Cerebral dysfunctions caused by sepsis during ageing

Abstract

Systemic inflammation elicited by sepsis can induce an acute cerebral dysfunction known as sepsis-associated encephalopathy (SAE). Recent evidence suggests that SAE is common but shows a dynamic trajectory over time. Half of all patients with sepsis develop SAE in the intensive care unit, and some survivors present with sustained cognitive impairments for several years after initial sepsis onset. It is not clear why some, but not all, patients develop SAE and also the factors that determine the persistence of SAE. Here, we first summarize the chronic pathology and the dynamic changes in cognitive functions seen after the onset of sepsis. We then outline the cerebral effects of sepsis, such as neuroinflammation, alterations in neuronal synapses and neurovascular changes. We discuss the key factors that might contribute to the development and persistence of SAE in older patients, including premorbid neurodegenerative pathology, side effects of sedatives, renal dysfunction and latent virus reactivation. Finally, we postulate that some of the mechanisms that underpin neuropathology in SAE may also be relevant to delirium and persisting cognitive impairments that are seen in patients with severe COVID-19.

Fig. 1. Long-term trajectory of sepsis and SAE.

a | Long-term sequelae of sepsis. Sepsis causes excessive inflammation (often referred to as a ‘cytokine storm’), and subsequent chronic alterations in the peripheral immune system. Compared with healthy individuals, patients with sepsis show both features of enhanced inflammation and enhanced immunosuppression. For example, there is expansion of myeloid-derived suppressor cell populations and higher plasma levels of C-reactive protein (CRP), IL-6 and IL-8 in patients with sepsis^,. Immunoparalysis is linked to low lymphocyte counts and increased levels of immunosuppressive proteins in plasma with an elevated risk of infections^,. b | Proposed model of dynamic changes seen in cognitive functions following onset of sepsis. Around half of the patients present with delirium and coma in the intensive care unit (ICU)^,, but whereas some survivors show restoration of cognitive functions during the recovery phase, others show persistence of cognitive impairments for 2 years or more after sepsis onset^,–. CNS, central nervous system; SAE, sepsis-associated encephalopathy.

Fig. 2. Proposed pathological mechanisms behind SAE.

a | Blood–brain barrier (BBB) breakdown mediated by microglia during sepsis. Microglia migrate to blood vessels and remove tight junctions in the endothelium following sepsis. This results in the extravasation of dextrans and heparan sulfate fragments into the brain. If the BBB is compromised by a prior pathology such as amyloid pathology, sepsis may induce a more robust increase in BBB permeability, allowing entry of larger fibrinogen molecules along with monocytes and T cells. b | Synaptic pruning by microglia via complement activation. Sepsis can activate the complement pathway and increase production of C3 by astrocytes. Following sepsis, phosphatidylserine (PS) exposure is likely to occur and recruits C1q at synapses, which cleaves C3 to C3a and C3b in the extracellular space^,. In parallel, C3 may accumulate at synapses for as yet unknown mechanisms^,. Following recognition of C3a/C3b (via C3a receptor (C3aR) and complement receptor 3 (CR3))^, and the exposed PS (via TREM2 (refs^,) and GPR56 (ref.)), microglia initiate synaptic pruning. c | Nucleotide binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome activation links sepsis to premorbid neuropathology. Sepsis can activate the NLRP3 inflammasome via pattern recognition receptors (PRRs) and cytokine receptors in the brain via systemic inflammation^,. Because this pathway plays an important role in the pathogenesis of amyloid and tau pathology (via ASC speck formation and kinase activity^,), sepsis may exacerbate the progression of dementia-related neuropathology. Aβ, amyloid-β; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; GPR56, G-protein-coupled receptor 56; SAE, sepsis-associated encephalopathy; TREM2, triggering receptor expressed on myeloid cells 2.

Fig. 3. Mechanisms associated with neurological manifestations in patients with COVID-19.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection can affect functioning of the brain owing to the loss of neuron and neuronal integrity by various possible mechanisms. This includes, but is not restricted to, encephalitis^,,,, vasculopathy or vasculitis^,, effects of systemic inflammation^,, induction of autoimmune reactions^– and peripheral organ dysfunctions^,. How SARS-CoV-2-directed therapies eventually affect brain function and structure also remains to be seen .