14800-DvRappard

134 Chapter 8 compared to controls. Whereas AD was increased in thalamus, it was unchanged in the pyramidal tracts and decreased in the corpus callosum and, to a lesser degree, in NAWM. All differences were most pronounced between controls and HCT-non-eligible patients. Longitudinally, in treated HCT-eligible patients diffusion measures remained stable or showed onlyminor changes. FA remained constant or even tended to increase in NAWM, pyramidal tracts, and thalamus, whereas it slightly decreased in the corpus callosum. HCT-non-eligible patients had less follow-up examinations than eligible patients, but those available showed clear increases of RD and AD, causing a small FA reduction in all investigated regions. The treatment effect of HCTmost likely influenced the longitudinal differences between treated eligible patients (approaching control values in NAWM and pyramidal tracts), and untreated non-eligible patients (increasingly abnormal values). This is in line with our observation that metabolite concentrations observed with magnetic resonance spectroscopy partially normalized in successfully transplanted patients, whilst concentrations for non-treated patients further deteriorated. 29 Limitations of this study were its retrospective character, a large age range of patients (inherent to the inclusion of patients with all disease types), and a limited age range of controls at 3T. The combination of 1.5T and 3T data also introduced some variability, although these differences were typically smaller than differences between controls and patients. Also, the diffusion tensor model itself has limitations. Most importantly, it reflects the underlying structural characteristics in a simplified manner, hampered by partial volume effects and crossing fibers. 18 Advanced multi-compartment diffusion models, such as the composite hindered and restricted model of diffusion (CHARMED), are more sensitive than the conventional ones. 30-32 However, since our study, ongoing since 2007, concerns a rare disease, application of these advanced diffusion models was not feasible. These issues imply that we can merely hypothesize about the precise mechanism responsible for the observed differences rather than draw general conclusions because different cellular processes may lead to identical changes. 9-11 Since both animal 13,33,34 and human studies 35 have shown an increased RD parallel to myelin loss, our results of increased RD in WM suggest myelin loss in patients, in line with histopathological findings. 36 This is also supported by our observation that high RD and low FA in the pyramidal tracts at baseline indicate poor motor function at follow-up. With regard to AD, animal and human studies provide discrepant results, correlating axonal damage to either an AD decrease 13,17 or increase 37,38 , respectively. This reflects the difficulty in relating AD to underlying pathological processes. Our observation