Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI

Abstract

Protein-coding variants in the GBA gene modulate susceptibility and progression in ~10% of patients with Parkinson’s disease (PD). GBA encodes the β-glucocerebrosidase enzyme that hydrolyzes glucosylceramide. We hypothesized that GBA mutations will lead to glucosylceramide accumulation in cerebrospinal fluid (CSF). Glucosylceramide, ceramide, sphingomyelin, and lactosylceramide levels were measured by liquid chromatography-tandem mass spectrometry in CSF of 411 participants from the Parkinson’s Progression Markers Initiative (PPMI) cohort, including early stage, de novo PD patients with abnormal dopamine transporter neuroimaging and healthy controls. Forty-four PD patients carried protein-coding GBA variants (GBA-PD) and 227 carried wild-type alleles (idiopathic PD). The glucosylceramide fraction was increased (P = 0.0001), and the sphingomyelin fraction (a downstream metabolite) was reduced (P = 0.0001) in CSF of GBA-PD patients compared to healthy controls. The ceramide fraction was unchanged, and lactosylceramide was below detection limits. We then used the ratio of glucosylceramide to sphingomyelin (the GlcCer/SM ratio) to explore whether these two sphingolipid fractions altered in GBA-PD were useful for stratifying idiopathic PD patients. Idiopathic PD patients in the top quartile of GlcCer/SM ratios at baseline showed a more rapid decline in Montreal Cognitive Assessment scores during longitudinal follow-up compared to those in the lowest quartile with a P-value of 0.036. The GlcCer/SM ratio was negatively associated with α-synuclein levels in CSF of PD patients. This study highlights glucosylceramide as a pathway biomarker for GBA-PD patients and the GlcCer/SM ratio as a potential stratification tool for clinical trials of idiopathic PD patients. Our sphingolipids data together with the clinical, imaging, omics, and genetic characterization of PPMI will contribute a useful resource for multi-modal biomarkers development.

Changes in the cerebrospinal fluid proteome precede and stratify the course of Parkinson’s Disease

“…Therefore, this methodology should be appropriate for highly heterogeneous diseases, such as PD, where many biological processes intersect to form a slightly different pathology in each individual. [21][22][23][24][25] It should be noted that patients with PD were often subgrouped by the presence or absence of GBA1, LRRK2, and SNCA mutations because these mutations affect the PD phenotype and biomarker profiles, [26][27][28][29][30][31][32] indicating the possibility that proteomic characteristics are also different among these subtypes. With this background, the aim of this study, which measured 4071 human proteins in the CSF of 1149 subjects recruited in the Parkinson's Progression Markers Initiative (PPMI) study, was threefold.…”

Update on CSF Biomarkers in Parkinson’s Disease

“…Some studies even suggest a prognostic value of lysosomal markers. In the longitudinal observation of the PPMI cohort including GBA-PD and sPD, the glucosylceramide fraction was increased, whereas the sphingomyelin fraction was reduced in the CSF of GBA-PD patients compared to controls [ 73 ]. However, a higher ratio of glucosylceramide to sphingomyelin significantly associated with an accelerated cognitive decline in sPD compared to the sPD subjects with a lower ratio.…”

Lipidomics of Bioactive Lipids in Alzheimer’s and Parkinson’s Diseases: Where Are We?

“…Mutations in this gene are found in up to 10% of patients with PD, thus implicating aberrant sphingolipid metabolism [ 135 ]. Indeed, the CSF lipidome signatures of Parkinson’s patients at early stages, de novo PD patients with abnormal dopamine transporters, and healthy controls show distinct lipidome changes, with a significant increase in glucosylceramide (GlcCer), while sphingomyelin (SM) was significantly reduced in GBA-PD patients [ 93 ]. Furthermore, applying the ratio of GlcCer to SM for stratifying cases of idiopathic PD revealed that patients with a high GlcCer/SM ratio present increased cognitive deterioration compared to those in the lowest quartiles.…”