14800-DvRappard

124 Chapter 8 ABSTRACT Objective: We aimed to gain more insight into the pathomechanisms of metachromatic leukodystrophy (MLD), by comparing magnitude and direction of diffusion between patients and controls at diagnosis and during follow-up. Methods: Four late-infantile, 16 juvenile and 8 adult onset MLD patients (of which 13 considered eligible for hematopoietic cell transplantation (HCT)) and 47 controls were examined using diffusion tensor imaging. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were quantified and compared between groups using tract-based spatial statistics (TBSS). Diffusion measures were determined for normal-appearing white matter (NAWM), corpus callosum, thalamus (all based on subject-wise segmentation), and pyramidal tracts, determined with probabilistic tractography. Measures were compared between HCT-eligible patients, non-eligible patients and controls using general linear model and permutation analyses (randomise) for TBSS data. Results: In both patient groups FA was decreased and MD and RD increased throughout WM, while AD was decreased in NAWM and corpus callosum. In the thalamus no differences in FA were observed, but all diffusivities were increased in both patient groups. Differences were most pronounced between controls and patients non-eligible for HCT. Longitudinally, diffusion measures remained relatively stable for HCT-treated patients, but were progressively abnormal for non-eligible patients. Interpretation: The observed diffusion measures confirm that brain microstructure is changed in MLD, reflecting different pathological processes including loss of myelin and sulfatide accumulation. The observation of both increased and decreased AD probably reflects a balance between myelin and axonal loss versus intracellular storage in macrophages, depending on region and disease stage.