米诺环素改善血管性痴呆大鼠认知功能障碍的机制研究

目的探索米诺环素是否在血管性痴呆导致的认知功能损害发生发展中发挥一定的神经保护作用,并进一步分析参与其中的相关分子机制。 方法SD大鼠随机分为假手术组、模型组和米诺环素治疗组。结扎双侧颈总动脉建立大鼠血管性痴呆模型,术后腹腔注射米诺环素（25,50 mg/kg）,28 d后进行水迷宫行为学实验检测认知变化,HE染色和Western blotting分析大鼠海马神经细胞凋亡的相关机制。 结果（1）水迷宫认知功能测试显示,米诺环素能够显著缩短血管性痴呆大鼠寻找平台的潜伏期,并且明显延长在目标象限的停留时间,P<0.05为差异具有统计学意义。（2）HE染色显示米诺环素能够显著减轻模型组大鼠海马神经细胞损伤。（3）米诺环素治疗组含半胱氨酸的天冬氨酸蛋白水解酶-3（Caspase-3）蛋白表达水平及Bax/Bcl-2比值较模型组明显下降,P<0.05为差异具有统计学意义。（4）与模型组相比,米诺环素组磷脂酰肌醇3-激酶（PI3K）及磷酸化蛋白激酶B（p-AKT）蛋白表达水平明显升高,磷酸化糖原合酶激酶-3β（p-GSK-3β）蛋白表达却显著下降,P<0.05为差异具有统计学意义。 结论米诺环素通过激活PI3K/AKT信号通路,抑制该通路下游靶分子GSK-3β活性,减少海马神经细胞凋亡的发生,在神经细胞保护和改善认知功能障碍中发挥重要作用。     

Enriched environment prevents cognitive impairment and tau hyperphosphorylation after chronic cerebral hypoperfusion

Chronic cerebral hypoperfusion (CCH) has been gradually prevalent in the patients over middle age, especially the old over 60 years. It has been proved that CCH is highly related with cognitive impairment. CCH emerges not only in vascular dementia (VaD), but also in Alzheimer's disease (AD), which regarded as a critical causative for cognitive impairment in these diseases. Nevertheless, the mechanisms underlying cognitive deficit remain elusive. Moreover, there are no dramatically effective preventions. In the present study, by employing a recognized CCH rat model, we found that CCH induced spatial learning/memory deficits with simultaneously increasing tau hyperphosphorylation at multiple Alzheimer-related phosphorylation sites with activation of glycogen synthase kinase-3β (GSK-3β), Cyclin-dependent kinase (Cdk5), Calcium/calmodulin-dependent protein kinase II (CaMKII), and protein kinase B (Akt), and inhibition of protein phosphatase (PP) 2A (PP-2A). Interestingly, enriched environment (EE) treatment, an effect environment stimuli filled with various novel objects, could prevent rats from the EE-induced memory deficits and alterations of tau hyperphosphorylation. Our data suggested that EE might be potentially used for attenuating the detrimental cognition induced by CCH through regulating tau hyperphosphorylation.     

