Metachromatic leukodystrophy (MLD) is an inherited lysosomal disorder caused by recessive mutations in the ARSA gene.¹ Consequently, sulfatides accumulate in the central and peripheral nervous system, eventually resulting in demyelination.¹ Onset is from infancy to adulthood, with the late-infantile form starting before 30 months, the juvenile form before 16 years and the adult form from 16 years of age. In affected white matter (WM) in MLD patients, spectra are characterized by a reduced NAA and elevated Cho and Ins – such that ratios Cho/NAA and Ins/NAA are sensitive markers of disease status.^2,3 Hematopoietic stem cell transplantation (HSCT) is at present the best treatment option, once performed in an early stage of the disease and mainly for patients with the juvenile and adult onset type.⁴ Currently, the decision whether patients are eligible for HSCT is based on neurological examination and cognitive function. This study investigates the possible additional prognostic value of quantitative MRSI. HSCT treated patients were examined longitudinally to obtain quantitative information about the long term effects.

23 MLD patients (demographics in Table 1) and 20 control subjects were examined at 1.5T (Siemens Sonata, Erlangen, Germany) using the 8-channel phased-array head coil. Twelve patients were considered eligible for transplantation, 11 were not eligible.

MRI included 3D T1 and axial FLAIR images. 2D PRESS MRSI (TR/TE 3000/30 ms) was obtained in a transverse oblique 15 mm slab centered onto the corpus callosum.⁵ All spectra within the VOI were quantified using LCModel.^5,6

The following procedure was applied to obtain tissue-specific metabolite concentrations as illustrated in Figure 1: Lesions were outlined and quantified on FLAIR using the semi-automatic tool clusterize⁷ and registered to 3D T1. Lesion-filled 3D T1 images were segmented with FSL’s SIENAX into frontal and parietal GM and WM. Combination of MRSI voxels and tissue partial volume estimates within a linear model allowed to extrapolate the pure tissue concentrations, resulting in concentrations in frontal and parietal GM, in WM, and in NAWM and lesions separately.

Statistical analysis was performed with a general linear model, including age as covariate. P<0.05 was considered significant.

Comparison between patients and controls at baseline

WM spectra of patients who were considered not eligible for HSCT were characterized by low NAA, high Cho and Ins, and presence of Lac, whereas the spectra of patients who were considered eligible had much milder abnormalities in comparison to controls (Figure 2). Quantitative analysis showed that in WM (NAWM +lesions) NAA was lower in all patient groups than in controls, especially in the non-eligible patients (Table 2). Ins did not differ between patient groups, but was higher than in controls. Cho was variable among groups, with even lower concentrations in the non-eligible than in the eligible patients, probably due to a decrease of cell density (also evidenced by reduced Cr). The concentration ratios Cho/NAA and Ins/NAA were significantly higher in non-eligible patients than in eligible patients, not only in overall WM, but also in NAWM. In lesions, the differences were only trend-significant due to the large variability in this tissue type.

Baseline and longitudinal values of Cho/NAA and Ins/NAA in WM in all patients are shown in Figure 3. Remarkably, one adult patient who was considered not eligible for HSCT had relatively low ratios Cho/NAA and Ins/NAA within the range of eligible patients (see also Figure 3).

Monitoring patients after HSCT

Thirteen patients received HSCT: 11 out of 12 eligible patients (one eligible patient was not transplanted for personal reasons), and two of the non-eligible patients (after careful consideration and discussions with parents). The latter patients and one eligible late-infantile patient died within one year after HSCT. Follow-up data were available for two of them, and demonstrated an increase in Ins/NAA and especially Cho/NAA compared to their baseline values (Figure 3, red symbols).

In all ten surviving patients, Cho/NAA and Ins/NAA ratios remained stable after treatment or even improved, approaching normal values.

At diagnosis, patients who were not eligible for HSCT according to their neurological and cognitive status had significantly higher ratios of Cho/NAA and Ins/NAA in WM than eligible patients. In the latter patient group, metabolite concentrations were closer to normal. Strikingly, follow-up of successfully treated patients showed partial normalization of concentrations and ratios. This study suggests that quantitative MRS can support the decision whom to treat, especially when neurological and cognitive examinations are ambiguous.