Tau蛋白靶向的阿尔茨海默病免疫治疗研究现状

正阿尔茨海默病(Alzheimer's disease,AD)是一种隐匿起病,全面性和进行性发展的认知功能障碍,最突出的病理特征为细胞外Aβ异常大量沉积和细胞内神经原纤维缠结(neurofibrillary tangles,NFTs)形成。目前全球约有3600万AD患者,并随着人口的老龄化,以每二十年翻一番的     

微栓子对血管性认知功能障碍的影响及可能机制

随着社会人口老龄化,我国乃至全球血管性认知功能障碍(VCI)的发病率呈上升趋势。据统计,全球约有1/3的人罹患卒中,64%的卒中患者存在一定程度的认知功能障碍,其中又有1/3发展为痴呆[1]。大量的研究[2-5]表明,高血压、糖     

脑卒中患者呼吸训练研究进展

脑卒中是全球第2大死因,也是全球主要致残原因。目前,脑卒中后的康复训练主要关注于运动功能的恢复,但由于脑卒中患者也存在呼吸肌力量减弱且伴随膈肌和腹肌功能障碍,继而引起呼吸肌功能障碍,因此影响脑卒中患者的康复进程。呼吸肌力量的改善在脑卒中患者的康复训练中具有举足轻重的作用。本文阐述呼吸训练对脑卒中患者预后的影响以及呼吸训练干预法及其观察指标,旨在探讨呼吸训练在脑卒中患者中的应用价值,为其在临床上的进一步推广应用提供依据。     

中老年OSAHS并发急性脑出血患者执行功能障碍与血清Hcy相关性的多因素分析

目的分析中老年阻塞性睡眠呼吸暂停低通气综合征(OSAHS)并发急性脑出血(AICH)患者执行功能障碍与血清同型半胱氨酸(Hcy)的相关性。方法 264例中老年OSAHS并发AICH患者为研究对象。根据执行缺陷综合征的行为评价测验(BADS)结果分为无和有执行功能障碍组,对两组患者年龄、性别、体质量、受教育年限、出血部位、出血量、有无慢性病、OSAHS程度以及Hcy水平等执行功能障碍的潜在因素进行单因素和多因素分析;运用χ~2和Pearson检验分析执行功能障碍程度与血清Hcy的相关性。结果 Hcy水平升高是中老年OSAHS并发AICH患者执行功能障碍的影响因素;高Hcy患者相比非高Hcy患者发生执行功能障碍的风险显著增加(P=0.000,OR=2.45,95%CI:1.382~2.986);Hcy水平与BADS各项及总分评分呈负相关,差异有统计学意义(P<0.01)。结论血清Hcy水平升高是老年OSAHS并发AICH患者执行功能障碍的独立危险因素,Hcy水平与执行功能障碍程度有关。     

脑小血管病患者病程进展与血管内皮功能障碍因子表达水平的相关性研究

目的探讨脑小血管病(CSVD)患者病程进展与血管内皮功能障碍(ED)因子[同型半胱氨酸(IIcy)、肿瘤坏死因子α(TNF-α)、白细胞介素6(IL-6)和C反应蛋白(CRP)]表达水平的相关性。方法选取2016年6月至2017年9月在我科诊断为CSVD的患者60例作为研究对象,所有患者均进行了头颅MRI检查。采集外周血,利用ELISA检测与血管内皮功能障碍相关因子Hcy、TNF-α、IL-6和CRP的表达水平。对所纳入患者进行1年时间的随访,随访期内均进行头颅MRI检查。根据随访观察结果,将所纳入患者分为进展组和无进展组,比较两组患者血清Hcy、TNF-α、IL-6和CRP表达水平的差异,并分析它们与CSVD进展的相关性。结果在60例患者中,病程进展的有38例,病程无进展的有22例。与病程无进展组相比,病程进展组患者血清Hcy(17.62±7.23 VS 11.35±5.41,P=0.007)和IL-6 (17.46±6.97 VS8.48±4.67,P=0.001)的表达水平高;TNF-α和CRP的表达水平在两组间无差异。经Spearman等级相关分析发现,CSVD患者的病程进展与血清Hcy(r=0.587,P=0.015)和IL-6(r=0.644,P=0.009)的表达水平存在相关性;而与TNF-α和CRP的表达水平不存在相关性。结论 CSVD患者血清中血管内皮功能障碍因子Hcy、IL-6的表达水平与病程进展存在相关性,检测这些因子的表达对于判断病情预后具有一定参考意义。     

