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Background: Spouses of Alzheimer's disease (AD) patients are at a higher risk of developing incidental dementia. However, the causes and underlying mechanism of this clinical observation remain largely unknown. One possible explanation is linked to microbiota dysbiosis, a condition that has been associated with AD. However, it remains unclear whether gut microbiota dysbiosis can be transmitted from AD individuals to non‐AD individuals and contribute to the development of AD pathogenesis and cognitive impairment. Method: We, therefore, set out to perform both animal studies and clinical investigation by co‐housing wild‐type mice and AD transgenic mice, analyzing microbiota via 16S rRNA gene sequencing, measuring short‐chain fatty acid amounts, and employing behavioral test, mass spectrometry, site‐mutations and other methods. Result: The present study revealed that co‐housing between wildtype mice and AD transgenic mice or administrating feces of AD transgenic mice to wild‐type mice resulted in AD‐associated gut microbiota dysbiosis, Tau phosphorylation, and cognitive impairment in the wild‐type mice. Gavage with Lactobacillus and Bifidobacterium restored these changes in the wild‐type mice. The oral and gut microbiota of AD patient partners resembled that of AD patients but differed from healthy controls, indicating the transmission of microbiota. The underlying mechanism of these findings includes that the butyric acid‐mediated acetylation of GSK3β at lysine 15 regulated its phosphorylation at serine 9, consequently impacting Tau phosphorylation. Conclusion: This initial proof‐of‐concept study demonstrated the potential transmission of microbiota from AD patients or ADTg mice to non‐AD controls or WT mice housed together. This transmission may contribute to the development of AD‐associated microbiota dysbiosis and metabolite alterations, ultimately leading to AD pathogenesis and cognitive impairment. However, these findings should be validated in future studies. The results of this study are expected to drive further research to explore gut microbiota dysbiosis and its connection to AD in both preclinical and clinical contexts. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Tau phosphorylated at threonine‐217 (pT217‐tau) is a novel fluid‐based biomarker that predicts onset of Alzheimer's disease (AD) symptoms, but little is known about how pT217‐tau arises in the brain, as soluble pT217‐tau is dephosphorylated post mortem in humans. METHODS: We used multilabel immunofluorescence and immunoelectron microscopy to examine the subcellular localization of early‐stage pT217‐tau in entorhinal and prefrontal cortices of aged macaques with naturally occurring tau pathology and assayed pT217‐tau levels in plasma. RESULTS: pT217‐tau was aggregated on microtubules within dendrites exhibiting early signs of degeneration, including autophagic vacuoles. It was also seen trafficking between excitatory neurons within synapses on spines, where it was exposed to the extracellular space, and thus accessible to cerebrospinal fluid (CSF)/blood. Plasma pT217‐tau levels increased across the age span and thus can serve as a biomarker in macaques. DISCUSSION: These data help to explain why pT217‐tau predicts degeneration in AD and how it gains access to CSF and plasma to serve as a fluid biomarker. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Anesthesia often exacerbates memory recall difficulties in individuals with Alzheimer's disease (AD), but the underlying mechanisms remain unclear. METHODS: We used in vivo Ca2+ imaging, viral‐based circuit tracing, and chemogenetic approaches to investigate anesthesia‐induced remote memory impairment in mouse models of presymptomatic AD. RESULTS: Our study identified pyramidal neuron hyperactivity in the anterior cingulate cortex (ACC) as a significant contributor to anesthesia‐induced remote memory impairment. This ACC hyperactivation arises from the disinhibition of local inhibitory circuits and increased excitatory inputs from the hippocampal CA1 region. Inhibiting hyperactivity in the CA1‐ACC circuit improved memory recall after anesthesia. Moreover, anesthesia led to increased tau phosphorylation in the hippocampus, and inhibiting this hyperphosphorylation prevented ACC hyperactivity and subsequent memory impairment. DISCUSSION: Hippocampal‐cortical hyperactivity plays a role in anesthesia‐induced remote memory impairment. Targeting tau hyperphosphorylation shows promise as a therapeutic strategy to mitigate anesthesia‐induced neural network dysfunction and retrograde amnesia in AD. [ABSTRACT FROM AUTHOR]

