睡眠-觉醒节律与围术期神经认知障碍的研究进展

<正>随着社会老龄化的到来,老年手术患者日益增加,围术期神经认知障碍(perioperative neurocognitive disorders, PND)也逐渐被人们关注。PND是指患者术前、术后短时间和术后长时间的认知功能损害或改变,包括了以往临床上所说的术后认知功能障碍(postoperative cognitive dysfunction, POCD)~([1])。PND是老年患者围术期常见的问题之一,主要表现为定向力、注意力、记忆力、思     

细胞焦亡与术后神经认知障碍关系的研究进展

术后神经认知障碍（PND）指经历麻醉、手术后,患者出现的认知功能减退,包括人格改变、学习能力下降、记忆受损等症状,尤其好发于高龄患者。PND会导致手术疗效不佳、术后并发症增多等问题,但目前PND的确切机制还未完全揭示,且无有效治疗方法。细胞焦亡是一种新型的炎症相关的细胞死亡方式,在多种中枢神经系统疾病的发生发展中起着重要作用。麻醉、手术引起的神经炎症、氧化应激以及二者引起的后续改变会导致中枢神经系统内炎性小体的激活,触发级联放大的炎症反应促使细胞焦亡,从而引起或加重PND。本文就细胞焦亡与PND发生、发展、诊断、防治方面的相关联系进行综述,为早期识别和治疗PND,降低PND发生率提供新思路。     

围术期神经认知障碍脑源性生物标志物的研究进展

围术期神经认知障碍（PND）是一种常见于老年患者的术后并发症，其特征是患者出现认知功能下降、记忆受损、注意力不能集中等改变。随着老年患者手术数量的持续增长，出现PND的患者数量也将随之上升。PND的危险因素及诱发因素十分复杂，具体机制尚不清楚，且无统一的诊断标准。本文总结近年来各类PND脑源性生物标志物的研究进展，以期为PND的预测和诊断提供参考。     

围术期神经认知障碍患者远期认知功能下降的研究进展

围术期神经认知障碍（PND）是老年患者围术期常见的并发症之一，表现为围术期注意力不集中、思维逻辑能力下降、学习记忆能力减退，严重影响患者术后康复。近年来，大量研究表明术前已存在或术后早期出现的认知功能损害与术后远期认知功能下降相关，而干预术后早期认知功能改变或可影响术后远期认知发展轨迹，因此探索术后早期认知功能改变的干预方法和相关机制至关重要。本文对PND患者术后12个月后患者认知功能的发展轨迹及影响因素进行综述，以提供干预术后早期认知功能改变的思路或方法。     

肺移植患者围手术期神经认知障碍发生率及危险因素分析

目的了解肺移植患者围手术期神经认知障碍(perioperative neurocognitive disorders,PND)的发生率,探究PND的危险因素及其模型预测效能。方法选择2019年6月—2020年5月于无锡市人民医院行肺移植手术患者为研究对象,于术前1 d和术后第7天、1个月、3个月分别接受简易精神状态检查(Mini Mental Status Examination,MMSE)量表及蒙特利尔认知评估(Montreal Cognitive Assessment,MoCA)量表检测判定是否发生PND,根据是否发生PND分为非PND组和PND组。记录患者一般资料、围手术期情况[包括ASA分级、入室肺动脉压、供肺冷缺血时间、体外膜氧合器(extracorporeal membrane oxygenator,ECMO)使用、肺动脉阻断时间、麻醉时间、手术时间、术中出血量、术中尿量、术中总输液量、术中总输血量、去甲肾上腺素用量、术中Hb下降率等]、术后入ICU后ECMO转流时间、拔管时间、ICU滞留时间、术后前3 d乳酸值等情况。采用Logistic回归模型分析肺移植患者术后第7天发生神经认知障碍的独立危险因素,构建受试者工作特征(receiver operating characteristic,ROC)曲线检验相关模型对PND的预测效能。结果共纳入101例患者,术后第7天PND发生率为32.7%(33/101),术后1个月PND发生率降至14.9%(15/101),术后3个月PND发生率为8.9%(9/101)。在单因素分析中,术后第7天PND组供肺冷缺血时间、ECMO的使用、术后ECMO转流时间、ICU滞留时间和术后第2天乳酸值高于非PND组;术后1个月时PND组术后ECMO转流时间高于非PND组;术后3个月时PND组ICU滞留时间高于非PND组。多因素Logistic回归分析显示,供肺冷缺血时间和ICU滞留时间是肺移植患者术后第7天发生PND的独立危险因素,术后第7天ROC曲线下面积(area under curve,AUC)为0.709(95%CI 0.603~0.815,P<0.01),预测PND敏感度为45.5%,特异性为88.2%。结论肺移植患者术后第7天、1个月、3个月PND发生率分别为32.7%、14.9%和8.9%,供肺冷缺血时间和ICU滞留时间是肺移植患者术后第7天发生PND的早期危险因素。     