高压氧预处理对异氟醚所致中年小鼠认知障碍的改善作用及海马脑源性神经营养因子和胶质细胞源性神经营养因子表达水平的影响

目的 探讨高压氧预处理对异氟醚（ISO）所致中年小鼠认知障碍的改善作用及海马 脑源性神经营养因子（BDNF）和胶质细胞源性神经营养因子（GDNF）蛋白表达和mRNA 水平的影响。 方法 将32 只8 月龄雄性C57BL/6J小鼠按随机数字表随机分为对照组（sham组）、高压氧组（HBO 组）、异 氟醚组（ISO 组）和高压氧预处理+ 异氟醚组（HBO+ISO 组），每组8 只。HBO 组和ESPS+HBO 组小鼠置于 高压氧舱进行1 h 高压氧（2.5 个大气压，100% O2）干预，对照组小鼠常压空气干预（模拟除压力和氧浓度 以外的其他过程和环境条件）1 h，均连续5 d。在第3 天HBO 或常压空气干预结束后2 h，各组小鼠进行 水迷宫训练，连续3 d。最后1 次水迷宫训练后24 h，ISO 组和HBO+ISO 组小鼠经异氟醚吸入麻醉构建认 知障碍模型，其他2 组吸入对照气体。24 h后进行水迷宫检测认知功能，并通过蛋白免疫印迹（Western Blot）和实时定量聚合酶链式反应（RT-PCR）检测小鼠海马BDNF和GDNF蛋白表达和mRNA水平的变化。 结果 （1）各处理组水迷宫总运动距离和平均运动速度的差异均无统计学意义（均P＞ 0.05）；ISO 组目标 象限停留时间百分比为（26.74±10.52）%，显著低于sham 组［（48.33±9.18）%，P ＜ 0.01］，而HBO+ISO 组 ［（39.06±8.39）%］则显著高于ISO 组（P ＜ 0.05）。（2）ISO 组海马BDNF（0.56±0.09）和GDNF（0.52±0.10） 的蛋白相对表达水平均显著低于sham组和HBO+ISO 组（均P ＜ 0.01 或0.05）。（3）ISO 组海马BDNF （0.51±0.08）和GDNF（0.25±0.09）的mRNA 相对水平也均显著低于sham 组和HBO+ISO 组（均P ＜ 0.01）。 （4）sham组与HBO 组在上述行为和分子水平之间的差异均无统计学意义（均P＞ 0.05）。结论 高压氧预 处理可能通过调节海马的BDNF 和GDNF表达水平，改善异氟醚所致认知损伤。     

The cognitive and neural expression of semantic memory impairment in mild cognitive impairment and early Alzheimer's disease

Semantic deficits in Alzheimer's disease have been widely documented, but little is known about the integrity of semantic memory in the prodromal stage of the illness. The aims of the present study were to: (i) investigate naming abilities and semantic memory in amnestic mild cognitive impairment (aMCI), early Alzheimer's disease (AD) compared to healthy older subjects; (ii) investigate the association between naming and semantic knowledge in aMCI and AD; (iii) examine if the semantic impairment was present in different modalities; and (iv) study the relationship between semantic performance and grey matter volume using voxel-based morphometry. Results indicate that both naming and semantic knowledge of objects and famous people were impaired in aMCI and early AD groups, when compared to healthy age- and education-matched controls. Item-by-item analyses showed that anomia in aMCI and early AD was significantly associated with underlying semantic knowledge of famous people but not with semantic knowledge of objects. Moreover, semantic knowledge of the same concepts was impaired in both the visual and the verbal modalities. Finally, voxel-based morphometry analyses revealed that semantic impairment in aMCI and AD was associated with cortical atrophy in the anterior temporal lobe (ATL) region as well as in the inferior prefrontal cortex (IPC), some of the key regions of the semantic cognition network. These findings suggest that the semantic impairment in aMCI may result from a breakdown of semantic knowledge of famous people and objects, combined with difficulties in the selection, manipulation and retrieval of this knowledge.     

Premorbid exercising in specific cognitive tasks prevents impairment of performance in parkinsonian monkeys

Adult Cebus apella monkeys were exposed to either one, two or four series of cognitive tasks that place a demand on working memory and inhibitory control (Spatial Delayed Response and Object Retrieval Detour), before administration of the neurotoxin 1-methyl-1-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Following MPTP treatment, monkeys receiving more than one series successfully reached criteria at delays similar to those attained during the pre-MPTP stage for the Spatial Delayed Response task and avoided increased perseveration in the Object Retrieval Detour task. Results provide evidence that protection towards a neurotoxin in specific cognitive performances can be increased by repeated exposure to task-specific cognitive demands and that motor and cognitive impairment following MPTP treatment can be effectively dissociated in primates.     