Introduction: Current approaches for treating sporadic Alzheimer's disease (sAD) focus on removal of amyloid beta 1‐42 (Aβ1‐42) or phosphorylated tau, but additional strategies are needed to reduce neuropathology at earlier stages prior to neuronal damage. Longstanding data show that calcium dysregulation is a key etiological factor in sAD, and the cortical neurons most vulnerable to tau pathology show magnified calcium signaling, for example in dorsolateral prefrontal cortex (dlPFC) and entorhinal cortex (ERC). In primate dlPFC and ERC, type 3 metabotropic glutamate receptors (mGluR3s) are predominately post‐synaptic, on spines, where they regulate cAMP‐calcium signaling, a process eroded by inflammatory glutamate carboxypeptidase II (GCPII) actions. The current study tested whether enhancing mGluR3 regulation of calcium via chronic inhibition of GCPII would reduce tau hyperphosphorylation in aged macaques with naturally‐occurring tau pathology. Methods: Aged rhesus macaques were treated daily with the GCPII inhibitor, 2‐MPPA (2‐3‐mercaptopropyl‐penanedioic acid (2‐MPPA)), Aged rhesus macaques were treated daily with the GCPII inhibitor, 2‐MPPA (2‐3‐mercaptopropyl‐penanedioic acid (2‐MPPA)), Results: Aged macaques that received 2‐MPPA had significantly lower pT217Tau levels in dlPFC and ERC, and had lowered plasma pT217Tau levels from baseline. pT217Tau levels correlated significantly with GCPII activity in dlPFC. Both 2‐MPPA‐ and vehicle‐treated monkeys showed cognitive improvement; 2‐MPPA had no apparent side effects. Exploratory CSF analyses indicated reduced pS202Tau with 2‐MPPA administration, confirmed in dlPFC samples. Discussion: These data provide proof‐of‐concept support that GCPII inhibition can reduce tau hyperphosphorylation in the primate cortices most vulnerable in sAD. GCPII inhibition may be particularly helpful in reducing the risk of sAD caused by inflammation. These data in nonhuman primates should encourage future research on this promising mechanism. Highlights: Inflammation is a key driver of sporadic Alzheimer's disease.GCPII inflammatory signaling in brain decreases mGluR3 regulation of calcium.Chronic inhibition of GCPII inflammatory signaling reduced pT217Tau in aged monkeys.GCPII inhibition is a novel strategy to help prevent tau pathology at early stages. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Blood phosphorylated tau at threonine 217 (tau‐PT217) is a newly established biomarker for Alzheimer's disease and postoperative delirium in patients. However, the mechanisms and consequences of acute changes in blood tau‐PT217 remain largely unknown. METHODS: We investigated the effects of anesthesia/surgery on blood tau‐PT217 in aged mice, and evaluated the associated changes in B cell populations, neuronal excitability in anterior cingulate cortex, and delirium‐like behavior using positron emission tomography imaging, nanoneedle technology, flow cytometry, electrophysiology, and behavioral tests. RESULTS: Anesthesia/surgery induced acute increases in blood tau‐PT217 via enhanced generation in the lungs and release from B cells. Tau‐PT217 might cross the blood–brain barrier, increasing neuronal excitability and inducing delirium‐like behavior. B cell transfer and WS635, a mitochondrial function enhancer, mitigated the anesthesia/surgery‐induced changes. DISCUSSION: Acute increases in blood tau‐PT217 may contribute to brain dysfunction and postoperative delirium. Targeting B cells or mitochondrial function may have therapeutic potential for preventing or treating these conditions. [ABSTRACT FROM AUTHOR]

Delirium is a common, morbid, and costly syndrome that is closely linked to Alzheimer's disease (AD) and AD‐related dementias (ADRD) as a risk factor and outcome. Human studies of delirium have advanced our knowledge of delirium incidence and prevalence, risk factors, biomarkers, outcomes, prevention, and management. However, understanding of delirium neurobiology remains limited. Preclinical and translational models for delirium, while challenging to develop, could advance our knowledge of delirium neurobiology and inform the development of new prevention and treatment approaches. We discuss the use of preclinical and translational animal models in delirium, focusing on (1) a review of current animal models, (2) challenges and strategies for replicating elements of human delirium in animals, and (3) the utility of biofluid, neurophysiology, and neuroimaging translational markers in animals. We conclude with recommendations for the development and validation of preclinical and translational models for delirium, with the goal of advancing awareness in this important field. [ABSTRACT FROM AUTHOR]

