Longitudinal analyses are increasingly used in clinical studies as they allow the study of subtle changes over time within the same subjects. In most of these studies, it is necessary to align all the images studied to a common reference by registering them to a template. In the study of white matter using the recently developed fixel-based analysis (FBA) method, this registration is important, in particular because the fiber bundle cross-section metric is a direct measure of this registration. In the vast majority of longitudinal FBA studies described in the literature, sessions acquired for a same subject are directly independently registered to the template. However, it has been shown in T1-based morphometry that a 2-step registration through an intra-subject average can be advantageous in longitudinal analyses. In this work, we propose an implementation of this 2-step registration method in a typical longitudinal FBA aimed at investigating the evolution of white matter changes in Alzheimer's disease (AD). We compared at the fixel level the mean absolute effect and standard deviation yielded by this registration method and by a direct registration, as well as the results obtained with each registration method for the study of AD in both fixelwise and tract-based analyses. We found that the 2-step method reduced the variability of the measurements and thus enhanced statistical power in both types of analyses.

4 pages, 6 figures, submitted to IEEE International Symposium on Biomedical Imaging (ISBI 2025)