Remote Cortical Network for Frontal Cognitive Symptoms Derived from Tau Accumulation in Progressive Supranuclear Palsy.

Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder characterized by impaired movement and frontal cognitive dysfunctions. While motor symptoms have been linked with subcortical tau deposits, network mechanisms underlying the frontal cognitive symptoms remain unclear because pathological tau accumulation is quite limited within the frontal cortex and heterogeneously distributed primarily in the subcortical regions. Here, we combined tau-PET using a high-contrast probe we have recently developed with normative connectome to resolve this issue. Tau-deposition sites were connected to a common cortical network that could not be identified through similar analyses based on atrophy detected by structural MRI. This network was predominantly overlapped with canonical action-mode and frontoparietal networks, which jointly support adaptive and goal-directed behavior. Critically, while the degree of subcortical primary tau deposition correlated with motor symptoms, only the degree of connectivity from tau-deposition sites to the derived cortical network explained the frontal cognitive deficits of individual patients. These findings suggest a novel mechanism that frontal cognitive impairments, but not motor deficits, in PSP are derived from remote effects of tau deposits, independent of atrophy, through the convergent connectivity to the identified common cortical network.