(1) Background: Previous evidence demonstrates that tight glycemic control and good physical function could reduce the risk of delirium. This study aimed to investigate whether the occurrence of postoperative delirium (POD) in older hip fracture surgery patients is associated with preoperative glycemic control factors or pre-injury physical performance. (2) Methods: Three-hundred and nine individuals aged over 65 years and scheduled for hip fracture surgery were included at a single center. Glycemic control factors and pre-injury physical performance were assessed preoperatively. The presence of delirium was assessed using the Confusion Assessment Method on postoperative hospitalization days. Univariate and multivariable logistic regression models and a risk prediction model of POD were established. (3) Results: Among the 309 patients, 52 (16.83%) experienced POD during the hospital stay. The numbers of pre-injury physical performance and type 2 diabetes mellitus (T2DM) patients were significantly different in the POD and non-POD groups. The multivariable model showed that development of delirium was significantly explained by preoperative fasting blood glucose (FBG) (OR 0.804, p = 0.004), stair climbing (OR 0.709, p = 0.003), T2DM (odds ratio (OR) 3.654, p = 0.001), and age-adjusted Charlson comorbidity index (ACCI) (OR 1.270, p = 0.038). The area under the receiver operating characteristic curve (AUROC) of the risk prediction model including those covariates was 0.770. (4) Conclusions: More older T2DM patients develop POD after hip fracture surgery than patients without T2DM. A simple assessment of preoperative FBG and pre-injury stair climbing capacity may identify those at high risk for the development of POD. Higher preoperative FBG and good pre-injury stair climbing capacity are protective factors for POD.

Delayed neurocognitive recovery (dNCR) is a major complication after anesthesia and surgery in older adults. Alpha‐synuclein (α‐syn; encoded by the gene, SNCA) has recently been shown to play an important role in hippocampus‐dependent working memory. Aggregated forms of α‐syn are associated with multiple neurotoxic mechanisms, such as mitochondrial dysfunction and cell death. In this study, we found that blocking α‐syn improved both mitochondrial function and mitochondria‐dependent neuronal apoptosis in a mouse model of dNCR. Various forms of α‐syn (including total α‐syn, phosphorylated‐Ser129‐α‐syn, and oligomers) were upregulated in hippocampal tissue and extracted mitochondria after surgical challenge. Clenbuterol is a novel transcription modulator of Scna. Clenbuterol significantly attenuated surgery‐induced progressive accumulation of various toxic α‐syn forms in the hippocampus, as well as mitochondrial damage and memory deficits in aged mice following surgery. We also observed excessive mitochondrial α‐syn accumulation and increased mitochondria‐mediated apoptosis in vitro using nerve growth factor‐differentiated PC12 cells and primary hippocampal neurons exposed to lipopolysaccharide. To further validate the neuroprotective effect of α‐syn inhibition, we used a lentiviral Snca‐shRNA (Lv‐shSnca) to knockdown Snca. Of note, Lv‐shSnca transfection significantly inhibited neuronal apoptosis mediated by the mitochondrial apoptosis pathway in neurons exposed to lipopolysaccharide. This α‐syn inhibition improved the disruption to mitochondrial morphology and function, as well as decreased levels of apoptosis. Our results suggest that targeting pathological α‐syn may achieve neuroprotection through regulation of mitochondrial homeostasis and suppression of apoptosis in the aged hippocampus, further strengthening the therapeutic potential of targeting α‐syn for dNCR.

Postoperative neurocognitive impairment is an urgent problem with global aging accelerating. The prevention and treatment of postoperative neurocognitive impairment have been widely investigated but lack effective strategies. Low-intensity pulsed ultrasound (LIPUS), a non-invasive tool, has shown an effect on neuroprotection, but whether it could attenuate the postoperative neurocognitive impairment and the underlying mechanisms remains unknown. An experimental setup for LIPUS stimulation of the hippocampus was well established. A laparotomy model in aged mice was applied, and a Morris water maze was used to assess cognitive function. RT-qPCR and western blotting were used to detect levels of Piezo1, synapse-associated proteins in the hippocampus, respectively. Immunofluorescent staining was also used to determine the neural activation and Piezo1 expression. The results showed that LIPUS increased synapse-related proteins of the hippocampus and attenuated cognitive impairment in aged mice. Meanwhile, LIPUS suppressed the overexpression of Piezo1 in the hippocampus. We further found that LIPUS promoted Calpain1 activity and increased extracellular regulated protein kinases (Erk) phosphorylation. Our results suggested that LIPUS could improve cognitive impairment and increase hippocampal synaptogenesis through the Piezo1-mediated Calpain1/ Erk pathway. LIPUS could be used as an effective physical intervention to alleviate postoperative cognitive dysfunction in the aged population.

Delayed neurocognitive recovery (dNCR) is a common complication that occurs post-surgery, especially in elderly individuals. The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex plays an essential role in various membrane fusion events, such as synaptic vesicle exocytosis and autophagosome–lysosome fusion. Although SNARE complex dysfunction has been observed in several neurodegenerative disorders, the causal link between SNARE-mediated membrane fusion and dNCR remains unclear. We previously demonstrated that surgical stimuli caused cognitive impairment in aged rats by inducing α-synuclein accumulation, inhibiting autophagy, and disrupting neurotransmitter release in hippocampal synaptosomes. Here, we evaluated the effects of propofol anesthesia plus surgery on learning and memory and investigated levels of SNARE proteins and chaperones in hippocampal synaptosomes. Aged rats that received propofol anesthesia and surgery exhibited learning and memory impairments in a Morris water maze test and decreased levels of synaptosome-associated protein 25, synaptobrevin/vesicle-associated membrane protein 2, and syntaxin 1. Levels of SNARE chaperones, including mammalian uncoordinated-18, complexins 1 and 2, cysteine string protein-α, and N-ethylmaleimide-sensitive factor, were all significantly decreased following anesthesia with surgical stress. However, the synaptic vesicle marker synaptophysin was unaffected. The autophagy-enhancer rapamycin attenuated structural and functional disturbances of the SNARE complex and ameliorated disrupted neurotransmitter release. Our results indicate that perturbations of SNARE proteins in hippocampal synaptosomes may underlie the occurrence of dNCR. Moreover, the protective effect of rapamycin may partially occur through recovery of SNARE structural and functional abnormalities. Our findings provide insight into the molecular mechanisms underlying dNCR.