Neuroinflammation-Induced Downregulation of Hippocampacal Neuregulin 1-ErbB4 Signaling in the Parvalbumin Interneurons Might Contribute to Cognitive Impairment in a Mouse Model of Sepsis-Associated Encephalopathy.

Sepsis-associated encephalopathy (SAE) is a common complication associated with poor prognosis in septic patients, but the underlying mechanism remains unclear. We hypothesized that disturbed neuregulin 1 (NRG1)-ErbB4 signaling in the parvalbumin interneurons was involved in sepsis-induced cognitive impairment in a mouse model of SAE. The SAE model was induced by cecal ligation/perforation (CLP). Animals were randomly divided into the following six groups: sham + vehicle group, sham + NRG1 group, CLP + vehicle group, CLP + NRG1 group, CLP + NRG1 + AG1478 (ErbB4 inhibitor) group, and CLP + minocycline group. Behavioral tests and in vivo electrophysiology were performed at the indicated time points. The brain tissues were harvested to determine the levels of hippocampcal cytokines, IBA1-positive cells, NRG1, ErbB4, and parvalbumin. In the present study, sepsis induced the anxiety-like behavior and hippocampal-dependent cognitive impairment, as reflected by significantly increased distance spent in the open field test and decreased freezing time to context in the fear conditioning test. The abnormal behavioral changes co-occurred with significant increases in hippocampal IBA1-positive cells, IL-1ß and IL-6 levels, and decreased NRG1, ErbB4, parvalbumin expressions, and evoked gamma activity. NRG1 treatment attenuated the sepsis-induced cognitive impairment and the associated biochemical markers, which were abolished by AG1478 administration. Notably, minocycline treatment attenuated neuroinflammation and mimicked the beneficial effects of NRG1 treatment. In summary, we provided additional evidence that the disruption of NRG1-ErbB4 signaling in the parvalbumin interneurons mediated by neuroinflammation might lead to abnormal gamma oscillations and thus contribute to cognitive impairment in a mouse model of SAE.

Disrupted Tryptophan Metabolism Induced Cognitive Impairment in a Mouse Model of Sepsis-associated Encephalopathy.

Sepsis-associated encephalopathy (SAE) is a common complication in critically ill patients and is associated with a poor prognosis. However, the precise mechanisms underlying sepsis-induced cognitive impairment remain largely to be elucidated. The aim of the present study was to investigate whether indoleamine 2, 3-dioxygenase (IDO) activation-mediated neurotoxicity is involved in the pathophysiology of sepsis-induced cognitive impairment. Sepsis was induced by cecal ligation/perforation (CLP). The animals were randomly divided into the following five groups: Sham + vehicle group; Sham + 1-methyl-D, L-tryptophan group; Sham + L-Kynurenine group; CLP + vehicle group; or CLP + 1-methyl-D, L-tryptophan group. The survival rate was estimated by the Kaplan-Meier method. Behavioral tests were performed by the open field and fear conditioning tests at days 13 and 14 after operation. In the present study, we demonstrated that sepsis induced a deficit in hippocampus-dependent cognitive impairment in a mouse model of SAE. Furthermore, a single peripheral kynurenine administration, the metabolic product of IDO, induced a deficit in the cognitive impairment in the sham mice. However, mice treated with IDO inhibitor 1-methyl-D, L-tryptophan were protected from sepsis-induced cognitive impairment. In conclusion, our study implicates IDO-dependent neurotoxic kynurenine metabolism as a critical factor responsible for the sepsis-induced cognitive impairment and a potential novel target for the treatment of SAE.

Characteristics of participants' and caregivers' influence on non-response in a cross-sectional study of dementia in an older population.

OBJECTIVE: The issue of non-response in dementia epidemiological studies, which may result in the underestimation of the prevalence of dementia, has attracted little attention. We aimed to explore the causes and related factors of non-response in a dementia survey among Chinese veterans. METHODS: A two-phase, cross-sectional study investigated the prevalence of dementia and mild cognitive impairment in Chinese veterans aged ≥ 60 years. We collected the socio-demographic data and prior medical history, evaluated the health status of veterans and their caregivers, assessed the cognitive status of veterans, and evaluated the care burden of caregivers by Caregiver Burden Inventory (CBI). RESULTS: Of 9676 eligible participants, 525 (5.4%) veterans in phase 1 and 1706 (35.0%) veterans among 4875 veterans in phase 2 did not respond. Illness, hospitalization and death accounted for 63.0% and 75.5% non-response in phases 1 and 2, respectively. Non-participation in social activities, self-perceived poor health status, worsened health changes, self-reported need for life care, and history of hearing loss or glaucoma independently predicted non-response in phase 1 or 2. The heavy care burden, suggested by the higher CBI scores and self-reported health deterioration of the primary caregivers, predicted non-response in phase 1 or 2. CONCLUSIONS: The negative factors from both the participants and their caregivers independently predicted the non-response in the dementia study in an older population. Preventative strategies from the perspectives of the participants and caregivers should be developed to improve the response rates in both phases in a cross-sectional study.