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

Michelle M Mielke,Rodolfo Savica,Thomas Gasser,Christian Deuschle,Daniela Berg,Inga Liepelt-Scarfone,Walter Maetzler,Susanne Gräber-Sultan,Veera V R Bandaru,Norman J Haughey,Ann-Kathrin Hauser,Erwin Schleicher

doi:10.1371/journal.pone.0073094

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.

Highlights

The deposition of brain alpha-synuclein, a lipid-binding protein [1], [2], is the hallmark pathology of the neurodegenerative process underlying Parkinson’s disease (PD)
Mutations in the beta-glucosidase gene (GBA) coding for glucocerebrosidase, which breaks down glucosylceramide into glucose and ceramide (Figure 1) [6], are the most common genetic risk factors for sporadic PD, comprising about 7% of all cases [7], [8]
Patients, 26 cognitively non-affected PD patients (PD-cognitively normal (CN)), 14 PD-mild cognitive impairment (PD-MCI) patients, and 12 PDdementia (PDD) patients recruited from the ward and outpatient clinic of the Department of Neurodegenerative Diseases, Neurology Center of Tuebingen (WM, DB, TG)

Summary

Introduction

The deposition of brain alpha-synuclein, a lipid-binding protein [1], [2], is the hallmark pathology of the neurodegenerative process underlying Parkinson’s disease (PD). PD patients who are GBA mutation carriers are more likely to have an earlier age of onset and to develop cognitive impairment and dementia [8], [9], [10]. These findings may suggest the critical role of glucosylceramide and ceramide metabolism in the development of PD and subsequent cognitive impairment. Mutations 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). We hypothesized that plasma levels of lipids involved in ceramide metabolism would be altered in PD nonGBA mutation carriers and associated with worse cognition

Methods

Results

Discussion

Conclusion