Age at onset of Parkinson's disease modulates the sphingolipid-dopaminergic interplay in autonomic progression

To investigate whether age of onset (AAO) affects cerebrospinal fluid (CSF) C16 glucosylceramide (C16 GlcCer) and striatal dopamine transporter-specific binding ratios (DAT-SBRs) in Parkinson's disease (PD), and their associations with longitudinal autonomic and cognitive outcomes, we conducted a large-scale, multicenter, prospective observational cohort study. Late-onset PD (LOPD, AAO > 50 years) patients showed higher baseline CSF C16 GlcCer and lower DAT‑SBR in some striatal regions compared to early‑onset PD (EOPD, AAO ≤ 50 years). Higher DAT-SBR was associated with a lower risk of autonomic dysfunction (AutD) in both groups and with better longitudinal cognitive performance in LOPD. Importantly, only in LOPD did the interaction between C16 GlcCer and DAT‑SBR predict more favorable autonomic progression, independent of CSF α‑synuclein. In EOPD, AutD risk was primarily related to regional DAT loss. These findings suggest that AAO modulates sphingolipid‑dopaminergic crosstalk and supports the combined use of these biomarkers for risk stratification.