Decoding sepsis-associated encephalopathy: From blood–brain barrier injury to mechanism-based subphenotypes
Year: 2025
Type: article
Abstract: Sepsis-associated encephalopathy (SAE) is a frequent but underrecognized complication of systemic infection, characterized by acute brain dysfunction and long-term cognitive impairment in the absence of direct central nervous system infection. Despite its high morbidity and mortality, the mechanistic basis of SAE remains poorly defined, limiting early diagnosis and targeted intervention. This review synthesizes recent advances in the molecular and cellular pathophysiology of SAE, with emphasis on blood–brain barrier (BBB) disruption, neuroinflammation, glial cell activation, mitochondrial dysfunction, and neurotransmitter imbalance. We highlight the central role of BBB breakdown in facilitating peripheral-to-central immune signaling, which triggers a cascade of neuroinflammatory and metabolic events that collectively disrupt synaptic homeostasis and neuronal integrity. Emerging evidence also supports the existence of biologically distinct SAE subphenotypes, such as ischemic-hypoxic, inflammatory-dominant, and metabolic-degenerative types—each associated with specific molecular features and clinical outcomes. These insights underscore the need for biomarker-driven patient stratification and mechanism-targeted therapeutic strategies. Future research should prioritize the development of integrated diagnostic platforms, molecular phenotyping tools, and neuroprotective therapies that address the heterogeneous nature of SAE. A refined understanding of its pathogenesis holds promise for transforming the clinical management of SAE and improving long-term neurological recovery in sepsis survivors. • BBB disruption framed as an early driver and sustained amplifier linking systemic inflammation to glial activation, mitochondrial stress, and synaptic failure in SAE. • Mechanism-based subphenotypes defined with pragmatic clinical anchors (ischemic–hypoxic, metabolic–inflammatory, inflammatory-dominant, mixed), each tied to bedside indicators, biomarkers, prognosis, and therapeutic implications. • Fig. 1 , Fig. 2 together translate mechanism to practice: Fig. 1 maps the causal cascade and intervention entry points across BBB injury, neuroinflammation, and mitochondrial dysfunction, while Fig. 2 provides a clinician-facing workflow—tiered acquisition with defined cadence, a phenotype index, decision rules, and trial-relevant endpoints—to operationalize these mechanisms at the bedside. • Clear bridge to clinical translation: guidance on phenotype-enriched enrollment, sedation-aware primary outcomes, BBB integrity readouts, EEG/cytokine/neuronal-injury markers, and 90-day cognition.
Source: Brain Research Bulletin
Authors: Qin Song, Bo Song
Institution: Yantaishan Hospital
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,280
OpenAlex ID: W4416767863