Peripheral sphingolipids are associated with variation in white matter microstructure in older adults

Abstract

Sphingolipids serve important structural and functional roles in cellular membranes and myelin sheaths. Plasma sphingolipids have been shown to predict cognitive decline and Alzheimer’s disease (AD). However, the association between plasma sphingolipid levels and brain white matter (WM) microstructure has not been examined. We investigated whether plasma sphingolipids (ceramides, sphingomyelins) were associated with MRI-based diffusion measures, fractional anisotropy (FA) and mean diffusivity (MD), 10.5 years later in 17 WM regions of 150 cognitively normal adults (mean age 67.2). Elevated ceramide species (C20:0, C22:0, C22:1, and C24:1) were associated with lower FA in multiple WM regions, including total cerebral WM, anterior corona radiata, and the cingulum of the cingulate gyrus. Higher sphingomyelins (C18:1, C20:1) were associated with lower FA in regions such as the anterior corona radiata and body of the corpus callosum. Furthermore, lower sphingomyelin to ceramide ratios (C 22:0, C24:0, C24:1) were associated with lower FA or higher MD in regions including the superior and posterior corona radiata. However, while these associations were significant at the a priori p<0.05, only associations with some regional diffusion measures for ceramide C22:0 and sphingomyelin C18:1 survived correction for multiple comparisons. These findings suggest plasma sphingolipids are associated with variation in WM microstructure in cognitively normal aging.

Differential regulation of sphingolipid metabolism in plasma, hippocampus, and cerebral cortex of mice administered sphingolipid modulating agents

“…Mielke et al (2010a) reported that elevated SM and Cer(d18:1) are early predictors of memory impairment in a longitudinal study. Another study revealed that higher plasma Cer(d18:1) were associated with poorer cerebral white matter microstructure (Gonzalez et al 2016). These studies suggest that plasma sphingolipids may have a biological role in the pathogenesis in neurodegenerative disorders.…”

“…Interestingly, increases in plasma ceramides have been shown to predict cognitive decline and hippocampal volume loss in patients with mild cognitive impairment (Mielke et al 2010b). Furthermore, elevated circulating ceramides were associated with a worsening of white matter microstructure in cognitively normal patients (Gonzalez et al 2016). These studies highlight the importance of sphingolipid metabolism for central nervous system function and the potential for peripheral ceramides to influence the brain.…”

“…Another study revealed that higher plasma Cer(d18:1) were associated with poorer cerebral white matter microstructure (Gonzalez et al . ). These studies suggest that plasma sphingolipids may have a biological role in the pathogenesis in neurodegenerative disorders.…”

“…Furthermore, elevated circulating ceramides were associated with a worsening of white matter microstructure in cognitively normal patients (Gonzalez et al . ). These studies highlight the importance of sphingolipid metabolism for central nervous system function and the potential for peripheral ceramides to influence the brain.…”

Subventricular zone lipidomic architecture loss in Huntington's disease

“…; Gonzalez et al . ). Although elevated ceramide was not observed in our study, an approximately fivefold increase in its phosphorylated form, Cer‐1‐phosphate, was seen in the HD myelin layer.…”