Free water in the external globus pallidus predicts mild cognitive impairment in Parkinson’s disease and is associated with serum neurofilament light chain levels

This study explored free-water diffusion tensor imaging (FW-DTI) in the basal ganglia as a biomarker for mild cognitive impairment (MCI) in Parkinson's disease (PD). One hundred and fourteen drug-naïve PD patients (without MCI at baseline) and 102 healthy controls (HC) from Parkinson's Progression Markers Initiative (PPMI) were included, and FW-DTI metrics were extracted from the bilateral putamen, caudate, external globus pallidus (GPe), and internal globus pallidus (GPi). The result showed that PD-MCI convertors had significantly higher FW in GPe and GPi. Cox regression identified that GPe FW, MDS-UPDRS Part I score, and CSF Aβ₄₂/pTau were significantly associated with MCI conversion in PD during 5-year follow-up. GPe FW > 0.328 predicted a 4.698-fold increased MCI risk (95% CI: 1.974-11.179) in PD in 5 years, after adjusting for CSF Aβ₄₂/pTau value and MDS-UPDRS part I score. Furthermore, higher GPe FW correlated with executive dysfunction (symbol digit modalities: R = -0.272, P = 0.004; letter number sequencing: R = -0.199, P = 0.035) and elevated serum neurofilament light chain (R = 0.322, P < 0.001) in PD, but not HC. In conclusion, GPe FW may serve as a sensitive imaging biomarker reflecting neuronal injury and MCI conversion risk in PD.