Acute neuroimmune stimulation impairs verbal memory in adults: A PET brain imaging study

Highlights

• LPS increased whole-brain TSPO availability, indicative of a neuroimmune response.

• LPS impaired verbal memory but not psychomotor, attention, or executive processes.

• The TSPO increase in the hippocampus correlated with the decrement in verbal memory.

• Hippocampal memory processes may be sensitive to neuroimmune stimulation.

Abstract

Psychiatric and neurologic disorders are often characterized by both neuroinflammation and cognitive dysfunction. To date, however, the relationship between neuroinflammation and cognitive dysfunction remains understudied in humans. Preclinical research indicates that experimental induction of neuroinflammation reliably impairs memory processes. In this paradigm development study, we translated those robust preclinical findings to humans using positron emission tomography (PET) imaging with [¹¹C]PBR28, a marker of microglia, and lipopolysaccharide (LPS), a potent neuroimmune stimulus. In a sample of 18 healthy adults, we extended our previous findings that LPS administration increased whole-brain [¹¹C]PBR28 availability by 31–50%, demonstrating a robust neuroimmune response (Cohen’s ds > 1.6). We now show that LPS specifically impaired verbal learning and recall, hippocampal memory processes, by 11% and 22%, respectively (Cohen’s ds > 0.9), but did not alter attention, motor, or executive processes. The LPS-induced increase in [¹¹C]PBR28 binding was correlated with significantly greater decrements in verbal learning performance in the hippocampus (r = −0.52, p = .028), putamen (r = −0.50, p = .04), and thalamus (r = −0.55, p = .02). This experimental paradigm may be useful in investigating mechanistic relationships between neuroinflammatory signaling and cognitive dysfunction in psychiatric and neurologic disorders. It may also provide a direct approach to evaluate medications designed to rescue cognitive deficits associated with neuroinflammatory dysfunction.

Introduction

Aberrant neuroimmune signaling is implicated in cognitive dysfunction that is characteristic of both neurologic (e.g., Alzheimer’s disease) and psychiatric (e.g., major depression) disorders (McAfoose and Baune, 2009). However, these relationships are complex and clinical investigations conducted to date have been limited, perhaps due to the absence of human experimental models. Lipopolysaccharide (LPS) administration produces a robust proinflammatory response, which can be quantified using positron emission tomography (PET) imaging with [¹¹C]PBR28, a radiotracer that binds the 18 kDa translocator protein (TSPO), a marker found primarily in microglia, but also present in endothelial cells, neurons, and astrocytes (Hannestad et al., 2012, Hillmer et al., 2017, Sandiego et al., 2015, Tournier et al., 2019). LPS administration increases proinflammatory cytokine/chemokine levels (Sandiego et al., 2015), upregulates brain TSPO availability (Hannestad et al., 2012, Sandiego et al., 2015), and activates microglia (Hannestad et al., 2012, Tournier et al., 2019). Using fluorescence-activated cell sorting and TSPO imaging, Tournier and colleagues showed that the cellular source of LPS-induced TSPO increase was microglial proliferation and that TSPO binding did not change in neurons, astrocytes, or endothelial cells after LPS (Tournier et al., 2019). Whereas LPS-induced neuroimmune stimulation reliably impairs cognitive function in animals, especially hippocampal memory processes (Jo et al., 2001); the extent to which these brain-behavior relationships translate to humans is not known.

To address this gap, we developed an experimental paradigm to determine the effect of proinflammatory signaling, induced by systemic LPS administration, on cognitive function and TSPO availability in healthy adults. In this paradigm, the magnitude of LPS-induced neuroimmune stimulation was quantified via brain PET TPSO imaging with [¹¹C]PBR28. This within-subject, repeated-measures design facilitated quantification of the main effects of LPS on cognitive function and regional TSPO availability, as well as examination of correlations between the change in cognitive performance and regional TSPO availability. For each cognitive domain affected by LPS, follow-up brain-behavior correlation analyses investigated the relationship between the magnitude change in cognitive performance and TSPO availability in the brain region/s thought to underly that cognitive domain.