Sex, sepsis and the brain: defining the role of sexual dimorphism on neurocognitive outcomes after infection

Abstract

Sexual dimorphisms exist in multiple domains, from learning and memory to neurocognitive disease, and even in the immune system. Male sex has been associated with increased susceptibility to infection, as well as increased risk of adverse outcomes. Sepsis remains a major source of morbidity and mortality globally, and over half of septic patients admitted to intensive care are believed to suffer some degree of sepsis-associated encephalopathy (SAE). In the short term, SAE is associated with an increased risk of in-hospital mortality, and in the long term, has the potential for significant impairment of cognition, memory, and acceleration of neurocognitive disease. Despite increasing information regarding sexual dimorphism in neurologic and immunologic systems, research into these dimorphisms in sepsis-associated encephalopathy remains critically understudied. In this narrative review, we discuss how sex has been associated with brain morphology, chemistry, and disease, sexual dimorphism in immunity, and existing research into the effects of sex on SAE.

Keywords: dementia; neurocognition; neurocognitive disease; sepsis; sepsis-associated encephalopathy; sexual dimorphism.

Figure 1. Sexual dimorphism in brain morphology and neurochemistry.

Several sex-dependent differences in lateralization, brain structure, function, and even neurotransmitter synthesis and concentrations exist between males and females, as depicted here.

Figure 2. Sexual dimorphism and the immune system.

Males are more prone to infections from a variety of pathogens and have a tendency for more severe infections compared with females in epidemiological studies; by contrast, females’ more robust immune response may contribute to the increased prevalence of autoimmune diseases seen in this group. Key distinctions in sex-hormone mediated innate immunity (A), adaptive (B) immunity and both immunoglobulin and cytokine production (C) are believed to drive these differences.

Figure 3. Sexual dimorphism in sepsis-associated encephalopathy.

While studies in humans are lacking, animal models of sepsis-associated encephalopathy show key differences in hippocampal microglial cell activation, differential gene expression (DEGs), and microRNA (miRNA) production.