Synopsis

Parkinson's disease (PD) is characterised by dopaminergic neuronal loss and iron overload in the nigrostriatum. Diffusion Kurtosis Imaging (DKI) and Quantitative Susceptibility Mapping (QSM) allow quantification of alterations in tissue microstructure based on water diffusion and iron deposition respectively. Our case-control study in PD using DKI revealed greater cellular loss in the lateral SN and complex microstructural degradation in the putamen. QSM showed spatially variant iron deposition (Δχ) in the grey nuclei congruent with histochemical reports, and multivariate analysis showed that putaminal and lateral nigral Δχ significantly predicted UPDRS. Significant correlations between Δχ and DKI indices were found in the putamen.

Introduction

Methods

The study was approved by the institutional ethics committee. Newly diagnosed PD patients with diagnosis made within a year before recruitment by Movement Disorders specialists and sex-, age-matched healthy controls (HC) were recruited. All participants underwent clinical evaluation using the Unified Parkinson’s Disease Rating Scale (UPDRS), and brain MRI on a 3T scanner using standardized protocol, including multi-echo GRE (TR=53 ms, TE=7.5/14.8/20/26.4 ms, FA=15°, matrix=256x192, 2 mm slices) and DKI (SE-EPI with 63 diffusion-encoding directions, b-values=0/1000/2000 s/mm²,TR=10118 ms, TE=102 ms, matrix=122x122, 2.5 mm slices) sequences.

QSM post-processing was performed using SPIN (MR Innovations Inc., Detroit, USA) and DKI post-processing using Diffusion Kurtosis Estimator (Medical University of South Carolina, Charleston, USA). Regions of interest (ROIs) in the caudate, putamen, globus pallidus (GP), and medial and lateral SN were manually drawn by two independent raters to compare the mean susceptibility (Δχ) and DKI indices (mean, axial and radial diffusivity-MD, AD, RD; fractional anisotropy-FA; mean, axial and radial kurtosis-MK, AK, RK; kurtosis fractional anisotropy-KFA) between PD patients and HC. Statistical analyses were performed using R 3.4.2. Intra- and inter-rater reliability were assessed by Intraclass Correlation Coefficient (ICC). Student’s t-tests were carried out to compare differences of Δχ and DKI indices between PD patients and HC. Univariable linear regression models were performed between Δχ and DKI indices with clinical motor scores. Multivariable linear regression models were subsequently developed using metrics with p-value <0.1 from the univariate analysis.

Results

Forty-seven PD patients (M/F 23/24; mean age=64 years) and 16 HC (M/F 9/7; mean age=66.5 years) were included in this study. 53% of PD patients presented with dominant right-sided symptoms. The ICC were >0.7 for all ROIs. There was a gradient of Δχ in the gray nuclei (Figure 1), and Δχ tended to be higher in the SN, putamen and GP for PD patients compared to HC, although these were not statistically significant. Δχ was significantly higher (p<0.05) in the medial than lateral SN in PD patients but not in HC. Multivariate analysis showed that Δχ in the putamen and left lateral SN significantly predicted UPDRS (p<0.05) after adjusting for age and gender (Table 1).

There were significant changes of DKI indices (e.g., Figures 2-3) in the lateral SN [increases in MD (p=0.02), RD (p=0.017)], putamen [increases in MD (p<0.001), AD (p=0.012), RD (p<0.001), RK (p=0.018) and decrease in KFA (p=0.042)] and caudate [increases in MD (p<0.001), AD (p<0.001), RD (p<0.001) and decrease in FA (p=0.036), KFA (p<0.001)] between PD patients and HC. Significant correlations (p<0.05) between Δχ and MD, AD, RD, MK and AK were found in the putamen.

Discussion

Iron deposition was spatially variant in the grey nuclei, being highest in the GP and lowest in the caudate (Figure 1). Our results corresponded with histochemical values in the literature.¹ We found a trend of greater iron deposition in PD patients than HC, albeit not statistically significant, which could be attributed to the early stages of PD in our patient group. Nevertheless, changes in iron deposition in the lateral SN and putamen were sensitive enough to detect and predict the clinical motor scores.

Significant increases of MD and RD in PD patients suggest cellular loss and injury in the lateral SN compared to HC. Significant changes in various DKI indices suggest more complex microstructural degradation in the putamen and caudate in PD. The difference in correlation between iron deposition and DKI indices in the SN and putamen (Table 1) could be a result of the spatial differences in iron content in these areas (Figure 1). Increase of local magnetic susceptibility by iron may cause signal perturbation in diffusion-weighted images and artefactually alter diffusion indices in iron-rich grey nuclei such as GP and SN.^2-3 A threshold iron content may exist beyond which diffusion indices would be confounded.

Conclusion

Acknowledgements

References

1. Hallgren B, Sourander P. The effect of age on the non-haemin iron in the human brain. J Neurochem. 1958 Oct;3(1):41-51.

2. Rulseh AM, Keller J, Tintěra J, et al. Chasing shadows: what determines DTI metrics in gray matter regions? An in vitro and in vivo study. J Magn Reson Imaging. 2013;38(5):1103-10.

3. Gong NJ, Wong CS, Hui ES, et al. Hemisphere, gender and age-related effects on iron deposition in deep gray matter revealed by quantitative susceptibility mapping. NMR Biomed. 2015 Oct;28(10):1267-74.