The quest for the best: manual, atlas- and spatial prior-based delineation of locus coeruleus

Despite advances in neuromelanin-sensitive brain imaging and a plethora of software solutions, the reliable non-invasive delineation of the locus coeruleus (LC) in the human brainstem remains challenging. We sought to evaluate the spatial accuracy and consistency of atlas- and probabilistic spatial prior-based LC delineation. We acquired neuromelanin-sensitive 3 T MRI data in healthy volunteers (n = 24; mean age 40.0 ± 16.8 years; 42% female). Manual labelling by 9 raters performed twice provided the basis for individual- and group-level comparisons, showing moderate inter-rater agreement (mean Dice = 0.7). For the atlas-based labelling, we tested seven open-access LC atlases, a consensus reference representing the atlases' overlap and the averaged manual labelling. Open-access atlases demonstrated low spatial concordance (Dice = 0.2-0.4), while the averaged manual labelling atlas had higher spatial overlap (Dice = 0.6). Probabilistic delineation using spatial priors showed the strongest voxel-wise similarity with manual labelling (r = 0.3) when the averaged manual labelling atlas was used as prior. Principal component analysis confirmed the greater spatial compactness for atlas-based labelling. Atlas-based labelling using the averaged manual labelling atlas in an extended 3 T cohort (n = 2393, mean age 58.44 ± 13.75 years) identified that tissue myelin and iron declined continuously from early adulthood, while free tissue water increased - a neurobiological trend robust to atlas choice. LC volume showed an inverted-U trajectory. Our results highlight the potential of atlas-based labelling for LC identification and demonstrate its sensitivity to physiologically grounded aging processes, suggesting that harmonised validation strategies and context-sensitive approaches can improve reliability.