Cerebrospinal fluid dopamine 3-O-sulfate as a novel biomarker for predicting motor complications in Parkinson’s disease: insights from the PPMI cohort

TL;DR

This study identifies a new biomarker in spinal fluid that can predict motor complications from Parkinson's disease treatment, helping personalize therapy.

Contribution

CSF dopamine 3-O-sulfate (DA3S) is shown as a novel, independent predictor of levodopa-induced motor complications in Parkinson’s disease.

Findings

DA3S levels are strongly correlated with levodopa exposure and predict motor complications.

A model combining DA3S, LEDD, and disease duration achieved 80.6% accuracy in predicting complications.

DA3S is a pharmacodynamic marker of central levodopa metabolism and aids in risk stratification.

Abstract

Long-term levodopa treatment for Parkinson’s disease (PD) is often complicated by motor fluctuations and dyskinesia. Predictive biomarkers for these debilitating side effects are currently lacking, hindering personalized treatment.

This study aimed to characterize the cerebrospinal fluid (CSF) metabolome across the PD continuum, distinguish disease-related from medication-related changes, and identify predictive biomarkers for levodopa-induced motor complications.

We analyzed targeted CSF metabolomic data from the Parkinson’s Progression Markers Initiative (PPMI) cohort, which included healthy controls, prodromal, and PD participants. Statistical analyses revealed differentially abundant metabolites. The association of the metabolite dopamine 3-O-sulfate (DA3S) with motor complications was assessed using logistic regression and decision tree models.

DA3S was the most significantly altered metabolite in PD patients, with its elevation exclusively driven by levodopa treatment. DA3S levels were strongly correlated with levodopa exposure (LEDD) and demonstrated a significant independent association with the development of motor complications. A multivariable model combining DA3S, disease duration, and LEDD was used to predict motor complications, with an AUC of 0.806. A decision tree further confirmed the value of DA3S for risk stratification in specific patient subgroups.

CSF DA3S is a pharmacodynamic marker of central levodopa metabolism and a robust, independent predictor of the onset of motor complications in PD patients. When combined with clinical variables, it facilitates effective risk stratification, providing a novel tool for personalizing therapy to mitigate treatment-related adverse effects.

The online version contains supplementary material available at 10.1186/s12967-026-07761-7.

CSF Dopamine 3-O-Sulfate (DA3S) is identified as a potent pharmacodynamic marker of central levodopa metabolism.

Elevated DA3S levels are independently associated with the risk of levodopa-induced motor complications in PD patients.

A multivariable model combining DA3S, LEDD, and disease duration demonstrates high predictive accuracy (AUC = 0.806).

DA3S provides a novel tool for risk stratification and personalized levodopa therapy management.

The online version contains supplementary material available at 10.1186/s12967-026-07761-7.

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