Dietary DHA prevents cognitive impairment and inflammatory gene expression in aged male rats fed a diet enriched with refined carbohydrates

The consumption of a processed foods diet (PD) enriched with refined carbohydrates, saturated fats, and lack of fiber has increased in recent decades and likely contributed to increased incidence of chronic disease and weight gain in humans. These diets have also been shown to negatively impact brain health and cognitive function in rodents, non-human primates, and humans, potentially through neuroimmune-related mechanisms. However, mechanisms by which PD impacts the aged brain are unknown. This gap in knowledge is critical, considering the aged brain has a heightened state of baseline inflammation, making it more susceptible to secondary challenges. Here, we showed that consumption of a PD, enriched with refined carbohydrate sources, for 28 days impaired hippocampal- and amygdalar-dependent memory function in aged (24 months), but not young (3 months) F344 × BN rats. These memory deficits were accompanied by increased expression of inflammatory genes, such as IL-1β, CD11b, MHC class II, CD86, NLRP3, and complement component 3, in the hippocampus and amygdala of aged rats. Importantly, we also showed that when the same PD is supplemented with the omega-3 polyunsaturated fatty acid DHA, these memory deficits and inflammatory gene expression changes were ameliorated in aged rats, thus providing the first evidence that DHA supplementation can protect against memory deficits and inflammatory gene expression in aged rats fed a processed foods diet. Lastly, we showed that while PD consumption increased weight gain in both young and aged rats, this effect was exaggerated in aged rats. Aging was also associated with significant alterations in hypothalamic gene expression, with no impact by DHA on weight gain or hypothalamic gene expression. Together, our data provide novel insights regarding diet-brain interactions by showing that PD consumption impairs cognitive function likely through a neuroimmune mechanism and that dietary DHA can ameliorate this phenomenon.     

丁酸钠和维甲酸可上调肌肉特异性基因的表达

目的 探讨组蛋白去乙酰化酶(histonedeacetylase,HDAC)抑制剂丁酸钠和维甲酸体外诱导大鼠骨髓间质干细胞(rat mesenchymal stem cells,rMSC)分化为肌样细胞的作用.方法 分离、培养、增殖rMSC,用HDAC抑制剂丁酸钠和维甲酸诱导rMSC分化为肌样细胞,免疫细胞化学方法 检测诱导前后细胞肌肉特异性蛋白desmin和a-sarcomerie actin的表达,RT-PCR方法 检测诱导前后骨骼肌特异性转录因子MyoD、myogenin、MRF 4和肌肉特异性肌酸磷酸激酶(muscle specific creatine kinase,MCK)mRNA的表达.结果 rMSC诱导后可见多核肌管样细胞,且肌肉特异性蛋白desmin和a-sarcomeric actin的表达呈阳性.MyoD基因mRNA在诱导前后均有表达,但诱导1 d后表达上调,差异有统计学意义(P＜0.05);myogenin和MRF 4基因mRNA在诱导前无表达,诱导1 d后开始表达,MCK基因mRNA在诱导7 d后开始表达.结论 HDAC抑制剂丁酸钠和维甲酸可诱导rMSC分化成肌样细胞,并上调骨骼肌特异性转录因子和肌肉特异性肌酸磷酸激酶的表达.     

Improving cognitive impairment by Tongxinluo via inhibiting expression of beta-secretase 1/beta-amyloid peptide in experimental vascular dementia

