Assessing neuraxial microstructural changes in a transgenic mouse model of early stage Amyotrophic Lateral Sclerosis by ultra-high field MRI and diffusion tensor metrics.

Rodolfo G Gatto,Manish Amin,Richard L Magin,Ronen Sumagin,Osvaldo D Uchitel,Ariel Finkielsztein,Thomas H Mareci,Carina Weissmann

doi:10.1002/ame2.12112

Abstract

ObjectiveCell structural changes are one of the main features observed during the development of amyotrophic lateral sclerosis (ALS). In this work, we propose the use of diffusion tensor imaging (DTI) metrics to assess specific ultrastructural changes in the central nervous system during the early neurodegenerative stages of ALS.MethodsUltra‐high field MRI and DTI data at 17.6T were obtained from fixed, excised mouse brains, and spinal cords from ALS (G93A‐SOD1) mice.ResultsChanges in fractional anisotropy (FA) and linear, planar, and spherical anisotropy ratios (CL, CP, and CS, respectively) of the diffusion eigenvalues were measured in white matter (WM) and gray matter (GM) areas associated with early axonal degenerative processes (in both the brain and the spinal cord). Specifically, in WM structures (corpus callosum, corticospinal tract, and spinal cord funiculi) as the disease progressed, FA, CL, and CP values decreased, whereas CS values increased. In GM structures (prefrontal cortex, hippocampus, and central spinal cord) FA and CP decreased, whereas the CL and CS values were unchanged or slightly smaller. Histological studies of a fluorescent mice model (YFP, G93A‐SOD1 mouse) corroborated the early alterations in neuronal morphology and axonal connectivity measured by DTI.ConclusionsChanges in diffusion tensor shape were observed in this animal model at the early, nonsymptomatic stages of ALS. Further studies of CL, CP, and CS as imaging biomarkers should be undertaken to refine this neuroimaging tool for future clinical use in the detection of the early stages of ALS.

Highlights

The introduction of animal models has been one of the major steps forward towards a better understanding of the neuropathological processes occurring in humans
From the original Amyotrophic Lateral Sclerosis (ALS) mouse model representing the familiar form of ALS with the mutation of the superoxide dismutase 1 (G93ASOD1) gene,[5] a growing number of rodent models that express different mutations, such as the fused in sarcoma (FUS),[6] the C9orf[72] hexanucleotide repeat expansion mice,[7,8] and the transactive response DNA binding protein 43 kDa TDP-439,10 have been increasingly developed to address the effects of molecular changes on neuronal degeneration and death
Additional animals wild-type control group (WT), postnatal day 80 (P80), and postnatal day 120 (P120) were used for further histological analysis, we evaluated morphologic neuronal anomalies in the context of ALS, using additional mouse reporters expressing a yellow fluorescent protein (YFP) transgene associated with a neuronal Thy[1] promoter, were chosen

Summary

| INTRODUCTION

The introduction of animal models has been one of the major steps forward towards a better understanding of the neuropathological processes occurring in humans. From the original ALS mouse model representing the familiar form of ALS with the mutation of the superoxide dismutase 1 (G93ASOD1) gene,[5] a growing number of rodent models that express different mutations, such as the fused in sarcoma (FUS),[6] the C9orf[72] hexanucleotide repeat expansion mice,[7,8] and the transactive response DNA binding protein 43 kDa TDP-439,10 (among others) have been increasingly developed to address the effects of molecular changes on neuronal degeneration and death Such models represent less than 10% of the sporadic cases of ALS. We analyzed CNS tissues of an animal model of ALS (G93A-SOD1 mice) with UHF-MRI to determine the potential role of derived DTI anisotropic parameters in ALS

| METHODS

Findings

| DISCUSSION

| CONCLUSIONS