T1-and diffusion tensor-based fractal dimension of White and Grey Matter in Multiple Sclerosis

Weronika Mazur-Rosmus¹Agnieszka Słowik²Artur Tadeusz Krzyzak^1*

• ¹AGH University of Krakow, Krakow, Poland
• ²Department of Neurology, University Hospital in Krakow, Krakow, Lesser Poland, Poland

Multiple sclerosis (MS) changes brain microstructure even at early disease stages, with changes detectable in normal-appearing white matter (NAWM) and grey matter (GM). Diffusion tensor imaging (DTI) is sensitive to such alterations, while fractal dimension (FD) provides complementary information on tissue complexity. In this study, we propose that T1-based FD offers complementary diagnostic value to DTI-derived metrics of tissue integrity (fractional anisotropy, FA and mean diffusivity, MD). By examining both global brain structures and white matter (WM) skeletons, with and without lesion masking, we explored how FD captures subtle architectural irregularities that may be overlooked by DTI alone. MRI data were acquired from 120 relapsing-remitting multiple sclerosis patients (MS) with low mean Expanded Disability Status Scale (EDSS) and 75 healthy control (HC) participants. WM in MS exhibited reduced FD and FA alongside elevated MD, consistent with demyelination and axonal degradation. GM demonstrated higher FD, FA and MD, suggesting a more nuanced interplay of inflammatory remodeling, dendritic reorganization and compensatory structural adaptation. The limited impact of lesion masking on group-average metrics, but its marked effect on FD-DTI interactions, revealed that lesions regulate structural variance without dominating global tissue complexity. FD proved particularly sensitive at tissue interfaces, where geometry is disrupted, while WM skeleton analyses reflected preserved regularity of core tracts, even amidst microstructural degeneration. These findings support the concept of a surface-in gradient of complexity loss in MS. Combining FD with FA and MD substantially improved classification accuracy, particularly in WM skeleton-based models, emphasizing the diagnostic potential of geometric-microstructural integration. Widespread associations of FA with clinical covariates and age further suggest that diffuse WM alterations underpin both cognitive and clinical decline.