A Biomarker Study in Patients with GBA1‐Parkinson's Disease and Healthy Controls

Abstract

A BS TRACT: Background: Molecules related to glucocerebrosidase (GCase) are potential biomarkers for development of compounds targeting GBA1-associated Parkinson's disease (GBA-PD). Objectives: Assessing variability of various glycosphingolipids (GSLs) in plasma, peripheral blood mononuclear cells (PBMCs), and cerebrospinal fluid (CSF) across GBA-PD, idiopathic PD (iPD), and healthy volunteers (HVs). Methods: Data from five studies were combined. Variability was assessed of glucosylceramide (various isoforms), lactosylceramide (various isoforms), glucosylsphingosine, galactosylsphingosine, GCase activity (using fluorescent 4-methylumbeliferryl-β-glucoside), and GCase protein (using enzyme-linked immunosorbent assay) in plasma, PBMCs, and CSF if available, in GBA-PD, iPD, and HVs. GSLs in leukocyte subtypes were compared in HVs. Principal component analysis was used to explore global patterns in GSLs, clinical characteristics (Movement Disorder Society -Unified Parkinson's Disease Rating Scale Part 3 [MDS-UPDRS-3], Mini-Mental State Examination [MMSE], GBA1 mutation type), and participant status (GBA-PD, iPD, HVs). Results: Within-subject between-day variability ranged from 5.8% to 44.5% and was generally lower in plasma than in PBMCs. Extracellular glucosylceramide levels (plasma) were slightly higher in GBA-PD compared with both iPD and HVs, while intracellular levels were comparable. GSLs in the different matrices (plasma, PBMCs, CSF) did not correlate. Both lactosylceramide and glucosylsphingosine were more abundant in granulocytes compared with monocytes and lymphocytes. Absolute levels of GSL isoforms differed greatly. GBA1 mutation types could not be differentiated based on GSL data. Conclusions: Glucosylceramide can stably be measured over days in both plasma and PBMCs and may be used as a biomarker in clinical trials targeting GBA-PD. Glucosylsphingosine and lactosylceramide are stable in plasma but are strongly affected by leukocyte subtypes in PBMCs. GBA-PD could be differentiated from iPD and HVs, primarily based on glucosylceramide levels in plasma.

How close are we to a breakthrough? The hunt for blood biomarkers in Parkinson's disease diagnosis

“…In PD patients with GBA mutations (GBA-PD), both GCase and α-Gal activity were reduced in dry blood spot samples but not sphingomyelinase, alpha-iduronidase or alpha-glucosidase activity (Pchelina et al, 2017). Interestingly, levels of GCase protein in PD without GBA mutations increased compared with HC, although it should be confirmed in a larger cohort (den Heijer et al, 2023).…”

“…Interestingly, glucosylsphingosine was also noticed in PD patients and was able to participate in the α‐syn aggregation (Taguchi et al, 2017). Glucosylsphingosine were significantly higher in GBA‐PD plasma (den Heijer et al, 2023; Surface et al, 2022). In GBA‐PD, abnormalities in ceramide metabolism in plasma have also been detected.…”

Biomarkers for Managing Neurodegenerative Diseases

“…Importantly, elevated CSF ratios of glucosylceramide to sphingomyelin correlate with accelerated cognitive decline [119]. Glucosylceramide also is elevated in GBA-PD plasma, which parallels reduced GC activity in GBA-PD whole blood [121,122]. 4.1.5.…”

“…Due to the documented role that dysregulated gut microbiota play in promoting neuroinflammation and accelerating DA neurodegeneration, rebalancing aberrant patient microbiomes is an ongoing field of research in PD-therapy development [121,123]. Interestingly, fecal microbiota transplants in patients with mild to moderate PD has improved GI motility and motor scores, although whether these benefits are long-lasting remains to be determined [121,132]. Expanded longitudinal studies with DAT-SPECT imaging in early-and preclinical-PD patients would greatly help to elucidate whether fecal microbiota transplants may slow the progression of DA neurodegeneration.…”

Interaction between α-Synuclein and Bioactive Lipids: Neurodegeneration, Disease Biomarkers and Emerging Therapies

“…Extracellular and intracellular levels of different sphingolipids (including glucosylceramide, lactosylceramide, galactosylsphingosine and glucosylsphingosine) were assessed in a large cohort across GBA-associated PD (GBA-PD), idiopathic PD and HS. In the plasma of GBA-PD, glucosylceramide levels were slightly higher in comparison to iPD and HS, suggesting a possible application of this metabolite as a biomarker for the differentiation of GBA-PD from iPD [174]. In the Parkinson Progression Markers Initiative (PPMI) biomarkers of altered sphingolipid metabolism were invariably higher in the CSF of PD patients with increased values in patients carrying GBA mutations in comparison to patients GBA wildtype [175,176].…”