14800-DvRappard

165 Discussion, summary and future perspectives 10 In chapter 6 we compared brain tissue of transplanted and non-transplanted patients to compare the inflammatory response and oligodendrocyte numbers between these two groups to gain further insight into the exact mechanism by which HCT halts further demyelination or even improves myelination. We found that in transplanted patients, there is presence of metabolically competent macrophages that are able to digest sulfatides, with a polarization of these macrophages towards an M2-like phenotype. There was a higher number of oligodendrocyte precursors and mature myelin forming oligodendrocytes in transplanted than untreated patients. These data suggest additional beneficial effects of HCT beyond cross-correction of enzyme deficiency that could be further exploited in order to improve outcome. That these changes could be demonstrated in spite of the fact that transplantation was not successful, underlines the robustness of these findings. Quantitative MRI techniques Quantitative MRI techniques such as proton MRS and DTI broaden our knowledge about the pathomechanisms involved in the disease. In chapter 7 we described that MRS at diagnosis is predictive for clinical outcome. 7 Patients with abnormal concentrations (severely reduced NAA, Glu and Glx and increased Lac and Ins) had poor outcome, whilst patients with concentrations closer to normal had moderate outcome. NAA was the main explanatory variable. Notably, in some patients in whom we observed a normalization in the ratio of Cho/NAA, this improvement did not coincide with an improvement in MRI score or reduction in lesion volume. The MRI score also includes other WM regions and cerebral and cerebellar atrophy, which forms a partial explanation. MRS concentrations at diagnosis are of aid in deciding whether HCT will be beneficial, especially for patients with a borderline neurological and cognitive examination. If baseline metabolite concentrations are severely abnormal, there is low probability of a good outcome. In chapter 8 we studied DTI parameters at diagnosis and follow-up in MLD patients and found decreased FA and increased MD and RD in NAWM, corpus callosum, and pyramidal tracts in patients compared to controls. In the thalamus no differences in FA were observed, but all diffusivities were increased in both patient groups. We found increased AD in the thalamus but decreased AD in the corpus callosum and NAWM of patients. These changes are most likely reflective of different pathological processes occurring in MLD, reflecting a balance between neuro-axonal loss and intracellular storage accumulation, depending on region and disease stage.