Introduction

Parkinson's disease (PD) is characterized by both a degeneration of dopaminergic neurons in the substantia nigra¹ and the accumulation of 𝛼-synuclein². Although PD has long been associated with brain pathology, signs of the disease such as the accumulation of 𝛼-synuclein has been reported in the spinal cord³, suggesting that it could contain information that might lead to a better understanding of the disease. However, studies that have explored the impact of PD in the spinal cord in vivo in humans are limited and much remains unknown about the microstructure of the spinal cord in PD patients.

Methods

In this exploratory study, we aim to establish magnetization transfer ratio (MTR), T2*-weighted (T2*w) and diffusion-weighted imaging (DWI) metrics for exploring microstructural alterations in the spinal cord in the context of PD. In this study, we compare these metrics in a PD population and in healthy controls, using the same participants as Landelle et al.⁴. Participants were scanned at the Montreal Neurological Institute-Hospital under the C-BIG repository (parameters shown in Figure 1A). Those with PD were divided into PD_low, PD_med and PD_adv categories according to their motor symptoms component assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS)⁵(Figure 1B). For the DWI images, both DTI⁶ and NODDI⁷ models were used, from which we explored the orientation dispersion index (ODI), intracellular volume fraction (FICVF), isotropic volume fraction (FISO), fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD).

Individual images were pre-processed using the Spinal Cord Toolbox⁸, then registered to the PAM50 template⁹ to generate average group-level metric maps. The PAM50 atlas⁹ was then registered to the participant space to extract metrics inside the spinal cord and subregions. Metric values were compared with UPDRS scores using an ordinary least squares regression model with age correction to ensure the observed effects were due to disease progression and not to aging.

Results

Average metric maps (Figure 2) suggest an increase in ODI and a decrease in FA in the white matter in PD participants compared to healthy individuals. We also notice a decrease in the global intensity as we progress through the more caudal vertebral levels, which is very apparent in T2*w, MTR and FA maps. Results in Figure 3 show a significant increase in ODI in the white matter at C4 and C5 levels, and a significant increase in FICVF in the spinal cord, white matter and gray matter at C4. For FA (Figure 4), a global decrease is observed, although only significant for the spinal cord and dorsal columns at C5. Results for MTR show a significant decrease in the gray matter for C2 to C4 combined (Figure 5). As for T2*w, a significant increase was observed in the white matter to gray matter ratio for C4 and for combined C2 to C4 levels.

Discussion

In the brain, studies have reported lower values for FICVF and ODI in the substantia nigra pars compacta in subjects with PD^10,11, which is suspected to be linked to the loss of dopaminergic neurons that is associated with PD in the brain¹¹. However, to our knowledge, no existing work has shown neuronal loss related to PD in the spinal cord. Post-mortem studies have demonstrated an increase in 𝛼-synuclein in the PD spinal cord¹². Furthermore, Del Tredici & Braak¹² found globules filled with 𝛼-synuclein in subjects with advanced PD, instead of small varicosities in earlier stages. These findings are consistent with those of Sekigawa et al.¹³, who observed axonal swelling related to 𝛼-synuclein in the spinal cord of transgenic mice. These results suggest that the spinal cord is indeed affected by PD, hence the relevance of studying its microstructure in PD patients. Further studies will be needed to better understand the relationship between the microstructural changes suggested by the MR metrics in the spinal cord and identify potential biomarkers for the early diagnosis of PD in the spinal cord.

Conclusion

In conclusion, this exploratory study is the first to establish values for MTR, T2*w and DWI metrics in the spinal cord of a population with PD. Significant correlations between these metrics and the UPDRS score were found in several regions of the spinal cord, particularly for ODI, FICVF and FA at the C4 and C5 vertebral levels, suggesting the relevance of further studying these metrics in the PD spinal cord. Further analyses of these metrics could lead to identifying potential biomarkers of PD in the spinal cord and gain a better understanding of this disease in the central nervous system.

Acknowledgements

This work is supported by the TransMedTech Institute, thanks to the financial support of the Canada First Research Excellence Fund and the Fonds de recherche du Québec, the Fondation Courtois, the Natural Sciences and Engineering Research Council of Canada (NSERC), and Polytechnique Montreal. We thank the Clinical, Biospecimen, Imaging & Genetic (C-BIG) repository for help in participant recruitment and the brain imaging centre of The Neuro for help in data acquisition. We thank all participants involved in this study.

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