BACKGROUND: Tongxinluo has been clinically proven to be effective in improving memory and cognitive function in patients with post-stroke vascular dementia. Is the mechanism related to the deposition of beta-amyloid peptide (Aβ) in hippocampus? OBJECTIVE: To observe the effect of Tongxinluo on cognitive impairment in a mouse model with vascular dementia and the changes of Aβ deposition andβ-secretase 1 (BACE1) expression.DESIGN: Randomized controlled study.SETTING: State Key Laboratory of Pharmaceutical Biotechnology of Nanjing University and Affiliated Drum Tower Hospital of Nanjing University Medical School.MATERIALS: The experiment was carried out in the State Key Laboratory of Pharmaceutical Biotechnology of Nanjing University and Affiliated Drum Tower Hospital of Nanjing University Medical School from March 2006 to January 2007. A total of 36 healthy Kunming mice, 18 of each gender, were chosen. The study was conducted in accordance with the National Regulations of Experimental Animal Administration, and all animal experiments were approved by the Committee of Experimental Animal Administration of Nanjing University. Tongxinluo was provided by Shijiazhuang Yiling Pharmaceutical Co., Ltd.METHODS: All mice were randomly divided into 6 groups, including naive control (n=6), sham-operated control (n=6) and experimental groups treated with different doses of Tongxinluo (0.2, 0.4, and 0.6 g/kg/d; n=6 for each group) or vehicle (n=6). Five groups were subjected to bilateral common carotid arteries (2-VO) occlusion to produce a vascular dementia model(noocclusion was performed in sham-operated group). The mice in the Tongxinluo treatment groups were intragastricly administered daily with a Tongxinluo suspension (40 g/L in distilled water) at doses of 0.2, 0.4 or 0.6 g/kg/d from day 1 to day 30 post-surgery. The animals in vehicle, sham-operated and naive groups were administered an equal volume of distilled water. MAIN OUTCOME MEASURES: ①Escape latency time determined in all groups of mice before and after 2-VO occlusion by Morris water maze. ②Changes in BACE1 mRNA expression in the hippocampi of mice among the six groups by RT-PCR assay, and BACE1 and Aβ protein expression in the hippocampi of mice by Western blot.RESULTS: All 36 mice were involved in the final analysis. ① No difference was detected in escape latency time to a hidden platform among all groups in water maze test before surgery (P > 0.05) At 30 days after 2-VO occlusion, the vehicle animals exhibited a significantly longer latency in finding the hidden platform compared to that of sham-operated and naive animals (P < 0.01). The prolonged escape latency was significantly reduced by oral administration of 0.4 g or 0.6 kg/day (P < 0.01, P < 0.05). BACE1 mRNA and protein expression in vehicle animals were much higher than in sham-operated and naive animals (P < 0.01). The ischemia-induced increases in BACE1 mRNA and protein level were attenuated by all three doses of Tongxinluo treatment (P < 0.01), and the 0.4 g/kg/d treatment was the most effective. Aβ protein expression in vehicle animals after 2-VO occlusion were much higher than in sham-operated and na?ve animals (P < 0.01). 2-VO occlusion-induced Aβ generation was significantly attenuated by all doses of Tongxinluo treatment, with the most effective dose being 0.4 g/kg/d (P < 0.01).CONCLUSION: BACE1 mRNA levels and protein levels of BACE1 and Aβare reduced in the hippocampi of vascular dementia model mice by all three doses of Tongxinluo treatment, with the most effective dose being 0.4 g/kg/d. The results suggest that inhibition of post-ischemia BACE1 expression and Aβ generation in brain might underlie Tongxinluo's effects in improving cognitive impairment.     

Improving cognitive impairment by Tongxinluo via inhibiting expression of beta-secretase 1/beta-amyloid peptide in experimental vascular dementia**☆

BACKGROUND： Tongxinluo has been clinically proven to be effective in improving memory and cognitive function in patients with post-stroke vascular dementia. Is the mechanism related to the deposition of beta-amyloid peptide （A β ） in hippocampus？ OBJECTIVE： To observe the effect of Tongxinluo on cognitive impairment in a mouse model with vascular dementia and the changes of A β deposition and β -secretase 1 （BACE1） expression. DESIGN： Randomized controlled study. SETTING： State Key Laboratory of Pharmaceutical Biotechnology of Nanjing University and Affiliated Drum Tower Hospital of Nanjing University Medical School. MATERIALS： The experiment was carried out in the State Key Laboratory of Pharmaceutical Biotechnology of Nanjing University and Affiliated Drum Tower Hospital of Nanjing University Medical School from March 2006 to January 2007. A total of 36 healthy Kunming mice, 18 of each gender, were chosen. The study was conducted in accordance with the National Regulations of Experimental Animal Administration, and all animal experiments were approved by the Committee of Experimental Animal Administration of Nanjing University. Tongxinluo was provided by Shijiazhuang Yiling Pharmaceutical Co., Ltd. METHODS： All mice were randomly divided into 6 groups, including naive control （n=6）, sham-operated control （n=6） and experimental groups treated with different doses of Tongxinluo （0.2, 0.4, and 0.6 g/kg/d; n=6 for each group） or vehicle （n=6）. Five groups were subjected to bilateral common carotid arteries （2-VO） occlusion to produce a vascular dementia model （no occlusion was performed in sham-operated group）. The mice in the Tongxinluo treatment groups were intragastricly administered daily with a Tongxinluo suspension （40 g/L in distilled water） at doses of 0.2, 0.4 or 0.6 g/kg/d from day 1 to day 30 post-surgery. The animals in vehicle, sham-operated and naive groups were administered an equal volume of distilled water. MAIN OUTCOME MEASURES： ①Escape late     

