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Cited by 191Intensive Care Unit Cognitive DisordersSepsis Diagnosis and TreatmentBacterial Infections and Vaccines

Cerebral dysfunctions caused by sepsis during ageing

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Manabe, Tatsuya, Heneka, Michael T.·2022·Nature Reviews Immunology
DOI 10.1038/s41577-021-00643-7PMC PMC8582341
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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.

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  • Bacterial sepsis is linked to systemic inflammation, mainly through LPS engagement with Toll-like receptors (TLR), which may result in acute brain dysfunction, particularly in older patients.

    “Bacterial sepsis is linked to systemic inflammation, mainly through LPS engagement with Toll-like receptors (TLR), which may result in acute brain dysfunction, particularly in older patients [100].”

    From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [100]

    The ‘Acute phase of sepsis’ section describes inflammation through innate immune receptors, and ‘Immediate neuroinflammation’ says circulating LPS can activate TLR2 and TLR4, contributing to brain inflammation. The paper also reports acute cerebral dysfunction after sepsis and heightened responses with ageing. It does not establish that LPS–TLR engagement is the main route of systemic inflammation; it describes other triggers and pathways as well. Page numbers were not available in our copy. (LLM, conf=0.86)

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References 237 · Cited by 191

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Authors
Manabe, T., & Heneka, M. T.
Affiliations
University of Bonn (DE)
Corresponding author
Heneka, Michael T.
ORCID
Venue
Nature Reviews Immunology
Publisher
Springer Science and Business Media LLC
Published
2021-11-11
Volume
22
Issue
7
Pages
444-458
ISSN
  • 1474-1733 (ISSN-L)
  • 1474-1741
DOI
10.1038/s41577-021-00643-7
PMC
PMC8582341
OpenAlex
W3214216551
Cited by
191
References
237
Citations by year
2026: 32 · 2025: 64 · 2024: 37 · 2023: 39 · 2022: 19
FWCI
5.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature reviews. Immunology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Open Repository and Bibliography (University of Luxembourg) (submittedVersion)
  • DZNE Pub (submittedVersion)
Funders
Deutsche Forschungsgemeinschaft
Topics
  • Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Intensive Care Unit Cognitive Disorders
  • Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
  • Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
Keywords
sepsis-associated encephalopathy, sepsis, aging, systemic inflammation, neuroinflammation, cognitive impairment, delirium, COVID-19 pandemic, neurodegenerative diseases, sedative side effects, renal dysfunction, latent virus reactivation, neurovascular dysfunction, intensive care
MeSH terms
COVID-19, Aged, Aging, Brain Diseases, Humans, Sepsis, Sepsis-Associated Encephalopathy

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