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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 ηρ2 = 0.43), although microstructural measures also had very large effects in the superior and inferior cerebellar peduncles and brainstem (ηρ2 > 0.37). Across all regions and metrics, effect sizes were largest in the superior cerebellar peduncles (ηρ2 > 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. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation is proposed to accompany, or even contribute to, neuropathology in Friedreich ataxia (FRDA), with implications for disease treatment and tracking. Objectives: To examine brain glial activation and systemic immune dysfunction in people with FRDA and quantify their relationship with symptom severity, duration, and onset age. Methods: Fifteen individuals with FRDA and 13 healthy controls underwent brain positron emission tomography using the translocator protein (TSPO) radioligand [18F]‐FEMPA, a marker of glial activation, together with the quantification of blood plasma inflammatory cytokines. Results: [18F]‐FEMPA binding was significantly increased in the dentate nuclei (d = 0.67), superior cerebellar peduncles (d = 0.74), and midbrain (d = 0.87), alongside increased plasma interleukin‐6 (IL‐6) (d = 0.73), in individuals with FRDA compared to controls. Increased [18F]‐FEMPA binding in the dentate nuclei, brainstem, and cerebellar anterior lobe correlated with earlier age of symptom onset (controlling for the genetic triplet repeat expansion length; all rpart < −0.6), and in the pons and anterior lobe with shorter disease duration (r = −0.66; −0.73). Conclusions: Neuroinflammation is evident in brain regions implicated in FRDA neuropathology. Increased neuroimmune activity may be related to earlier disease onset and attenuate over the course of the illness. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation is proposed to accompany, or even contribute to, neuropathology in Friedreich ataxia (FRDA), with implications for disease treatment and tracking., Objectives: To examine brain glial activation and systemic immune dysfunction in people with FRDA and quantify their relationship with symptom severity, duration, and onset age., Methods: Fifteen individuals with FRDA and 13 healthy controls underwent brain positron emission tomography using the translocator protein (TSPO) radioligand [ 18 F]-FEMPA, a marker of glial activation, together with the quantification of blood plasma inflammatory cytokines., Results: [ 18 F]-FEMPA binding was significantly increased in the dentate nuclei (d = 0.67), superior cerebellar peduncles (d = 0.74), and midbrain (d = 0.87), alongside increased plasma interleukin-6 (IL-6) (d = 0.73), in individuals with FRDA compared to controls. Increased [ 18 F]-FEMPA binding in the dentate nuclei, brainstem, and cerebellar anterior lobe correlated with earlier age of symptom onset (controlling for the genetic triplet repeat expansion length; all r part  < -0.6), and in the pons and anterior lobe with shorter disease duration (r = -0.66; -0.73)., Conclusions: Neuroinflammation is evident in brain regions implicated in FRDA neuropathology. Increased neuroimmune activity may be related to earlier disease onset and attenuate over the course of the illness. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)