title: Imaging robust microglial activation after lipopolysaccharide administration in humans with PET.
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.
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT 06511; PET Center, Diagnostic Radiology, Yale University, New Haven, CT 06520;
authors.forename: Christine M
authors.initials: CM
authors.lastname: Sandiego
authors.affiliation: PET Center, Diagnostic Radiology, Yale University, New Haven, CT 06520;
authors.forename: Jean-Dominique
authors.initials: JD
authors.lastname: Gallezot
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT 06511;
authors.forename: Brian
authors.initials: B
authors.lastname: Pittman
authors.affiliation: PET Center, Diagnostic Radiology, Yale University, New Haven, CT 06520;
authors.forename: Nabeel
authors.initials: N
authors.lastname: Nabulsi
authors.affiliation: PET Center, Diagnostic Radiology, Yale University, New Haven, CT 06520;
authors.forename: Keunpoong
authors.initials: K
authors.lastname: Lim
authors.affiliation: PET Center, Diagnostic Radiology, Yale University, New Haven, CT 06520;
authors.forename: Shu-Fei
authors.initials: SF
authors.lastname: Lin
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT 06511; PET Center, Diagnostic Radiology, Yale University, New Haven, CT 06520;
authors.forename: David
authors.initials: D
authors.lastname: Matuskey
authors.affiliation: Department of Neurology, Yale University, New Haven, CT 06511;
authors.forename: Jae-Yun
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Neurology, Yale University, New Haven, CT 06511;
authors.forename: Kevin C
authors.initials: KC
authors.lastname: O'Connor
authors.affiliation: PET Center, Diagnostic Radiology, Yale University, New Haven, CT 06520;
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: PET Center, Diagnostic Radiology, Yale University, New Haven, CT 06520;
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.affiliation: UCB Pharma, Braine-l'Alleud, Belgium.
authors.forename: Jonas
authors.initials: J
authors.lastname: Hannestad
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT 06511; PET Center, Diagnostic Radiology, Yale University, New Haven, CT 06520; kelly.cosgrove@yale.edu.
authors.forename: Kelly P
authors.initials: KP
authors.lastname: Cosgrove
mesh_terms: D000081:Acetamides / Q000378:metabolism / Q000493:pharmacokinetics; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000276:immunology* / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000378:metabolism / Q000493:pharmacokinetics; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology*; D008297:Male; D017628:Microglia / Q000276:immunology* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D011725:Pyridines / Q000378:metabolism / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000378:metabolism / Q000493:pharmacokinetics; D018079:Receptors, GABA / Q000378:metabolism; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: D000081:Acetamides; D015415:Biomarkers; D002250:Carbon Radioisotopes; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C526798:N-(2-methoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide; D011725:Pyridines; D019275:Radiopharmaceuticals; D018079:Receptors, GABA; C499229:TSPO protein, human
keywords: PBR28; cytokines; endotoxin; microglia; neuroinflammation