Imaging robust microglial activation after lipopolysaccharide administration in humans with PET
Open accessAbstract
Significance: Neuroinflammation is a brain immune response that is associated with neurodegenerative diseases and is primarily driven by activation of microglia, the brain’s resident macrophages. Dysfunctional microglial activation may contribute to the behavioral changes observed in neurodegenerative diseases. Upon activation, microglia express translocator protein, which can be imaged with the radiotracer [ 11 C]PBR28 and positron emission tomography (PET) in the living human brain. We imaged healthy human subjects with [ 11 C]PBR28 and PET before and after i.v. administration of lipopolysaccharide (LPS), a potent immune activator. LPS produced a marked increase in brain microglial activation, peripheral inflammatory cytokine levels, and self-reported sickness symptoms. This imaging paradigm can provide a direct approach to test new medications for their potential to reduce acute neuroinflammation.
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Data from endotoxin administration to healthy volunteers indicate that radiolabelled TSPO ligands can readily identify cellular activation in several regions of the brain following a potent peripheral immune stimulus.
“data from endotoxin administration to healthy volunteers indicates that radiolabelled TSPO ligands can readily identify cellular activation in several regions of the brain following a potent peripheral immune stimulus63.”
From The role of inflammation in depression: from evolutionary imperative to modern treatment target (2016) · cites this paper as [63]
Adding endotoxin at levels found in disease to blood of healthy humans induces systemic inflammation and brain microglial activation.
“Adding endotoxin at such levels to blood of healthy humans induces systemic inflammation and brain microglial activation.”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [15]
A relatively mild dose of blood endotoxin (e.g. less than that found in Alzheimer's patients) can cause acute microglial activation within the brain.
“Thus, a relatively mild dose of blood endotoxin (e.g. less than that found in Alzheimer’s patients) can cause acute microglial activation within the brain.”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [15]
Human neuroimaging findings show heightened microglia activation after lipopolysaccharide administration that produces depressive-like sickness symptoms.
“Human neuroimaging findings show heightened microglia activation after LPS administration that produces depressive-like sickness symptoms [79].”
From The menace of obesity to depression and anxiety prevalence (2022) · cites this paper as [79]
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“Likewise, data showing a robust increase in CNS (11)C-PBR28 PET signal following systemic LPS administration to both humans and nonhuman primates may need to be reassessed.(57,58) In these experiments, the increased TSPO PET signal was interpreted as evidence of microglial activation.”
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Self-citation
- Authors
- Sandiego, C. M., Gallezot, J.-D., Pittman, B., Nabulsi, N., Lim, K., Lin, S.-F., Matuskey, D., Lee, J.-Y., O’Connor, K. C., Huang, Y., Carson, R. E., Hannestad, J., & Cosgrove, K. P.
- Affiliations
- Yale University (US)
- UCB Pharma (Belgium) (BE)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-09-18
- Volume
- 112
- Issue
- 40
- Pages
- 12468-12473
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4603509
- OpenAlex
- W2145625835
- Cited by
- 356
- References
- 66
- Citations by year
- 2026: 19 · 2025: 30 · 2024: 29 · 2023: 21 · 2022: 30 · 2021: 42 · 2020: 49 · 2019: 38 · 2018: 32 · 2017: 40 · 2016: 23 · 2015: 3
- FWCI
- 17.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Yale University
- National Institute on Aging (P50AG047270)
- UCB Pharma
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Keywords
- microglial activation, neuroinflammation, lipopolysaccharide challenge, [11C]PBR28, translocator protein (TSPO), inflammatory cytokines, sickness behavior, systemic inflammation, anti-inflammatory drug testing
- MeSH terms
- Acetamides, Adult, Brain, Carbon Radioisotopes, Humans, Lipopolysaccharides, Male, Protein Binding, Pyridines, Reproducibility of Results, Biomarkers, Cytokines, Microglia, Receptors, GABA, Inflammation Mediators, Radiopharmaceuticals, Positron-Emission Tomography, Young Adult
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