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Imaging robust microglial activation after lipopolysaccharide administration in humans with PET
Christine M Sandiego1, Jean-Dominique Gallezot2, Brian Pittman3
1Department of Psychiatry, Yale University, New Haven, CT 06511; PET Center, Diagnostic Radiology, Yale University, New Haven, CT 06520;
Abstract:
Neuroinflammation is associated with a broad spectrum of neurodegenerative and psychiatric diseases. The core process in neuroinflammation is activation of microglia, the innate immune cells of the brain. We measured the neuroinflammatory response produced by a systemic administration of the Escherichia coli lipopolysaccharide (LPS; also called endotoxin) in humans with the positron emission tomography (PET) radiotracer [11C]PBR28, which binds to translocator protein, a molecular marker that is up-regulated by microglial activation. In addition, inflammatory cytokines in serum and sickness behavior profiles were measured before and after LPS administration to relate brain microglial activation with systemic inflammation and behavior. Eight healthy male subjects each had two 120-min [11C]PBR28 PET scans in 1 d, before and after an LPS challenge. LPS (1.0 ng/kg, i.v.) was administered 180 min before the second [11C]PBR28 scan. LPS administration significantly increased [11C]PBR28 binding 30-60%, demonstrating microglial activation throughout the brain. This increase was accompanied by an increase in blood levels of inflammatory cytokines, vital sign changes, and sickness symptoms, well-established consequences of LPS administration. To our knowledge, this is the first demonstration in humans that a systemic LPS challenge induces robust increases in microglial activation in the brain. This imaging paradigm to measure brain microglial activation with [11C]PBR28 PET provides an approach to test new medications in humans for their putative antiinflammatory effects.
Insights
Systemic administration of lipopolysaccharide (LPS) in humans activates brain microglia, the brain's immune cells. This neuroinflammation was visualized using [11C]PBR28 positron emission tomography (PET) scans, showing increased microglial activation.
Area of Science:
- Neuroscience
- Immunology
- Radiochemistry
Background:
- Neuroinflammation, driven by microglial activation, is implicated in various neurological and psychiatric disorders.
- Microglia are the primary innate immune cells in the central nervous system.
- Translocator protein (TSPO) is a marker upregulated on activated microglia.
Purpose of the Study:
- To measure neuroinflammation and microglial activation in humans following systemic lipopolysaccharide (LPS) administration.
- To correlate brain microglial activation with peripheral inflammatory markers and sickness behavior.
- To validate [11C]PBR28 PET as a tool for assessing neuroinflammation in humans.
Main Methods:
- Eight healthy male subjects underwent two [11C]PBR28 PET scans before and after intravenous LPS administration.
- Systemic inflammation was assessed by measuring serum cytokines and behavioral symptoms.
- LPS challenge was administered 180 minutes prior to the second PET scan.
Main Results:
- LPS administration significantly increased [11C]PBR28 binding by 30-60% in the brain, indicating widespread microglial activation.
- Increased microglial activation correlated with elevated serum inflammatory cytokines, vital sign changes, and sickness symptoms.
- This study provides the first human demonstration of LPS-induced increases in brain microglial activation.
Conclusions:
- Systemic LPS challenge robustly induces neuroinflammation and microglial activation in humans, detectable by [11C]PBR28 PET.
- The [11C]PBR28 PET imaging paradigm offers a valuable approach for evaluating anti-inflammatory drugs in clinical trials.
- This method can advance the study of neuroinflammatory diseases and therapeutic interventions.
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