Perioperative neurocognitive disorder may develop in vulnerable patients following major operation. While neuroinflammation is linked to the cognitive effects of surgery, how surgery and immune signaling modulate neuronal circuits, leading to learning and memory impairment remains unknown. Using in vivo two‐photon microscopy, Ca2+ activity and postsynaptic dendritic spines of layer 5 pyramidal neurons in the primary motor cortex of a mouse model of thoracic surgery are imaged. It is found that surgery causes neuronal hypoactivity, impairments in learning‐dependent dendritic spine formation, and deficits in multiple learning tasks. These neuronal and synaptic alterations in the cortex are mediated by peripheral monocytes through the NLRP3 inflammasome‐dependent IL‐1β production. Depleting peripheral monocytes or inactivating NLRP3 inflammasomes before surgery reduces levels of IL‐1β and ameliorates neuronal and behavioral deficits in mice. Furthermore, adoptive transfer of IL‐1β‐producing myeloid cells from mice undertaking thoracic surgery is sufficient to induce neuronal and behavioral deficits in naïve mice. Together, these findings suggest that surgery leads to excessive NLRP3 activation in monocytes and elevated IL‐1β signaling, which in turn causes neuronal hypoactivity and perioperative neurocognitive disorder. [ABSTRACT FROM AUTHOR]

Delirium is the most common postoperative complication in older patients after prolonged anesthesia and surgery and is associated with accelerated cognitive decline and dementia. The neuronal pathogenesis of postoperative delirium is largely unknown. The unfolded protein response (UPR) is an adaptive reaction of cells to perturbations in endoplasmic reticulum function. Dysregulation of UPR has been implicated in a variety of diseases including Alzheimer's disease and related dementias. However, whether UPR plays a role in anesthesia‐induced cognitive impairment remains unexplored. By performing in vivo calcium imaging in the mouse frontal cortex, we showed that exposure of aged mice to the inhalational anesthetic sevoflurane for 2 hours resulted in a marked elevation of neuronal activity during recovery, which lasted for at least 24 hours after the end of exposure. Concomitantly, sevoflurane anesthesia caused a prolonged increase in phosphorylation of PERK and eIF2α, the markers of UPR activation. Genetic deletion or pharmacological inhibition of PERK prevented neuronal hyperactivity and memory impairment induced by sevoflurane. Moreover, we showed that PERK suppression also reversed various molecular and synaptic changes induced by sevoflurane anesthesia, including alterations of synaptic NMDA receptors, tau protein phosphorylation, and dendritic spine loss. Together, these findings suggest that sevoflurane anesthesia causes abnormal UPR in the aged brain, which contributes to neuronal hyperactivity, synapse loss and cognitive decline in aged mice. [ABSTRACT FROM AUTHOR]

Generation of circulating tumor cells (CTCs), a key step in tumor metastasis, occurs during surgical tumor resection, often performed under general anesthesia. Propofol is the commonly used anesthetic, but its effects on CTCs and tumor metastasis remain largely unknown. Propofol effects are investigated in an experimental metastasis model by injecting tumor cells and, subsequently, low‐ or standard‐dose propofol to nude mice through tail vein. Propofol‐ or vehicle‐treated tumor cells are also injected to the mice. An in vitro tumor cell–vascular endothelial cell adhesion assay, immunofluorescence, and other methods are employed to assess how propofol affects tumor cell adhesion and extension. Propofol induces more lung tumor metastasis in mice than control. Mechanistically, propofol enhances tumor cell adhesion and extension through GABAAR to downregulate TRIM21 expression, leading to upregulation of Src, a protein associated with cell adhesion. These results demonstrate that propofol may promote tumor metastasis through GABAAR–TRIM21–Src mechanism. [ABSTRACT FROM AUTHOR]

