Quantifying white matter tract diffusion parameters in the presence of increased extra-fiber cellularity and vasogenic edema

Abstract

The effect of extra-fiber structural and pathological components confounding diffusion tensor imaging (DTI) computation was quantitatively investigated using data generated by both Monte-Carlo simulations and tissue phantoms. Increased extent of vasogenic edema, by addition of various amount of gel to fixed normal mouse trigeminal nerves or by increasing non-restricted isotropic diffusion tensor components in Monte-Carlo simulations, significantly decreased fractional anisotropy (FA), increased radial diffusivity, while less significantly increased axial diffusivity derived by DTI. Increased cellularity, mimicked by graded increase of the restricted isotropic diffusion tensor component in Monte-Carlo simulations, significantly decreased FA and axial diffusivity with limited impact on radial diffusivity derived by DTI. The MC simulation and tissue phantom data were also analyzed by the recently developed diffusion basis spectrum imaging (DBSI) to simultaneously distinguish and quantify the axon/myelin integrity and extra-fiber diffusion components. Results showed that increased cellularity or vasogenic edema did not affect the DBSI-derived fiber FA, axial or radial diffusivity. Importantly, the extent of extra-fiber cellularity and edema estimated by DBSI correlated with experimentally added gel and Monte-Carlo simulations. We also examined the feasibility of applying 25-direction diffusion encoding scheme for DBSI analysis on coherent white matter tracts. Results from both phantom experiments and simulations suggested that the 25-direction diffusion scheme provided comparable DBSI estimation of both fiber diffusion parameters and extra-fiber cellularity/edema extent as those by 99-direction scheme. An in vivo 25-direction DBSI analysis was performed on experimental autoimmune encephalomyelitis (EAE, an animal model of human multiple sclerosis) optic nerve as an example to examine the validity of derived DBSI parameters with post-imaging immunohistochemistry verification. Results support that in vivo DBSI using 25-direction diffusion scheme correctly reflect the underlying axonal injury, demyelination, and inflammation of optic nerves in EAE mice.

Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis

“…Moreover, DBSI-derived radial diffusivity negatively correlated with myelin content as quantified by Luxol Fast Blue staining, and did so better than radial diffusivity measured by DTI. This finding is consistent with our previous study in an animal model of CNS inflammatory demyelination that radial diffusivity derived by DTI reflected both myelin integrity and extra-axonal water content; it was not specific for myelin integrity (Wang et al, 2011bChiang et al, 2014). Only one of the three autopsy spinal cord specimens exhibited significant correlation between haematoxylin-positive counts and restricted isotropic diffusion (Fig.…”

“…This is in accord with previous studies showing that MTR reduction is not only associated with demyelination but also is related to increased tissue water content (Vavasour et al, 2011). Similar to MTR, DTI radial diffusivity was affected by both myelin integrity and tissue water content, and was therefore also less specific than DBSI radial diffusivity (Wang et al, 2011b;Chiang et al, 2014).…”

“…*P 5 0.05. significant axon and myelin injury. Our interpretation of DBSI restricted isotropic fraction as a metric of cellularity is supported by its close correlation with 4',6-diamidino-2-phenylindole (DAPI)-positive nuclear counts in animal models of inflammatory demyelination (Wang et al, 2011b;Chiang et al, 2014.…”

“…Despite that DTI-derived axial diffusivity and radial diffusivity can concurrently quantify coexisting axonal injury and demyelination in some settings (Song et al, 2002(Song et al, , 2003(Song et al, , 2005, DTI becomes inaccurate in the presence of inflammation (Sun et al, 2006b;Lodygensky et al, 2010;Xie et al, 2010), tissue loss (Kim et al, 2007), crossing fibres (Wheeler-Kingshott and Cercignani, 2009), and CSF contamination (Karampinos et al, 2008;Cheng et al, 2011) and cannot measure the inflammatory components. We thus developed DBSI and have previously accurately captured the severity of axonal injury, demyelination, and inflammation in white matter tracts from mouse models of CNS inflammatory demyelination (Wang et al, 2011bChiang et al, 2014).…”

“…DBSI-derived fibre fraction, axial diffusivity and radial diffusivity reflected the integrity of white matter fibres comprising anisotropic diffusion components. Although the definitive classification of the spectrum of isotropic diffusion components has not yet been reached, previous experimental observations suggested that restricted isotropic (associating with cells) and non-restricted isotropic diffusion (associating with vasogenic oedema and tissue loss) may be distinguished using a threshold of isotropic diffusivity of 0.3 mm 2 /ms (Wang et al, 2011bChiang et al, 2014).…”