Advances in PET imaging of protein aggregates associated with neurodegenerative disease

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.