOR COGNITIVE RESPONSE TO EXERCISE

Abstract

Early subtle deficits in verbal memory, which may indicate early neural risk, are common in those with coronary artery disease (CAD). Accordingly, CAD is associated with increased risks of mild cognitive impairment and Alzheimer's disease. While cognition may be improved by exercise interventions, cognitive response to exercise is heterogeneous. Altered lipid metabolism, a common feature of the clinical presentation of CAD, may be a fundamental mechanism underlying neural risk in CAD. In particular, sphingolipids have been associated with the development and progression of CAD, and suggested to play a role in impairing neural adaptation to exercise and inducing neurodegeneration. In this study, plasma concentrations of sphingolipids were assessed as predictors of verbal memory performance and performance in other cognitive domains in CAD subjects undertaking a 6-month cardiac rehabilitation (CR) program using a lipidomics approach. Verbal memory, visuospatial memory, processing speed, executive function and global cognition were assessed at entry into CR and at 3- and 6-months and Z-scores based on age, gender and education were calculated. Z-scores of related tests were summed into composite Z-scores to reflect performance in a cognitive domain. Plasma sphingolipid concentrations were measured at each time point from fasting blood samples using high performance liquid chromatography coupled electrospray ionization tandem mass spectrometry (LC/MS/MS). Bivariate associations using mixed models were used to identify sphingolipids that were significantly associated with performance in verbal memory and other cognitive domains over CR. Multivariate mixed models were used to assess the sphingolipid profile associated with change in cognitive performance over CR controlling for potential confounders. In patients with CAD (n=120, mean age=64±6 years, 84% male, years of education=16±3 years), an increase in fitness was associated with significant improvement in processing speed over CR (b[SE] = 0.02 [0.009], p=0.05). Lower ceramide C18:0 concentrations significantly predicted improvement in verbal memory performance (b[SE]=-0.55 [0.25], p=0.03), visuospatial memory (b[SE]=-0.44 [0.22], p=0.05), processing speed (b[SE]=-0.89 [0.32], p=0.006) and global cognition (b[SE]=-1.47 [0.59], p=0.01) over CR. Plasma ceramide C18:0 concentrations may be a sensitive marker of cognitive response to exercise in an at-risk population such as those with CAD.