Background: Delirium is the most common postoperative complication in senior patients and is associated with accelerated cognitive decline and Alzheimer's disease and related dementia (ADRD). However, the neuropathogenesis of POD remains mostly unknown and no effective medication to prevent or treat POD. Gut microbiota dysbiosis, a condition of microbiota imbalance or maladaptation inside the gut, which could lead to altered immune functions and associated with disorders of POD. Aging and neuroinflammation may also contribute to the neuropathogenesis of POD. However, while all patients may have neuroinflammation, not all patients develop POD. Thus, neuroinflammation alone (single‐factor model of postoperative delirium) is not sufficient to cause POD. Therefore, the objective of the current study was to test the hypothesis that anesthesia/surgery causes age‐dependent gut microbiota dysbiosis, changes in brain IL‐6 level, and mitochondrial function, leading to postoperative delirium‐like behavior in mice. Method: Female 9 or 18 months old mice received abdominal surgery under 1.4% isoflurane for two hours. We employed a battery of natural and learned behavioral tests to determine the delirium‐like behavior, assessed the gut microbiota before and after the anesthesia/surgery by gene pyrosequencing of 16S rRNA, and measured levels of brain IL‐6(ELISA), synaptic marker(Western blot) and mitochondrial function (Seahorse XFp Extracellular Flux Analyzer) as measures of neuroinflammation and cerebral dysfunction. For intervention, intragastric administration of lactobacillus and probiotic were used to mitigate the anesthesia/surgery‐induced above changes. Result: Anesthesia/surgery caused different alterations in gut microbiota, including change rate of reduction in the levels of gut lactobacillus, between the 18 and 9 months old mice. The anesthesia/surgery induced greater postoperative delirium‐like behavior, increased brain IL‐6 levels, decreased PSD‐95 and synaptophysin levels, and mitochondrial dysfunction in 18 than 9 months old mice. Treatments with lactobacillus and probiotic mitigated the anesthesia/surgery‐induced changes. Conclusion: We demonstrated that anesthesia/surgery induces age‐dependent changes in the gut microbiota(reduction in lactobacillus), increases brain levels of IL‐6, decreases levels of synaptic marker, and reduces mitochondrial function while also promoting the development of postoperative delirium‐like behaviors in the mice. Treatment with lactobacillus or probiotic mitigated these detrimental effects, strongly suggesting that abnormalities in the gut microbiota contribute to the development of postoperative delirium. [ABSTRACT FROM AUTHOR]

Introduction: Apolipoprotein E (APOE) status may modify the risk of postoperative delirium conferred by inflammation. Methods: We tested whether APOE modifies the established association between C‐reactive protein (CRP) and delirium incidence, severity, and duration in 553 noncardiac surgical patients aged 70 and older. High postoperative plasma CRP (≥234.12 mg/L) was defined by the highest sample‐based quartile. Delirium was determined using the Confusion Assessment Method and chart review, and severity was determined by the Confusion Assessment Method—Severity score. Results: APOE ε4 carrier prevalence was 19%, and postoperative delirium occurred in 24%. The relationship between CRP and delirium incidence, severity, and duration differed by ε4 status. Among ε4 carriers, there was a strong relationship between high CRP (vs. low CRP) and delirium incidence (relative risk [95% confidence interval], 3.0 [1.4–6.7]); however, no significant association was observed among non‐ε4 carriers (relative risk [95% CI], 1.2 [0.8–1.7]). Discussion: Our findings raise the possibility that APOE ε4 carrier status may modify the relationship between postoperative day 2 CRP levels and postoperative delirium. [ABSTRACT FROM AUTHOR]

