Summary: Using an in-house high-contrast tau PET tracer, researchers mapped tau deposits in 37 people with progressive supranuclear palsy (PSP) and combined those maps with normative functional connectivity data from 100 healthy brains. This integrated approach revealed a shared, remote circuit—the “PSP-tau network”—through which localized subcortical tau lesions appear to disrupt distant cortical regions that support higher-order cognition.
The study provides evidence that concentrated tau pathology in deep brain structures can impair cognition not only by local tissue damage but also by perturbing functional networks and broadcasting disruptive signals to anatomically distant cortical areas.
Key Facts
- Remote network hypothesis supported: Clinical symptoms in neurodegenerative disease are not determined only by the anatomical location of protein aggregates. Localized tau pathology can affect distant cortical regions by traveling along or functionally disrupting established neural pathways.
- Discovery of the “PSP-tau network”: Although individual patients showed variable local patterns of tau accumulation, connectome-based analysis revealed that affected subcortical regions converge on a common set of cortical targets. That vulnerable circuit includes the prefrontal cortex, anterior cingulate cortex, anterior insula, and parietal cortex, areas that govern executive function, attention, working memory, and behavioral control.
- Distinct mechanisms for motor and cognitive symptoms: Quantitative PET and connectivity analyses separated symptom origins:
- Motor deficits (local): The volume of tau concentrated in deep motor-related structures (for example, midbrain, caudate, putamen) predicted movement problems such as gaze palsy and rigidity, but did not predict cognitive decline.
- Cognitive deficits (remote): The strength of functional connectivity linking those subcortical tau deposits to the PSP-tau network correlated with the severity of frontal cognitive impairment.
- Explaining clinical heterogeneity: The circuit-based model explains why patients with very different or asymmetric visible pathology can develop similar cognitive and behavioral symptoms: distinct local lesions can intersect the same vulnerable network, producing convergent clinical outcomes.
- Relevance for other tauopathies: Because tau accumulation is central to Alzheimer’s disease and some forms of frontotemporal degeneration, mapping disease-related proteins onto normative connectomes can identify symptom-specific networks across multiple neurodegenerative disorders.
- Implications for precision therapies: Moving beyond a focus on isolated lesions toward protecting and modulating vulnerable circuits opens new possibilities for tailored interventions—early prediction of symptom trajectories, personalized neuromodulation, and therapies aimed at preserving network integrity.
Source: QST
Researchers at Japan’s National Institutes for Quantum Science and Technology (QST) report that tau accumulation in progressive supranuclear palsy (PSP) can impair brain networks that support cognition and behavior. Their findings indicate that clinical symptoms may reflect not only where tau aggregates but also how those affected sites are connected to distant cortical regions.
The study was published online on July 10, 2026, in Science Advances.
PSP is a rare neurodegenerative disorder marked by abnormal tau accumulation. Clinically it causes falls, impaired eye movements, stiffness, and cognitive or behavioral changes including reduced attention and difficulty regulating emotions. A key puzzle has been why patients often show prominent cognitive symptoms even when tau appears concentrated in deep subcortical structures rather than the outer cerebral cortex, which mediates attention, decision-making, and flexible behavior.
To address this mismatch, the QST team combined tau positron emission tomography (tau-PET) using a tracer developed at QST with connectome mapping. They imaged tau in 37 PSP patients and then used functional connectivity data from 100 healthy individuals to identify cortical regions that are normally connected to each patient’s tau-positive sites.
Despite variability in exact tau distribution across individuals, the affected subcortical regions consistently linked to the same cortical targets: prefrontal cortex, anterior cingulate, anterior insula, and parietal cortex. The authors named this convergent pathway the “PSP-tau network.” Importantly, the connectivity strength from subcortical tau sites to this cortical network predicted the degree of frontal cognitive impairment, while the sheer amount of local tau in motor centers predicted motor dysfunction but not cognition.