编者按

正中国是全世界卒中发病率最高的国家之一。卒中存活患者中70%～80%遗留有不同程度的神经功能障碍,包括感觉和运动功能障碍、言语和交流功能障碍、认知功能障碍、吞咽障碍、情感障碍、心肺功能障碍等,这些功能障碍严重影响患者的日常生活活动能力及社会参与能力,给患者、家庭及社会造成沉重的负担。针对卒中导致的各种功能障碍,进行早期、全面的康复治疗,能够改善患者的功能障碍,     

脑卒中的遗传学进展

脑卒中(stroke)为世界第二大常见死亡因为及成人致残的首要因为[1],全球每年约有1500万卒中患者,其中1/3死亡,存活的1/3遗留有长期的神经功能障碍[2],给家庭和社会带来沉重负担.在中国,每年新发脑卒中患者约为100～200万[3].     

抑郁症患者认知功能障碍的研究进展

本文对抑郁症患者认知功能障碍的特点、发生机理及治疗和预后进行了综述。抑郁症患者存在明显的注意、记忆、执行功能等认知功能障碍,但其发病机理目前还不十分清楚。抑郁症患者的社会功能障碍很大程度上由认知功能障碍导致,因此对此类患者认知功能障碍的评估与治疗是抑郁症治疗的重要方面。     

吞咽功能障碍对脑卒中患者预后的影响及对策

目的探讨吞咽功能障碍对脑卒中患者预后的影响,及针对性治疗对吞咽功能障碍和患者预后的改善作用。方法收集40例伴吞咽功能障碍的脑卒中患者,采用洼田式的饮水试验进行吞咽能力评估,对比不同级别患者的预后;将40例患者分为实验组和对照组,实验组采用针对性的治疗,对比2组患者吞咽功能改善及预后情况。结果吞咽功能障碍级别越高的患者预后较差,且差异具有统计学意义(P<0.05),使用针对性治疗后,实验组患者吞咽功能改善有效率95%,明显高于对照组65%,差异具有统计学意义(P<0.05),实验组患者预后优于对照组,差异具有统计学意义(P<0.05)。结论吞咽功能障碍对脑卒中患者预后有明显影响,针对吞咽功能障碍的治疗能改善脑卒中患者吞咽功能,对脑卒中患者的预后有较好改善作用。     

帕金森病与线粒体功能障碍

概述了帕金森病(PD)患者线粒体功能障碍的组织、异常的酶复合体及其原因,讨论了线粒体功能障碍在PD中的发病机制和监测PD患者周围组织中的线粒体酶复合体活性的临床意义。     

Environmental factors in the development and progression of late-onset Alzheimer＇s disease

Late-onset Alzheimer＇s disease （LOAD） is an age-related neurodegenerative disorder characterized by gradual loss of synapses and neurons, but its pathogenesis remains to be clarified. Neurons live in an environment constituted by neurons themselves and glial cells. In this review, we propose that the neuronal degeneration in the AD brain is partially caused by diverse environmental factors. We first discuss various environmental stresses and the corresponding responses at different levels. Then we propose some mechanisms underlying the specific pathological changes, in particular, hypothalamic-pituitary adrenal axis dysfunction at the systemic level; cerebrovascular dysfunction, metal toxicity, glial activation, and Aβ toxicity at the intercellular level; and kinase-phosphatase imbalance and epigenetic modification at the intracellular level. Finally, we discuss the possibility of developing new strategies for the prevention and treatment of LOAD from the perspective of environmental stress. We conclude that environmental factors play a significant role in the development of LOAD through multiple pathological mechanisms.     

