Axial Diffusivity Is the Primary Correlate of Axonal Injury in the Experimental Autoimmune Encephalomyelitis Spinal Cord: A Quantitative Pixelwise Analysis

Abstract

The dissociation between magnetic resonance imaging (MRI) and permanent disability in multiple sclerosis (MS), termed the clinicoradiological paradox, can primarily be attributed to the lack of specificity of conventional, relaxivity-based MRI measurements in detecting axonal damage, the primary pathological correlate of long-term impairment in MS. Diffusion tensor imaging (DTI) has shown promise in specifically detecting axonal damage and demyelination in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). To quantify the specificity of DTI in detecting axonal injury, in vivo DTI maps from the spinal cords of mice with EAE and quantitative histological maps were both registered to a common space. A pixelwise correlation analysis between DTI parameters, histological metrics, and EAE scores revealed a significant correlation between the water diffusion parallel to the white matter fibers, or axial diffusivity, and EAE score. Furthermore, axial diffusivity was the primary correlate of quantitative staining for neurofilaments (SMI31), markers of axonal integrity. Both axial diffusivity and neurofilament staining were decreased throughout the entire white matter, not solely within the demyelinated lesions seen in EAE. In contrast, although anisotropy was significantly correlated with EAE score, it was not correlated with axonal damage. The results demonstrate a strong, quantitative relationship between axial diffusivity and axonal damage and show that anisotropy is not specific for axonal damage after inflammatory demyelination.

MRI signature in a novel mouse model of genetically induced adult oligodendrocyte cell death

“…It has been shown that axial diffusivity is highly correlated with axonal damage in EAE mice (DeBoy et al, 2007;Budde et al, 2008) and mouse models of other white matter injuries (Sun et al, 2006;Kim et al, 2007;Mac Donald et al, 2007) resulting from the loss of coherent organization of the axon. Decreased axial diffusivity has been associated with axonal swelling (Song et al 2005), Wallerian degeneration (Song et al 2003), diffuse axonal injury (Arfanakis et al 2002) or axonal integrity/neurofilament dysfunction (positive SMI-32 staining) (Budde et al, 2009;Sun et al 2006). We attribute the strongly reduced λ║ values to axonal damage, which has been demonstrated by marker analysis for axonal impairment and disorganization, as well as morphological findings typical for axonal defects (Pohl et al, 2011) in regions affected by oligodendrocyte cell death.…”

“…These models display disseminated and variable focal lesions at brain or spinal cord level (for review see Lassmann, 2008), which are difficult to interpret when using conventional T1-and T2-weighted MRI techniques sensitive for inflammatory processes only (Nessler et al, 2007;Serres et al, 2009). Therefore, in parallel to the clinical situation both DTI and MTR measures are currently being investigated as measures of demyelination, axonal damage or myelin integrity in EAE (Budde et al, 2008;Budde et al, 2009;DeBoy et al, 2007;Serres et al, 2009;Rausch et al, 2003;Rausch et al, 2009) and CNS demyelination and remyelination in a mouse model of cuprizone-mediated demyelination (Sun et al, 2006;Zaaraoui et al, 2008). Furthermore, the use of ultra-small particles of iron oxide (USPIOs) to visualize macrophage infiltration has been proposed as refined marker for inflammatory events in MS and animal models thereof (Dousset et al, 1999a;Rausch et al, 2003;Floris et al, 2004;Berger et al, 2006;Brochet et al, 2006;Ladewig et al, 2009).…”

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

“…Diffusion-weighted images were then co-registered to the anatomical 3D magnetization prepared rapid acquisition of gradient echo (MPRAGE), and fluid attenuated inversion recovery (FLAIR) images using FLIRT (FMRIB's Linear Registration Tool) (Jenkinson et al, 2002). The DTI maps of fractional anisotropy, axial diffusivity ( k ), and radial diffusivity ( o ), were computed using an in-house developed algorithm described previously (Budde et al, 2009). Highresolution 1 Â 1 Â 1 mm 3 sagittal FLAIR images were used for multiple sclerosis lesion identification.…”

Magnetic resonance microimaging of the spinal cord in the SOD1 mouse model of amyotrophic lateral sclerosis detects motor nerve root degeneration

“…In the experimental allergic encephalomyelitis model of multiple sclerosis, contrast changes have been observed in conventional anatomic images (Schellenberg et al, 2007), axial diffusivity has been correlated with axonal damage (Budde et al, 2008;Budde et al, 2007;Budde et al, 2009), and decreased quantitative T2 and magnetic transfer values have been shown (McCreary et al, 2009). Numerous studies have also assessed white matter integrity in mouse models of spinal cord injury, using diffusion tensor imaging Kim et al, 2010;Loy et al, 2007;Tu et al, 2010), T1-and T2-weighted imaging (Gonzalez-Lara et al, 2009;Levene et al, 2008;Nishi et al, 2007), and MRM (Bilgen, 2007).…”