QST identifies PET biomarker for PSP progression

Trainee Yoshikazu Chishiki (also at the Department of Neurology, Graduate School of Medicine, Chiba University), Senior Researcher Hironobu Endo, and colleagues at the Advanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology (QST), visualized how tau accumulation in the living brains of patients with progressive supranuclear palsy (PSP) increases and spreads over time. They showed for the first time that patients with greater increases in tau accumulation in the globus pallidus, a deep brain structure, experience more rapid disease progression. The findings were published in Movement Disorders.

PSP is a progressive neurodegenerative disorder that develops in middle-aged and older adults and is characterized by worsening symptoms including frequent falls, movement difficulties, impaired eye movements, and cognitive dysfunction. It affects approximately 10 to 20 people per 100,000. Although it is about one-tenth as common as Parkinson's disease, it is often difficult to distinguish from Parkinson's disease in the early stages. There is currently no disease-modifying therapy that can slow the progression of PSP, and establishing objective biomarkers for evaluating disease progression remains a major challenge in the development of new treatments.

Previous postmortem studies have shown that tau accumulation is a major pathological feature of PSP. However, because postmortem studies cannot follow the same patient over time, it has remained unclear how the amount and distribution of tau accumulation change over the course of the disease and how these changes relate to clinical progression.

In recent years, positron emission tomography (PET) has enabled the visualization of tau accumulation in the living brain, and efforts have been made to track longitudinal changes. However, the PET tracers used previously lacked sufficient sensitivity and specificity, and although increases in tau accumulation could be detected over time, their relationship with symptom progression had not been demonstrated.

The research group used [18F]PM-PBB3, a PET tracer developed by QST that can detect tau in the brain with high sensitivity, to clarify how tau accumulation in PSP spreads through the brain over time and to examine its relationship with disease progression. The researchers performed PET scans in 26 patients with PSP and 10 healthy controls at baseline and again approximately one year later. Using 57 regions of interest defined by MRI, they conducted a multivariate analysis comparing baseline PET signals and one-year changes in PET signals associated with tau accumulation between patients with PSP and healthy controls, identifying regions that showed PSP-specific tau accumulation.

Consistent with previous reports, the baseline analysis showed tau accumulation primarily in subcortical regions such as the globus pallidus and midbrain. In contrast, the longitudinal analysis revealed further increases in tau accumulation in the globus pallidus, as well as significant increases in the frontoparietal cortex and cerebellar white matter. These findings demonstrated that the progression of PSP pathology, in which tau accumulation continues to increase in the globus pallidus and spreads to the cerebral cortex and cerebellum, can be visualized in the living brain.

The researchers next focused on Richardson's syndrome (18 of the 26 patients), the most common and characteristic subtype of PSP, and examined the relationship between longitudinal changes in tau accumulation and disease progression. This subtype is known to progress rapidly, and the PSP Rating Scale score, an indicator of disease severity, increased significantly over the one-year study period.

The analysis showed that increases in tau accumulation in the globus pallidus were most strongly correlated with the degree of symptom progression, indicating that patients with faster tau accumulation experienced more rapid disease progression. Furthermore, analysis of changes in tau accumulation and disease severity in individual patients showed that tau accumulation in the globus pallidus consistently reflected disease progression across the entire course of PSP, from mild to severe stages.

These findings suggest that longitudinal tau PET imaging could serve as a new imaging biomarker for objectively assessing disease progression in PSP. The results also suggest that suppressing tau accumulation through tau-targeted therapies may help slow disease progression.

Chishiki commented, "Because the number of cases was limited, we used partial least squares analysis to investigate the relationship between brain regions and clinical symptoms. This enabled us to identify brain regions associated with disease progression and symptom worsening based on whole-brain patterns of tau accumulation."

Endo commented, "Various therapies aimed at reducing tau are currently under development. Because PET imaging has begun to reveal correlations between tau accumulation and clinical symptoms, we hope these findings will contribute to the development of new treatments. We also hope to apply this approach to the development of diagnostic methods that can objectively monitor the progression of PSP."

Journal Information
Publication: Movement Disorders
Title: Spatiotemporal Tau Accumulation and its Clinical Impact on Progressive Supranuclear Palsy: Longitudinal Florzolotau (18F) Positron Emission Tomography
DOI: 10.1002/mds.70468