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

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.

Molecular and microstructural biomarkers of neuroplasticity in neurodegenerative disorders through preclinical and diffusion magnetic resonance imaging studies

“…Maintaining the appropriate motor patterns and coordination of limb movements depends on plasticity within these MN networks. During the last decade, invertebrates and vertebrate transgenic models have been developed to recapitulate some of the genetic, anatomical, and func-tional defects observed in human genes (SOD1, TARDBP, FUS, C9ORF72, TNK, and VCP, among others) as part of the current strategy to help our understanding of the pathophysiology of ALS and the development of therapeutic strategies (Gatto et al, 2020a;Gatto and Weissmann, 2020;McGoldrick et al, 2013).…”

“…Some of them are related to changes in axonal structure or possibly to structures part of myelinproducing cells. Despite these incredible capabilities, the possibility of DTI to dissect NP-related events at the sub voxel level is substantially limited due to: a) the significantly lower resolution compared with standard optical imaging techniques, b) the assumption of homogenous diffusivity along the voxel, and c) the limited histological co-registration and neuropathological validation (Gatto et al, 2018), all of them still a topic for further investigations and development (Gatto et al, 2020a). Although the use of DTI has been growing exponentially in the neuroscience field (Mori and Zhang, 2006), the interpretations of each diffusivity indices and their biological significance should be held with extreme caution due to a significant amount of limitations.…”

“…With further development and applications of ultra-high field dMRI systems (Gatto et al, 2020a), DTI has been the upfront imaging technique to study microstructural changes associated with NP mechanisms across different experimental animal models. For example, this imaging technique has been applied to investigate structural neuroplasticity and gender differences among songbirds.…”

Traumatic subaxial cervical spine injury – Improving initial evaluation through correlation of diffusion tensor imaging and subaxial cervical spine injury classification SLIC score

“…In his study, Gatto et al . [ 8 ] found clear differences in microstructural white matter tract information in a murine model of ALS. As it progresses, the neurodegenerative disease manifests through a combination of elements of neuroinflammation and microstructural remodeling that can be measured with DTI parameters.…”

New molecular insights, innovative technologies, and medical approaches in the “Exploration of mechanisms in cortical plasticity”

“…In that regard, the growing use of structural diffusion magnetic resonance imaging (dMRI) technologies and the increasing development of high magnetic fields (Gatto et al, 2018) have been some of the rapidly evolving features of this technology,and one of the most promising tools in neurosciences, particularly applied to (in vivo) NP research (Gatto et al, 2020). Recently, to address some of the limitations associated with monoexponential diffusion models like diffusion tensor imaging (DTI) (Gatto et al, 2020), new sequences have been developed to explore inhomogeneous biological media (GM brain tissue) utilizing alternative non-Gaussian diffusion models (Gatto et al, 2019). In clinical settings, the use of dMRI makes it also possible to study compensatory axonal connectivity mechanisms (hypertrophic olivary degeneration) after vascular-related injuries (Wang et al, 2020).…”