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.

Keywords: PBR28; cytokines; endotoxin; microglia; neuroinflammation.

Fig. 1.

LPS administration significantly increases [¹¹C]PBR28 binding (V_T) from baseline in healthy control subjects (n = 8) shown in A, regional percent increase in V_T averaged across subjects (error bars are SEM). (B) V_T for each subject averaged across regions examined in high-affinity (squares) and mixed-affinity binders (circles), and (C) average V_T images with the magnetic resonance image (MRI) shown for anatomical reference (Top row). Significance level was *P < 0.01 (linear mixed models) of the difference between baseline and post-LPS challenge scans.

Fig. 2.

LPS administration significantly increased (A) inflammatory cytokine serum levels, (B) sickness symptom levels, and (C) sickness symptoms measured on a visual analog scale (VAS) from baseline levels (t = −10 min). Times are relative to LPS administration at t = 0 min. LPS was administered 180 min before the start of the [¹¹C]PBR28 post-LPS scan. Data shown are the mean (n = 8 subjects) and error bars are SEM.