Current Understanding of Long-Term Cognitive Impairment After Sepsis

Abstract

Sepsis is recognized as a life-threatening multi-organ dysfunction resulting from a dysregulated host response to infection. Although the incidence and mortality of sepsis decrease significantly due to timely implementation of anti-infective and support therapies, accumulating evidence suggests that a great proportion of survivors suffer from long-term cognitive impairment after hospital discharge, leading to decreased life quality and substantial caregiving burdens for family members. Several mechanisms have been proposed for long-term cognitive impairment after sepsis, which are not mutually exclusive, including blood-brain barrier disruption, neuroinflammation, neurotransmitter dysfunction, and neuronal loss. Targeting these critical processes might be effective in preventing and treating long-term cognitive impairment. However, future in-depth studies are required to facilitate preventive and/or treatment strategies for long-term cognitive impairment after sepsis.

Keywords: BBB dysregulation; cognitive impairment; neuroinflammation; neuronal loss; neurotransmitter dysfunction; sepsis.

Figure 1

Neurotransmitter dysfunction mechanism underlying long-term cognitive impairment after sepsis. After sepsis, the AChE is activated and the ACh level is thus decreased. Meanwhile the cholinergic innervation is inhibited, as reflected by reduction of VAChT. The α7nAChRs are also downregulated. The suppression of ACh function is associated with cognitive impairment following sepsis. PV⁺ interneurons are activated after sepsis resulting in cognitive impairment. The activated microglia secret more glutamate while the damaged astrocytes reuptake less glutamate, causing excitotoxicity to the brain and cognitive impairment. The level of dopamine is decreased and the receptors are inhibited by sepsis, which is involved in cognitive impairment. The LC is the only source of NE in the brain. NE level decreases in response to sepsis, which contributes to cognitive impairment. AChE, acetylcholinesterase; ACh, acetylcholine; VAChT, vesicular acetylcholine transporter; α7nAChR, α7-nicotinic acetylcholine receptor; GABA, Gamma-aminobutyric acid; GABA_A, GABA A receptor; PV, parvalbumin; DRD1, dopamine receptor D1; DRD4, dopamine receptor D4; LC, locus coeruleus; NE, norepinephrine.

Figure 2

Mechanisms of neuronal loss in sepsis. During sepsis, the AKT/mTOR pathway is activated and inhibits the normal autophagy process in neurons, leading to autophagic neuronal death. Suppression of SIRT1 by LPS activates NF-κB and FOXO1, triggering neuron apoptosis. Inflammasome generated in sepsis activates casepase-1 while LPS activates casepase-4/5/11, both of which promotes the generation of GSDMD. Cleavage of GSDMD produces GSDMD-NT which forms membrane pores and lead to neuronal pyroptosis. LPS, lipopolysaccharides; mTOR, mammalian/mechanistic target of rapamycin; LC3, SIRT1, silent information regulator 1; FOXO1, forkhead box protein O1; GSDMD, gasdermin D; GSDMD-NT, GSDMD-N-terminal products.

Figure 3

Mechanisms of long –term cognitive impairment after sepsis. Blood brain barrier is composed of endothelial cells, astrocytes and pericytes. These cells are connected by tight junctions, adherens junctions and gap junctions. Dysfunction of these components leads to increased permeability of BBB in response to sepsis, which facilitates long-term cognitive impairment. Microglia and astrocyte are over-activated mainly through the activation of NF-κB signaling when PAMPs and DAMPs including LPS by binding to their ligands (namely, TLRs) on cell membrane. Pro-inflammatory cytokines are subsequently over-produced while anti-inflammatory cytokines are down-regulated. Neuroinflammation further leads to cognitive impairment. Overproduction of ROS is medicated by NOX2 in activated microglia and astrocytes. Neuronal loss is common in sepsis. Apoptosis, autophagy, and pyroptosis are involved in the modulation of neuronal death. Finally, dysregulation of neurotransmitters including ACh, GABA, glutamate, dopamine and NE also contributes to cognitive impairment in sepsis. BBB, blood brain barrier; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; LPS, lipopolysaccharide; TLRs, toll like receptors; ROS, reactive oxidative species; NOX2, NADPH oxidase 2; ACh, acetylcholine; GABA, Gamma-aminobutyric acid; NE, norepinephrine.