Ian H. Harding

Background The neurological phenotype of Friedreich ataxia (FRDA) is characterized by neurodegeneration and neuroinflammation in the cerebellum and brainstem. Novel neuroimaging approaches quantifying brain free‐water using diffusion magnetic resonance imaging (dMRI) are potentially more sensitive to these processes than standard imaging markers. Objectives To quantify the extent of free‐water and microstructural change in FRDA‐relevant brain regions using neurite orientation dispersion and density imaging (NODDI), and bitensor diffusion tensor imaging (btDTI). Method Multi‐shell dMRI was acquired from 14 individuals with FRDA and 14 controls. Free‐water measures from NODDI (FISO) and btDTI (FW) were compared between groups in the cerebellar cortex, dentate nuclei, cerebellar peduncles, and brainstem. The relative sensitivity of the free‐water measures to group differences was compared to microstructural measures of NODDI intracellular volume, free‐water corrected fractional anisotropy, and conventional uncorrected fractional anisotropy. Results In individuals with FRDA, FW was elevated in the cerebellar cortex, peduncles (excluding middle), dentate, and brainstem ( P < 0.005). FISO was elevated primarily in the cerebellar lobules ( P < 0.001). On average, FW effect sizes were larger than all other markers (mean η ρ 2 = 0.43), although microstructural measures also had very large effects in the superior and inferior cerebellar peduncles and brainstem ( η ρ 2 > 0.37). Across all regions and metrics, effect sizes were largest in the superior cerebellar peduncles ( η ρ 2 > 0.46). Conclusions Multi‐compartment diffusion measures of free‐water and neurite integrity distinguish FRDA from controls with large effects. Free‐water magnitude in the brainstem and cerebellum provided the greatest distinction between groups. This study supports further applications of multi‐compartment diffusion modeling, and investigations of free‐water as a measure of disease expression and progression in FRDA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.