术后神经认知障碍中枢机制的研究进展

正术后神经认知障碍(postoperative neurocognitive disorders,PND)是麻醉手术后常见的并发症,主要表现为认知能力下降,严重影响术后恢复、降低生活质量、增加术后死亡率,在老年患者中尤甚[1]。PND是多因素作用的结果,手术创伤通过破坏血脑屏障(blood brain barrier,BBB)导致中枢神经系统(central nervous system,CNS)炎症继而引发PND[2],而神经网络对神经炎症损伤的个体差异决定了PND是否发生以及如何发展。本文旨在从细胞学角度总结近年来PND的CNS相关研究进展,对其病理机制进行综述,为今后的临床预防与治疗研究提供参考。     

补体系统在围术期神经认知障碍中的研究进展

围术期神经认知障碍（PND）是一种常见的围术期神经系统并发症,表现为注意力不集中,学习能力下降和记忆受损,可影响患者术后短期功能恢复及预后,延长患者的住院时间。目前PND的发生机制仍存在争议。补体系统是一种生物级联反应体系,已被证实在多种神经退行性疾病的发生发展过程中起着重要作用。麻醉及手术刺激可激活中枢神经系统中的补体系统,影响神经炎症反应、突触功能、血脑屏障、血脑脊液屏障,引起或加重PND。本文章就补体系统对围术期神经认知功能的影响做一系统综述,以期为PND的潜在药物靶点和治疗提供参考。     

围术期神经认知障碍的中枢机制：基于脑电图和磁共振成像的研究进展

围术期神经认知障碍(PND)是围术期常见疾病,给患者及社会带来沉重负担。由于PND的发病机制复杂且缺乏可靠的诊断及干预手段,而脑电图(EEG)及磁共振成像(MRI)具备提供客观指标的优势,因此两者应用于PND的研究逐渐成为热点。本文对PND患者术中量化脑电指标、EEG频谱分析、EEG功能连通性分析、EEG非线性动力学分析以及围术期MRI分析进行综述,旨在探索EEG和MRI对预测及诊断PND的临床价值。     

神经炎症与围术期神经认知障碍关系的研究进展

围术期神经认知障碍(PND)是一种常见的术后并发症, 多见于老年患者, 随着人口老龄化进程以及老年患者手术量的增加, PND的发生率也逐步增加。近年来, 神经炎症与PND的关系受到了广泛关注, 其在PND的发生机制中起主要作用[1]。本文就神经炎症与PND关系的研究进展进行综述, 以了解现状、预测未来研究趋势及寻求新的研究突破点。     

肠道菌群紊乱与围术期神经认知障碍的研究进展

正随着手术麻醉的普及和医学人文的发展,围术期神经认知障碍(perioperative neurocognitive disorders,PND)受到越来越多的关注。2018年11月麻醉学领域6大权威期刊同步刊发关于PND的最新定义,明确PND是指发生在术前和术后12个月内,且符合第五版神经障碍手册(diagnostic and statistical manual of mental disorders-fifth edition,DSM-5)中神经认知障碍诊断标准的围术期认知功能损害[1]。PND好发于老年患者,主要表现为注意力、记忆力、语言思维能力等减     

