Objective: Determine metabolites associated with cerebrospinal fluid (CSF) measured α-synuclein (α-syn) using untargeted metabolomics measured in the serum and CSF.

Background: Several large studies have reported that α-syn levels in the CSF are lower among Parkinson’s disease (PD) patients relative to both controls and those with non-synucleinopathy neurodegenerative disease. This is likely due to the sequestration of α-syn into Lewy bodies among patients and CSF levels may be an indicator of increasing Lewy body pathology.

Method: We performed a metabolome-wide association study of CSF-measured α-syn (n=81, S4 study) using serum- and CSF-based untargeted metabolomics data derived from liquid chromatography with high-resolution mass spectrometry (LC-HRMS). We adjusted for PD severity, medication, and demographic variables.

Results: We identified 81 metabolite features associated with CSF α-syn at FDR<0.05 (30 CSF-measured metabolites and 51 serum-measured metabolites). Among the most statistically significantly associated metabolites were two metabolite features related to pirbuterol (adj-p>1.9e-08), lysyl-valine metabolites (adj-p>3.7e-04), citric acid (adj-p=2.1e-03), ceramide (adj-p=2.8e-03), and glucosylceramide (adj-p=7.3e-03), along with several likely PD medication and supplement-related metabolites, including progabide, benzothiazole, and n-acetylneuraminic acid. Overrepresented pathways among features associated in the CSF metabolome include glycine and serine metabolism, lysine metabolism, pentose and glucuronate interconversions, and sphingolipid metabolism. Pathways overrepresented in the serum metabolome included glycosphingolipid metabolism, androgen and estrogen metabolism, and c21-steroid hormone biosynthesis and metabolism.

Conclusion: The current study links a range of metabolic features and pathways to CSF-measured α-syn among PD patients. Among other pathways, this research further highlights ceramide and bioactive sphingolipid metabolism in PD and specifically in the accumulation of α-synuclein and formation of Lewy bodies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cerebrospinal-fluid-measured-%ce%b1-synuclein-is-related-to-metabolite-profile-in-the-serum-and-csf/