Demyelination load as predictor for disease progression in juvenile metachromatic leukodystrophy

Abstract

ObjectiveThe aim of this study was to investigate whether the extent and topography of cerebral demyelination correlates with and predicts disease progression in patients with juvenile metachromatic leukodystrophy (MLD).MethodsA total of 137 MRIs of 46 patients with juvenile MLD were analyzed. Demyelination load and brain volume were quantified using the previously developed Software “clusterize.” Clinical data were collected within the German Leukodystrophy Network and included full scale intelligence quotient (FSIQ) and gross motor function data. Voxel‐based lesion‐symptom mapping (VLSM) across the whole brain was performed to investigate the spatial relationship of cerebral demyelination with motor or cognitive function. The prognostic value of the demyelination load at disease onset was assessed to determine the severity of disease progression.ResultsThe demyelination load (corrected by the individual brain volume) correlated significantly with gross motor function (r = +0.55) and FSIQ (r = −0.55). Demyelination load at disease onset was associated with the severity of disease progression later on (P < 0.01). VLSM results associated frontal lobe demyelination with loss in FSIQ and more central region demyelination with decline of motor function. Especially progression of demyelination within the motor area was associated with severe disease progression.InterpretationWe were able to show for the first time in a large cohort of patients with juvenile MLD that the demyelination load correlates with motor and cognitive symptoms. Moreover, demyelination load at disease onset, especially the involvement of the central region, predicts severity of disease progression. Thus, demyelination load seems a functionally relevant MRI parameter.

Recognizing early MRI signs (or their absence) is crucial in diagnosing metachromatic leukodystrophy

“…Thus, we could substantiate our earlier findings that in late‐infantile MLD MRI abnormalities gradually evolve after symptom onset while in juvenile MLD MRI abnormalities are already present at symptom onset, in a larger cohort and describe early signs in more detail 14 . Part of the present cohort was previously published 4,6,7,14–16,20,25–32 . Fumagalli et al.…”

Neurofilament light chain and glial fibrillary acidic protein levels in metachromatic leukodystrophy

“… 27 Rapid disease progression and slow disease progression at diagnosis were defined as a time interval ≤27 months and >27 months, respectively, in line with previous publications. 2 , 5 For the second purpose, a validated measure of brain demyelination, the MRI severity score, 28 was used to quantify disease progression at any available time point during follow-up. We analysed the correlation with the crude MRI severity score at blood sampling and with ‘MRI deterioration’.…”

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

“…As mentioned before, to quantify the volume of T2 hyperintense white matter, the demyelination load was measured in all 26 patients using multispectral segmentation of high-resolution T1-weighted and axial T2-weighted images [ 11 , 21 ]. The ratio of the demyelination load and total WM volume was calculated [ 9 ].…”

“…Particularly in the late-infantile type, which begins within the first 2 years of life, there is a relatively uniform pattern of spread parallel to the loss of motor function [ 7 ]. In addition, 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 ].…”