Synopsis

Keywords: Spinal Cord, Neurodegeneration, Degenerative Cervical Myelopathy

Degenerative cervical myelopathy (DCM) is the most common form of non-traumatic spinal cord injury, mainly caused by chronic cervical cord compression. Impaired spinal cord perfusion is a central pathophysiological tenet in DCM patients. This study aims at investigating non-invasively DCM-induced changes of blood perfusion in the spinal cord above a cervical myelopathy using quantitative MRI techniques. Cardiac-gated intravoxel incoherent motion (IVIM) 3T MRI, sensitive to perfusion, was applied to the cervical cord (C1-C3) in 25 DCM patients and 27 healthy controls. DCM showed tissue-specific perfusion impairment. IVIM maps suggested remote hemodynamic deficit induced by cervical cord compression in DCM.

Introduction

Cervical cord compression in DCM patients triggers a cascade of pathophysiological processes including microvascular deficits, neuroinflammation and apoptosis^1–5. Impaired spinal cord perfusion plays an important role as a central pathophysiological tenet in DCM⁶. However, underlying mechanisms of hemodynamic changes are understudied.
Therefore this study aims at using intravoxel incoherent motion (IVIM), a non-invasive diffusion-based MRI method, sensitive to tissue microcirculation and perfusion⁷. IVIM has been previously successfully applied in different brain pathologies^8–10 and other organs^11–14, as well as in spinal cord at 7T¹⁵. A cardiac-gated 3T IVIM protocol was applied in the cervical cord (C1-C3) of DCM patients and healthy controls (HC) to investigate vascular impairment in the grey matter (GM) and white matter (WM) rostral to the compression site in patients.

Methods

In vivo image acquisition
Clinical and MRI data were acquired in 25 DCM patients (mean age: 57.8 ± 10.2 years, 15 males, mJOA ≥14) and 27 HC (mean age: 54.3 ± 11.7 years, 11 males) on a 3T system (MAGNETOM Prisma, Siemens Healthcare, Erlangen, Germany) with a Siemens Healthcare 64-channel head/neck RF coil. The entire protocol (38-minute nominal acquisition time) included:
- Cardiac-gated IVIM sequence: axial 2D-RF spin-echo EPI ZOOMit sequence with 0.9x0.9 mm² in-plane resolution, 5 mm-slice thickness, 34x108 matrix size, with 14 b-values ranging from 0 to 650 s/mm² with increment of 50 s/mm². Twenty repetitions per b-value were acquired in three in-plane diffusion encoding directions, split into forward and reverse phase encoding acquisitions for subsequent distortion correction. FOV was centered on the C2/C3 vertebral level, covering C1-C3 levels for all subjects.
- T2*-weighted axial 3D multi-echo gradient-echo sequence, for ROI segmentation and calculation of cross-sectional areas.
- Standard axial and sagittal T2-weighted turbo spin echo sequences for lesion segmentation and cervical level localization, respectively.
As a severe compression affects the IVIM scans and subsequently biases the parameter quantification, scans were conducted above the compression level¹⁶.

Data processing and fitting
The IVIM toolbox¹⁵ was used to generate the perfusion maps. Denoising¹⁸, Gibbs artefacts removal^19,20 (DIPY²¹), motion (sct_dmri_moco²²) and distortion correction (FSL topup²³) were performed. Voxel-wise fitting of the IVIM signal was based on the biexponential IVIM model⁷:
$$S(b)=S_0 e^{-bD} [F e^{-bD^*}+1-F]$$
where $$$F$$$ is the microvascular volume fraction, $$$D^*$$$ is the pseudo-diffusion coefficient and $$$D$$$ is the diffusion coefficient. The fit was performed using a one-step approach, with an initial estimation of $$$D$$$ using b-values ≥ 400 s/mm² and consecutive fitting of all model parameters.
Registration to template²⁴/atlas²⁵ (SpinalCordToolbox version 4.3²²) was performed based on T2*-weighted images. Perfusion parameters $$$F$$$, $$$D^*$$$ (providing information on blood volume and blood velocity²⁶, respectively), $$$F$$$∙$$$D^*$$$ (sensitive to blood flow²⁶) and $$$D$$$ were extracted in subject space across C1-C3 levels, slice-by-slice, in the total spinal cord (SC), WM and GM. ROIs were eroded at the cord periphery to prevent partial volume effect.
The frequency map of the T2-hyperintensity in DCM patients with radiological myelopathy¹⁷ was calculated for presenting the frequency of lesion. Spinal cord atrophy was assessed using cross-sectional areas (CSA) derived from segmentations of the T2*-weighted MRI. Two-sample t-tests were conducted in R (version 4.1.2) to compare IVIM-derived perfusion parameters and CSA between HC and DCM. Relationships between perfusion parameters and CSA were explored using linear regression and Pearson's correlation coefficient.

Results & Discussion

Eight DCM patients showed radiological evidence of cervical myelopathy (n=2 at C3/C4, n=2 at C4/C5, and n=4 at C5/C6) (Figure 1B). The lesion frequency maps indicated higher frequency of myelopathy in GM at C3-C5 levels in the DCM group (Figure 1C). Atrophy was observed in WM (Δ = -9.7%; p = 0.006) and GM (Δ = -6.8%; p = 0.005) of DCM patients (Figure 2), which is in agreement with previous findings²⁷. Perfusion maps, averaged across subjects, depicted the distribution of the IVIM parameters in different ROIs (Figure 3). $$$F$$$ was greater in GM compared to WM in both cohorts, in alignment with previous studies^15,28,29. The maps visually suggested a gradient of $$$F$$$ in GM in DCM, decreasing from C1 to C3 (Figure 3B). While $$$D^*$$$ and blood flow ($$$F$$$∙$$$D^*$$$) were reduced in GM, cord region mainly affected by DCM¹, only $$$D^*$$$ decreased in WM of DCM (Figure 4B-C). Of note, a positive correlation was found between $$$F$$$ and GM area (Figure 5). Although group interaction (HC ~ DCM) was not significant, post-hoc analysis indicated that the correlation was mainly driven by DCM (R = 0.69, p = 0.02), while no correlation was observed in HC (R = 0.04, p = 0.90). This suggests a possible alteration in microvasculature volume in GM related to the atrophy observed in DCM patients.

Conclusion

Perfusion maps provide novel insights into tissue-specific changes in DCM, with regard to blood flow and velocity, indicating perfusion deficit in the rostral atrophied cervical cord. Current findings suggest that IVIM is sensitive to the hemodynamic impairment in the cervical cord of DCM. In the next steps, we will explore different optimization approaches (e.g. Bayesian methods³⁰) for the IVIM fit and track perfusion deficit longitudinally following traumatic injury.

Acknowledgements

The authors would like to thank all the participants for their time. This work is based on experiments performed at the Swiss Center for Musculoskeletal Imaging, SCMI, Balgrist Campus AG, Zurich. This project has received funding from the Wings for Life charity (No WFL-CH-19/20) and Balgrist Stiftung 2021.

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