BDNF Val66Met polymorphism is associated with cognitive impairment in Italian patients with Parkinson's disease

Background and purpose:  A possible association between Parkinson's disease (PD) and the polymorphism of Brain Derived Neurotrophic Factor (BDNF) G196A (Val66Met) has been suggested by different studies that nevertheless yielded-contrasting result. The purpose of this study was to analyze such possible association in a cohort of Italian PD patients.
Methods:  The BDNF polymorphisms were analyzed in 294 Italian patients with PD; results were compared to those obtained in 233 age- and sex-matched healthy controls (HC) enrolled from two tertiary centres in Italy. Polymorphisms were determined by Restriction Fragment Length Polymorphism (RFLP) analysis; correlations between BDNF G196A polymorphism, and cognitive function were established by sub analyzing the results upon dividing PD patients based on their Mini Mental State Examination (MMSE) score.
Results:  Univariate analysis showed a highly significant correlation between the BDNF(AA) genotype and a MMSE score ≤24. Hence, the distribution of this genotype in PD individuals with a MMSE score ≤24 was significantly increased compared to PD patients with an MMSE score >24 and HC ( P  < 0.001 in both cases). Multivariate analyses showed that BDNF (AA) genotype was associated to a sixfold risk of cognitive impairment.
Conclusions:  The BDNF(AA) homozygote genotype is over-represented in PD patients compared with normal individuals; this genotype was significantly correlated to cognitive impairment, age and disease severity. These results, although preliminary, could be important in establishing novel diagnostic and therapeutic approaches to PD.     

Sodium butyrate and mood stabilizers block ouabain-induced hyperlocomotion and increase BDNF,NGF and GDNF levels in brain of Wistar rats

Bipolar Disorder (BD) is one of the most severe psychiatric disorders. Despite adequate treatment, patients continue to have recurrent mood episodes, residual symptoms, and functional impairment. Some preclinical studies have shown that histone deacetylase inhibitors may act on manic-like behaviors. Neurotrophins have been considered important mediators in the pathophysiology of BD. The present study aims to investigate the effects of lithium (Li), valproate (VPA), and sodium butyrate (SB), an HDAC inhibitor, on BDNF, NGF and GDNF in the brain of rats subjected to an animal model of mania induced by ouabain. Wistar rats received a single ICV injection of ouabain or artificial cerebrospinal fluid. From the day following ICV injection, the rats were treated for 6 days with intraperitoneal injections of saline, Li, VPA or SB twice a day. In the 7th day after ouabain injection, locomotor activity was measured using the open-field test. The BDNF, NGF and GDNF levels were measured in the hippocampus and frontal cortex by sandwich-ELISA. Li, VPA or SB treatments reversed ouabain-related manic-like behavior. Ouabain decreased BDNF, NGF and GDNF levels in hippocampus and frontal cortex of rats. The treatment with Li, VPA or SB reversed these impairment induced by ouabain. In addition, Li, VPA and SB per se increased NGF and GDNF levels in hippocampus of rats. Our data support the notion that neurotrophic factors play a role in BD and in the mechanisms of the action of Li, VPA and SB.     