Edema and neuronal apoptosis in the hippocampus and cortex of elderly rats following transient cerebral ischemia/reperfusion injury

BACKGROUND： Previous studies of cerebral ischemia have used young animals, with an ischemic time greater than 5 minutes （safe time limit）. Despite an increased understanding of neuronal apoptosis, it remains uncertain whether brief cerebral ischemic events of 5 minutes or less damage brain tissue in elderly rodents. OBJECTIVE： To investigate the effects of transient cerebral ischemia （5 minutes）/reperfusion injury on brain cortical and hippocampal edema, aquaporin-4 （AQP-4） expression, and neuronal apoptosis in aged rats, and to compare ischemic sensitivity between cortex and hippocampus. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Institute of Cerebrovascular Disease, Qingdao University Medical School from April 2008 to March 2009. MATERIALS： Rabbit anti-AQP-4 polyclonal antibody, TUNEL kit, and SABC immunohistochemistry kit were purchased from Wuhan Boster Bioengineering, China. METHODS： A total of 160 healthy, male, aged 19-21 months, Wistar rats were randomly assigned to 4 groups： sham-surgery, and ischemia 1-, 3-, and 5-minute groups, with 40 rats in each group. The global cerebral ischemia model was established using the Pusinelli four-vessel occlusion, and the three cerebral ischemia groups were subdivided into reperfusion 12-hour, 1-, 2-, 3-, and 7-day subgroups, with 8 rats in each subgroup. The sham-surgery group was subjected to exposure of the first cervical bilateral alar foramina and bilateral common carotid arteries. MAIN OUTCOME MEASURES： The dry-wet weight assay was used to measure brain water content and histopathology of the cortex and hippocampus was observed following hematoxylin-eosin staining. In addition, cortical and hippocampal AQP-4 expression was detected by streptavidin-biotin complex immunohistochemistry, and neuronal apoptosis was detected by the TUNEL method. RESULTS： There was no significant difference in brain water content or AQP-4 expression in the cortex and hippocampus between ischemia 1- and 3-minute groups and the sham-surgery group or brain water content or AQP-4 expression in the cortex between ischemia 5-minute group and sham-surgery group （P 〉 0.05）. However, brain water content and AQP-4 expression in the hippocampus after 5 minutes of cerebral ischemia were significantly increased compared with the sham-surgery group （P 〈 0.05 or P 〈 0.01）. Several TUNEL-positive cells were observed in the cortex and hippocampus of the sham-surgery group and ischemia 1-minute group, as well as in the cortex of the ischemia 3-minute group. In addition, the number of apoptotic neurons in the hippocampus of ischemia 3-minute group and in the cortex and hippocampus of ischemia 5-minute group was significantly increased （P 〈 0.05 or P 〈 0.01 ）. Neuronal apoptosis was increased after 12 hours of ischemia/reperfusion, and it reached a peak by 2 days （P 〈 0.01）. CONCLUSION： Transient cerebral ischemia （5 minutes） resulted in increased hippocampal edema, AQP-4 expression, and neuronal apoptosis. Moreover, cerebral ischemia had a greater effect on neuronal apoptosis than brain edema or AQP-4 expression, and the hippocampus was more sensitive than the cortex.     

Total saponins of Panax ginseng effects on proliferation and differentiation of human embryonic neural stem cells and in a Parkinson’s disease mouse model

