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Optimization of cervical cord synthetic T1-weighted MRI for enhancing clinical application1Spinal Cord Injury Center, Balgrist University Hospital, Zürich, Switzerland, 2Department of Neurophysics, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany, 3Felix Bloch Institute for Solid State Physics, Leipzig University, Leipzig, Germany, 4Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom
Synopsis
Keywords: Synthetic MR, Precision & Accuracy
Motivation: MRI acquisition time is a critical factor for patient comfort and motion artifacts. To reduce total acquisition time, synthetic MRI is a flexible solution.
Goal(s): To optimize synthetic T1-w (synT1-w) MRI for increasing the accuracy (i.e. difference between synT1-w and MPRAGE) of spinal cord cross-sectional area measurements.
Approach: We optimized and validated synT1-w for tracking neurodegeneration in the cervical cord after spinal cord injury and assessed the required sample size for detecting hypothetical treatment effects.
Results: Accuracy of synT1-w improved considerably with a minor remaining bias of -0.5% compared to MPRAGE. 13.5% less participants are required when using synT1-w instead of MPRAGE.
Impact: Synthetic MRI can help to optimize imaging protocols in clinical trials by reducing acquisition time and the number of required participants. By improving the accuracy of synthetic T1-weighted images, better comparability with different studies using acquired MRI can be achieved.
Introduction
T1-weighted 3D Magnetization Prepared Rapid Acquisition Gradient-Echo (MPRAGE) MRI is routinely used for imaging the central nervous system and to assess macrostructural changes such as regional brain atrophy and changes in cross-sectional area (CSA) of the spinal cord1-4.Acquisition time is a critical factor that significantly impacts patient comfort, the quality of scans and the occurrence of artifacts. Prolonged scanning protocols can compromise image quality and subsequent diagnostic accuracy5. One solution for reducing total scan time is synthetic MRI, since various contrast weightings can be flexibly estimated from quantitative MRI scans6-8.
In a previous study, we investigated the precision of synthetic T1-w (synT1-w) MRI for assessing CSA of the upper cervical cord and could show high test-retest repeatability both within the same scanner and between different scanners9. However, CSA measurements from synT1-w showed a remaining systematic bias of -2.5% compared to MPRAGE, which could affect the direct comparability with studies using the MPRAGE standard 1,2,4,10. Increasing the accuracy of CSA measurements based on synT1-w with respect to the established MPRAGE sequence may improve the comparability and facilitate the implementation of synthetic MRI in clinical routine.
The aim of this study therefore was (1) to optimize the reconstruction parameters of synT1-w for minimizing the bias in CSA (i.e. difference between synT1-w and MPRAGE), (2) to validate the optimized synT1-w images for tracking atrophy in the upper cervical cord following spinal cord injury (SCI), and (3) to compare the required sample sizes for detecting potential treatment effects between MPRAGE and synT1-w.
Methods
This retrospective study includes a longitudinal dataset (part of data already published)9,11-16 of 23 SCI patients and 21 healthy controls who were scanned at 5 visits over 2 years using an MPRAGE scan and the quantitative MPM protocol17. SynT1-w images were reconstructed from quantitative maps of proton density (PD), longitudinal (R1) and effective transverse (R2*) relaxation rates using the MPRAGE signal equation6,18. Using the Spinal Cord Toolbox19, the spinal cord was automatically segmented on synT1-w and MPRAGE images and the average CSA was extracted for vertebral levels C1-C3.The accuracy of synT1-w was assessed by comparing CSA measurements obtained from synT1-w and MPRAGE images using the Bland-Altman method. Linear mixed effect models were created to investigate spinal cord atrophy. Estimates of atrophy rates and CSA at baseline and the 2-year follow-up were compared between synT1-w and MPRAGE. Post-hoc pairwise comparison was performed using Tukey's correction (p<0.05). Moreover, a sample size calculation was conducted to estimate the required sample size for a hypothetical treatment for detecting a reduction of cord atrophy at the 2-year follow-up in spinal cord injury patients compared to patients who received the current standard of care.
