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Protein aggregation has been widely implicated in neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia, Parkinson's disease, and Huntington disease, as well as in systemic amyloidoses and conditions associated with localized amyloid deposits, such as type-II diabetes. The pressing need for a better understanding of the factors governing protein assembly has driven research for the development of molecular sensors for amyloidogenic proteins. To date, a number of sensors have been developed that report on the presence of protein aggregates utilizing various modalities, and their utility demonstrated for imaging protein aggregation in vitro and in vivo . Analysis of these sensors highlights the various advantages and disadvantages of the different imaging modalities and makes clear that multimodal sensors with properties amenable to more than one imaging technique need to be developed. This critical review highlights the key molecular scaffolds reported for molecular imaging modalities such as fluorescence, positron emission tomography, single photon emission computed tomography, and magnetic resonance imaging and includes discussion of the advantages and disadvantages of each modality, and future directions for the design of amyloid sensors. We also discuss the recent efforts focused on the design and development of multimodal sensors and the value of cross-validation across multiple modalities.

Amyloid protein fibrillation is associated with a variety of neurodegenerative and other diseases, and their efficient detection and monitoring can greatly advance early diagnosis and therapy. Herein, we report a fluorescent "switch-on" probe for the reliable detection and monitoring of amyloid fibrils. The probe consists of a peptide component for binding with amyloid structure and a color component with an aggregation-induced green emission property. This probe is nonfluorescent in the presence of amyloid forming monomer protein/peptide, but fluorescence "switch-on" occurs after binding with amyloid fibrils. Compared to conventionally used thioflavin T, this probe offers a high signal-to-noise ratio, which is unaffected by the quencher ion/nanoparticle. The proposed new probe has been used for the detection and monitoring of amyloid fibrils produced by a wide variety of amyloid protein/peptides and can be extended for in vitro diagnostic applications.