Effects of ATP1A3 Mutations on Default Mode Network Connectivity (N1.002)

Objective: The purpose of this study was to characterize the effects of ATP1A3 gene mutations of rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) on brain default mode network (DMN) connectivity, which has been implicated in other forms of dystonia. We hypothesized that ATP1A3 gene mutations would be associated with decreases in DMN connectivity compared to controls. Background: ATP1A3 is in the P2 family of ion transport ATPases that establish and maintain electrochemical gradients for Na+ and K+ across the plasma membrane. Little is known about brain network connectivity associated with ATP1A3 disease phenotypes, including RDP and AHC. Design/Methods: Twenty-three patients with ATP1A3 mutations of RDP or AHC, as well as seven age/sex matched controls were recruited for this IRB approved study. Brain magnetic resonance imaging (MRI) data were acquired from all participants, including 10-minutes of resting-state BOLD data. Image pre-processing included file conversion to NIFTI format, brain segmentation, head motion correction, and artifact removal from functional MRI time-series data. BOLD data were then co-registered to structural T1 images, and a DMN seed created from the orthogonal slices of spatial cross-correlation of independent component analysis spatial maps, which were used to extract individual DMNs for estimating changes in connectivity strength. T-tests were conducted to examine between-group differences. Results: There were statistically significant (p Conclusions: Differences between patients with ATP1A3 mutations and controls in DMN connectivity suggest disruption of integrated functional brain circuitry, and reveal similarities with other forms of dystonia. Non-invasive neuroimaging allows quantitative measurement of brain function that may provide insights into brain phenotypes of ATP1A3-related disease, and lead to the development of imaging biomarkers for future treatment or prevention trials. Disclosure: Dr. Whitlow has nothing to disclose. Dr. Kim has nothing to disclose. Dr. Kim has nothing to disclose. Dr. Jung has nothing to disclose. Dr. Cook has nothing to disclose. Dr. Snively has nothing to disclose. Dr. Haq has nothing to disclose. Dr. Sweadner has nothing to disclose. Dr. Ozelius has nothing to disclose. Dr. Brashear has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ipsen and Revance. Dr. Brashear has received research support from Wake Forest.