“We started with a clinical question that could not be answered by considering only where tau accumulates,” said Dr. Toshiyuki Hirabayashi, Senior Principal Researcher at QST’s Advanced Neuroimaging Center. “Our goal was to test whether local pathology could influence distant brain regions via neural circuits, and whether that remote effect might explain the cognitive symptoms patients experience.”
These results support a model in which cognitive deficits in PSP can arise from remote network disruption caused by subcortical tau deposition—an effect that is independent of cortical atrophy. That circuit-based perspective helps explain why different visible pathology patterns can produce similar clinical syndromes and suggests a framework for identifying symptom-specific networks in other tau-related diseases.
Longer term, this network-focused viewpoint could improve early diagnosis, enhance prediction of symptom progression, and guide more personalized treatment strategies such as targeted neuromodulation to support vulnerable circuits before irreversible tissue loss occurs.
Funding information
This work was supported by AMED (Grant Numbers JP25wm0625307 and JP25wm0625001), JST (Grant Number JPMJMS2024), and JSPS KAKENHI (Grant Numbers JP24H00734, JP25H01767, JP23K11796).
Key Questions Answered:
A: Traditional neurology often links a lost function to local damage in a corresponding brain region. In PSP, however, patients display frontal cognitive problems while clinical scans show tau concentrated in deep, movement-related structures. This mismatch puzzled clinicians because the cortical areas responsible for executive functions often appear relatively spared on standard imaging, yet patients exhibit severe cognitive dysfunction.
A: The brain is a highly interconnected network. Deep subcortical structures act as relay hubs that continuously interact with cortical control centers. When tau damages these relay stations, it alters the timing and quality of signals arriving at the cortex. Even if the cortex itself shows little tau pathology, it can lose critical input and synchronization, producing remote cognitive dysfunction.
A: By shifting from a static “lesion-centered” model to a dynamic “network-centered” model, this study provides a blueprint for protecting functional circuits rather than focusing solely on clearing local protein aggregates. That approach could enable earlier prediction of cognitive decline and support targeted interventions—such as neuromodulation—that aim to preserve or reinforce vulnerable networks.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional context was added by the editorial staff.
About this PSP and cognition research news
Author: Rin Suzuki
Source: QST
Contact: Rin Suzuki – QST
Image: The image is credited to Neuroscience News
Original Research: Open access. “Remote network for cognitive symptoms derived from tau accumulation in progressive supranuclear palsy” by Chie Seki, Hironobu Endo, Hitoshi Shimada, Hitoshi Shinotoh, Keisuke Takahata, Kenji Tagai, Makoto Higuchi, Naomi Kokubo, Ryoji Goto, Shin Kurose, Sho Moriguchi, Takafumi Minamimoto, Takahiko Tokuda, Toshiyuki Hirabayashi, Yuki Hori, Yuki Momota, Yuko Kataoka. Science Advances. DOI: 10.1126/sciadv.aed0348
Abstract
Remote network for cognitive symptoms derived from tau accumulation in progressive supranuclear palsy
Progressive supranuclear palsy (PSP) causes motor and cognitive impairments. Motor symptoms associate with subcortical tau deposits, but the origin of cognitive symptoms has been unclear because pathological tau in PSP is often heterogeneous and primarily subcortical.
Combining tau-PET—using a high-contrast tracer developed by the authors—with a normative connectome in 37 PSP patients and 48 healthy controls, the study found that tau deposition sites are functionally connected to a common cortical network not predicted by atrophy measures. This network substantially overlaps canonical action-mode and frontoparietal systems that support adaptive, goal-directed behavior.
While the extent of primary tau deposition predicted motor impairment, the normative connectivity strength from tau deposition sites to the identified cortical network explained the severity of cognitive deficits. These findings suggest a mechanism whereby cognitive, but not motor, deficits in PSP result from remote effects of tau deposition via convergent connectivity to a common cortical network, independent of local atrophy.