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BackgroundLevodopa is the gold-standard therapy for motor symptoms in Parkinson's disease (PD). However, individual responses vary substantially among patients, and the biological mechanisms underlying this heterogeneity remain incompletely understood.ObjectiveThis study aimed to investigate the neural substrates associated with variability in levodopa responsiveness using multimodal magnetic resonance imaging (MRI).MethodsData were retrieved for this ancillary study from the PREDISTIM cohort, that aims to define predictors for deep brain stimulation outcomes. Patients were stratified through a data-driven clustering approach according to their dopa responsiveness and disease duration. MRI analyses included T1-weighted imaging and multi-echo fast gradient-echo sequences. Structural and iron-sensitive MRI measures were compared across clusters within key regions.ResultsA three-phenotype response pattern previously reported in the Parkinson's Progression Markers Initiative dataset was identified, extending beyond the conventional binary classification of good (C3) and poor responders (C1). An intermediate phenotype (C2) showed preserved pharmacological responsiveness despite longer disease duration. Structural MRI revealed significant putaminal atrophy in this cluster. In contrast, patients in cluster C1 exhibited reduced grey matter in the temporo-parietal operculum and inferior frontal cortex as well as an increased iron deposition in the substantia nigra and globus pallidus internus.ConclusionThese findings, that should be validated in other populations, suggest that variability in levodopa responsiveness reflects distinct neurobiological substrates rather than a simple continuum of disease severity. Integrating markers of structural degeneration and iron-related microenvironmental changes within basal ganglia-cortical circuits may improve phenotypic stratification and support the development of precision therapeutic strategies in PD.
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