• Central nervous system
• Cognition
• Diffusion Tensor Imaging
• Fabry disease
• White matter pathology

White matter pathology, visualised as white matter hyperintensities on MRI, is a common central nervous system manifestation of Fabry disease, affecting 42-81% of patients. Diffusion tensor imaging MRI is a sensitive technique to quantify microstructural damage within the white matter. We evaluated the pattern of diffusion tensor imaging abnormalities in Fabry disease, and its correlation with cognitive impairment, mood, anxiety, disease severity and plasma Lyso-Gb3 levels in 31 patients with genetically-proven Fabry disease and 19 age-matched healthy controls. We obtained average values of fractional anisotropy and mean diffusivity within the white matter, and performed voxelwise analysis with Tract-Based Spatial Statistics. We assessed processing speed, executive function, anxiety, depression and disease severity using validated scales and scores. The mean age (% male) of the Fabry disease cohort and for the healthy control groups were 44.1 (45%) and 37.4 (53%), respectively. Compared to healthy controls, the mean average white matter fractional anisotropy was lower in Fabry disease patients (0.423 (SD 0.23) vs. 0.446 (SD 0.16), p=0.002), while mean average white matter mean diffusivity was higher in Fabry disease patients (749 x 10-6 mm2/s (SD 32 x 10-6) vs 720 x 10-6 mm2/s (SD 21 x 10-6), p=0.004). Voxelwise statistics showed that these diffusion abnormalities (for both fractional anisotropy and mean diffusivity) were anatomically widespread. In patients, average white matter fractional anisotropy and white matter lesion volume showed strong correlations with Digit Symbol Coding Test score (r=0.558, p=0.001; and r=-0.634, p=<0.001, respectively). Average white matter fractional anisotropy correlated with the overall Mainz Severity Score Index (r=-0.661, p=<0.001). Finally, average white matter mean diffusivity showed a strong correlation with plasma Lyso-Gb3 levels (r=0.559, p=0.001). In Fabry disease white matter diffusion tensor imaging measures correlate with processing speed, disease severity and plasma Lyso-Gb3, making them promising quantitative biomarkers for monitoring disease severity and progression.