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Measuring white matter damage in different types of MS
Chunyu Song1, Peng Sun2, Anne H. Cross3, Zezhong Ye4, and Sheng-Kwei (Victor) Song5

1Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States, University City, MO, United States, 2Radiology, Washington University School of Medicine, St. Louis, MO, United States, University City, MO, United States, 3Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States, Saint Louis, MO, United States, 4Chemistry, Washington University in St. Louis, st louis, MO, United States, 5Radiology, Washington University School of Medicine, St. Louis, MO, United States, Saint Louis, MO, United States

Synopsis

A new diffusion histology imaging (DHI) is proposed to model intra and extra axonal diffusion along with isotropic diffusion within an image voxel of diffusion-weighted MR images. It resolves crossing fibers while more accurately detecting and quantifying axonal injury, axon loss, demyelination, edema and inflammation. Through the multiple-tensor modelling of diffusion-weighted MRI signals, DHI has shown the potential to detect underlying pathologies of normal appearing corpus callosum in all clinical subtypes of multiple sclerosis.

Introduction

Various diffusion MRI derived metrics have been proposed as markers to detect white matter lesions in CNS disease and injury1. Inflammatory demyelination and axonal damages are the hallmark pathologies of multiple sclerosis (MS)2,3. The inability of conventional MRI to detect and quantify MS-related white matter pathologies has been recognized. We have recently developed a diffusion basis spectrum imaging (DBSI1) to effectively detect, differentiate and quantify axonal injury or loss, demyelination and inflammation in human CNS. In this study, we modified DBSI, i.e., diffusion histology imaging (DHI), adding an intra-axonal compartment to quantify underlying pathologies in normal appearing corpus callosum (CC) in patients with relapsing-remitting (RR), secondary progressive (SP), and primary progressive (PP) MS. Our results suggested that DHI holds promise to more accurately characterize the heterogeneous white matter pathology in multiple sclerosis patients. It can be used as a non-invasive biomarkers to assess various extent of normal appearing white matter damages in subtypes of multiple sclerosis.

Materials and Methods

DHI: The new diffusion histology imaging (DHI) models CNS white matter structures and pathologies considering water diffusion in three types of microstructural environments within an image voxel: 1) intra-axonal diffusion 2) anisotropic extra-axonal diffusion; 3) isotropic extra-axonal diffusion (Fig. 1). Human Subjects: Procedures involving human subjects were all approved by the Institutional Review Board of Washington University. All subjects provided informed consent before their participation in the study. In-Vivo DW-MRI: All subjects underwent diffusion-weighted MRI at 3.0T using a multi-b value diffusion weighting scheme (Trio; Siemens, Erlangen, Germany). Diffusion-weighted images (DWIs) were collected with a 99-direction multiple b-value diffusion scheme using a single-shot spin-echo echo-planar imaging sequence with the following key parameters : voxel size = 2×2×2 mm3; Maximum b-value = 1500 s/mm2; acquisition time = 15 minutes. DTI, DBSI and DHI metrics were computed using the in-house software developed using Matlab.

Results and Discussion

DTI derived metrics are confounded by coexisting axonal injury/loss, myelin damage and inflammation (Fig. 2). Significantly decreased DBSI-fiber fraction was seen in PPMS and SPMS patients comparing to that of the control (Fig. 3A). Corpus callosum DBSI-λǁ (Fig. 3C) slightly increased in all three subtypes of MS contradicting the conventional wisdom of axonal injury associated λǁ decrease. Increased DBSI-λ⊥ in CC reflects conventional wisdom of demyelination (Fig. 3D). Significantly decreased intra-axonal fraction derived from DHI was seen in all three subtypes of MS patients (Fig. 4D). The DHI-λǁ (Fig. 4E) significantly decreased reflecting axonal injury in all MS subtypes. Demyelination in PPMS and SPMS patients was evidenced by the increased extra-axonal (EA)-λ⊥ (Fig. 4C). The increased EA fraction in PPMS/RRMS subtypes comparing with that of the control was statistically significant reflecting edema in normal appearing CC (Fig. 4A).

Conclusion

We investigated whether changes in normal appearing CC are present in clinical subtypes of MS by DHI. We observed that normal appearing CC axonal injury in subtypes of MS as clearly seen in DHI derived lǁ that was missed by DBSI and DTI. It is clear that DHI eliminated the confounding effects from reduced extent of fiber component resulting from the dilution of edema and other extra-axonal pathologies seen in DTI and less prominent in DBSI.

Acknowledgements

This work was supported in part by NIH R01-NS047592, P01-NS059560, U01-EY025500, and National Multiple Sclerosis Society (NMSS) RG 5258-A-5, RG 1701-26617.

References

1. Wang Y, Wang Q, Song SK et al. Quantification of increased cellularity during inflammatory demyelination. Brain. 2011; 134: 3590–601.

2. Yaniv Assaf, Peter J. Basser. Composite hindered and restricted model of diffusion (CHARMED) MR imaging of the human brain. NeuroImage 2005; 27:48 – 58

3. Benoit Scherrer, Armin Schwartzman, Maxime Taquet et al. Characterizing Brain Tissue by Assessment of the Distribution of Anisotropic Microstructural Environments in Diffusion-Compartment Imaging (DIAMOND). Magnetic Resonance in Medicine 2016; 76:963–977

Figures

Figure 1 Pictorial depiction of microenvironment including crossing fibers, infiltrating/resident cells, and edema modeled by diffusion histology imaging (DHI). Ellipsoids represent the diffusion tensor profile for white matter axon (yellow) and extra axonal anisotropic diffusion (green). Spheres represent isotropic diffusion tensors associated with cell (blue) and hindered/free water (red). Crossing fibers are separated by the direction of different anisotropic diffusion tensors. Intra axonal diffusion tensor is modeled by close to zero radial diffusivity.

Figure 2 Box plots of corpus callosum DTI metrics from control, PPMS, RRMS and SPMS patients (n = 10, each group). Decreased DTI-FA was observed in all subtypes of MS patients (A), DTI-λǁ increased in SPMS patients (fiber loss or edema?). DTI- λ⊥ increased (D) in PPMS and SPMS patients suggesting demyelination. * indicates p < 0.05.

Figure 3 Box plots of corpus callosum DBSI metrics from control, PPMS, RRMS and SPMS patients (n = 10, each group). Decreased DBSI fiber fraction was observed in PPMS and SPMS patients potentially reflecting fiber loss (A), DBSI-λǁ increased in all MS subtypes contradicting to the notion of axonal injury in MS white matter tracts. DBSI- λ⊥ increased (D) in all MS subtypes reflecting demyelination. DBSI results are more specific than DTI, however increased DBSI-λǁ is difficult to interpret. * indicates p < 0.05.

Figure 4 Box plots of corpus callosum DHI metrics from control, PPMS, RRMS and SPMS patients (n = 10, each group). Decreased DHI intra-axonal fraction was observed in all MS subtypes, DHI-intra axonal λǁ significantly decreased in all MS subtypes reflecting axonal injury in normal appearing CC. Extra-axonal (EA)-λ⊥ increased in PPMS and SPMS reflecting demyelination. DHI results suggest axonal injury and loss, demyelination are present in normal appearing CC of all MS subtypes. * indicates p < 0.05.

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