Zhongcong Xie

Background: Preoperative blood Tau phosphorylated at threonine 217 (Tau-PT217), a newly identified blood biomarker of Alzheimer disease, is associated with postoperative delirium in patients. Anesthesia/surgery is also associated with postoperative increased blood Tau-PT217 amounts in patients. Moreover, in female aged mice, anesthesia/surgery increases Tau-PT217 in lungs, blood, and brain tissues, leading to behavioral changes. However, whether these effects are sex-dependent remains largely undetermined. Methods: Eighteen-month-old female and male mice (C57BL/6J) underwent abdominal surgery during general anesthesia (1.4% isoflurane and 40% oxygen). Levels of Tau-PT217, inflammatory markers, and glycogen synthase kinase 3 β (GSK3β) activity were measured in lungs, blood, and brain tissues of aged mice using Nanoneedle technology, Western blot, immunohistochemistry, reverse-transcription polymerase chain reaction, and others. Postoperative delirium–like behavior was assessed using a battery of behavioral tests (buried food, open field, and Y-maze). To explore causality, the authors performed orchiectomy and administered androgen receptor antagonist enzalutamide in aged male mice. Finally, testosterone was delivered via inhalation to aged female mice. Results: Anesthesia/surgery increased the amounts of Tau-PT217 in lungs (2.29 ± 0.16-fold vs. 1.15 ± 0.71-fold; P < 0.01), blood, and brain tissues of aged female but not male mice compared to control condition, leading to postoperative delirium–like behavior, as evidenced by increases in the composite Z-score (3.74 ± 1.46 vs. 0.60 ± 1.17; P < 0.01) in the aged female but not male mice. Anesthesia/surgery elevated inflammatory markers and GSK3β activity in aged female mice, which exhibited lower baseline testosterone levels and androgen receptor expression in lungs compared to males. Both orchiectomy and enzalutamide treatment in male mice reduced testosterone levels and androgen receptor expression, leading to elevation of Tau-PT217 amounts and behavior changes after anesthesia/surgery. Conversely, testosterone inhalation in aged female mice mitigated the anesthesia/surgery–induced elevation of Tau-PT217 amounts and behavior changes. Conclusions: Testosterone and androgen receptor signaling may contribute to the sex-dependent differences in Tau phosphorylation and postoperative behavior changes in aged mice.

Optimization of the individual topicalization technique during awake tracheal intubation (ATI) is critical, but how to accomplish this is still unknown. We hypothesized that there would be a difference between nebulization with different sizes of 2% lidocaine atomized particles in ATI by video laryngoscopy. A total of 230 patients scheduled for ATI were recruited from September 2024 through January 2025. Forty-six participants were excluded, and 184 participants were randomly assigned to 4 treatment groups according to the size of the atomized particles of 2% lidocaine: A3 (3–4 μm), A6 (6–7 μm), A9 (9–10 μm), or A11 (11–12 μm). There were statistically significant differences among the four groups. Post hoc analysis using Dunnett test showed that, compared with the A3 group, the A9 group had greater feelings of comfort (cough score: P = 0.005; reaction score: P = 0.024; discomfort score: P = 0.003). the A9 group had lower heart rates at endotracheal tube insertion(P = 0.015), at inflation of the tracheal tube cuff (P = 0.001) and 1 min after endotracheal tube insertion(P = 0.009); The A9 group had fewer applications of the airway spray and fewer times the patient vomited (P<0.001), but exhibited a longer nebulization time (P<0.0001). In conclusion, we demonstrated that there were differences between nebulization with different sizes of 2% lidocaine atomized particles in ATI. In addition, 2% lidocaine administered via a nebulizer with 9–10-µm atomized particles performed better during ATI. Therefore, we recommend a nebulizer and the 9–10-µm particle-size range for patients who need ATI. Clinicaltrials.gov, NCT06420947. Date of Registration: May 12th, 2024.

JOURNAL/nrgr/04.03/01300535-202606000-00060/figure1/v/2026-04-16T195327Z/r/image-tiff Delayed neurocognitive recovery following anesthesia and surgery is a common complication in older adult patients. Synapses are fundamental to cognitive function. The activity of synapses heavily depends on the energy supplied by synaptic mitochondria, which are significantly influenced by oxidative stress. Sirtuin 3 is a histone deacetylase located in the mitochondrial matrix that plays a pivotal role in regulating mitochondrial function. However, it remains unclear whether and how sirtuin 3 is involved in the development of delayed cognitive recovery. Therefore, in this study, we investigated the potential role of sirtuin 3 in synapses during delayed neurocognitive recovery. Our results showed that anesthesia and surgery induced cognitive impairment in mice and reduced sirtuin 3 protein expression. Overexpression of sirtuin 3 inhibited opening of the mitochondrial permeability transition pore by reducing acetylation of K166 on cyclophilin D and also rescued cognitive impairment. Aged mice carrying the cyclophilin D-K166R mutation exhibited significantly reduced cognitive impairment. Similarly, administering the mitochondrial permeability transition pore blocker, cyclosporine A, effectively alleviated the decline in synaptic mitochondrial function and cognitive impairment caused by anesthesia and surgery in aged mice. These results indicate that the sirtuin 3/cyclophilin D-K166/mPTP signaling pathway in hippocampal synaptic mitochondria is involved in delayed neurocognitive recovery of aged mice, suggesting this pathway could serve as a potential target for treatment.

