Mapping the multiscale neuroanatomy of GRN-related frontotemporal dementia using mode-based morphometry

Individuals carrying Progranulin (GRN) mutations show asymmetrical grey matter atrophy, which could be used for early detection in the long asymptomatic phase. To capture these alterations, we employed both conventional Surface-Based Morphometry (SBM) and Mode-Based Morphometry (MBM). While the former provides high-resolution, location-specific estimates of cortical thickness (CT) differences, the latter has recently been introduced as a novel framework that decomposes CT maps into geometric eigenmodes, allowing a multiscale characterization of brain structural variability. Using both approaches enables the detection of complementary aspects of GRN-related neurodegeneration across spatial scales.

SBM and MBM were applied to CT maps to quantify structural alterations in individuals, 15 presymptomatic and 27 symptomatic, compared to 19 healthy controls (HC). SBM was used to assess vertex-wise CT differences, whereas MBM was used to decompose individual CT maps into geometric eigenmodes and quantify alterations across spatial scales. From both pipelines asymmetry indices (SBM-AI and MBM-AI) were computed. Associations between SBM/MBM-derived measures and domain-specific cognitive performance as well as global disease severity scores were then assessed.

Compared with HC, symptomatic GRN showed significant alterations in seven eigenmodes in the left hemisphere, while only two modes contributed to CT differences in the right hemisphere. For MBM-AI and SBM-AI symptomatic GRN exhibited significantly different values compared to HC and presymptomatic GRN (p < 0.001). Although both asymmetry indices showed significant differences across disease stages (p = 1.3 × 10^-5 SBM-AI; p = 3.5 × 10^-5 MBM-AI), only the MBM-AI revealed a U-shaped trajectory across disease progression, characterized by an early increase in asymmetry followed by a partial re-symmetrisation in later stages.

MBM revealed multiscale cortical alterations in symptomatic GRN mutation carriers, capturing both large-scale hemispheric differences and more localized regional variations in CT that are less apparent with conventional SBM. These findings indicate that GRN-related neurodegeneration involves complex spatial pattern across multiple anatomical scales. Brain asymmetry remains a core hallmark of GRN-related pathology, supporting the use of asymmetry indices (derived from both SBM and MBM) as potential markers of disease progression at the symptomatic stage.