T2-Pseudonormalization and Microstructural Characterization in Advanced Stages of Late-infantile Metachromatic Leukodystrophy

Pascal Martin,Klaus Scheffler,Uwe Klose,Thomas Schultz,Ingeborg Krägeloh-Mann,Benjamin Bender,Klaus Harzer,Gisela E. Hagberg,Thomas Nägele,Samuel Groeschel

doi:10.1007/s00062-020-00975-2

Abstract

PurposeT2-weighted signal hyperintensities in white matter (WM) are a diagnostic finding in brain magnetic resonance imaging (MRI) of patients with metachromatic leukodystrophy (MLD). In our systematic investigation of the evolution of T2-hyperintensities in patients with the late-infantile form, we describe and characterize T2-pseudonormalization in the advanced stage of the natural disease course.MethodsThe volume of T2-hyperintensities was quantified in 34 MRIs of 27 children with late-infantile MLD (median age 2.25 years, range 0.5–5.2 years). In three children with the most advanced clinical course (age >4 years) and for whom the T2-pseudonormalization was the most pronounced, WM microstructure was investigated using a multimodal MRI protocol, including diffusion-weighted imaging, MR spectroscopy (MRS), myelin water fraction (MWF), magnetization transfer ratio (MTR), T1-mapping and quantitative susceptibility mapping.ResultsT2-hyperintensities in cerebral WM returned to normal in large areas of 3 patients in the advanced disease stage. Multimodal assessment of WM microstructure in areas with T2-pseudonormalization revealed highly decreased values for NAA, neurite density, isotropic water, mean and radial kurtosis, MWF and MTR, as well as increased radial diffusivity.ConclusionIn late-infantile MLD patients, we found T2-pseudonormalization in WM tissue with highly abnormal microstructure characterizing the most advanced disease stage. Pathological hallmarks might be a loss of myelin, but also neuronal loss as well as increased tissue density due to gliosis and accumulated storage material. These results suggest that a multimodal MRI protocol using more specific microstructural parameters than T2-weighted sequences should be used when evaluating the effect of treatment trials in MLD.

Highlights

Metachromatic leukodystrophy (MLD) is an autosomal recessive inherited lysosomal storage disease caused by the deficiency of the lysosomal sulfatide degrading enzyme arylsulfatase A
The resulting accumulation of sulfatides in the central nervous system leads to the dysfunction and progressive destruction of microglia and oligodendrocytes [1, 2]
This gives rise to a progressive demyelination as the main driver of the pathology leading to impaired motor and cognitive abilities [3,4,5]

Summary

Introduction

Metachromatic leukodystrophy (MLD) is an autosomal recessive inherited lysosomal storage disease caused by the deficiency of the lysosomal sulfatide degrading enzyme arylsulfatase A. The resulting accumulation of sulfatides in the central nervous system leads to the dysfunction and progressive destruction of microglia and oligodendrocytes [1, 2]. This gives rise to a progressive demyelination as the main driver of the pathology leading to impaired motor and cognitive abilities [3,4,5]. The quantification of T2 signal hyperintensity in the form of a demyelination load was found to show good correlation with motor and cognitive symptoms in the late-infantile [9] and juvenile types [10, 11]

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Results

Discussion

Conclusion