Remote network for cognitive symptoms derived from tau accumulation in progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder with motor and cognitive impairments. Whereas motor symptoms are associated with subcortical tau deposits, the mechanisms underlying the cognitive symptoms remain unclear due to heterogeneous and primarily subcortical distribution of pathological tau deposits. Here, we combined tau-PET (tau positron emission tomography) using a high-contrast probe we developed with a normative connectome in 37 patients with PSP and 48 healthy controls. We found that tau deposition sites functionally connected to a common cortical network that could not be derived from atrophy. This network predominantly overlapped with canonical action-mode and frontoparietal networks, which support adaptive, goal-directed behavior. Whereas the extent of primary tau deposition predicted motor symptoms, the normative connectivity strength from tau deposition sites to the identified cortical network explained the severity of cognitive deficits. These findings suggest a previously unknown mechanism that cognitive, but not motor, deficits in PSP arise from remote effects of tau deposition—independent of atrophy—via convergent connectivity to a common cortical network.