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Muscle Injury Induces Postoperative Cognitive Dysfunction.

ABSTRACT: Postoperative cognitive dysfunction (POCD) is a major complication affecting patients of any age undergoing surgery. This syndrome impacts everyday life up to months after hospital discharge, and its pathophysiology still remains unclear. Translational research focusing on POCD is based on a wide variety of rodent models, such as the murine tibial fracture, whose severity can limit mouse locomotion and proper behavioral assessment. Besides, influence of skeletal muscle injury, a lesion encountered in a wide range of surgeries, has not been explored in POCD occurrence. We propose a physical model of muscle injury in CX3CR1GFP/+ mice (displaying green fluorescent microglial cells) to study POCD, with morphological, behavioral and molecular approaches. We highlighted: alteration of short- and long-term memory after muscle regeneration, wide microglial reactivity in the brain, including hippocampus area, 24?hours after muscle injury, and an alteration of central brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) balance, 28 days after muscle injury. Our results suggest for the first time that muscle injury can have early as well as late impacts on the brain. Our CX3CR1GFP/+ model can also facilitate microglial investigation, more specifically their pivotal role in neuroinflammation and synaptic plasticity, in the pathophysiology of POCD.

SUBMITTER: Gueniot L

PROVIDER: S-EPMC7026159 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Muscle Injury Induces Postoperative Cognitive Dysfunction.

Guéniot Lorna L Lepere Victoria V De Medeiros Gabriela Ferreira GF Danckaert Anne A Flamant Patricia P Le Dudal Marine M Langeron Olivier O Goossens Pierre L PL Chrétien Fabrice F Jouvion Grégory G

Scientific reports 20200217 1

Postoperative cognitive dysfunction (POCD) is a major complication affecting patients of any age undergoing surgery. This syndrome impacts everyday life up to months after hospital discharge, and its pathophysiology still remains unclear. Translational research focusing on POCD is based on a wide variety of rodent models, such as the murine tibial fracture, whose severity can limit mouse locomotion and proper behavioral assessment. Besides, influence of skeletal muscle injury, a lesion encounter ...[more]

PMID: 32066806

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Project description:BACKGROUND:Postoperative cognitive dysfunction (POCD) affects a large number of post-surgery patients, especially for the elderly. However, the etiology of this neurocognitive disorder is largely unknown. Even if several studies have reported a small number of miRNAs as the essential modulatory factors in POCD, these findings are still rather limited. The aim of current study was to screen the POCD-related miRNAs in the hippocampus tissues and investigate the target genes of differentially expressed miRNAs and their biological functions underlying POCD pathophysiology. METHODS:The miRNA microarray was used to find the abnormal expression of miRNAs in the hippocampus tissues from the POCD model mice to normal mice (Discovery cohort, 3 vs 3). The nominal significant results were validated in an independent sample of hippocampus tissues of 10 mice based on same miRNA microarray (Replication cohort, 5 vs 5). Expression level of the most significantly abnormal miRNA was further validated by real-time quantitative polymerase chain reaction (PCR). To determine the expression pattern among miRNAs and genes and detect the interactions, we conducted a weighted gene co-expression network analysis (WGCNA) in the miRNAs and genes expression data from hippocampus tissue of wild type mice (n?=?24). The target genes of miRNAs were predicted using the miRWalk3.0 software. Furthermore, we used the ClueGO software to decipher the pathways network and reveal the biological functions of target genes of miRNAs. RESULTS:We found that nine miRNAs showed significant associations with POCD in both datasets. Among these miRNAs, mmu-miR-190a-3p was the most significant one. By performing WGCNA analysis, we found 25 co-expression modules, of which mmu-miR-190a-3p was significantly anti-correlated with red module. Moreover, in the red module, 314 genes were significantly enriched in four pathways such as axon guidance and calcium signaling pathway, which are well-documented to be associated with psychiatric disorders and brain development. Also, 169 of the 314 genes were highly correlated with mmu-miR-190a-3p, and four genes (Sphkap, Arhgef25, Tiam1, and Ntrk3) had putative binding sites at 3'-UTR of mmu-miR-190a-3p. Based on protein-protein network analysis, we detected that Tiam1 was a central gene regulated by the mmu-miR-190a-3p. CONCLUSIONS:Taken together, we conclude that mmu-miR-190a-3p is involved in the etiology of POCD and may serve as a novel predictive indicator for POCD.

Project description:BackgroundMembers of the aging population who undergo surgery are at risk of postoperative cognitive dysfunction (POCD). Exploring an effective and reliable early predictor of POCD is essential to the identification of high-risk patients and to making prospective decisions. The purpose of this study was to examine whether preoperative insulin resistance is an independent predictor of POCD.MethodsA total of 124 patients aged 60 years and older and who were scheduled for gastrointestinal surgery were enrolled in a prospective observational clinical study. All participants completed a battery of neuropsychological tests before surgery and 7 days later. POCD was defined as a decline of at least 1.5 SD on two or more of neuropsychological tests. Plasma concentration of the tumor necrosis factor α (TNF-α), C-reactive protein (CRP), and S-100β protein were measured. The status of insulin resistance was assessed by Homeostasis Model Assessment-Insulin Resistance (HOMA-IR). The relationship between HOMA-IR and POCD was assessed by Multivariable logistic regression models and the receiver operating characteristic (ROC) curve.ResultsFifty one patients (41.1%) were diagnosed with POCD at 7 days after surgery. Preoperative HOMA-IR values of the POCD group were significantly higher than the non-POCD group. Furthermore, CRP and TNF-α levels of the POCD group were significantly higher at each postoperative time point (P < 0.05). The preoperative HOMA-IR value was an independent predictor of POCD (adjusted OR 1.88, 95% CI, 1.18-2.99) even after adjust for confounding variables, and when dichotomized, individuals above the HOMA-IR threshold (HOMA-IR > 2.6) had a three-times higher risk of POCD (OR 3.26; 95% CI, 1.07-9.91) compared to individuals below the threshold. The areas under the ROC curve of HOMA-IR was 0.804 (95% CI, 0.725-0.883; P < 0.001). The optimal cut-off value was found to be 0.583, with a sensitivity of 84.3% and specificity of 74%. The HOMA-IR value was positively associated with the TNF-α concentration at baseline (R 2 = 0.43, P < 0.01) and 1 day after surgery (R 2 = 0.3861, P < 0.01).ConclusionPreoperative insulin resistance is an effective predictor for the occurrence of POCD. Targeted prevention and treatment strategies of insulin resistance may be effective interventions of patients at risk for POCD.

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Muscle Injury Induces Postoperative Cognitive Dysfunction.

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Muscle Injury Induces Postoperative Cognitive Dysfunction.

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