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Updated: Jul 28, 2026
An In Vitro Model for the Study of Cellular Pathophysiology in Globoid Cell Leukodystrophy
Published on: October 21, 2014
T2-Pseudonormalization and Microstructural Characterization in Advanced Stages of Late-infantile Metachromatic
Pascal Martin1, Gisela E Hagberg2,3, Thomas Schultz4
1Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. pascal.martin@med.uni-tuebingen.de.
Purpose:
T2-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.
Methods:
The 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.
Results:
T2-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.
Conclusion:
In 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.
Insights
In late-infantile metachromatic leukodystrophy (MLD), T2-pseudonormalization in white matter (WM) indicates advanced disease. This MRI finding masks severe microstructural abnormalities, including myelin and neuronal loss.
Area of Science:
- Neurology
- Radiology
- Biochemistry
Background:
- T2-weighted signal hyperintensities in white matter (WM) are a key MRI finding in metachromatic leukodystrophy (MLD).
- Understanding the evolution of these hyperintensities is crucial for assessing disease progression and treatment efficacy.
Purpose of the Study:
- To describe and characterize T2-pseudonormalization in the advanced stage of late-infantile MLD.
- To investigate WM microstructure in areas exhibiting T2-pseudonormalization using multimodal MRI.
Main Methods:
- Quantified T2-hyperintensity volume in 27 children with late-infantile MLD.
- Conducted multimodal MRI (diffusion-weighted imaging, MRS, MWF, MTR, T1-mapping, QSM) on three children with advanced disease and T2-pseudonormalization.
Main Results:
- Observed normalization of T2-hyperintensities in cerebral WM in three advanced-stage MLD patients.
- Multimodal MRI revealed significantly decreased NAA, neurite density, MWF, MTR, and increased radial diffusivity in T2-pseudonormalized areas.
Conclusions:
- T2-pseudonormalization in late-infantile MLD signifies severe WM microstructural abnormalities, including myelin and neuronal loss, gliosis, and storage material.
- Multimodal MRI protocols with specific microstructural parameters are recommended over T2-weighted sequences for evaluating MLD treatment trials.
