Objective: To longitudinally characterize substantia nigra (SN) neuromelanin (NM) and free-water (FW) MRI biomarkers by comparing control, REM sleep behaviour disorder (RBD), and Parkinson’s disease (PD) groups, and examining NM-FW associations.

Background: NM loss and increased SN FW are proposed MRI biomarkers of PD neurodegeneration. However, their longitudinal trajectories across PD, RBD, and control groups and their direct association remain unclear.

Method: Participants included 25 controls (24 follow-up; age 65.6+/-8.8; sex 7/18 M/F), 49 PD (44 follow-up; age 67.3+/-7.9; disease duration 4.0+/-3.5; sex 35/14), and 51 RBD (41 follow-up; age 65.4+/-7.6; disease duration 6.8+/-6.1; sex 37/13) from the Québec Parkinson Network and Parkinson Disease Biomarkers Study.

MRI included T1-MPRAGE, T1-TSE, and diffusion-weighted imaging. FW maps were derived using micapipe (v0.2.3)[1]. SN labels from the PD126 template[2] were brought to native space using concatenated T1w NIST Longitudinal[3] transformations. NM volume was defined as voxels exceeding a cerebral peduncle intensity threshold x voxel size, normalized by intracranial capacity.

Longitudinal associations between diagnostic group and SN biomarkers were assessed using mixed-effects models with subject random intercepts. Age was decomposed into within- and between-subject components to distinguish longitudinal change from cross-sectional effects. NM-FW associations were examined using correlation and mixed-effects models adjusting for group, age, and sex.

Results: FW differed by group, with higher values in PD compared with controls (p<0.001), while RBD showed a non-significant increase [Figure 1]. FW was not associated with age and slopes did not differ between groups. NM volume also differed by group, with values in PD (p<0.001) and RBD (p<0.05) compared with controls. NM was not associated with age and slopes did not differ between groups. In sensitivity analyses including sex, NM was lower in males, driven primarily by the RBD group.

NM and FW were significantly associated, with lower NM corresponding to higher FW (r=-0.39, p<0.001). Mixed-effects modeling confirmed NM significantly predicted FW independent of group, age and sex.

Conclusion: NM loss is associated with increased SN FW across controls, RBD and PD. These findings support complementary roles for NM and FW MRI measures as markers of nigral neurodegeneration.

Figure 1

References: 1. Cruces, R. R., Royer, J., Herholz, P., Lariviere, S., Vos de Wael, R., Paquola, C., Benkarim, O., Park, B. Y., Degre-Pelletier, J., Nelson, M. C., DeKraker, J., Leppert, I. R., Tardif, C., Poline, J. B., Concha, L., & Bernhardt, B. C. (2022). Micapipe: A pipeline for multimodal neuroimaging and connectome analysis. Neuroimage, 263, 119612. https://doi.org/10.1016/j.neuroimage.2022.119612

2. Madge, V., Fonov, V. S., Xiao, Y., Zou, L., Jackson, C., Postuma, R. B., Dagher, A., Fon, E. A., & Collins, D. L. (2023). A dataset of multi-contrast unbiased average MRI templates of a Parkinson’s disease population. Data in Brief, 48, 1-9. https://doi.org/10.1016/j.dib.2023.109141

3. Aubert-Broche, B., Fonov, V. S., Garcia-Lorenzo, D., Mouiha, A., Guizard, N., Coupe, P., Eskildsen, S. F., & Collins, D. L. (2013). A new method for structural volume analysis of longitudinal brain MRI data and its application in studying the growth trajectories of anatomical brain structures in childhood. Neuroimage, 82, 393-402. https://doi.org/10.1016/j.neuroimage.2013.05.065

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neuromelanin-loss-is-associated-with-increased-substantia-nigra-free-water-a-longitudinal-study-of-controls-rbd-and-pd/