Multicompartment Models of Free-Water Imaging Shows Distinctive Brain Pathology in Friedreich Ataxia


A recent study showed the efficacy of multicompartment diffusion measures in distinguishing patients with Friedreich ataxia from controls, emphasizing the potential for these metrics in tracking disease expression and progression.

Ian H. Harding, PhD, senior research fellow in the department of neuroscience at Central Clinical School of Monash University, in Melbourne, Victoria, Australia

Ian H. Harding, PhD

In a cross-sectional study newly published in the journal of Movement Disorders, multicompartment diffusion measures of free-water and neurite integrity had the ability to significantly identify the difference between patients with Friedreich ataxia (FA) and the controls. The free-water magnitude in the brainstem and cerebellum revealed the greatest distinction between the 2 groups. These findings support further applications of multicompartment diffusion modeling, and investigations of free-water as a measure of disease expression and progression in FA.1

Among patients with FA, the free-water measure of the bitensor diffusion tensor imaging (FW) was elevated in the cerebellar cortex, peduncles, dentate, and brainstem (P <.005). Notably, the free-water measure of the neurite orientation dispersion and density imaging (FISO) was elevated primarily in the cerebellar lobules (P <.001). O average, FW effect sizes were larger than all the other markers (mean, ηρ 2 = .43). However, microstructural measures also had large effects in the superior and inferior cerebellar peduncles and brainstem (ηρ 2 >.37). Across all the regions and metrics, the effect sizes were largest in the superior cerebellar peduncles (ηρ 2 >.46).

Clinical Takeaways

  • Multicompartment diffusion measures, notably free-water and neurite integrity, prove to be potentially effective in identifying Friedreich ataxia (FA) from controls.
  • Elevated free-water measures in specific brain regions of patients with FA surpassed the conventional markers, emphasizing their sensitivity to neuropathology.
  • Overall, the study advocates for the integration of multicompartment diffusion models as standard approaches in FA research.

"There is a critical need to not only describe the brain changes that underlie FA, but to also identify measures that we can use to track disease progression and drug effects in clinical trials. This work shows that a relatively new MRI measure called 'brain free water' may be more sensitive to brain degeneration in FA than outcomes like brain volume or the breakdown of brain pathways," senior author Ian H. Harding, PhD, senior research fellow in the department of neuroscience at Central Clinical School of Monash University, in Melbourne, Victoria, Australia, told NeurologyLive®.

READ MORE: CSA Spinal Cord Damage Identified as Potential Biomarker of Friedreich Ataxia Disease Progression

In the study, investigations explored the extent of free-water and microstructural change in FA-relevant brain regions using neurite orientation dispersion and density imaging, and bitensor diffusion tensor imaging. The researchers collected multishell diffusion MRI data from 14 patients with FA and 14 controls. During the study, FISO and FW were compared between the patients with FA and the controls in the cerebellar cortex, dentate nuclei, cerebellar peduncles, and brainstem. Additionally, the relative sensitivity of the free-water measures to group differences were compared with microstructural measures of neurite orientation dispersion and density imaging intracellular volume, free-water corrected fractional anisotropy, and conventional uncorrected fractional anisotropy.

“Brain free water changes are likely the result of multiple pathological processes in the brain, including neurodegeneration, immune activity, and fluid dysregulation between the blood and the brain. All of these processes are implicated in FA, and our results suggest that a marker that is sensitive to these multiple disease processes may be more useful in tracking disease progression than each process individually,” Harding told.

All told, limitations of the study included the cross-sectional design in which no firm inferences could be made on the progressive nature of these indices in the context of FA. The authors noted that further research should consider how the markers of neuroinflammation and regional volume correlate with free-water volume in the critical brain sites. The sample in this study was small and only had adults with an average disease duration of more than 13 years. Thus, investigators suggested the replication of this study in independent cohorts to ensure the generalizability of the findings. Additionally, the researchers recommended larger, longitudinal studies in further research to resolve any of the present limitations.

“This study was undertaken only in a small group of participants, and only at one point in time. Larger studies are now necessary to confirm the results and to investigate how brain free water changes over time. We can then determine whether this measure should be included in future clinical trials to measure treatment effects,” Harding told.

1. Fernandez L, Corben LA, Bilal H, Delatycki MB, Egan GF, Harding IH. Free-Water Imaging in Friedreich Ataxia Using Multi-Compartment Models. Mov Disord. Published online November 6, 2023. doi:10.1002/mds.29648
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