Background: Postoperative neurocognitive disorder (PND) is a severe postoperative complication with no effective therapy that affects up to 19–52% of senior patients. Age and surgery type have been identified as risk factors. However, what caused the increased risk in the elderly is poorly understood. Methods: We utilized a PND model in aged mice undergoing experimental laparotomy with general anesthesia to evaluate the causal relationship between hyperhomocysteinemia and increased PND susceptibility. PND was assessed by Novel Object Tasks, Fear Conditioning Tests, and Barnes Maze Tests. Serum homocysteine (Hcy) as well as vitamin B12 and folate acid levels were tested before, immediately after surgery and from day 1 to day 29 after surgery by ELISA. The effectiveness of preventative strategy including diet supplementation of vitamin B12 + folic acid (Vit B12 + FA) and S‐adenosylmethionine (SAM) injection targeting hyperhomocysteinemia were also tested. Results: PND in aged mice lasted for at least 2 weeks after experimental laparotomy, which was not observed in young adult mice. Serum Hcy results indicated a significant correlation between postoperative cognitive performance and perioperative Hcy level. Preoperative supplementation with VB12 and folic acid (FA) in the diet or S‐adenosylmethionine (SAM) injection reduced perioperative serum Hcy level and inhibited the development of PND in aged mice. Conclusions: Serum homocysteine accumulation is a fundamental cause for increased susceptibility of PND in aged mice. Preoperative diet supplementation of VitB12 + FA can effectively reduce PND in aged mice, which may be a promising prophylaxis treatment in clinical settings. [ABSTRACT FROM AUTHOR]

Objective The neuropathogenesis of postoperative delirium remains unknown. Low cerebrospinal fluid ( CSF) β-amyloid protein (A β) and high CSF Tau levels are associated with Alzheimer's disease. We, therefore, assessed whether lower preoperative CSF A β/Tau ratio was associated with higher incidence and greater severity of postoperative delirium. Methods One hundred and fifty-three participants (71 ± 5 years, 53% men) who had total hip/knee replacement under spinal anesthesia were enrolled. CSF was obtained during initiation of spinal anesthesia. The incidence and severity of postoperative delirium were determined by Confusion Assessment Method ( CAM) and Memorial Delirium Assessment Scale ( MDAS) on postoperative day 1 and 2. A β40, A β42, and Tau levels in the CSF were measured by enzyme-linked immunosorbent assay. The relationships among these variables were determined, adjusting for age and gender. Results Participants in the lowest quartile of preoperative CSF A β40/Tau and A β42/Tau ratio had higher incidence (32% vs. 17%, P = 0.0482) and greater symptom severity of postoperative delirium (A β40/Tau ratio: 4 vs. 3, P = 0.034; A β42/Tau ratio: 4 vs. 3, P = 0.062, the median of the highest MDAS score) as compared to the combination of the rest of the quartiles. The preoperative CSF A β40/Tau or A β42/Tau ratio was inversely associated with MDAS score (A β40/Tau ratio: −0.12 ± 0.05, P = 0.014, adj. −0.12 ± 0.05, P = 0.018; A β42/Tau ratio: −0.65 ± 0.26, P = 0.013, adj. −0.62 ± 0.27, P = 0.022). Interpretation Lower CSF A β/Tau ratio could be associated with postoperative delirium, pending confirmation of our preliminary results in further studies. These findings suggest potential roles of A β and/or Tau in postoperative delirium neuropathogenesis. [ABSTRACT FROM AUTHOR]

Objective: There are approximately 8.5 million Alzheimer disease (AD) patients who need anesthesia and surgery care every year. The inhalation anesthetic isoflurane, but not desflurane, has been shown to induce caspase activation and apoptosis, which are part of AD neuropathogenesis, through the mitochondria-dependent apoptosis pathway. However, the in vivo relevance, underlying mechanisms, and functional consequences of these findings remain largely to be determined. Methods: We therefore set out to assess the effects of isoflurane and desflurane on mitochondrial function, cytotoxicity, learning, and memory using flow cytometry, confocal microscopy, Western blot analysis, immunocytochemistry, and the fear conditioning test. Results: Here we show that isoflurane, but not desflurane, induces opening of mitochondrial permeability transition pore (mPTP), increase in levels of reactive oxygen species, reduction in levels of mitochondrial membrane potential and adenosine-5′-triphosphate, activation of caspase 3, and impairment of learning and memory in cultured cells, mouse hippocampus neurons, mouse hippocampus, and mice. Moreover, cyclosporine A, a blocker of mPTP opening, attenuates isoflurane-induced mPTP opening, caspase 3 activation, and impairment of learning and memory. Finally, isoflurane may induce the opening of mPTP via increasing levels of reactive oxygen species. Interpretation: These findings suggest that desflurane could be a safer anesthetic for AD patients as compared to isoflurane, and elucidate the potential mitochondria-associated underlying mechanisms, and therefore have implications for use of anesthetics in AD patients, pending human study confirmation. ANN NEUROL 2012; [ABSTRACT FROM AUTHOR]