BACKGROUND： Total saponins of Panax ginseng （TSPG） exhibits neuroprotection against Parkinson＇s disease in the substantia nigra. OBJECTIVE： To investigate the effects of TSPG on human embryonic neural stem cells （NSCs） proliferation and differentiation into dopaminergic neurons using in vitro studies, and to observe NSC differentiation in a mouse model of Parkinson＇s disease, as well as behavioral changes before and after transplantation. DESIGN, TIME AND SETTING： In vitro neural cell biology trial and in vivo randomized, controlled animal trial were performed at the Institute of Basic Medical Sciences, Chongqing Medical University between September 2004 and December 2007. MATERIALS： TSPG （purity 〉 95%） was isolated, extracted, and identified by Chongqing Academy of Chinese Materia Medica. Recombinant human basic fibroblast growth factor （bFGF） and recombinant human epidermal growth factor （EGF） were purchased from PeproTech, USA. A total of 25 C57/BL6J mice, aged 18-20 weeks were included. Twenty were used to establish a Parkinson＇s disease model with i.p. injection of MPTP （1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine） and TSPG alone or combined with interleukin-1 （IL-1）-treated NSCs prior to transplantation into the corpus striatum. The remaining five mice were pretreated for 3 days with TSPG prior to MPTP injection, serving as the TSPG prevention group. METHODS： Primary NSCs were isolated, cultured and purified from embryonic cerebral cortex. Immunocytochemistry was employed to detect specific antigen expression in the NSCs. In vitro experiment： （1） to induce proliferation, NSCs were treated with TSPG, EGF＋bFGF, or TSPG＋EGF＋bFGF, respectively; （2） to induce dopaminergic neuronal differentiation, NSCs were treated with TSPG, IL-1, or TSPG＋IL-1, respectively. MAIN OUTCOME MEASURES： In vitro experiment： the effects of TSPG on NSCs proliferation were evaluated with flow cytometry and MTT assay. Tyrosine hydroxylase expression was determined by immunocytochemistry assay to observe effects of TSPG on dopaminergic neuronal differentiation. In vivo experiment： differentiation of grafted NSCs in the mouse brain was determined by immunohistochemical staining. Behavioral changes were evaluated by spontaneous activity frequency, memory function, and score of paralysis agitans. RESULTS： （1） NSCs were cultured and passaged for more than three passages. Immunocytochemistry revealed positive nestin staining, as well as neurofilament protein and glial fibrillary acidic protein. （2） TSPG significantly increased NSC proliferation, in particular when combined with EGF and bFGF, which was twice as effective as FGF or bFGF alone. TSPG also induced dopaminergic differentiation in NSCs, in particular when TSPG was added together with IL-1, resulting in an effect five times greater than that of IL-1 alone. （3） At day 30 following transplantation, most NSCs in the TSPG prevention group differentiated into dopaminergic neurons, and the scores of paralysis agitans, spontaneous activity, and memory function were significantly increased compared with TSPG alone or TSPG＋IL-1 groups （P 〈 0.05）. CONCLUSION： TSPG stimulated NSC proliferation, in particular when combined with FGF and bFGF. TSPG significantly induced dopaminergic neuronal differentiation of NSCs, and the effect was greater when combined with IL-1. In addition, TSPG greatly improved behavior in the Parkinson＇s disease mouse model following NSC transplantation. Following NSC transplantation, TSPG pretreatment exhibited superior efficacy over either TSPG alone or TSPG in combination with IL-1, in terms of behavioral improvements in the Parkinson＇s disease mouse model.     

Targeting 13-secretase with RNAi in neural stem cells for Alzheimer＇s disease therapy

There are several major pathological changes in Alzheimer＇s disease, including apoptosis of cho- linergic neurons, overactivity or overexpression of 13-site amyloid precursor protein cleaving enzyme 1 （BACE1） and inflammation. In this study, we synthesized a 19-nt oligonucleotide targeting BACE1, the key enzyme in amyloid beta protein （AI3） production, and introduced it into the pSilenCircle vector to construct a short hairpin （shRNA） expression plasmid against the BACE1 gene. We transfected this vector into C17.2 neural stem cells and primary neural stem cells, resulting in downregulation of the BACE1 gene, which in turn induced a considerable reduction in reducing AI3 protein production. We anticipate that this technique combining cell transplantation and gene ther- apy will open up novel therapeutic avenues for Alzheimer＇s disease, particularly because it can be used to simultaneously target several pathogenetic changes in the disease.     

