Plasma Ceramide and Glucosylceramide Metabolism Is Altered in Sporadic Parkinson's Disease and Associated with Cognitive Impairment: A Pilot Study

Abstract

BackgroundMutations in the gene coding for glucocerebrosidase (GBA), which metabolizes glucosylceramide (a monohexosylceramide) into glucose and ceramide, is the most common genetic risk factor for sporadic Parkinson's disease (PD). GBA mutation carriers are more likely to have an earlier age of onset and to develop cognitive impairment and dementia. We hypothesized that plasma levels of lipids involved in ceramide metabolism would also be altered in PD non-GBA mutation carriers and associated with worse cognition.MethodsPlasma ceramide, monohexosylceramide, and lactosylceramide levels in 26 cognitively normal PD patients, 26 PD patients with cognitive impairment or dementia, and 5 cognitively normal non-PD controls were determined by LC/ESI/MS/MS.ResultsLevels of all lipid species were higher in PD patients versus controls. Among PD patients, levels of ceramide C16:0, C18:0, C20:0, C22:0, and C24:1 and monohexosylceramide C16:0, C20:0 and C24:0 species were higher (all P<0.05) in those with versus without cognitive impairment.ConclusionThese results suggest that plasma ceramide and monohexosylceramide metabolism is altered in PD non-GBA mutation carriers and that higher levels are associated with worse cognition. Additional studies with larger sample sizes, including cognitively normal controls, are needed to confirm these findings.

Plasma sphingolipids and depressive symptoms in coronary artery disease

“…The current research adds to the growing body of clinical evidence that plasma sphingolipids may reflect central processes, either as by‐products of disease states in the central nervous system or as contributors to these disease states, or both (Assies et al., 2010; Demirkan et al., 2013; Hammad et al., 2012; Han et al., 2011; Mielke et al., 2011). Numerous studies have observed associations between peripheral sphingolipid concentrations and psychiatric symptoms (Demirkan et al., 2013; Mielke et al., 2013; Xing et al., 2016) as well as elevated concentrations of sphingolipids in the periphery of individuals with psychiatric disorders such as depression and posttraumatic stress disorder (Gracia‐Garcia et al., 2011; Hammad et al., 2012). Currently, little is known about the relationship between peripheral and central biomolecules such as sphingolipids.…”

Identification of disease-distinct complex biomarker patterns by means of unsupervised machine-learning using an interactive R toolbox (Umatrix)

“…1) assayed in probes drawn from Parkinson patients and healthy controls. The assessment of lipid markers in the context of Parkinson's disease is based on evidence of an involvement of lipid regulation [15][16][17][18][19][20][21].…”

Demographic and clinical variables affecting mid‐ to late‐life trajectories of plasma ceramide and dihydroceramide species

“…Thus, the homeostasis of ceramide metabolism may be critical in regulating lifespan and age‐associated diseases (Cutler & Mattson, 2001; Rao et al ., 2007). Indeed, it has been increasingly recognized, from the cellular to human level, that perturbations in ceramide metabolism are associated with longevity (Yu et al ., 2012; Gonzalez‐Covarrubias et al ., 2013; Cutler et al ., 2014; Huang et al ., 2014) and the development and progression of many age‐related diseases including cancer (Alberg et al ., 2013), atherosclerosis (Ichi et al ., 2006), insulin resistance and diabetes (Holland et al ., 2007; Holland & Summers, 2008; Boon et al ., 2013), Alzheimer's disease (Mielke et al ., 2012), and Parkinson's disease (Mielke et al ., 2013). …”