Tau deposits linked to cognitive decline through neural networks

A research group, led by Researcher Yuki Hori, Principal Researcher Hironobu Endo and Senior Principal Researcher Toshiyuki Hirabayashi of the Advanced Neuroimaging Center at the Institute for Quantum Medical Science at the National Institutes for Quantum Science and Technology (QST), has elucidated the mechanism of how abnormal aggregation of tau protein causes cognitive symptoms in progressive supranuclear palsy (PSP), an intractable neurodegenerative disorder characterized by tau lesions. The group revealed that tau deposition impairs remote brain regions through a neural network. The finding is considered to reflect a common mechanism shared among many neurodegenerative diseases including Alzheimer's disease and potentially contributes to the establishment of novel treatment strategies. The results were published in Science Advances on July 10.

Tau proteins are known to aggregate and deposit (abnormal aggregation) in the brain to induce neuronal dysfunction and cell death in many neurodegenerative diseases, including Alzheimer's disease. Such neurodegenerative disorders are collectively called tauopathy. One such disease is PSP, in which the abnormal aggregation of tau protein mainly occurs in the deep brain (subcortical) regions responsible for motor functions, but the disease is also associated with progressive cognitive decline.

In PSP, the locations of abnormal aggregation of tau protein vary from patient to patient and are not necessarily in the subcortical regions involved in cognitive function. Due to this, it had been unclear why cognitive impairment is commonly observed in PSP.

The research group had previously succeeded in developing a probe capable of visually detecting the abnormal aggregation of tau protein with high sensitivity. In this study, the group focused on neural networks spreading throughout the brain. They hypothesized that abnormal aggregations remotely affect common brain regions to cause cognitive impairment.

Unlike Alzheimer's disease, which involves not only tau protein but also other abnormal proteins such as amyloid beta protein, PSP can serve as a model for examining the effects of tau protein alone.

First, they visualized and identified the sites of tau protein accumulation in 37 PSP patients with moderate symptoms using the previously developed probe. They also evaluated brain atrophy by MRI.

Next, using a large-scale connectome database (CONNECTOME) that shows brain connections based on publicly available fMRI images of healthy individuals, they calculated the patterns of functional connections between subcortical regions and the abnormal aggregation in the patients. The data obtained for individual patients were compared and contrasted.

The results of a network analysis revealed that, although the locations of abnormal aggregation varied from patient to patient, certain brain regions (remote core regions) were commonly affected across patients. As in previous reports, the patients participating in the study showed abnormal aggregation in deep brain regions responsible for motor functions and no clear accumulation in the cortex. No significant atrophy was observed at that time.

The remote core regions were formed in a broad cortical region including the prefrontal cortex, anterior cingulate cortex, anterior insular cortex and parietal cortex; the research group referred to this region as the "PSP-Tau network." This region overlapped with a brain network important for executive function, which is involved in goal-directed behavioral switching, inhibition and attention retention.

The group further investigated the association between this network and clinical symptoms. They found that the amount of tau deposition in the subcortical region was associated with the severity of eye movement deficit (motor symptom) but not with the impairment in cognitive (MMSE score) or executive (FAB score) function.

Meanwhile, the strength of connectivity between the abnormal aggregation site and the PSP-Tau network in each patient was strongly associated with frontal cognitive impairment. It was found that cognitive symptoms of PSP are remotely triggered by abnormal aggregation of tau protein via a neural network.

Hori commented, "Patients with dementia or neurodegenerative diseases may develop multiple symptoms. We believe that the current approach can be used to identify the networks related to the symptoms of not only PSP but also various other neurodegenerative diseases such as Alzheimer's disease. In the future, we may be able to improve cognitive symptoms with ultrasound or magnetic stimulation using the identified networks as targets. By identifying the networks related to individual symptoms and diseases, we hope to contribute to the establishment of personalized treatments that target the identified networks."

Journal Information
Publication: Science Advances
Title: Remote network for cognitive symptoms derived from tau accumulation in progressive supranuclear palsy
DOI: 10.1126/sciadv.aed0348