Abstract
Neurodegenerative diseases characterized by pathological protein accumulation in cells are termed “proteinopathies.” Although various protein aggregates share cross-β-sheet structures, actual conformations vary among each type of protein deposit. Recent progress in the development of radiotracers for positron emission tomography (PET) has enabled the visualization of protein aggregates in living brains. Amyloid PET tracers have been developed, and are widely used for the diagnosis of Alzheimer’s disease and non-invasive assessment of amyloid burden in clinical trials of anti-dementia drugs. Furthermore, several tau PET tracers have been successfully developed and used in the clinical studies. However, recent studies have identified the presence of off-target binding of radiotracers in areas of tau deposition, suggesting that concomitant neuroinflammatory changes might affect tracer binding. In contrast to amyloid and tau PET, there are no established tracers for imaging Lewy bodies in the human brain. In this review, we describe lessons learned from the development of PET tracers and discuss the future direction of tracer development for protein misfolding diseases.
Highlights
Proteinopathies are neurodegenerative diseases characterized by pathological accumulation of amyloid-β (Aβ), tau, α-synuclein, and TDP-43 in the cells
Tauopathies, characterized by tau protein accumulation, include Alzheimer’s disease (AD), some variants of frontotemporal lobar degeneration (FTLD), frontotemporal dementia with parkinsonism linked to chromosome-17 (FTLD-17), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), argyrophilic grain disease (AGD), and chronic traumatic encephalopathy (CTE)
AD is a mixed proteinopathy characterized by abnormal accumulation of extracellular Aβ and intracellular tau protein. α-Synucleinopathies, characterized by pathological accumulation of α-synuclein, include Parkinson’s disease (PD), Lewy bodies disease (LBD), and multiple system atrophy (MSA)
Summary
Proteinopathies are neurodegenerative diseases characterized by pathological accumulation of amyloid-β (Aβ), tau, α-synuclein, and TDP-43 in the cells. Pathological, and biochemical evidence strongly suggests that protein accumulation causes neurodegenerative disease, the precise etiology and mechanisms underlying these processes remain unknown These neuropathological lesions could only be identified by histopathological examination at autopsy. Following the successful imaging of amyloid with Pittsburgh compound B (PiB; Klunk et al, 2004), fluorinated alternatives have been developed in clinical studies and approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA; Mathis et al, 2017) These tracers are thioflavin and stilbene derivatives, which bind the crossβ-sheet structures of aggregated proteins. We describe our experiences and lessons learned from the development of tau PET tracers, and discuss the future of radiotracer development for other proteinopathies
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