Alzheimer’s disease (AD) is a complex, progressive neurodegenerative disorder, impacting millions of geriatric patients globally. Unfortunately, AD can only be diagnosed post-mortem, through the analysis of autopsied brain tissue in human patients. This renders early detection and countering disease progression difficult. As AD progresses, the metabolomic profile of the brain and other organs can change. These alterations can be detected in peripheral systems (i.e., blood) such that biomarkers of the disease can be identified and monitored with minimal invasion. In this work, High-Resolution Magic Angle Spinning (HRMAS) Nuclear Magnetic Resonance (NMR) spectroscopy is used to correlate biochemical changes in mouse brain tissues, from the cortex and hippocampus, with blood plasma. Ten micrograms of each brain tissue and ten microliters of blood plasma were obtained from 5XFAD Tg AD mice models (n = 15, 8 female, 7 male) and female C57/BL6 wild-type mice (n = 8). Spectral regions-of-interest (ROI, n = 51) were identified, and 121 potential metabolites were assigned using the Human Metabolome Database and tabulated according to their trends (increase/decrease, false discovery rate significance). This work identified several metabolites that impact glucose oxidation (lactic acid, pyruvate, glucose-6-phosphate), allude to oxidative stress resulting in brain dysfunction (L-cysteine, galactitol, propionic acid), as well as those interacting with other neural pathways (taurine, dimethylamine). This work also suggests correlated metabolomic changes within blood plasma, proposing an avenue for biomarker detection, ideally leading to improved patient diagnosis and prognosis in the future.

Perioperative neurocognitive disorder (PND) is a significant neurological complication in aging perioperative patients that impacts post-operative cognition. PND is currently diagnosed through cognitive function testing, which is limited by its subjectivity and time requirements. Thus, the identification of biomarkers to assess PND onset is a priority to identify at-risk individuals and enable interventions and treatments to patient outcomes. This article synthesizes expert perspectives on brain aging and PND, presents the latest clinical evidence on PND biomarkers (imaging, electroencephalography, and molecular biomarkers), and delves into the relationship between PND and other age-related cognitive disorders. Thorough review of PND research identified several biomarkers with high sensitivity and specificity, offering a solid scientific foundation to predict and diagnose PND. These biomarkers not only enhance diagnostic accuracy for clinicians but also provide opportunities for earlier intervention and more effective treatment, potentially enhancing patient outcomes and quality of life.

Preoperative risk biomarkers for delirium may aid in identifying high-risk patients and developing intervention therapies, which would minimize the health and economic burden of postoperative delirium. Previous studies have typically used single omics approaches to identify such biomarkers. Preoperative cerebrospinal fluid (CSF) from the Healthier Postoperative Recovery study of adults ≥ 63 years old undergoing elective major orthopedic surgery was used in a matched pair delirium case–no delirium control design. We performed metabolomics and lipidomics, which were combined with our previously reported proteomics results on the same samples. Differential expression, clustering, classification, and systems biology analyses were applied to individual and combined omics datasets. Probabilistic graph models were used to identify an integrated multi-omics interaction network, which included clusters of heterogeneous omics interactions among lipids, metabolites, and proteins. The combined multi-omics signature of 25 molecules attained an AUC of 0.96 [95% CI: 0.85–1.00], showing improvement over individual omics-based classification. We conclude that multi-omics integration of preoperative CSF identifies potential risk markers for delirium and generates new insights into the complex pathways associated with delirium. With future validation, this hypotheses-generating study may serve to build robust biomarkers for delirium and improve our understanding of its pathophysiology.

Alzheimer’s disease (AD) is a complex, progressive neurodegenerative disorder, impacting millions of geriatric patients globally. Unfortunately, AD can only be diagnosed post-mortem, through analysis of autopsied brain tissue in human patients. This renders early detection and countering disease progression difficult. As AD progresses, the metabolomic profile of the brain and other organs can change. These alterations can be detected in peripheral systems (i.e., blood) such that biomarkers of the disease can be identified and monitored with minimal invasion. In this work, High-Resolution Magic Angle Spinning (HRMAS) Nuclear Magnetic Resonance (NMR) spectroscopy is used to correlate biochemical changes in mouse brain tissues, from the cortex and hippocampus to blood plasma. 10 µg of each brain tissue and 10 µL of blood plasma were obtained from 5XFAD Tg AD mice models (n=15, 8 female, 7 male) and female C57/BL6 wild-type mice (n=8). 51 spectral regions-of-interest (ROI) were identified, and 121 potential metabolites were assigned using the Human Metabolome Database and tabulated according to their trends (increase/decrease, false discovery rate significance). This work identified several metabolites that impact glucose oxidation (lactic acid, pyruvate, glucose-6-phosphate), allude to oxidative stress resulting in brain dysfuncton(L-cysteine, galactitol, propionic acid), as well as those interacting with other neural pathways (taurine, dimethylamine). This work also suggests correlated metabolomic changes within blood plasma, proposing an avenue for biomarker detection, ideally leading to improved patient diagnosis and prognosis in the future.

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.