Objective: To examine whether iron dysregulation and neurodegeneration influences the motor system outside of the cerebellum in Friedreich ataxia (FRDA).

Background: FRDA is an autosomal recessive movement disorder defined by reduced expression of the iron-regulating protein frataxin. Metabolic dysfunction, oxidative stress, and progressive cell death occurs in tissues with high frataxin expression, including the dentate nuclei of the cerebellum. However, the impact of reduced frataxin, which is universally expressed in human cells, on other iron-laden brain structures within the extra-pyramidal motor system remains unknown.

Methods: Individuals with FRDA (n=30) and age/gender matched healthy controls (n=33) underwent magnetic resonance imaging (MRI). Iron deposition in subcortical nuclei of the cerebellum (dentate nuclei), midbrain (red nuclei, substantia nigra), basal ganglia (caudate, putamen, pallidum), and thalamus was measured in vivo using a novel contrast mechanism called quantitative susceptibility mapping (QSM). The volume of each structure was quantified using tissue segmentation and tensor-based morphometry approaches.

Results: The dentate nuclei in individuals with FRDA had significantly greater iron concentration and smaller volumes as compared to healthy individuals, replicating existing findings. Both measures were associated with greater disease severity and poorer performance on tasks of motor dexterity. Outside of the cerebellum, iron accumulation was also evident in the red nuclei, and significant volume decreases were observed in the red nuclei, substantia nigra, thalamus, and pallidum. Disease severity and motor dysfunction were associated with lesser volume in these nuclei.

Conclusions: Clinically-relevant iron dysregulation and tissue atrophy extends beyond the cerebellum in FRDA. These novel findings may reflect either more widespread effects of frataxin deficiency, or anterograde degeneration in brain regions downsteam of the cerebellum. The role that more subtle or secondary pathology in the extra-pyramidal system plays in the expression and progression of FRDA should be considered in ongoing clinical and basic science research.

Australian Neurodegeneration and Dementia Conference, August 2015, Melbourne, Australia.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/iron-accumulation-and-volume-loss-in-the-extrapyramidal-motor-system-in-friedreich-ataxia-the-image-frda-study/