Sepsis-associated encephalopathy(SAE)is a severe neurological syndrome marked by widespread brain dysfunctions due to sepsis,yet the underlying mechanisms remain elusive.The current study,using a Lipopolysaccharide(LP...Sepsis-associated encephalopathy(SAE)is a severe neurological syndrome marked by widespread brain dysfunctions due to sepsis,yet the underlying mechanisms remain elusive.The current study,using a Lipopolysaccharide(LPS)-induced septic rat model,revealed the hyperphosphorylation of tau and cognitive impairments,accompanied by the release of inflammatory cytokines and activation of glial cells in the hippocampal dentate gyrus region of septic rats.Proteomic and bioinformatic analyses identified C-X-C motif chemokine ligand 10(CXCL10)as a central regulator of neuroinflammation.LPS triggered CXCL10 secretion in astrocytes,and astrocyte-conditioned medium from LPS-treated astrocytes induced tau hyperphosphorylation and synaptic deficits.Recombinant CXCL10 recapitulated these effects in vitro and in vivo.Blocking CXCL10–CXCR3 interaction reversed tau phosphorylation,synaptic impairment,and cognitive decline.Mechanistically,CXCL10–CXCR3 interaction activated CaMKII,driving tau hyperphosphorylation,while CaMKII inhibition restored synaptic protein levels.These findings establish CXCL10 as a key driver of tau pathology in SAE and suggest CXCL10–CXCR3 as a therapeutic target for sepsis-induced cognitive impairments.展开更多
BACKGROUND:Although the Confusion Assessment Methods for the Intensive Care Unit(CAMICU) is a recommended tool for diagnosing sepsis-associated encephalopathy(SAE),it has several limitations.Mismatch-negativity(MMN) a...BACKGROUND:Although the Confusion Assessment Methods for the Intensive Care Unit(CAMICU) is a recommended tool for diagnosing sepsis-associated encephalopathy(SAE),it has several limitations.Mismatch-negativity(MMN) and P3a are components of event-related potentials(ERPs) used with electroencephalography(EEG) and are associated with cerebral function changes in critically ill patients.This study aimed to provide a quantitative,non-invasive method to guide SAE diagnosis in nonsedated patients.METHODS:From January 2022 to March 2023,sepsis patients without sedation were enrolled and assessed via the CAM-ICU,Glasgow Coma Scale(GCS),and ERP under standard procedures.Both MMN and P3a data were collected.The diagnostic value of MMN and P3a was assessed with processed ERP data.RESULTS:Thirty-six patients were included in this study,comprising 19 patients with SAE and 17 patients without SAE(NSAE).MMN and P3a amplitudes decreased,and only FzMMN amplitude significantly decreased in SAE patients(2.03 [1.08,2.93] mV vs.3.21 [1.92,4.34] mV,P=0.040).After median dichotomization,low F3P3a and FzP3a amplitudes were associated with higher CAM-ICU positivity rates and APACHE II scores.Both amplitude in F3P3a(AUC=0.710,95%CI:0.527–0.893,P=0.034) and FzP3a(AUC=0.700,95%CI:0.519–0.881,P=0.041) exhibited moderate diagnostic efficacy for SAE,while FzMMN amplitude lacks effective diagnostic value.CONCLUSION:In this pilot study,ERP components F3P3a and FzP3a amplitudes demonstrated moderate diagnostic value for SAE.These exploratory findings require confirmation in larger and powered cohorts.展开更多
基金supported by Grants from the National Natural Science Foundation of China(82330041 and 82201326)the China Postdoctoral Research Foundation(GZC20230898)the Science and Technology Innovation Team Project to Xiaochuan Wang from the Department of Science and Technology of Hubei Province(2022-72-18).
文摘Sepsis-associated encephalopathy(SAE)is a severe neurological syndrome marked by widespread brain dysfunctions due to sepsis,yet the underlying mechanisms remain elusive.The current study,using a Lipopolysaccharide(LPS)-induced septic rat model,revealed the hyperphosphorylation of tau and cognitive impairments,accompanied by the release of inflammatory cytokines and activation of glial cells in the hippocampal dentate gyrus region of septic rats.Proteomic and bioinformatic analyses identified C-X-C motif chemokine ligand 10(CXCL10)as a central regulator of neuroinflammation.LPS triggered CXCL10 secretion in astrocytes,and astrocyte-conditioned medium from LPS-treated astrocytes induced tau hyperphosphorylation and synaptic deficits.Recombinant CXCL10 recapitulated these effects in vitro and in vivo.Blocking CXCL10–CXCR3 interaction reversed tau phosphorylation,synaptic impairment,and cognitive decline.Mechanistically,CXCL10–CXCR3 interaction activated CaMKII,driving tau hyperphosphorylation,while CaMKII inhibition restored synaptic protein levels.These findings establish CXCL10 as a key driver of tau pathology in SAE and suggest CXCL10–CXCR3 as a therapeutic target for sepsis-induced cognitive impairments.
基金supported by the CAMS Innovation Fund for Medical Sciences (CIFMS)(No.2021-1-I2M-020)National High Level Hospital Clinical Research Funding (No.2022-PUMCH-B-109)National Natural Science Foundation of China (82402543)。
文摘BACKGROUND:Although the Confusion Assessment Methods for the Intensive Care Unit(CAMICU) is a recommended tool for diagnosing sepsis-associated encephalopathy(SAE),it has several limitations.Mismatch-negativity(MMN) and P3a are components of event-related potentials(ERPs) used with electroencephalography(EEG) and are associated with cerebral function changes in critically ill patients.This study aimed to provide a quantitative,non-invasive method to guide SAE diagnosis in nonsedated patients.METHODS:From January 2022 to March 2023,sepsis patients without sedation were enrolled and assessed via the CAM-ICU,Glasgow Coma Scale(GCS),and ERP under standard procedures.Both MMN and P3a data were collected.The diagnostic value of MMN and P3a was assessed with processed ERP data.RESULTS:Thirty-six patients were included in this study,comprising 19 patients with SAE and 17 patients without SAE(NSAE).MMN and P3a amplitudes decreased,and only FzMMN amplitude significantly decreased in SAE patients(2.03 [1.08,2.93] mV vs.3.21 [1.92,4.34] mV,P=0.040).After median dichotomization,low F3P3a and FzP3a amplitudes were associated with higher CAM-ICU positivity rates and APACHE II scores.Both amplitude in F3P3a(AUC=0.710,95%CI:0.527–0.893,P=0.034) and FzP3a(AUC=0.700,95%CI:0.519–0.881,P=0.041) exhibited moderate diagnostic efficacy for SAE,while FzMMN amplitude lacks effective diagnostic value.CONCLUSION:In this pilot study,ERP components F3P3a and FzP3a amplitudes demonstrated moderate diagnostic value for SAE.These exploratory findings require confirmation in larger and powered cohorts.