Objective An estimated 200 million patients worldwide have surgery each year. Anesthesia and surgery have been reported to facilitate emergence of Alzheimer's disease. The commonly used inhalation anesthetic isoflurane has previously been reported to induce apoptosis, and to increase levels and aggregation of Alzheimer's disease-associated amyloid β-protein (Aβ) in cultured cells. However, the in vivo relevance has not been addressed. Methods We therefore set out to determine effects of isoflurane on caspase activation and levels of β-site amyloid precursor protein-cleaving enzyme (BACE) and Aβ in naive mice, using Western blot, immunohistochemistry, and reverse transcriptase polymerase chain reaction. Results Here we show for the first time that a clinically relevant isoflurane anesthesia (1.4% isoflurane for 2 hours) leads to caspase activation and modest increases in levels of BACE 6 hours after anesthesia in mouse brain. Isoflurane anesthesia induces caspase activation, and increases levels of BACE and Aβ up to 24 hours after anesthesia. Isoflurane may increase BACE levels by reducing BACE degradation. Moreover, the Aβ aggregation inhibitor, clioquinol, was able to attenuate isoflurane-induced caspase-3 activation in vivo. Interpretation Given that transient insults to brain may lead to long-term brain damage, these findings suggest that isoflurane may promote Alzheimer's disease neuropathogenesis and, as such, have implications for use of isoflurane in humans, pending human study confirmation. Ann Neurol 2008 [ABSTRACT FROM AUTHOR]

Objective: An estimated 200 million patients worldwide have surgery each year. Anesthesia and surgery have been reported to facilitate emergence of Alzheimer's disease. The commonly used inhalation anesthetic isoflurane has previously been reported to induce apoptosis, and to increase levels and aggregation of Alzheimer's disease-associated amyloid beta-protein (Abeta) in cultured cells. However, the in vivo relevance has not been addressed.Methods: We therefore set out to determine effects of isoflurane on caspase activation and levels of beta-site amyloid precursor protein-cleaving enzyme (BACE) and Abeta in naive mice, using Western blot, immunohistochemistry, and reverse transcriptase polymerase chain reaction.Results: Here we show for the first time that a clinically relevant isoflurane anesthesia (1.4% isoflurane for 2 hours) leads to caspase activation and modest increases in levels of BACE 6 hours after anesthesia in mouse brain. Isoflurane anesthesia induces caspase activation, and increases levels of BACE and Abeta up to 24 hours after anesthesia. Isoflurane may increase BACE levels by reducing BACE degradation. Moreover, the Abeta aggregation inhibitor, clioquinol, was able to attenuate isoflurane-induced caspase-3 activation in vivo.Interpretation: Given that transient insults to brain may lead to long-term brain damage, these findings suggest that isoflurane may promote Alzheimer's disease neuropathogenesis and, as such, have implications for use of isoflurane in humans, pending human study confirmation. [ABSTRACT FROM AUTHOR]

