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

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of upper motor neurons (UMNs) in the motor cortex and lower motor neurons (LMNs) in the brainstem and spinal cord 1. The loss of motor neurons leads to muscle atrophy, resulting in progressive paralysis of skeletal muscles, loss of voluntary movement, dysphagia, dyspnea, and lastly death. Most ALS patients die by respiratory failure 3 to 5 years after the beginning of the symptoms. To date, the diagnosis of ALS is based on clinical features, progression of symptoms, electromyography, and exclusion of other diseases 2. Neuroimaging is considered with increasing interest but thus far has not been extensively applied in the clinical routine. The absence of a disease marker for UMNs and LMNs involvement has a negative consequence: the delay from onset of the disease to diagnosis can vary between 9 and 13 months, precluding early initiation of neuroprotective treatments 3. Because of this, the investigation of early and specific biomarkers that could facilitate diagnosis and characterize the disease progression is crucial.
The etiology of ALS remains unknown, and although most cases are sporadic, the disease is familial (fALS) 4 in approximately 10% of patients, and 20% of fALS are due to mutation in superoxide dismutase gene (SOD1). Since the discovery that the SOD1 gene is responsible for familial forms of ALS, it was possible to develop etiological models for ALS 5. In particular, the transgenic SOD1(G93A) animal model carrying the substitution of glycine at residue 93 by alanine 2 is the most employed rodent model of ALS. Indeed, this animal model recapitulates several features of the disease, such as progressive loss of UMNs, progressive motor paralysis, muscle atrophy, and reduced lifespan 6. SOD1(G93A) mice show the first symptoms of the disease around 11 weeks of age and develop motor neuron dysfunctions that progress from hind limbs to forelimbs, with symptoms like weakness, tremors, reduced extension reflex, and total paralysis 2.
Thanks to the SOD1(G93A) animal model, neuroimaging modalities have been used to identify potential biomarkers of the disease 7. The accessible, noninvasive, and radiation‐free characteristics of MRI make this technique highly practical as a biomarker tool. Indeed, by using T2‐weighted (T2w) MR images, it is possible to visualize the degeneration of neurons in motor nuclei within the brainstem: T2w images reveal a clear signal intensity enhancement compared with surrounding tissue in various motor nuclei within the brainstem, including the hypoglossal, ambiguous, facial, and trigeminal nuclei 8. Furthermore, several studies on the SOD1(G93A) animal model focused on degeneration of the skeletal muscles 11. In particular, a concomitant longitudinal MRI study of brain and muscle revealed that muscular degeneration in SOD1(G93A) mice occurs prior to neurodegeneration: a reduction of hind limb muscle volume has been observed in mice at 8 weeks from birth, when the animals were still asymptomatic 12. However, it remains unclear whether the muscular atrophy precedes or follows the motor neuron loss and how these alterations relate to disease state 14. Moreover, essential differences in the severity of disease phenotype (eg, symptom onset, disease progression, and life span), have been noted in SOD1(G93A) mice, depending on transgene copy number 15 and genetic background 16. For this reason, it is important to validate already established MRI biomarkers and characterize them longitudinally along the disease progression.
Another essential application of this murine model is in preclinical testing of new therapies. To date, no clinically effective treatment is available for ALS: only riluzole (benzothiazole) has been proven to marginally prolong survival of few months 17.

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