A Longitudinal Neuromelanin MRI Processing Framework Reduces Measurement Variability and Improves Precision in Parkinson's Disease

Background: Neuromelanin-MRI enables in vivo assessment of the substantia nigra (SN) and locus coeruleus (LC) in individuals with Parkinson's disease (PD), yet longitudinal studies rely on cross-sectional processing that may introduce measurement variability and confound estimates of change over time. Objectives: In this paper, a longitudinal neuromelanin-MRI processing framework is presented that is designed and validated to improve measurement stability and reduce processing-related variability across repeated scans. Methods: Imaging and clinical data from the Quebec Parkinson Network were analyzed in 268 participants (199 PD, 69 controls), including a longitudinal subset of 74 participants (49 PD, 25 controls) scanned approximately one year apart. Validation experiments evaluated slice-by-slice intensity normalization for slice dependent intensity variation, bias field correction for LC signal asymmetry, and the effects of longitudinal registration on measurement stability and PD-control discrimination. Results: Slice-by-slice intensity normalization significantly reduced brainstem intensity variability by 3.6%. A systematic leftward signal asymmetry was observed in the LC and persisted following N4 bias field correction, suggesting a scanner-related effect not captured by conventional bias field modeling. Longitudinal registration reduced annualized change variability by 25-36% for SN_CR and 27-34% for LC_CR metrics in controls, indicating improved within-subject measurement stability. Residual variability was also reduced for contrast-based metrics by up to 28%. Longitudinal registration generally produced larger PD-control effect sizes at baseline and follow-up, particularly for SN volume metrics. However, no significant method x group x time interactions were observed, indicating that estimated longitudinal trajectories did not differ significantly between longitudinal and conventional cross-sectional processing. Conclusions: Longitudinal registration reduced technical variability and improved the precision of NM-MRI measurements. Although it did not significantly enhance detection of longitudinal PD-control differences over the follow-up interval examined here, it provides a more robust framework for longitudinal NM-MRI studies and may improve sensitivity to subtler biological effects in future investigations.