Preoperative Glymphatic Asymmetry Is Associated with Motor Outcomes Following STN ‐ DBS in Parkinson's Disease

BACKGROUND: Interindividual variability in motor outcomes after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) remains incompletely understood. Glymphatic-related imaging abnormalities have been reported in PD, but their relevance to neuromodulation response is unclear. OBJECTIVES: To investigate whether preoperative glymphatic function, assessed using the Diffusion Tensor Imaging along the Perivascular Space (DTI-ALPS) index, is associated with motor outcomes after STN-DBS and whether hemispheric asymmetry provides additional explanatory value. METHODS: We retrospectively evaluated 74 advanced PD patients undergoing bilateral STN-DBS with ≥6 months follow-up. Preoperative assessment included 3 T MRI-derived ALPS measures, Fazekas score, perivascular space burden, MDS-UPDRS-III, levodopa responsiveness, and metabolic markers. Primary outcome was percentage motor improvement at follow-up. Multivariable regression models assessed ALPS associations after adjustment for levodopa responsiveness and measured clinical covariates. RESULTS: Lower ALPS asymmetry index (AI) was independently associated with greater percentage motor improvement (standardized β = -0.508, p < 0.001), while greater preoperative levodopa responsiveness was also associated with improvement (β = 0.740, p < 0.001). Lower ALPS-AI was additionally associated with axial motor improvement and responder status at both ≥50% and ≥ 33% thresholds. All four principal levodopa-adjusted ALPS-AI associations remained significant after Benjamini-Hochberg correction (all pFDR≤0.0069). Mean ALPS index, Fazekas score, and perivascular space burden were not associated with motor outcomes. CONCLUSIONS: Preoperative glymphatic asymmetry was associated with motor outcomes after STN-DBS independently of levodopa responsiveness and measured clinical covariates. ALPS-derived asymmetry may capture outcome variability not reflected by conventional imaging, although prospective validation and evaluation alongside lead localization, stimulation parameters, and programming factors are required.