Abstract
Neurodegenerative diseases such as Alzheimer disease (AD), Parkinson disease, frontotemporal lobar degeneration and multiple system atrophy (MSA) are characterized pathologically by deposition of specific proteins in the brain. Five major neurodegenerative disease-associated proteins — amyloid-β (Aβ), tau, α-synuclein, TAR DNA-binding protein 43 (TDP43) and fused in sarcoma (FUS) — are commonly encountered, and the disease specificity and neurotoxicity of the fibrillar protein assemblies are determined by factors such as the protein type, fibril structure, degree of multimerization and post-translational modifications. This article reviews the latest advances in PET technologies aimed at visualizing neurodegenerative proteinopathies, and highlights the importance of these technologies for emerging diagnostic and therapeutic approaches. PET allows Aβ deposition to be visualized throughout the natural history of AD and following anti-Aβ immunotherapies. However, whether this technology can visualize specific Aβ assembly subspecies primarily targeted by the treatment remains inconclusive. Various PET radiotracers can capture AD-type tau deposits, although only a few are known to react with non-AD tau pathologies, and cryo-electron microscopy has revealed the mode of binding of these compounds to different tau protofibrils. High-contrast PET imaging of α-synuclein lesions in MSA is a recent development in the field, and gradual progress is being made towards visualization of other, less abundant α-synuclein pathologies. Imaging of TDP43 and FUS deposits presents particular challenges, which might be overcome by establishing public–private partnerships focused on biomarker development.
Key points
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Extensive research programmes have aimed to develop small-molecule PET radiotracers for protein aggregates that are implicated in Alzheimer disease (AD) and other neurodegenerative disorders.
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Amyloid-β (Aβ) PET has been applied in clinical practice, providing robust diagnostic indicators and neuropathology-based outcome measures for trials of anti-Aβ disease-modifying treatments.
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Diverse tau PET tracers can capture AD-type tau assemblies with varying degrees of off-target binding, whereas only a limited subset can yield high contrast for non-AD-type tau deposits.
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Cryo-electron microscopy of disease-specific tau fibril folds has identified at least two distinct binding modes of PET radioligands, explaining their selectivity for AD versus non-AD tau pathologies.
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Despite selectivity issues, high-contrast PET tracers for α-synuclein deposits in multiple system atrophy have become clinically available, and the possibility of visualizing α-synuclein fibrils in Parkinson disease and dementia with Lewy bodies has been demonstrated.
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All authors researched data for the article and reviewed and/or edited the manuscript before submission. M.H, K. Takahata. and H.E. contributed substantially to discussion of the content. M.H., K. Tagai. and H.E. wrote the article.
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M.H. holds patents on PBB3, florzolotau and related compounds (JP 5422782/EP 12 884 742.3/CA2894994/HK1208672) and α-synuclein ligands (JP7460176). M.H. is supported by research grants from the Japan Agency for Medical Research and Development (JP24zf0127012 and JP24wm0625001) and Japan Science and Technology Agency (JPMJMS2024). The other authors declare no competing interests.
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Higuchi, M., Tagai, K., Takahata, K. et al. Advances in PET imaging of protein aggregates associated with neurodegenerative disease. Nat Rev Neurol 21, 506–522 (2025). https://doi.org/10.1038/s41582-025-01126-2
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DOI: https://doi.org/10.1038/s41582-025-01126-2
