White Matter Connectome in Patients with Genetic Dystonia (P1.038)

Objective: This study investigated structural neural pathways in clinically manifesting and non-manifesting individuals with several dystonia (DYT) genotypes using a network approach. Background: DYT has traditionally been attributed to basal ganglia dysfunction. Recent studies expanded this picture suggesting DYT as a circuit disorder. 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 age- and sex-matched healthy controls were also studied. Subjects underwent 3D T1-weighted and diffusion tensor (DT) MRI. The human macroscale connectome - a comprehensive map describing all neural connections between large-scale brain regions - was constructed from DT MRI. Tissue segmentation was performed on T1-weighted images using Freesurfer. The affected structural connections in subjects with manifesting and non-manifesting DYT were investigated using Network-Based Statistic (p<0.01, 10.000 permutations). Results: Compared to controls, asymptomatic mutation carriers showed a basal ganglia/frontal subnetwork characterized by decreased fractional anisotropy and increased mean diffusivity (MD) including the left putamen, precentral gyrus, middle and superior frontal gyri, middle temporal, and insula. Clinically manifesting DYT mutation carriers relative to controls showed an altered subnetwork characterized by increased MD connecting left putamen, middle and superior frontal gyri, orbitofrontal cortex, middle temporal, insula and right anterior cingulate cortex. No differences were found between symptomatic and asymptomatic DYT subjects. A trend toward a greater disconnection was observed in symptomatic DYT1 relative to DYT6 subjects. Conclusions: Our findings suggest that structural brain abnormalities in both clinically manifesting and non-manifesting DYT mutation carriers are distributed at a network level, beyond the basal ganglia/sensorimotor cortex regions. Studying of asymptomatic mutation carriers offered the possibility of identifying genotype-related trait characteristics without the confound of clinical symptoms providing new insights into understanding dystonia generation.