In 45 Parkinson's patients, greater non-motor symptom burden predicted lower overall levodopa responsiveness, while poorer semantic fluency specifically predicted reduced levodopa responsiveness of axial symptoms.

Provides simple, clinically measurable markers (NMSS and semantic fluency) that could help stratify patients for trials targeting dopaminergic versus nondopaminergic axial features and guide therapeutic development, though findings need validation in larger cohorts.

BACKGROUND: Levodopa response (LDR) is central to the clinical assessment of Parkinson's disease (PD), yet the factors influencing axial motor responsiveness remain insufficiently explored. OBJECTIVE: To identify clinical determinants of overall LDR and the levodopa response of axial symptoms (LDR-axial). METHODS: Consecutive PD patients evaluated between January and August 2024 were included. MDS-UPDRS-3 was administered in defined "off" and suprathreshold "on" states. LDR and LDR-axial were calculated as proportional score changes. Motor, non-motor, and cognitive variables were analyzed using multiple regression models. RESULTS: Forty-five patients (mean age 61.9 ± 8.6 years) were enrolled. The mean LDR was 0.36 ± 0.14, and the median LDR-axial was 0.27. Group comparisons did not reveal significant differences. In regression analyses, the Non-Motor Symptoms Scale (NMSS) was the only independent predictor of overall LDR (β = -0.407). For LDR-axial, semantic fluency emerged as the sole significant predictor (β = 0.332), and patients with limited axial improvement had significantly lower semantic fluency scores. CONCLUSIONS: Higher non-motor symptom burden is associated with reduced dopaminergic motor responsiveness. Semantic fluency correlates with LDR-axial, suggesting a potential cognitive marker linked to nondopaminergic mechanisms underlying axial symptom resistance. These findings warrant further investigation in larger cohorts.