The Mutation Matters: CSF Profiles of GCase, Sphingolipids, α-Synuclein in PD_GBA

Background: With pathway-specific trials in PD associated with variants in the glucocerebrosidase gene (PD_GBA ) under way, we need markers that confirm the impact of genetic variants in patient-derived biofluids in order to allow patient stratification merely based on genetics and that might serve as biochemical read-out for target engagement.

Objective: To explore GBA-pathway-specific biomarker profiles cross-sectionally (TUEPAC-MIGAP, PPMI) and longitudinally (PPMI).

Methods: We measured enzyme activity of the lysosomal glucocerebrosidase, CSF levels of glucosylceramides (upstream substrate of glucocerebrosidase), CSF levels of ceramides (downstream product of glucocerebrosidase), lactosylceramides, sphingosines, sphingomyelin (by-products) and CSF levels of total α-synuclein in PD_GBA patients compared to PD_{GBA_wildtype} patients.

Results: Cross-sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PD_GBA compared to PD_{GBA_wildtype} . (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PD_GBA compared to PD_{GBA_wildtype} . (3) CSF levels of total α-synuclein were lower in PD_GBA compared to PD_{GBA_wildtype} . All of these findings were most pronounced in PD_GBA with severe mutations (PD_{GBA_severe} ). Cross-sectionally in TUEPAC-MIGAP and longitudinally in PPMI, CSF levels of downstream-products (ceramides) were higher in PD_{GBA_severe} . Cross-sectionally in TUEPAC-MIGAP by-products sphinganine and sphingosine-1-phosphate and longitudinally in PPMI species of by-products lactosylceramides and sphingomyelin were higher in PD_{GBA_severe} .

Interpretation: These findings confirm that GBA mutations have a relevant functional impact on biomarker profiles in patients. Bridging the gap between genetics and biochemical profiles now allows patient stratification for clinical trials merely based on mutation status. Importantly, all findings were most prominent in PD_GBA with severe variants. © 2021 International Parkinson and Movement Disorder Society.