Assessment of dysmyelination with RAFFn MRI: application to murine MPS I.

David Satzer,Walter C Low,Michael M Ritchie,Shalom Michaeli,Christine Storino,Christina Dibartolomeo,Timo Liimatainen,Ann M Parr,Hanne Hakkarainen,Silvia Mangia,Djaudat Idiyatullin,Mara Cercignani

doi:10.1371/journal.pone.0116788

David Satzer, Walter C Low + Show 10 more

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https://doi.org/10.1371/journal.pone.0116788

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Abstract

Type I mucopolysaccharidosis (MPS I) is an autosomal recessive lysosomal storage disorder with neurological features. Humans and laboratory animals with MPS I exhibit various white matter abnormalities involving the corpus callosum and other regions. In this study, we first validated a novel MRI technique, entitled Relaxation Along a Fictitious Field in the rotating frame of rank n (RAFFn), as a measure of myelination and dysmyelination in mice. We then examined differences between MPS I mice and heterozygotes using RAFF5 and histology. RAFF5 (i.e., RAFFn with n = 5) relaxation time constants were highly correlated with histological myelin density (R2 = 0.68, P<0.001), and RAFF5 clearly distinguished between the hypomyelinated and dysmyelinated shiverer mouse and the wild-type mouse. Bloch-McConnell theoretical analysis revealed slower exchange correlation times and smaller exchange-induced relaxation rate constants for RAFF4 and RAFF5 compared to RAFF1-3, T 1ρ, and T 2ρ. These data suggest that RAFF5 may assess methylene protons in myelin lipids and proteins, though other mechanisms (e.g. detection of myelin-bound water) may also explain the sensitivity of RAFF5 to myelin. In MPS I mice, mean RAFF5 relaxation time constants were significantly larger for the striatum (P = 0.004) and internal capsule (P = 0.039), and marginally larger for the fornix (P = 0.15). Histological assessment revealed no differences between MPS I mice and heterozygotes in myelin density or corpus callosum thickness. Taken together, these findings support subtle dysmyelination in the brains of mice with MPS I. Dysmyelination may result from myelin lipid abnormalities caused by the absence of α-L-iduronidase. Our findings may help to explain locomotor and cognitive deficits seen in mice with MPS I.

Highlights

Dysmyelination refers to abnormal myelin structure in the central or peripheral nervous system
We investigated the relationship between myelin content and RAFFn MRI in (1) wild-type mice, (2) severely hypomyelinated, dysmyelinated, myelin basic protein (MBP)-deficient shiverer mice, (3) mice with MPS I, and (4) mice heterozygous for IDUA
We looked for white matter abnormalities in MPS I mice by comparing RAFF5 relaxation time constants for several gray and white matter regions with unaffected IDUA heterozygotes, which served as controls

Summary

Introduction

Dysmyelination refers to abnormal myelin structure in the central or peripheral nervous system. Electron microscopy has revealed abnormal myelin structure in MPS VII [15] These white matter abnormalities accompany neuronal dysmorphism associated with lysosomal substrate accumulation [16,17,18]. A technique called Relaxation Along a Fictitious Field (RAFF) has recently been introduced as a means for myelin detection [24,25] This protocol operates in rotating frames of rank n (RAFFn), and has been found to yield high contrast between gray and white matter in ranks 4 (RAFF4) and 5 (RAFF5) [26]. We investigated the relationship between myelin content and RAFFn MRI in (1) wild-type mice, (2) severely hypomyelinated, dysmyelinated, myelin basic protein (MBP)-deficient shiverer mice, (3) mice with MPS I, and (4) mice heterozygous for IDUA. We compared histological myelin density and corpus callosum thickness between MPS I mice and IDUA heterozygotes

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