14800-DvRappard

135 Diffusion tensor imaging in metachromatic leukodystrophy 8 of opposing AD patterns in MLD suggests that different pathological mechanisms can cause either a decrease or an increase in AD, with the overall balance between these effects depending on brain region and disease stage. MLD is characterized by accumulation of sulfatides, major myelin lipids mainly synthesized by oligodendrocytes. Analytical studies of MLD patients’ brain tissue showed that metachromatic deposits are mainly present in the WM, with a sulfatide content up to eight times higher than normal, with relatively minor chemical GM changes. 36 Regarding WM, we assume that the massive intracellular sulfatide accumulation in swollen macrophages, in vain trying to digest these lipids, causes overall diffusion restriction and thereby AD reduction. Using conventional DWI, restricted diffusion in the outermost part of the demyelinatedWM has indeed been described for single cases in relatively early disease stage. 39,40 However, as the disease progresses, axons are increasingly damaged. Based on previous observations in human studies, we expect that loss of both myelin and axons will lead to an AD increase. 37,38 Our results suggest that, particularly in the corpus callosum of non-eligible patients at baseline, diffusion restriction due to sulfatide accumulation inmacrophages contributes more to the severely reduced AD values than increased diffusion due to myelin and axonal loss. Our longitudinal observation of an increase, and thereby a pseudo-normalization of AD, in the corpus callosum suggests that myelin and axonal loss likely becomes more prominent in progressive disease. The corpus callosum is, of the investigated ROIs, least hindered by limitations of the tensor model, suggesting that the interpretation of AD values is not much influenced by the presence of crossing fibers. The thalamus is a DGM structure, in which sulfatide accumulation is much more limited than in WM. 36 In addition, the thalamus has a different microstructure than WM as it largely consists of neurons and contains few axons. In control subjects, this is mirrored by low thalamic FA, as the difference between AD and RD is much smaller than for a WM structure like the corpus callosum. In the thalamus of patients, we observed an increase of AD and RD of similar relative magnitude, which had hardly any effect on FA. This increase of both AD and RD probably implies an increase in extracellular space due to neuronal loss, which apparently dominates reductions in diffusivity due to storage material. Overall, the observed changes of FA, RD, and especially AD indicate that MLD alters certain aspects of brain microstructure. These changes most likely reflect a multitude of pathological processes such as accumulation of metachromatic material, followed by myelin and axonal loss. The differences between untreated and treated patients indicate that diffusion measures are positively affected by HCT, further emphasizing the beneficial effects of this intervention on WM and supporting the findings of other