Cerebrospinal fluid leakage after posterior fossa surgery may impair brain metabolite clearance

The discovery of the important role of cerebrospinal fluid (CSF) drainage of cerebral metabolite waste, known as the glymphatic system, has changed our view of brain waste clearance. We recently performed experiments to evaluate the glymphatic system in non-human primates (NHP). Here, we report the case of an NHP with iatrogenic CSF leakage. In this animal, solute transport through the brain, assessed by gadolinium injection in the CSF, was severely impaired by iatrogenic pseudomeningocele. This observation raises an important question: does brain surgery, and particularly posterior fossa surgery, lead to chronic impairment of parenchymal CSF circulation and solute transport?     

肠道菌群与围手术期神经认知障碍研究进展

围手术期神经认知障碍(perioperative neurocognitive disorders,PND)是麻醉和手术相关的常见并发症,其机制和干预研究一直以来都是麻醉和围手术期医学领域的热点和重点问题。目前,大量证据证实肠道菌群与大脑之间存在着重要的交互关联,称为肠-脑轴。肠道菌群是肠-脑轴重要一环,其稳态对神经认知功能起着重要的调控作用。文章基于目前的研究,就麻醉和外科手术对肠道菌群的影响,肠道菌群失调在PND中的作用及其潜在机制,以及通过调节肠道菌群对PND的干预作用等方面进行综述,以期为临床及科学研究提供参考。     

Diffuse brain injury in the immature rat: evidence for an age-at-injury effect on cognitive function and histopathologic damage

Diffuse axonal injury is a significant component of the pathology of moderate-severe pediatric traumatic brain injury in children less than 4 years of age, and is associated with poor cognitive outcome. However, cognitive deficits or gross histopathologic abnormalities are typically not observed following moderate-severe diffuse brain injury in the immature (17-day-old) rat. In order to test whether the age of the immature animal may influence post-traumatic outcome, non-contusive brain trauma was induced in post-natal day (PND) 11 or 17 rats. Brain injury in the PND11 rat, but not in the PND17 rat, was associated with a significant acquisition deficit at 28 days post-injury (p<0.0005 compared with age-matched sham rats, and with brain-injured PND17 rats). All brain-injured animals exhibited a retention deficit in the probe trial (p<0.001), but also demonstrated a significant visual deficit in the visible platform trial (p<0.05 compared to sham animals). Although significantly longer times of apnea and loss of righting reflex were observed in brain-injured PND17 rats compared to PND11 rats (p<0.05), overt cytoarchitectural alterations and reactive gliosis were not observed in the older age group. No focal pathology was observed in the cortex below the impact site in the PND11 rat but by 28 days, the brain-injured PND11 rat exhibited atrophy in multiple brain regions and an enlarged lateral ventricle in the impact hemisphere. Quantitative analysis revealed a time-dependent increase in tissue loss in the injured hemisphere (7-10%) in the younger animals, and a modest extent of tissue loss in the older animals (3-4%). Traumatic axonal injury was observed to similar extents in the white matter and thalamus below the impact site in both brain-injured PND11 and 17 rats. These data demonstrate that non-contusive (diffuse) brain injury of moderate severity in the immature rat is associated with chronic cognitive deficits and long-term histopathologic alterations and suggest that the age-at-injury is an important parameter of behavioral and pathologic outcome following closed head injury in the immature age group.     

