Abstract
Neuroinflammation play an important role in Alzheimer’s disease pathogenesis. Advances in molecular imaging using positron emission tomography have provided insights into the time course of neuroinflammation and its relation with Alzheimer’s disease central pathologies in patients and in animal disease models. Recent single-cell sequencing and transcriptomics indicate dynamic disease-associated microglia and astrocyte profiles in Alzheimer’s disease. Mitochondrial 18-kDa translocator protein is the most widely investigated target for neuroinflammation imaging. New generation of translocator protein tracers with improved performance have been developed and evaluated along with tau and amyloid imaging for assessing the disease progression in Alzheimer’s disease continuum. Given that translocator protein is not exclusively expressed in glia, alternative targets are under rapid development, such as monoamine oxidase B, matrix metalloproteinases, colony-stimulating factor 1 receptor, imidazoline-2 binding sites, cyclooxygenase, cannabinoid-2 receptor, purinergic P2X7 receptor, P2Y12 receptor, the fractalkine receptor, triggering receptor expressed on myeloid cells 2, and receptor for advanced glycation end products. Promising targets should demonstrate a higher specificity for cellular locations with exclusive expression in microglia or astrocyte and activation status (pro- or anti-inflammatory) with highly specific ligand to enable in vivo brain imaging. In this review, we summarised recent advances in the development of neuroinflammation imaging tracers and provided an outlook for promising targets in the future.
Highlights
Neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal dementia, Parkinson’s disease (PD), and Lewy body dementia, represent a tremendous unmet clinical need
Other alternative targets are under rapid development (Table 1), such as monoamine oxidase-B (MAO-B), matrix metalloproteinases [144,145,146,147, 185, 186], colony-stimulating factor 1 receptor (CSF1R), imidazoline-2 binding sites (I2BS), cyclooxygenases, the phospholipase A2/arachidonic acid pathway, sphingosine-1-phosphate receptor-1, reactive oxygen species, cannabinoid-2 receptor, purinergic P2X7 receptor and P2Y12 receptor, the fractalkine receptor (CX3CR1) [187], triggering receptor expressed on myeloid cells 2 (TREM2) [140], and receptor for advanced glycation end products [36, 188] (Table 1)
Increased levels of [18F] GE-180 uptake indicative of microglial activation have been reported in patients with AD, semantic dementia, mild cognitive impairment (MCI), and four-repeat tauopathy compared to non-demented controls [88,89,90,91]
Summary
Neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal dementia, Parkinson’s disease (PD), and Lewy body dementia, represent a tremendous unmet clinical need. A1 astrocyte secretes and produces a large number of inflammatory factors and neurotoxins, whereas A2 astrocyte produces neurotrophic substances and supports neuronal growth. Reactive astrocytes precipitate both Ab and tau [20,21,22] and are closely linked with microgliosis [16]. Recent advances in molecular imaging have provided insights into the time course of AD pathology, including Ab, tau, synaptic deficits, and neuroinflammation, in patients and in animal disease models [1, 26,27,28,29,30,31,32,33,34,35]. One reason is that the astrocytes and microglia are highly dynamic and heterogeneous in their subtypes, locations, and activation status [1]
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