Childhood-onset HAM/TSP with progressive cognitive impairment

HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic myelopathy, usually with adult-onset. Very few cases of childhood-onset have been described, most presenting with progressive paraparesis and sphincteric disturbances as in the adult form. Here we report a young male with childhood-onset of HAM/TSP and progressive cognitive and behavioral disturbances. A serological screening revealed HTLV-I infection, confirmed by Western Immunoblotting analysis. Molecular characterization of amplified HTLV-I proviral DNA has been performed both in the patient and his mother by LTR sequence analysis, and HLA genotype inheritance was evaluated. Our case indicates the possibility that cognitive dysfunctions may be one manifestation of HTLV-I infection in childhood.     

Plasma BDNF levels are correlated with aggressiveness in patients with amnestic mild cognitive impairment or Alzheimer disease

In the present study, we examined whether neuropsychiatric symptoms were correlated with plasma brain-derived neurotrophic factor (BDNF) levels as a state marker or were associated with the BDNF polymorphism Val66Met in patients with amnestic mild cognitive impairment (A-MCI) or Alzheimer disease (AD). One hundred and seventy-six outpatients with AD (n = 129) or A-MCI (n = 47) were selected and their plasma BDNF concentrations measured. Next, we investigated the correlation between the plasma BDNF level and the Behavioral Pathology in Alzheimer Disease (Behave-AD) subscale scores, which reflect neuropsychiatric symptoms. We also compared the plasma BDNF level and the Behave-AD subscale scores among the BDNF Val66Met genotypic groups. Among the seven Behave-AD subscale scores, aggressiveness was positively correlated with the plasma BDNF level (ρ = 0.237, P < 0.005), but did not differ significantly among the three BDNF Val66Met genotypic groups. The Behave-AD total and other subscale scores did not differ significantly among the BDNF Val66Met genotypic groups and were not associated with the plasma BDNF level. Moreover, the plasma BDNF level did not differ significantly among the three BDNF Val66Met genotypic groups or between patients with A-MCI and those with AD. The plasma BDNF level was robustly correlated with aggressiveness, implying that the plasma BDNF level might be useful as a behavioral state marker in patients with AD or A-MCI.     

脑梗死后认知功能障碍患者血清BDNF水平及氟西汀的治疗作用

目的探讨脑梗死后认知功能障碍与血清BDNF的关系,观察氟西汀对血清BDNF和认知功能的影响。方法应用ELISA法检测血清BDNF水平,比较脑梗死后认知功能障碍组患者和认知功能正常组患者血清BDNF水平。将脑梗死后认知功能障碍组患者按照有无接受氟西汀治疗随机分为对照组和氟西汀组,观察两组治疗前后血清BDNF水平及MMSE分值的变化。分析血清BDNF与MMSE分值的相关性。结果脑梗死后认知功能障碍组患者血清BDNF水平低于认知功能正常组;对照组治疗前、后MMSE分值及血清BDNF水平无明显变化;氟西汀治疗组治疗后MMSE分值及血清BDNF水平均较治疗前升高;氟西汀治疗组治疗后MMSE分值及血清BDNF水平均较对照组治疗后升高;脑梗死后认知功能障碍患者MMSE分值与血清BDNF水平呈正相关。结论脑梗死后认知功能障碍的发生和程度与血清BDNF水平有关,氟西汀能改善脑梗死后认知功能患者的认知功能,并可能部分是通过增加血清BDNF来实现的。     

