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Patients with sickle cell disease have altered brain fractional anisotropy, axial, mean and radial diffusivity quantified by 7T MRI.
Elizabeth Meinert-Spyker1, Tales Santini2, Sharadhi Umesh Bharadwaj1, Enrico Novelli3,4,5, Tamer Ibrahim2,6,7, and Sossena Wood1,8
1Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, United States, 2Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States, 3Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA, United States, 4Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States, 5Sickle Cell Center of Excellence, University of Pittsburgh, Pittsburgh, PA, United States, 6Radiology, University of Pittsburgh, Pittsburgh, PA, United States, 7Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States, 8Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA, United States

Synopsis

Keywords: White Matter, Diffusion Tensor Imaging, Sickle cell disease

This abstract compares diffusion tensor imaging parameters between healthy controls and sickle cell disease (SCD) patients. Various softwares were utilized to obtain diffusion metrics and conduct voxelwise comparison was conducted. Fractional anisotropy (FA) and axial diffusivity (AD) values were significantly decreased in patients with SCD compared to controls, while mean diffusivity (MD) and radial diffusivity (RD) were primarily increased in patients compared to controls. Our FA and MD findings are consistent with other studies comparing diffusion metrics of individuals with SCD at a lower magnet field. We also present novel findings comparing AD and RD values for the SCD population.

Introduction

Sickle cell disease (SCD) is a genetic condition that results in the formation of an abnormal hemoglobin, HbS, leading to chronic hemolysis, anemia, abnormal perfusion, and decreased oxygen delivery to various tissues. There are multiple forms of SCD with homozygous hemoglobin S (HbSS) being a more severe form. Additional subtypes include HbSC and hemoglobin S beta+ (HbSβ+) thalassemia which generally present with milder phenotypes but can still lead to complications1,2,3. SCD predominantly affects people of African descent4,5 and affects millions of people worldwide. As neurological function is correlated and/or reliant on adequate blood and oxygen delivery, it is common for neurological complications such as white matter tissue damage to arise in patients with SCD6,7,8,9,10. In this work, we use diffusion tensor imaging (DTI) MRI to compare individuals with SCD to healthy race and age matched controls. To the best of our knowledge, this is the first study to use 7T MRI data to compare diffusion metrics between adult individuals with SCD and healthy controls. We hypothesized that fractional anisotropy (FA) and axial diffusivity (AD) would be significantly decreased in patients with SCD compared to healthy controls while radial diffusivity (RD) and mean diffusivity (MD) metrics would be increased, indicating white matter tissue damage which may result from SCD.

Methods

24 healthy controls (aged 38+/-15) and 24 patients with SCD (aged 35+/-13) were included. We recruited patients with various SCD genotypes (11 HbSS, 9 HbSC, and 4 HbSβ+ thalassemia). DTI data was acquired with a 7T MRI scanner (MAGNETOM, Siemens), and a customized 16Tx/32Rx head coil11,12,13. The sequence parameters were: 64 directions with b-value of 1ms/µm2, 2 acquisitions without diffusion gradients (with and without reversed phase encoding direction), TE/TR=80/10031 ms, total acquisition time 11:33 min. T1-weighted MPRAGE scans were acquired with 0.75 mm isotropic resolution, acquisition time of 5.02 mins, and TE/TR/TI=2.17/3000/1200 ms. Preprocessing of the data was conducted with the softwares MRtrix14 and FSL15. Preprocessing included denoising, removing Gibb’s ringing artifacts, and motion and distortion correction. In addition, masks were created from T1-weighted images using a five-tissue-type script (5ttgen) on MRtrix. Tensors were then calculated using the dwi2tensor and tensor2metric functions. Tract-based spatial statistics16 (TBSS) was used to compare diffusion metrics between healthy controls and patients with SCD. Voxelwise statistics on the skeletonized FA data was then conducted by creating design files for a simple t-test between controls and patients with SCD and running randomisation on FSL.

Results

After visual inspection, 48 subjects were included in this analysis. An example of a healthy participant after preprocessing can be visualized in Figure 1. Figure 2 illustrates the mean FA maps of healthy controls and patients with SCD, both separately and overlaid. These figures were generated through TBSS and indicate where diffusion is prominent in the brain. Voxel-wise comparison of FA, MD, AD, and RD metrics indicate that various brain regions of patients are significantly different from healthy controls (p-value<0.05, Figures 3 and 4). Results indicate decreased FA values and both increased and decreased MD values in patients with SCD compared to controls. Results also indicate primarily decreased AD values and primarily increased RD values.

Discussion

SCD causes stroke and potential alterations in the water diffusivity within the brain due to hypoperfusion and ischemia. Low FA has been associated with worse cognitive function17,18,19,20, a debilitating complication of SCD. Thus, the finding of lower FA values in patients with SCD compared to healthy controls is unsurprising and consistent with findings from 1.5T data21,22. MD values increase in damaged tissues due to increased, unorganized, diffusion23. Other studies have indicated that MD can be difficult to interpret in complex diseases due to brain regions experiencing unpredictable combinations of factors such as demyelination, cell proliferation, axon loss, and inflammation24. This may explain why some regions of the brain have higher MD values in patients than controls while others have lower MD values. Decreased AD values indicate that longitudinal diffusion along axons is decreased, potentially indicating decreased axonal integrity which results in unorganized diffusion throughout blood vessels. Our findings of increased RD values are consistent with our decreased AD values as it measures the water diffusion perpendicular to the fiber tracts, also indicating potential loss in axonal integrity or demyelination25. Viewed holistically, our findings indicate that there is potential white matter tissue damage in patients with SCD compared to healthy controls. These findings may help to explain the cognitive deficits experienced by patients with SCD26,27.

Conclusion

Our study is indicative of white matter tissue damage in patients with SCD and is the first to use 7T DTI in adults22,28. As SCD complications generally increase with age, analyzing the effects of SCD on the aging brain is essential to develop and analyze treatment methods. Studies should be conducted to investigate the specific fiber tracts that are most affected in SCD and the differences between sickle cell disease subtypes. This will increase our comprehension of SCD and allow for correlations to be made between clinical complications of SCD and DTI metrics.

Acknowledgements

This work was supported by the National Institutes of Health under award number: R01HL127107. Huge thank you to Dr. Sossena Wood for encouragement and resources.

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Figures

Figure 1: Characterization of DTI measurements on a healthy control, illustrating (left-right, top-bottom) fractional anisotropy (FA), absolute value of tensor vectors, axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD).

Figure 2: Average fractional anisotropy (FA) maps of healthy controls (top). Average FA image of patients with SCD (middle). Average FA maps of healthy controls (blue-light blue) and patients with SCD (red-yellow) with average FA of patients with SCD displayed at 50% opacity. All images overlaid onto the standardized 1mm template in MNI space.

Figure 3: 3a shows voxels where there is a significant difference between FA of controls and patients with SCD. 3b illustrates voxel-wise comparison between AD. Red-yellow colors indicate that patients have greater values than controls while the blue-light-blue indicates that patients have lower values than controls. FA and AD values are predominantly significantly decreased in patients.

Figure 4: 4a shows voxels where there is a significant difference between MD of controls and patients with SCD. 4b illustrates voxel-wise comparison between RD. Red-yellow colors indicate that patients have greater values than controls while the blue-light-blue indicates that patients have lower values than controls. MD values are both increased and decreased, with significant increases being more prominent. RD values are predominantly significantly increased in patients.

Proc. Intl. Soc. Mag. Reson. Med. 31 (2023)
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DOI: https://doi.org/10.58530/2023/3020