BACKGROUND: Cognitive impairment significantly contributes to the disease burden of progressive supranuclear palsy (PSP), however, the underlying pathophysiologiy is not well understood. OBJECTIVES: To gain a better understanding of the pathophysiology, we identified the brain regions associated with individual domains of impaired cognition. METHODS: We analyzed MRI data from a cohort of 31 patients with PSP (age 71.0 +-7.0 years, range 58-87; 15 females; disease duration 2.9 +- 1.8 years). Cerebral microstructure was approximated with Diffusion Microstructure Imaging and cognitive performance was measured using the Frontal Assessment Battery (FAB) and Montreal Cognitive Assessment (MoCA). To reveal the underlying affected brain regions, whole-brain voxel-wise associations were employed to test the microstructural metrics regarding their correlation with the FAB as well as the individual cognitive domains 'Attention', 'Execution', 'Language', 'Memory', 'Orientation', and 'Visuoconstruction' derived from MoCA. RESULTS: MoCA performance was impaired in 87.5% of patients (20.2 +- 5.4 points, range 8-28; cut-off value: <26/30). In the voxel-wise analyses, we noted significant associations of cerebral microstructure and FAB in the right-sided frontal and temporopolar white matter, deficits in 'Memory' with hippocampal and temporomesial regions, in reduced 'Orientation' with wide spread white-matter areas with a parietal accentuation, whereas deficits in 'Attention' correlated with frontal and prefrontal structures. CONCLUSIONS: Diffusion Microstructure Imaging revealed domain-specific regions of neurodegenerative alterations in PSP. The regions identified in this approach integrate well in existing disease concepts. They might therefore be a possible biomarker for cognitive impairment, as well as amonitoring parameter for future disease modifying therapeutics.