Objective: To evaluate whether integrated platelet lipidomic and α-synuclein signatures can distinguish idiopathic Parkinson’s disease (iPD), GBA1-associated PD (GBA-PD), and GBA1 non-manifesting carriers (GBA-NMC) from healthy controls, and to assess their relevance as clinically meaningful markers of motor severity and progression risk in GBA1 mutation carriers.

Background: GBA1 mutations are the most common genetic risk factor for PD and are associated with disrupted sphingolipid metabolism and enhanced α-synuclein aggregation. Clinically applicable, peripheral biomarkers that capture this lipid and protein dysregulation and reflect both current disease burden and future phenoconversion risk in GBA1 carriers are urgently needed to refine prognosis and stratify participants for disease-modifying trials.

Method: We studied 240 participants allocated to four groups (healthy controls, iPD, GBA-PD, GBA-NMC; n=60 each). Platelets were isolated from peripheral blood and subjected to high-resolution mass spectrometry–based lipidomic profiling. Platelet α-synuclein concentrations were quantified by immunoassay. Multivariate statistical approaches were used to identify group-specific lipidomic signatures, and regression analyses assessed associations between platelet α-synuclein levels and clinical scores.

Results: A distinct platelet lipidomic fingerprint clearly discriminated the four groups, with the largest contributions arising from sphingolipid and glycerophospholipid species. GBA-NMC showed intermediate lipid profiles between healthy controls and PD patients, indicating early biochemical alterations in clinically unaffected carriers. Platelet α-synuclein levels were higher in PD groups and correlated positively with MDS-UPDRS part III scores, supporting their relationship with motor impairment. The combination of selected lipid species and α-synuclein measurements improved classification across the clinical spectrum.

Conclusion: Platelet lipid and α-synuclein signatures delineate a biological continuum from non-manifesting GBA1 carriers to clinically manifest PD and provide minimally invasive, clinically relevant biomarkers for disease staging and progression. These findings support the use of platelet-based assays to identify high-risk GBA1 carriers, refine prognostic counselling, and enrich future neuroprotective trials for individuals most likely to convert.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/platelet-lipididomic-and-alpha-synuclein-as-peripheral-biomarkers-of-disease-progression-and-risk-in-gba1-associated-parkinsons-disease/