The landscape of functional brain network impairments in late-onset GM2 gangliosidosis

Late-onset GM2 gangliosidosis (LOGG) is an ultra-rare neurological disease with motor, cognitive and psychiatric manifestations. It is caused by mutations in the HEXA or HEXB genes. Although cerebellar structural and metabolic impairments have been established, global brain functional impairments in this disease remain unknown. In this first functional MRI (fMRI) report on LOGG (N=14), we took an exploratory, multi-pronged approach by assessing impairments in several resting-state fMRI signal characteristics: fMRI signal strength, neurovascular coupling, static and time-varying functional connectivity, and network topology. Contrary to the predominance of cerebellar aberrations in prior non-functional studies, we found more widespread cortical aberrations (p<0.05, FDR-corrected) mainly in cognitive control networks but also in the default mode and somatomotor networks. There was reduced fMRI signal strength, enhanced neurovascular coupling, pathological hyper-connectivity, and altered temporal variability of connectivity in the LOGG cohort. We also observed an imbalance between functional segregation and integration as seen in other psychiatric/neurological disorders, with heightened segregation and suppressed integration (i.e., inefficient brain-wide communication). Some of these imaging markers were significantly associated with clinical measures, as well as with HEXA and HEXB gene expression. These aberrations might contribute to psychiatric symptoms (psychosis, mood disturbances), cognitive impairments (memory, attention, executive function), and oculomotor disturbances commonly seen in LOGG. Future LOGG imaging studies should probe brain function in addition to structure/metabolism while looking for mechanistic insights beyond the cerebellum.