墨蝶呤还原酶基因与精神分裂症相关性的研究进展

墨蝶呤还原酶（SPR）催化四氢生物蝶呤（BH4）从头合成途径的最后一步反应。SPR基因遗传缺陷或突变可导致BH。的合成紊乱,影响单胺类神经递质（如多巴胺、5-羟色胺及谷氨酸等）的合成或释放,进而参与包括精神分裂症在内的多种神经精神系统疾病的发生发展过程。此外,SPR基因敲除小鼠表现出持续增强的自主活动等类精神分裂症症状,说明该基因在精神分裂症的发病中扮演重要的角色。进一步研究SPR基因及其单核苷酸多态性的功能,可为阐明精神分裂症的发病机制提供重要的线索,也为新一代抗精神病药物的研制及开发开拓新的视野。现对SPR基因与精神分裂症的相关研究做一综述。     

Disrupted structural and functional brain connectomes in mild cognitive impairment and Alzheimer＇s disease

Alzheimer＇s disease （AD） is the most common type of dementia, comprising an estimated 60-80% of all dementia cases. It is clinically characterized by impairments of memory and other cognitive functions. Previous studies have demonstrated that these impairments are associated with abnormal structural and functional connections among brain regions, leading to a disconnection concept of AD. With the advent of a combination of non-invasive neuroimaging （structural magnetic resonance imaging （MRI）, diffusion MRI, and functional MRI） and neurophysiological techniques （electroencephalography and magnetoencephaJography） with graph theoretical analysis, recent studies have shown that patients with AD and mild cognitive impairment （MCI）, the prodromal stage of AD, exhibit disrupted topological organization in large-scale brain networks （i.e., connectomics） and that this disruption is significantly correlated with the decline of cognitive functions. In this review, we summarize the recent progress of brain connectomics in AD and MCI, focusing on the changes in the topological organization of large-scale structural and functional brain networks using graph theoretical approaches. Based on the two different perspectives of information segregation and integration, the literature reviewed here suggests that AD and MCI are associated with disrupted segregation and integration in brain networks. Thus, these connectomics studies open up a new window for understanding the pathophysiological mechanisms of AD and demonstrate the potential to uncover imaging biomarkers for clinical diagnosis and treatment evaluation for this disease.     

Wnt信号通路与骨髓间充质干细胞增殖及分化的关系

骨髓间充质干细胞（bonemarrow—derived mesenchymal stem cells,BMSCs）是骨髓中不同于造血干细胞的一类细胞,其来源丰富,取材简便,易分离、纯化、培养,在一定的条件下可以迅速体外扩增,具有多向分化潜能,可以通过不同的方法被诱导分化成骨细胞、软骨细胞、肌细胞、神经胶质细胞、神经元细胞等,而且它具有低免疫源性,向病变部位迁移的能力,     

癫痫与自杀

自杀而导致死亡被为是增加癫痫患者死亡率的最重要原因之一。国外许多研究报道都表明癫痫患者的自杀率比普通人群的自杀率高几倍到二十几倍。可能导致癫痫患者自杀的危险性因素是有多方面的,本文将从5-HT、抗癫痫药及癫痫手术治疗、精神病理等方面对癫痫患者可能存在自杀危险因素进行综述,并希望在癫痫的综合治疗中对这些危险因素能加以考虑。     

高血压脑出血的显微外科治疗进展

高血压脑出血（Hypertensive intrac-rebral hemorrhage,HICH）是具有高发病率、高病死率、高致残率的急性脑血管疾病,占所有脑卒中患者的10%-20%,早期病死率可高达49.4%。随着人口老龄化,其发病率逐年提高;而外科手术的干预,使其病死率有所下降,但致残率居高不下。如何提高手术疗效和患者生存质量,一直是神经外科医师努力的方向。微侵袭血肿清除术因其手术创伤小,恢复快,是目前国内治疗高血压脑出血的重要手段。     

Neuronal failure in Alzheimer＇s disease： a view through the oxidative stress looking-glass

Considerable debate and controversy surround the cause（s） of AIzheimer＇s disease （AD）. To date, several theories have gained notoriety, however none is universally accepted. In this review, we provide evidence for the oxidative stress-induced AD cascade that posits aged mitochondria as the critical origin of neurodegeneration in AD.