Chronic cognitive deficits and long-term histopathological alterations following contusive brain injury in the immature rat

Although diffuse axonal injury is the primary pathology in pediatric brain trauma, the additional presence of focal contusions may contribute to the poor prognosis in brain-injured children younger than 4 years of age. Because existing models of pediatric brain trauma focus on diffuse brain injury, a model of contusive brain trauma was developed using postnatal day (PND) 11 and 17 rats, ages that are neurologically equivalent to a human infant and toddler, respectively. Closed head injury was modeled by subjecting the intact skull over the left parietal cortex of the immature rat to an impact with a metal-tipped indenter. Brain trauma on PND11 or PND17 led to significant spatial learning deficits at 28 days post-injury, compared to age-matched control rats (p < 0.05). Although both groups of rats sustained skull fractures on impact, the histopathologic response of the brain was distinctly age-dependent. At 3 days post-injury in PND11 rats, the cortex below the impact site was contused and hemorrhagic, and contained reactive astrocytes, while the subcortical white matter and thalamus contained injured (swollen) axons. At 14 and 28 days post-injury, the cortex, white matter, and hippocampus were substantially atrophied, and the lateral ventricle was enlarged. In contrast, in PND17 rats, the contused cortex observed at 3 days post-injury matured into a pronounced cavity lined with a glia limitans at 14 days; reactive astrocytes were present in both the hippocampus and thalamus up to 28 days post-injury. No evidence of traumatic axonal injury was observed in any region of the brain-injured PND17 rat. These data suggest that contusive brain trauma in the immature rat is associated with chronic cognitive deficits, but underscore the effect of the age-at-injury on behavioral and histopathologic outcomes.     

Ketogenic diet prevents alterations in brain metabolism in young but not adult rats after traumatic brain injury

Previous studies have shown that the change of cerebral metabolic rate of glucose (CMRglc) in response to traumatic brain injury (TBI) is different in young (PND35) and adult rats (PND70), and that prolonged ketogenic diet treatment results in histological and behavioral neuroprotection only in younger rat brains. However, the mechanism(s) through which ketones act in the injured brain and the biochemical markers of their action remain unknown. Therefore, the current study was initiated to: 1) determine the effect of injury on the neurochemical profile in PND35 compared to PND70 rats; and 2) test the effect of early post-injury administration of ketogenic diet on brain metabolism in PND35 versus PND70 rats. The data show that alterations in energy metabolites, amino acid, and membrane metabolites were not evident in PND35 rats on standard diet until 24 h after injury, when the concentration of most metabolites was reduced from sham-injured values. In contrast, acute, but transient deficits in energy metabolism were measured at 6 h in PND70 rats, together with deficits in N-acetylaspartate that endured until 24 h. Administration of a ketogenic diet resulted in significant increases in plasma β-hydroxybutyrate (βOHB) levels. Similarly, brain βOHB levels were significantly elevated in all injured rats, but were elevated by 43% more in PND35 rats compared to PND70 rats. As a result, ATP, creatine, and phosphocreatine levels at 24 h after injury were significantly improved in the ketogenic PND35 rats, but not in the PND70 group. The improvement in energy metabolism in the PND35 brains was accompanied by the recovery of NAA and reduction of lactate levels, as well as amelioration of the deficits of other amino acids and membrane metabolites. These results indicate that the PND35 brains are more resistant to the injury, indicated by a delayed deficit in energy metabolism. Moreover, the younger brains revert to ketones metabolism more quickly than do the adult brains, resulting in better neurochemical and cerebral metabolic recovery after injury.     

炎症反应在围术期神经认知障碍中的作用研究进展

围术期神经认知障碍(PND)患者有发生严重并发症的风险,可能出现痴呆甚至死亡。目前,关于发生PND的具体机制尚不明确。越来越多的研究表明,PND患者和动物模型中出现促炎信号分子。外周炎性因子的释放、血脑屏障的破坏、中枢神经炎症反应的发生、神经元的凋亡和突触的丧失,提示炎症机制可能在PND的发生中起关键作用。本文对神经炎症反应在PND中的作用以及干预措施的研究进展作一综述,以期为基础研究及临床实践提供新的思路。     

The absence of dominant alpha-oscillatory EEG activity during emergence from delta-dominant anesthesia predicts neurocognitive impairment- results from a prospective observational trial

