Non-invasive diffusion tensor imaging detects white matter degeneration in the spinal cord of a mouse model of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by selective degeneration of motor neurons. Here we examine the ability of magnetic resonance imaging (MRI) to measure axonal degeneration in the lumbar spinal cord of the SOD1 mouse model of ALS. Diffusion tensor imaging (DTI) was successful in detecting axonal spinal cord damage in vivo. Fractional anisotropy (FA) values were reduced exclusively in the ventral white matter tracts of the lumbar spinal cord of ALS-affected SOD1 mice compared to wild-type littermates, with this effect becoming more pronounced with disease progression. The reduced FA values were therefore limited to white matter tracts arising from the motor neurons, whereas sensory white matter fibers were preserved. Significant decreases in water diffusion parallel to the white matter fibers or axial diffusivity were observed in the SOD1 mice, which can be attributed to the axonal degeneration observed by electron microscopy. At the same time, radial diffusivity perpendicular to the spinal column increased in the SOD1 mice, reflecting reduced myelination. These results demonstrate the usefulness of MRI in tracking disease progression in live animals and will aid in the assessment of treatment efficacy. This method could also potentially be adapted to aid the diagnosis and assessment of ALS progression in humans.

Comparison of Diffusion MRI Acquisition Protocols for the In Vivo Characterization of the Mouse Spinal Cord: Variability Analysis and Application to an Amyotrophic Lateral Sclerosis Model

“…This is in agreement with previous studies that reported alterations on MRI only after the 12 th week in this ALS murine model [14]. However, TEM showed modifications in motor neurons of G93A-SOD1 spinal cord already at 10 weeks of age.…”

“…As expected [14,30], FA and AD are reduced as a consequence of the fiber disorganization shown by our TEM results. The unexpected reduction of MD, detected with all the three protocols, could be explained by the vacuolization phenomena observed in G93A-SOD1 motor neuron by our histology and TEM as well as in previous studies [66]; indeed vacuolization is associated with diffusivity reduction in other neurodegenerative pathologies such as Creutzfeldt-Jakob disease [67,68].…”

“…In demyelinating disease models [10–12], both a reduction of AD and an increase in RD were found. Considering ALS mice, the few DTI studies present in literature reported a reduction of FA and AD and less significant results on MD and RD values in the spinal cord [13,14]. …”

Assessment of Injured Spinal Cord Using Diffusion Tensor Tractography

“…Budde et al revealed that axial diffusion in the ventrolateral white matter in the experimental autoimmune encephalomyelitis (EAE) mouse model was significantly negatively correlated with the EAE clinical score and was significantly lower in mice with severe EAE than in mice with moderate EAE [45]. In the ventral white matter tracts of the spinal cord of ALS-affected mice, the diffusion values altered with disease progression [46,47]. In an SCI study, Kim et al identified the spared, normal ventrolateral white matter by the hyperacute axial diffusion 3 h after injury, and a histological analysis performed 14 days later showed a good correlation with the spinal contusion injury [48].…”

Fully automatic stitching of diffusion tensor images in spinal cord

“…To investigate potential subtle changes, it is crucial to obtain microstructure information of tissues throughout the length of the spinal cord. Current methods generally perform multiple investigations in laboratory by imaging the entire spinal cord on small animals (Ellingson et al, 2008;Cohen-Adad et al, 2011;Underwood et al, 2011). Nevertheless, the results demonstrated on the animals may not be same to the humans.…”