Abstract
Neuroinflammation is an inflammatory response in the brain and spinal cord, which can involve the activation of microglia and astrocytes. It is a common feature of many central nervous system disorders, including a range of neurodegenerative disorders. An overlap between activated microglia, pro-inflammatory cytokines and translocator protein (TSPO) ligand binding was shown in early animal studies of neurodegeneration. These findings have been translated in clinical studies, where increases in TSPO positron emission tomography (PET) signal occur in disease-relevant areas across a broad spectrum of neurodegenerative diseases. While this supports the use of TSPO PET as a biomarker to monitor response in clinical trials of novel neurodegenerative therapeutics, the clinical utility of current TSPO PET radioligands has been hampered by the lack of high affinity binding to a prevalent form of polymorphic TSPO (A147T) compared to wild type TSPO. This review details recent developments in exploration of ligand-sensitivity to A147T TSPO that have yielded ligands with improved clinical utility. In addition to developing a non-discriminating TSPO ligand, the final frontier of TSPO biomarker research requires developing an understanding of the cellular and functional interpretation of the TSPO PET signal. Recent insights resulting from single cell analysis of microglial phenotypes are reviewed.
Highlights
These results suggest that translocator protein (TSPO) is a good target for development of neuroinflammation imaging agents, the single nucleotide polymorphism (SNP) sensitivity of current TSPO positron emission tomography (PET) radioligands complicate interpretation of results and necessitate genotyping of patients
Stratifying for genotype has opened the door to TSPO PET radioligands being used to monitor therapeutic impact in neurodegeneration clinical trials [111], the ideal situation would see the development of a TSPO ligand with good PET imaging properties, which binds highly to TSPO WT and A147T
It will be important to evaluate the potential of [18F]GE-180 as a neuroinflammation imaging agent in studies with larger sample sizes to increase their power to detect genotype differences. Another important future study is to compare the quantitative potential of second-generation ligands alongside [18F]GE-180 in clinical trials with patients experiencing neurodegenerative diseases that do not show as pronounced blood-brain barrier (BBB) breakdown as in multiple sclerosis, as it has been suggested that the high lesion-specific signal in these patients may be due to BBB breakdown allowing entrance of the radioligand into brain parenchyma in damaged areas, but not in intact areas [126]
Summary
If the neuroinflammatory response is not transient or tightly controlled within the CNS, an uncontrolled, chronic neuroinflammatory response ensues, constituted by the prolonged overactivation of glial cells This chronic state is deleterious due to the excessive and dysregulated production of pro-inflammatory factors, resulting in prohibited neuronal repair, synaptic impairment, oxidative damage and mitochondrial dysfunction which can lead to or exacerbate neurodegeneration [11,12,13,14]. This highly damaging, chronic response may result in involvement of adaptive immunity, with the recruitment and infiltration of peripheral immune cells, via disruption of the blood-brain barrier (BBB), which can further initiate neurodegenerative mechanisms [15,16]. Increased glial activation and neuroinflammation are components of various pathologies and disease states, including but not limited to cancer, traumatic brain injury, stroke, psychiatric disorders, and neurodegenerative diseases, which are the focus of this review
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