Study objectivePostoperative neurocognitive disorders (PND) are common complications after surgery under general anesthesia. In our aging society the incidence of PND will increase. Hence, interdisciplinary efforts should be taken to minimize the occurrence of PND. Electroencephalographic (EEG) monitoring of brain activity during anesthesia or emergence from anesthesia is a promising tool to identify patients at risk. We therefore investigated whether we could identify specific EEG signatures during emergence of anesthesia that are associated with the occurrence of PND.Design and patientsWe performed a prospective observational investigation on 116 patients to evaluate the EEG features during emergence from general anesthesia dominated by slow delta waves in patients with and without delirium in the postoperative care unit (PACU-D) as assessed by the CAM-ICU and the RASS.Main resultsDuring emergence both the frontal and global EEG of patients with PACU-D were significantly different from patients without PACU-D. PACU-D patients had lower relative alpha power and reduced fronto-parietal alpha coherence.ConclusionsWith our analysis we show differences in EEG features associated with anesthesia emergence in patients with and without PACU-D. Frontal and global EEG alpha-band features could help to identify patients with PACU-D.Clinical trial number: NCT03287401     

Experience-dependent changes in basal dendritic branching of layer 2/3 pyramidal neurons during a critical period for developmental plasticity in rat barrel cortex

In rat barrel cortex, development of layer 2/3 receptive fields can be disrupted by sensory deprivation, with a critical period ending around postnatal day (PND) 14. To determine if experience-dependent plasticity of dendritic morphology could contribute to the reorganization of synaptic inputs, we analyzed dendritic structure in acute brain slices using two-photon laser scanning microscopy (2PLSM) and automated segmentation and analysis software. Layer 2/3 pyramidal cells from control and deprived rats were imaged from PND 9 to PND 20, spanning the critical period. Detailed analyses were performed on basal arbors, which receive the majority of synaptic input from layer 4. Some parameters (number of primary dendrites, volume subtended, aspect ratios) were stable, suggesting that development of several important properties of basal arbors has ceased by age PND 9. However, the spatial organization of secondary branching changed with age and experience. In older neurons there was a larger fraction of branch points farther from the soma. Deprivation from age PND 9 delayed these changes in secondary branching. This effect of deprivation was rapid (detectable at PND 10) and present at all ages observed. Deprivation initiated at PND 15 had no effect on basal branching measured at PND 20. Thus the spatial organization of secondary dendritic branching is experience-dependent and shares a critical period with receptive field plasticity.     

Growth of thalamic afferents into mouse barrel cortex.

We studied thalamocortical afferent (TCA) growth into somatosensory cortex as the whisker barrels emerge in postnatal mice. Ingrowing fibers from the ventrobasal (VB) thalamus were selectively labeled by two means. Under direct vision, individual axons and populations of axons were labeled in vitro with HRP, or in fixed tissue with Dil (1,1'-dioctodecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate), in pieces of brain containing both the source nucleus in the thalamus and its cortical target. Many simple thalamocortical afferents are already within the upper cortical plate at birth [postnatal day one (PND1)]. Initially, TCAs from each point in the thalamus distribute in the cortex as two-dimensional "Gaussians," which overlap laterally to constitute a uniform projection pattern. The projection is topographic, because adjacent focal injections within VB label adjacent cortical loci. Subsequent development of barreloids (thalamic representations of the whiskers) partitions the TCA projection into a set of whisker-related Gaussians, centered on cortical targets whose collective topography reflects that of the source pattern. After barreloids form on about PND3, but before barrels appear in cytoarchitecture on about PND5, the overlapping TCAs segregate into dense terminal clusters in layer IV, around which barrels later mature. Time series of single fibers traced with camera lucida explain this transformation that is so noticeable at the population level. As early as PND1, individual TCAs emit multiple ascending collaterals on their horizontal run through white matter and oblique ascent into upper cortex. Subsequently, by PND4, and proceeding at least through PND7, there is accelerated terminal arborization of selected appropriate collateral branches and pruning back of other inappropriate ones. The selection mechanism appears to result from within-group reinforcement events that are stronger for branches toward the center of each whisker-related Gaussian distribution.