Comparative Magnetic Resonance Imaging and Histopathological Correlates in Two SOD1 Transgenic Mouse Models of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal disease due to motoneuron degeneration. Magnetic resonance imaging (MRI) is becoming a promising non-invasive approach to monitor the disease course but a direct correlation with neuropathology is not feasible in human. Therefore in this study we aimed to examine MRI changes in relation to histopathology in two mouse models of ALS (C57BL6/J and 129S2/SvHsd SOD1G93A mice) with different disease onset and progression. A longitudinal in vivo analysis of T2 maps, compared to ex vivo histological changes, was performed on cranial motor nuclei. An increased T2 value was associated with a significant tissue vacuolization that occurred prior to motoneuron loss in the cranial nuclei of C57 SOD1G93A mice. Conversely, in 129Sv SOD1G93A mice, which exhibit a more severe phenotype, MRI detected a milder increase of T2 value, associated with a milder vacuolization. This suggests that alteration within brainstem nuclei is not predictive of a more severe phenotype in the SOD1G93A mouse model. Using an ex vivo paradigm, Diffusion Tensor Imaging was also applied to study white matter spinal cord degeneration. In contrast to degeneration of cranial nuclei, alterations in white matter and axons loss reflected the different disease phenotype of SOD1G93A mice. The correspondence between MRI and histology further highlights the potential of MRI to monitor progressive motoneuron and axonal degeneration non-invasively in vivo. The identification of prognostic markers of the disease nevertheless requires validation in multiple models of ALS to ensure that these are not merely model-specific. Eventually this approach has the potential to lead to the development of robust and validated non-invasive imaging biomarkers in ALS patients, which may help to monitor the efficacy of therapies.

Diffusion MRI of the spinal cord: from structural studies to pathology

“…These decreases correlated with axonal count in most WM regions. Interestingly, in the case of the 129Sv SOD1G93A mice the ad was reduced compared with the wild‐type mice prior to onset of the disease, whereas in the C57 SOD1G93A mice this occurred only at advanced stage of the disease . This was the first diffusion MRI study to demonstrate the differences in the time course of the axonal degeneration of motor neurons in these two strains of SOD1 mice.…”

In vivo diffusion MRI detects early spinal cord axonal pathology in a mouse model of amyotrophic lateral sclerosis

“…Previous studies have proposed AD and RD as presymptomatic MRI markers for axonal damage and demyelination in ALS SC . Our studies have shown that RD progressively increases from the presymptomatic stage (P80) [YFP,G93A‐SOD1 group = (3.2 ± 0.8) × 10 −4 mm 2 /s versus YFP group = (3.7 ± 0.7) × 10 −4 mm 2 /s] ( p < 0.02) to the symptomatic stage (P120) [YFP,G93A‐SOD1 group = (3.3 ± 0.7) × 10 −4 mm 2 /s versus YFP group = (3.9 ± 0.6) × 10 −4 mm 2 /s] ( p < 0.004) (Figure a).…”

“…The study of AD to measure axonal damage in ALS has been elusive because of the numerous different and contradictory results reported between animal models (decreased AD) and human studies (no significant changes in AD) . In that context, our data suggested that AD showed a decrease in values in the mutant group compared with controls, particularly at the presymptomatic stage (Figure c).…”

“…High spatial resolution is beneficial and theoretically easier to achieve at high magnetic fields (e.g. at 7‐ and 9.4‐T MRI), where it has been able to identify axonal degeneration in SCs from animals with ALS following the onset of symptoms . However, the underlying connections between diffusivity parameters and biological structural changes at the early stages of the disease remain to be investigated.…”

MRI reveals therapeutical efficacy of stem cells: An experimental study on the SOD1(G93A) animal model

“…All images (T2w and T2 maps) were aligned to the same mouse brain template that was built ad hoc for this experiment, allowing a serial processing of the subjects. Moreover, although we were working at a lower field strength (4.7 vs. 7 T) than Caron et al , and hence achieving a lower signal‐to‐noise ratio, we could detect a similar trend toward increase of the T2 relaxation time of the facial and trigeminal nuclei in SOD1(G93A) mice. The absolute values of T2 relaxation time are indeed different (as the B0 filed increases, the T2 shortens), but the measured trend from the presymptomatic phase to the end stage of the disease is similar .…”