This study finds that elevated free-water in limbic regions (notably the left insula and mid-cingulate, plus hippocampus and right orbitofrontal cortex) combined with RBD and anxiety scores predicts conversion from prodromal to clinical Parkinson's disease with a combined-model AUC ~0.76.

Provides a noninvasive, translatable biomarker signature that could be used to enrich and stratify prodromal PD cohorts for early intervention trials and longitudinal therapeutic evaluation, though it does not yet reveal targetable disease mechanisms.

BACKGROUND: Parkinson's disease (PD) diagnosis typically occurs after motor symptom onset, highlighting the need for biomarkers predicting phenoconversion from the prodromal parkinson's disease (pPD). Free-water (FW) imaging, reflecting extracellular microstructural changes, may capture early extrastriatal pathology. OBJECTIVE: To evaluate regional free-water alterations from whole-brain mapping as biomarkers predicting imminent pPD-to-PD phenoconversion. METHODS: Whole-brain FW mapping derived from diffusion tensor imaging was obtained for 51 healthy controls (HCs), 83 pPD, and 202 de novo PD (dnPD) subjects from the Parkinson's Progression Markers Initiative. The pPD cohort underwent ≥4-year longitudinal follow-up. Whole-brain FW values were compared across groups using false discovery rate correction. Predictors of phenoconversion to PD were identified via LASSO regression from baseline FW metrics and clinical covariates. A multivariable Cox proportional hazards model was subsequently constructed using the selected predictors, with model performance evaluated through Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curves. RESULTS: Cross-sectionally, elevation in FW values in the left insula and left middle cingulate gyrus were observed in pPD compared to HCs, alongside lower values than in dnPD. Longitudinally, LASSO-Cox analysis identified six predictors: FW in left insula, left mid-cingulate cortex, left hippocampus, right orbitofrontal cortex, RBDSQ, and STAI scores. Left insula FW (HR = 1.403,P = 0.004) and left mid-cingulate FW (HR = 1.325,P = 0.029) independently predicted conversion. The combined model integrating FW and clinical metrics demonstrated superior AUCs (0.755). CONCLUSION: Free-water changes particularly in limbic regions predict phenoconversion from prodromal to clinical Parkinson's disease.