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Background Deep gray nuclear pathology relates to motor deterioration in idiopathic Parkinson's disease (PD). Inconsistent deep nuclear diffusion tensor imaging (DTI) findings in cross-sectional or short-term longitudinal studies have been reported. Long-term studies in PD are clinically challenging; decade-long deep nuclear DTI data are nonexistent. We investigated serial DTI changes and clinical utility in a case-control PD cohort of 149 subjects (72 patients/77 controls) over 12 years. Methods Participating subjects underwent brain MRI at 1.5T; DTI metrics from segmented masks of caudate, putamen, globus pallidus and thalamus were extracted from three timepoints with six-year gaps. Patients underwent clinical assessment, including Unified Parkinson Disease Rating Scale Part 3 (UPDRS-III) and Hoehn and Yahr (H&Y) staging. A multivariate linear mixed-effects regression model with adjustments for age and gender was used to assess between-group differences in DTI metrics at each timepoint. Partial Pearson correlation analysis was used to correlate clinical motor scores with DTI metrics over time. Results MD progressively increased over time and was higher in the putamen (p<0.001) and globus pallidus (p=0.002). FA increased (p<0.05) in the thalamus at year six, and decreased in the putamen and globus pallidus at year 12. Putaminal (p=0.0210), pallidal (p=0.0066) and caudate MD (p<0.0001) correlated with disease duration. Caudate MD (p<0.05) also correlated with UPDRS-III and H&Y scores. Conclusion Pallido-putaminal MD showed differential neurodegeneration in PD over 12 years on longitudinal DTI; putaminal and …