Vacuolization correlates with spin–spin relaxation time in motor brainstem nuclei and behavioural tests in the transgenic G93A‐SOD1 mouse model of ALS

Abstract

In recent years, magnetic resonance imaging (MRI) has emerged as a preferred tool for the diagnosis of amyotrophic lateral sclerosis (ALS) in humans. A widely used animal model for human ALS is the G93A-superoxide dismutase 1 (G93A-SOD1) transgenic mouse model. However, the mechanisms for the selective degeneration of motor neurons in the brainstem and spinal cord are still uncertain. In our study, we applied MRI at 4.7 Tesla to non-invasively evaluate pathological alterations in the brainstem of this animal model and to follow the progression of the disease. Extending previous investigation, we used the relaxation parameter T(2) as a suitable measure for the progression of ALS, and evaluated the potential agreement with histological evaluation and behavioural data of open-field tests. In the brainstem of G93A-SOD1 mice, T(2) values were significantly increased in the motor nuclei Nc. V, Nc. VII and Nc. XII, as early as Day 80, i.e. before the average disease onset at about Day 90. Moreover, this increase is associated with a progressive development of vacuoles in the brainstem motor nuclei and a significantly decreased performance in behavioural tests. Overall, MRI is a very sensitive tool to obtain correlates for neuronal degeneration in vivo. Furthermore, MRI enables us to investigate a follow up at different time points of the disease. These advantages are especially useful for therapeutic studies with respect to survival rates of motor neurons using mouse models. Finally, our data suggest that MRI does not only resemble the findings of behavioural tests, but is potentially superior to behavioural studies.

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

“…In this respect, novel techniques need to be developed to monitor therapies that might slow or prevent the death of motor neurons in live experimental animals. Previous work using MRI techniques have detected differences in T 2 values within several brain stem motor nuclei in SOD1 transgenic mice compared to WT animals (Angenstein et al, 2004;Bucher et al, 2007;Niessen et al, 2006;Zang et al, 2004). Although it has been observed that there is reduced FA in the corticospinal tracts and other brain regions of human ALS sufferers (Blain et al, 2007), the change in FA in the lumbar spinal cord with the progression of ALS has not been assessed.…”

“…To date, in vivo MRI in the SOD1 mouse has been limited to the analysis of the brain, brain stem (Angenstein et al, 2004;Bucher et al, 2007;Niessen et al, 2006;Zang et al, 2004) and muscle (Brooks et al, 2004;Zhang et al, 2008). Only one of these studies evaluated diffusivity by measuring the apparent diffusion coefficient (ADC).…”

An Animal Model of Oral Dysphagia in Amyotrophic Lateral Sclerosis

“…The first of every three sections was stained with hematoxylin and eosin (H&E), as described elsewhere [49], for anatomical landmark studies and to permit visualization of vacuolation, a hallmark feature of neurodegeneration in ALS [50]. The second and third of every three sections were retained for additional staining as needed.…”

CNS-targeted glucocorticoid reduces pathology in mouse model of amyotrophic lateral sclerosis

“…Neuronal degeneration and tissue vacuolation is accompanied by changes in magnetic resonance imaging (MRI) parameters [3, 4] leading to the possibility of using MRI as an in vivo biomarker of pathology in addition to conventional behavioural and histological endpoints. In particular we have shown previously that T 2 MRI is a sensitive pathological biomarker in SOD1 G93A mice [5].…”