Background: Isoflurane, sevoflurane, and desflurane have been shown to have different neurotoxic effects. However, the underlying mechanism at the single molecular level remains unknown. Isoflurane, sevoflurane, and desflurane can differently induce mitochondrial dysfunction and ATP synthase is the critical component of mitochondrial function. We, therefore, set out to assess whether different anesthetics can selectively impair the interaction of ADP and ATP synthase at a single molecular level. Method: The human H4‐APP cells were treated with 2% isoflurane, 4% sevoflurane, or 12% desflurane for 6 hours. The mitochondrial function was measured by using a Seahorse XFp Extracellular Flux Analyzer. Next, we employed a nanobeam technology‐based single molecular dynamic interaction detection method to determine the interaction of ADP and ATP synthase following the administration of isoflurane, sevoflurane, and desflurane. Each of resonance shifts, detected by a nanosensor, corresponded to single molecular interaction of ADP and ATP synthase. Finally, the single molecular dynamics computer simulation was used to identify the binding sites between ATP synthase and each of the anesthetics. Result: The Seahorse XFp Extracellular Flux Analyzer demonstrated that isoflurane, but not sevoflurane or desflurane, induced mitochondrial dysfunction in the H4‐APP cells. The nanobeam technology‐based single molecular dynamic interaction detection method demonstrated that isoflurane significantly impaired the interaction of ADP and ATP synthase as evidenced by the decreased numbers of resonance shift, longer duration between the resonance shifts and decreased disassociation constant. Neither sevoflurane nor desfluraneimpaired such interaction. Mechanistically, the single molecular dynamics computer simulation study, assessing the various energy binding ability and different binding dynamic activity, demonstrated that there were 7, 1 and 2 binding sites in ATP synthase by isoflurane, sevoflurane and desflurane, respectively. Note that all of the identified 7 binding sites in ATP synthase by isoflurane are dominated binding position of amino acid related to the generation of ATP. Conclusion: These findings suggest that isoflurane has more binding sites with ATP synthase than sevoflurane or desflurane, which impairs the molecular interaction of ADP and ATP synthase, leading to the selective mitochondrial dysfunction and neurotoxicity observed following the administration of isoflurane but not sevoflurane or desflurane. [ABSTRACT FROM AUTHOR]

Background: Delirium and Alzheimer's disease (AD) are common causes of late‐life cognitive impairment with clear epidemiologic links; however, the pathophysiology underlying these links remains unclear. Our recent work suggests that Apolipoprotein E (APOE) ɛ4, the strongest genetic risk marker for AD, does not confer significantly increased risk of delirium in older surgical patients. However, APOE ɛ4 status did modify the relationship of C‐reactive protein (CRP) with delirium, with increased risk for delirium in ɛ4 carriers with high levels of CRP. We now examine whether APOE genotype modifies the established association between inflammatory marker chitinase‐3‐like protein‐1 (CHI3LI/YKL‐40) and postoperative delirium. Methods: We examined patients without dementia age≥70 undergoing major non‐cardiac surgery in the SAGES: Successful AGing after Elective Surgery study. We collected blood, extracted DNA, and performed APOE genotyping using allele specific polymerase chain reaction assays, considering APOE ɛ4 vs. non‐ɛ4 carriers. Plasma YKL‐40, measured on postoperative day 2 (POD2) by ELISA, was examined using sample‐based quartiles (Q1‐Q4). Delirium status was determined with daily interviews rating the Confusion Assessment Method, augmented by a validated chart review. We used generalized linear models adjusted for age, sex, surgery type, and stratified by APOE ɛ4 carrier status, to determine whether APOE modifies the association between YKL‐40 and delirium. Results: Among the 557 patients (mean age 76.7 [standard deviation 5.2], 58% female, 81% orthopedic), 19% were APOE ɛ4 carriers. Postoperative delirium occurred in 24%. The YKL‐40‐delirium relationship differed by APOE status. Among APOE non‐ɛ4 carriers, we found a significant relationship between YKL‐40 and delirium (relative risk [RR] (95% confidence interval [CI] for YKL‐40 Q4 vs. Q1: 2.6(1.4‐4.9) and Q3 vs. Q1: 2.3(1.2‐4.5); p‐trend<.01). Among APOE ɛ4 carriers, YKL‐40 was not significantly associated with delirium (RR(95% CI) for YKL‐40 Q4 vs. Q1: 2.0(0.6‐6.6) and Q3 vs. Q1:1.1(0.3‐3.5); p‐trend = 0.37). Conclusions: APOE non‐ɛ4 carriers may have increased risk of delirium conferred by post‐surgical inflammation specific to the type 2 immune response (high POD2 YKL‐40). These results differ from our prior results with CRP, and raise the intriguing possibility that differing APOE genotypes may interact at different points in the inflammatory pathway leading to delirium. [ABSTRACT FROM AUTHOR]