Increased brain white-matter extracellular free water is associated with memory function in end-stage renal disease patients

Previous studies have revealed brain white-matter microstructural alterations in hemodialysis patients. However, traditional diffusion tensor imaging cannot differentiate tissue-specific white matter alterations from extracellular free water changes. Here, we aimed to characterize white-matter microstructural alterations and extracellular free-water volume and their relationships with neurocognitive function in hemodialysis patients. Fifty-nine hemodialysis patients and 46 healthy controls underwent diffusion MRI and a series of neuropsychological assessments. A free-water imaging technique was applied to assess the microstructural alterations and extracellular free water volume. Group differences were examined using t-tests, Mann–Whitney U tests, chi-square tests, and tract-based spatial statistics with permutation testing. Associations between diffusion measures and neurocognitive performance was investigated using Pearson’s or Spearman’s correlation analyses. Hemodialysis patients had significantly higher white-matter extracellular free water than the healthy controls, particularly affecting projection fibers, callosal fibers, and association fibers ( p < 0.05, family-wise-error corrected). Increased white-matter free water was initially associated with poorer performance on trials 1–5 in hemodialysis patients (R = − 0.37, p = 0.025), although this association was attenuated after adjustment for age and sex. In contrast, hemodialysis patients exhibited reduced free-water-corrected fractional anisotropy compared to healthy controls and showed more robust associations hemoglobin levels and memory performance. Elevated extracellular free water in the white matter may reflect microvascular compromise or neuroinflammation, which could contribute to memory decline in hemodialysis patients. These findings suggest that free water imaging provides additional insight into white-matter alterations in this population.