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Investigation of microstructural differences in the nigrosome-1 region of the substantia nigra between healthy and Parkinson’s disease subjects at 7T
Yiming Xiao1, Jonathan C Lau1,2, Terry M Peters1,2,3, and Ali R Khan1,2,3,4

1Imaging Research Laboratories, Robarts Research Institute, Western University, London, ON, Canada, 2School of Biomedical Engineering, Western University, London, ON, Canada, 3Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, 4The Brain and Mind Institute, Western University, London, ON, Canada

Synopsis

The loss of hyperintense signals of the nigrosome-1 region within the substantia nigra on T2*w MRI has previously been investigated as a potential biomarker for Parkinson’s disease (PD). Although the radiological observation is expected to be induced by microstructural changes, which can provide more insights into the mechanisms of PD, no relevant MRI studies have been conducted so far. With ultra-high-field 7T MRI, we compared the microstructural features of the nigrosome-1 regions between healthy and PD subjects using quantitative MRI, and revealed alterations in T1, R2*, mode of anisotropy, and fractional anisotropy within this subregion due to the disease.

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra (SN). The nigrosome-1 region of the SN undergoes the greatest and earliest cellular changes in PD. Typically observed in T2*w MRI in the axial view, the healthy hyperintense nigrosome-1 divides the SN to form a “swallow tail” shape, which disappears in PD patients (Fig. 1). This phenomenon is currently being investigated as a biomarker for the disorder1. While understanding of the microstructural alterations of the nigrosome-1 can potentially reveal more insights of PD progression, there are few relevant studies to date. By leveraging the high sensitivity and increased resolution of 7T MRI, we are able to study, for the first time, microstructural changes in the nigrosome-1 due to PD using quantitative MRI measurements.

Methods

Five PD patients (age = 61±3y) and six healthy subjects (age = 47±11y) were scanned on the 7T Siemens Magnetom MRI scanner (Siemens Healthcare GmbH, Erlangen, Germany) with multiple protocols, including MP2RAGE2 (TE=2.73ms, TR=6000ms, TI=800/2700ms, FA=4°/5°, resolution=0.7x0.7x0.7mm3), 3D T2w SPACE (TE=398ms, TR=4000ms, resolution=0.7x0.7x0.7mm3), 3D four-echo GRE (TE=4.61/8.24/11.87/15.50ms, TR=35ms, FA=13°, resolution=0.8x0.8x0.8mm3), and 2D EPI DWI (TE=60.8ms, TR=5500ms, FA=100°, 5, 30 and 60 gradient directions at B=0,1000,2000, resolution=1.5x1.5x1.5mm3). T1w and quantitative T1 map images were obtained from the MP2RAGE sequence, and the SA2RAGE sequence3 was used to remove residual B1+ effects. T2*w images were generated by averaging the last 3 echoes of the GRE sequence to improve the contrast-to-noise ratio (CNR). Note that the “swallow tail” pattern can be observed bilaterally, to varying degrees, on T2*w MRI scans of all healthy subjects. Finally, R2* maps were computed from the multi-echo GRE sequence while the DTI-related metrics, including fractional anisotropy (FA), mean diffusivity (MD), and mode of anisotropy (MO) were derived from the DWI scans. All images were rigidly registered and resampled to the space of the individual’s T1w MRI for analysis. To obtain the regions of interest (ROIs) for analysis, averaged brain templates were created with deformation fields obtained from a multi-contrast group-wise nonlinear registration using all subjects’ T1w MRIs, T2w MRIs, and FA maps to ensure structural correspondence. The nigrosome-1 ROI was manually segmented in addition to the inner side of the “swallow tail” (medioposterior SN), which has a distinct feature on T2*w MRI, and the rest of the SN bilaterally based on the T2*w sub-group template of healthy subjects at 0.3x0.3x0.3mm3 resolution. Then, the labels were propagated back to the individual T1w images. Finally, the mean values of the quantitative MRI measures within the ROIs were taken for both healthy and patient groups, and compared using one-tailed two-sample t-tests.

Results

The results of the measurements are summarized in Fig. 2 and Fig. 3 as box plots. Statistical analysis demonstrates that in the nigrosome-1 of the PD cohort, T1 and MO are lower (p<0.05), and R2* is higher bilaterally (p<0.05) while increased FA (p<0.05) is only present on the right-hand side. For both the left and right medioposterior SN, T1 values are significantly higher (p<0.05) for the healthy subjects.

Discussion

As the hyperintensity of the nigrosome-1 is less pronounced in T2w MRIs, they were used to align the SN between the PD and healthy cohorts in the group-wise registration instead of T2*w MRIs. To ensure the CNR of the SN sub-regions for segmentation, we used the population-averaged T2*w template rather than individual scans. The observed higher R2* in nigrosome-1 for PD implies elevated iron content, and the iron deposition varies more notably among patients than healthy subjects. The T1 shortening of the same region in PD may come from iron content increase and a decrease in free water, possibly due to cellular death. Notably, the reduced MO suggests less “organization” of fibers in the nigrosome-1 among PD patients, with potential selective degeneration in certain pathways of the fiber crossing, as suggested by the increased FA on the right-hand side. One limitation of this pilot study lies in the small sample size. However, our on-going subject recruitment will further strengthen the analysis in the future. In addition, correlation with histological data will be highly instructive in developing a comprehensive picture for the results of the quantitative MRI assessments.

Conclusion

We measured the underlying microstructural differences within the nigrosome-1 regions of the SN using quantitative MRI techniques, and report significant changes in T1, R2*, MO, and FA within this sub-region in PD patients. Future investigation with a larger cohort will help further disclose the physiological changes within the SN to better understand PD and its progression.

Acknowledgements

This work was supported by CIHR, NSERC, the Canada First Research Excellence Fund, and Brain Canada.

References

  1. Schwarz et al. The ‘Swallow Tail’ Appearance of the Healthy Nigrosome – A New Accurate Test of Parkinson's Disease: A Case-Control and Retrospective Cross-Sectional MRI Study at 3T. PloS one. 2014;9(4): e93814.
  2. Marques et al., MP2RAGE, a self bias‐field corrected sequence for improved segmentation and T1‐mapping at high field, NeuroImage, 2010; 49(2): 1271-1281.
  3. Eggenschwiler et al., SA2RAGE: A new sequence for fast B1+ ‐mapping, Magnetic Resonance in Medicine, 2012; 67(6): 1609-1619.

Figures

Figure 1. Segmentations of substantia nigra (SN) sub-regions and comparison of T2*w group-averaged templates of healthy and Parkinson’s disease (PD) cohorts. The difference is highlighted with yellow arrows.

Figure 2. Mean FA, MD, and MO measurements of the substantia nigra (SN) sub-regions between healthy and Parkinson's disease (PD) subjects. The orange stars mark the “Healthy vs. PD” pairs that differ with statistical significance (p<0.05).

Figure 3. Mean T1 and R2* measurements of the substantia nigra (SN) sub-regions between healthy and Parkinson's disease (PD) subjects. The orange stars mark the “Healthy vs. PD” pairs that differ with statistical significance (p<0.05).

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)
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