A Lipidomics Approach to Assess the Association Between Plasma Sphingolipids and Verbal Memory Performance in Coronary Artery Disease Patients Undertaking Cardiac Rehabilitation: A C18:0 Signature for Cognitive Response to Exercise

Abstract

Background Early subtle deficits in verbal memory, which may indicate early neural risk, are common in patients with coronary artery disease (CAD). While exercise can improve cognition, cognitive response to exercise is heterogeneous. Sphingolipids have been associated with the development and progression of CAD, and impairments in sphingolipid metabolism may play roles in neurodegeneration, and in the neural adaptation response to exercise. In this study, change in plasma concentrations of sphingolipids were assessed in relation to change in verbal memory performance and in other cognitive domains among CAD subjects undertaking a 6-month cardiac rehabilitation (CR) program. Methods Patients with CAD (n=120, mean age=64±6 years, 84% male, years of education=16±3 years) underwent CR with neuropsychological assessments and blood collected at baseline, 3-, and 6-months. Z-scores based on age, gender and education were combined for verbal memory, visuospatial memory, processing speed, executive function and global cognition tasks to calculate cognitive domain Z-scores. Plasma sphingolipid concentrations were measured from fasting blood samples using high performance liquid chromatography coupled electrospray ionization tandem mass spectrometry (LC/MS/MS). Mixed models were used to identify sphingolipids significantly associated with performance in verbal memory and other cognitive domains, adjusting for potential confounders. Results A decrease in ceramide C18:0 concentrations was significantly associated with improvement in verbal memory performance (b[SE]=-0.51 [0.25], p=0.04), visuospatial memory (b[SE]=-0.44 [0.22], p=0.05), processing speed (b[SE]=-0.89 [0.32], p=0.007) and global cognition (b[SE]=-1.47 [0.59], p=0.01) over 6 months of CR. Conclusions Plasma ceramide C18:0 concentrations may be a sensitive marker of cognitive response to exercise in patients with CAD.

Ceramide Accumulation Is Associated with Declining Verbal Memory in Coronary Artery Disease Patients: An Observational Study

“…This study found a relationship between markers of aberrant sphingolipid metabolism and cognitive decline, corroborating our previous finding that baseline plasma CerC18:0 is a robust marker of verbal memory performance in a cohort of CAD patients [ 15 ]. We investigated the longitudinal relationships between the equilibrium of baseline CerC18:0 biosynthesis and verbal memory performance over time.…”

“…The present study builds upon our previous work [ 15 ] by evaluating the relationship between circulating ceramides and verbal memory performance among CAD subjects over a longer period of time, in which cognitive deterioration may be more apparent. Although cognitive trajectories have been investigated in those with mild cognitive impairment [ 17 ], it has not been studied in those with vascular risk factors.…”

“…In a cognitively asymptomatic population, higher levels of serum CerC18:0 were associated with an increased risk of incident memory impairment over 9 years of follow-up [ 14 ]. Moreover, we previously found that greater plasma CerC18:0 levels were associated with less improvement in verbal memory performance among CAD patients over 6 months [ 15 ]. Collectively, this evidence coupled with the abundance of CerC18:0 in brain tissue [ 16 ], demonstrates the potential and feasibility of CerC18:0 as a biomarker of the pre-symptomatic phases of cognitive impairment.…”

Endostatin as a Mediator Between Endothelial Function and Cognitive Performance in Those at Risk for Vascular Cognitive Impairment

“…Future studies should utilize more domain-specific neuropsychological tests to investigate the mediation effect. Two appropriate tests might include Trails B for executive function and processing speed and the California Verbal Learning Test for delayed recall, both of which assess domains that might be affected in patients with mild VCI and CAD [13,26,27,[71][72][73][74].…”

Validity of a novel screen for cognitive impairment and neuropsychiatric symptoms in cardiac rehabilitation

“…Participants had an average age of 62 years, 16 years of education and were predominantly Caucasian and male. While representative of the CR population [69, 70], the study sample may not represent all patients with CVD. However, results were adjusted for demographic characteristics such as age, sex and years of education and the full versions of the screen components have been validated in diverse populations [71–73], which may improve generalizability.…”