High-Resolution Magnetic Resonance Microscopy and Diffusion Tensor Imaging to Assess Brain Structural Abnormalities in the Murine Mucopolysaccharidosis VII Model

Abstract

High-resolution microscopic magnetic resonance imaging (μMRI) and diffusion tensor imaging (DTI) were performed to characterize brain structural abnormalities in a mouse model of mucopolysaccharidosis type VII (MPS VII). μMRI demonstrated a decrease in the volume of anterior commissure and corpus callosum and a slight increase in the volume of the hippocampus in MPS VII vs. wild-type mice. DTI indices were analyzed in gray and white matter. In vivo and ex vivo DTI demonstrated significantly reduced fractional anisotropy in the anterior commissure, corpus callosum, external capsule and hippocampus in MPS VII vs. control brains. Significantly increased mean diffusivity was also found in the anterior commissure and corpus callosum from ex-vivo DTI. Significantly reduced linear anisotropy was observed from the hippocampus from in-vivo DTI, whereas significantly decreased planar anisotropy and spherical anisotropy were observed in the external capsule from only ex-vivo DTI. There were corresponding morphological differences in the brains of MPS VII mice by hematoxylin and eosin staining. Luxol fast blue staining demonstrated less intense staining of the corpus callosum and external capsule; myelin abnormalities in the corpus callosum were also demonstrated quantitatively in toluidine blue-stained sections and confirmed by electron microscopy. These results demonstrate the potential for μMRI and DTI for quantitative assessment of brain pathology in murine models of brain diseases.

THAP1 Modulates Oligodendrocyte Maturation by Regulating ECM Degradation in Lysosomes

“…Complete loss of GUSB causes Sly syndrome (MPS VII) (Beaudet et al, 1974;Sly et al, 1974), a lysosomal storage disease with marked GAG elevations (Heuer et al, 2001;Kubaski et al, 2017;Ray et al, 1999), lysosomal abnormalities (Bayo-Puxan et al, 2018;Paigen, 1989;Vogler et al, 1990) and multi-organ defects including neurodevelopmental, cognitive and motor dysfunction (Montano et al, 2016;Sands, 2014;Tomatsu et al, 2009). Importantly and consistent with our findings, MPS VII patients and mouse models (GusB mps ) (Kumar et al, 2014) exhibit reductions in CNS myelination and altered expression of myelin component genes (Parente et al, 2012). Myelin abnormalities also occur in other MPS syndromes (Reichert et al, 2016;Seto et al, 2001).…”

Neuroimaging Findings in Patients with Mucopolysaccharidosis: What You Really Need to Know

“…White matter lesions are one of the most common findings described in patients with MPS and are related to deposition of partially degraded GAGs within neurons and oligodendrocytes in the CNS (4). Studies suggest the presence of myelin abnormalities in patients with MPS (32,33). However, the pathophysiologic process responsible for white matter lesions in these patients remains unclear.…”

Assessment of Dysmyelination with RAFFn MRI: Application to Murine MPS I

“…Cranial MRI of children with MPS I and other mucopolysaccharidoses reveals variable white matter changes, including cribriform changes in the corpus callosum and other myelinated regions [ 8 – 13 ]. Dogs with MPS I, as well as mice with MPS VII, demonstrate thinning of the corpus callosum relative to unaffected heterozygotes [ 14 , 15 ]. Electron microscopy has revealed abnormal myelin structure in MPS VII [ 15 ].…”

“…Dogs with MPS I, as well as mice with MPS VII, demonstrate thinning of the corpus callosum relative to unaffected heterozygotes [ 14 , 15 ]. Electron microscopy has revealed abnormal myelin structure in MPS VII [ 15 ]. These white matter abnormalities accompany neuronal dysmorphism associated with lysosomal substrate accumulation [ 16 – 18 ].…”