The Anatomical Basis of Genetic Dystonia: A Multimodal MRI Study (P1.018)

Objective: To investigate cortical thickness, white matter (WM) and resting state (RS) functional MRI (fMRI) alterations in asymptomatic and symptomatic dystonia (DYT) mutation carriers. Background: Most of DYT genotypes follow an autosomal dominant inheritance pattern with reduced penetrance; the mechanisms underlying the disease development remain unclear. Methods: This study included 9 asymptomatic mutation carriers (4 DYT1, 4 DYT6, 1 DYT10) and 26 symptomatic mutation carriers (7 DYT1, 7 DYT6, 9 DYT5, 1 DYT18, 1 DYT10, 1 DYT25). 37 matched healthy controls were studied. Subjects underwent 3D T1-weighted, diffusion tensor (DT) and RS fMRI to study cortical thickness, WM tracts and RS fMRI alterations. Results: Compared to controls and asymptomatic carriers, symptomatic DYT mutation carriers showed cortical thinning of motor and frontal areas, bilaterally. Compared to controls, asymptomatic carriers showed increased mean (MD) and radial diffusivity (radD) and decreased fractional anisotropy (FA) of the main motor tracts, while symptomatic patients showed decreased FA in the WM close to the right premotor cortex and a more widespread increase of MD, axial diffusivity (axD), and radD involving the main motor and associative WM tracts. No DT MRI differences were observed between asymptomatic and symptomatic mutation carriers. Compared to controls, symptomatic carriers showed reduced functional connectivity of insula and basal ganglia, and asymptomatic carriers of the fronto-insular areas. Conclusions: Brain network alterations in asymptomatic DYT mutation carriers support the hypothesis that these changes are causative rather than an effect of the disorder. An attractive hypothesis is also that the analysis of the DT MRI eigenvalues revealing a different pattern of abnormalities in symptomatic (increased axD and radD) and asymptomatic (increased radD, unchanged axD) mutation carriers may allow to gain insight into the possible determinants of penetrance. Whether different DYT mutations are associated with specific network changes remains to be tested in larger subject groups.