Results
The average CSA for MPRAGE was 63.02 ± 9.11 mm2 and for synT1-w 62.71 ± 8.70 mm2 (Figure 1A), which corresponds to a bias of -0.31 mm2 (-0.5%) for synT1-w (Figure 1B). Crucially, this bias was equivalent between controls and SCI patients (Bayes factor = 0.178, Figure 1C&D). This minor remaining bias was also observable in the linear mixed effect models as a general offset. However, both models resulted in similar estimates of linear and quadratic effects of CSA change and similar average estimates of CSA at baseline and the 2-year follow-up (Tables 1&2, Figure 2).The sample size calculation showed that overall the required sample size for detecting treatment effects with a power of 80% and a significance threshold of 5% can be reduced by 13.5% (±8.7%) when using synT1-w instead of MPRAGE (Figure 3).
Discussion
This study improved the accuracy of macrostructural measures of the spinal cord cross-sectional area derived from synthetic T1-w MRI by minimizing the difference to the reference standard MPRAGE compared to previous approaches 9. Reliable estimates of cord atrophy following SCI were obtained from synT1-w MRI. These findings could have significant implications for the planning of future MRI studies, as they demonstrate that after calibration of the synT1-w parameters, reliable and accurate estimates of CSA are obtained from synT1-w images. This suggests that synthetic MRI can replace MPRAGE in clinical studies, reducing total acquisition times. Moreover, fewer participants are required when using the specific MPM-based synT1-w approach instead of MPRAGE used in this study, which can help to further increase the efficiency of clinical trials.Conclusion
Improved synT1-w images allow for better comparability with different studies and for reliable tracking of cervical cord atrophy over two years following SCI. Crucially, fewer participants are required to detect a potential treatment effect in a clinical trial setting when using synthetic MRI.Acknowledgements
We want to thank all participants who took part in this study for their time, as well as the staff of the radiology department at the Balgrist University Hospital in Zurich, Switzerland for their help in acquiring the MR data. Simon Schading-Sassenhausen was supported by a national MD-PhD scholarship from the Swiss National Science Foundation (grant number: 323530_207038). Maryam Seif received grants from Wings for Life charity (No. WFL-CH-19/20), and International Foundation for Research in Paraplegia (IRP-158), and Patrick Freund received a personal grant from the Swiss national Science Foundation (SNF, No. 181362)
References
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Figures
Figure 1 Average spinal cord cross-sectional area (CSA) across C1-C3 for MPRAGE and synT1-w (A). Bland-Altman plot for CSA derived from MPRAGE and synT1-w for all subjects (B) and for healthy controls (C) and spinal cord injury (SCI) patients (D) separately.
Figure 2 Change in CSA over 2 years for healthy controls (dashed line) and SCI patients (solid line) estimated based on MPRAGE (light gray) and synT1-w (dark gray) across C1-C3 (A). Linear effects (i.e. linear atrophy rates) of controls, SCI patients and the difference between both groups estimated from linear mixed effects models (B). Average CSA at baseline, at the 2-year follow up, and the difference between SCI patients and controls estimated from linear mixed effects models (C). MPRAGE - light gray; synT1-w - dark gray
Figure 3 Sample size calculation for detecting effects of a hypothetical treatment as a reduction of CSA atrophy for MPRAGE (A) and synT1-w (B). It is based on a two-group trial (SCI patients receiving the hypothetical treatment, SCI patients receiving the current standard of care). A treatment effect of 100% indicates that no CSA atrophy is observable, while a 0% treatment effect corresponds to the same CSA atrophy detectable in the treatment as in the control SCI group. The correlation coefficients represent the Pearson correlation between the CSA at baseline and the 2-year follow-up.
Table 1 Linear rates of cross-sectional cord area atrophy averaged across C1-C3 for MPRAGE and synT1-w estimated from linear mixed effects models.
Table 2 Cross-sectional cord area averaged across C1-C3 for MPRAGE and synT1-w segmentations at baseline and 2-year follow-up estimated from linear mixed effects models. FUP follow-up