A combined voxel-based morphometry and ¹H-MRS study in patients with Friedreich’s ataxia

Friedreich’s ataxia (FA) is the most frequent autosomal recessive ataxia and essentially considered a disease of the dorsal root ganglia and spinal cord. It is caused by homozygous GAA expansions in the Frataxin gene in most cases. Although only a few studies have addressed cerebral involvement in FA, cognitive symptoms have lately been emphasized. To evaluate brain damage in vivo, we employed whole-brain VBM and analysis of pre-defined regions of interest (ROIs) over the cerebellum to compare 24 patients with 24 age-and-sex-matched normal controls. ¹H-MRS of deep cerebral white matter (WM) was subsequently performed. Mean age of patients was 28 years (range 14–45), mean duration of disease was 14 years (range 5–28) and 11 were men. Mean length of shorter (GAA1) and longer (GAA2) alleles were 735 and 863, respectively. VBM analysis identified WM atrophy in the posterior cyngulate gyrus, paracentral lobule and middle frontal gyrus. ROIs over the infero-medial cerebellar hemispheres and dorsal brainstem presented gray matter atrophy, which correlated with duration of disease (r = −0.4). NAA/Cr ratios were smaller among patients (P = 0.006), but not Cho/Cr (P = 0.08). Our results provide evidence of axonal damage in the cerebellum, brainstem and subcortical WM in FA. This suggests that neuronal dysfunction is more widespread than previously thought in FA.