MMSE和MoCA在不同类型轻度认知障碍筛查中的应用

目的探讨简易精神状态量表(MMSE)和蒙特利尔认知评估量表(Mo CA)在遗忘型轻度认知障碍(a MCI)和轻度血管性认知障碍(m VCI)患者中的应用。方法从2012年3月至2015年3月本科收治的年龄60~80岁近200例患者中筛选出a MCI组42例,m VCI组50例,采用分组对照研究,所有患者经过临床痴呆评定量表(CDR)和日常生活能力量表(ADL)评估与接受Mo CA量表中文版和MMSE量表进行认知功能评估。Mo CA与MMSE的评估间隔1h以上,在同一天进行。结果两组患者性别构成比、年龄及受教育程度间差异均无统计学意义(P>0.05)。MMSE量表测评两组间差异无统计学意义(P>0.05)。两组间MMSE分项比较,除a MCI组延迟回忆得分低于m VCI组(P<0.05)外,其余各分项得分无显著性差异(P>0.05)。m VCI组患者Mo CA总分较a MCI组水平低,差异有统计学意义(P<0.05)。两组间Mo CA分项比较,m VCI组视空间执行功能、注意力与计算各项得分低于a MCI组,差异有统计学意义(P<0.05)。a MCI组延迟回忆得分低于m VCI组,差异有统计学意义(P<0.05)。余各分项得分两组间无显著性差异(P>0.05)。m VCI组患者在交替连线、立方体画图及指针得分均低于a MCI组,差异有统计学意义(P<0.05)。相关性分析显示MMSE与Mo CA评分呈正相关关系,a MCI患者中相关系数为0.861,m VCI患者中相关系数为0.762,差异均有统计学意义(P<0.05)。结论 m VCI患者存在包括视空间执行功能、注意力及计算力等多个领域认知功能的损害,与a MCI患者相比,执行功能受损更明显。Mo CA是筛查a MCI及m VCI的一个简便、有效的工具,敏感性高于MMSE,尤其适于对m VCI患者的早期筛查。     

Brain erythropoietin receptor expression in Alzheimer disease and mild cognitive impairment

Cellular mechanisms conferring neuroprotection in the brains of patients with Alzheimer disease (AD) remain incompletely understood. Erythropoietin (Epo) and the erythropoietin receptor (EpoR) are expressed in neural tissues and protect against oxidative and other stressors in various models of brain injury and disease. Our objective in this study was to determine whether EpoR is upregulated in the brains of persons with sporadic AD and mild cognitive impairment (MCI). Postmortem hippocampus and temporal cortex from subjects with AD, MCI, and no cognitive impairment (NCI) were procured from the Religious Orders Study. Total immunoreactive EpoR protein was determined by Western blotting. Astrocytes expressing immunoreactive EpoR were quantified in 4 temporal and 6 hippocampal regions, and correlated with clinical, neuropsychologic, and neuropathologic indices. Total immunoreactive EpoR protein was markedly increased in AD and MCI temporal cortex versus NCI tissues. Composite measures of glial EpoR expression in temporal cortex layers I to IV were significantly greater in the MCI group compared with the NCI and AD groups. Hippocampal EpoR scores were increased in persons with MCI and AD relative to those with NCI. There was substantial subregional heterogeneity in disease-related EpoR expression patterns in AD and MCI temporal cortex and hippocampus. There was no association of EpoR-positive astrocytes with summary measures of global cognition or AD pathology. We conclude that upregulation of EpoR in temporal cortical and hippocampal astrocytes is an early, potentially neuroprotective, event in the pathogenesis of sporadic AD.     

脑出血患者血清NSE、GFAP、BDNF水平变化与认知障碍相关性研究

目的探讨脑出血患者血清神经元特异性烯醇化酶(NSE)、胶质纤维酸性蛋白(GFAP)、脑源性神经营养因子(BDNF)水平变化与认知障碍相关性。方法选择急性自发性脑出血患者100例,入院时均给予相应治疗,并进行NSE、GFAP、BDNF检测。将100例患者依据是否发生认知障碍分为认知障碍组(57例)和无认知障碍组(43例)。并比较不同损伤水平(MMSE评分)患者三个指标之间的差异、计算三个指标与MMSE水平的相关性。结果认知功能障碍组患者血清NSE、GFAP水平均显著高于无认知功能障碍组,BDNF显著低于无认知功能障碍组(t=7.039,t=2.247,t=4.847,P0.01)。轻度损伤组、中度损伤组和重度损伤组间血清NSE、GFAP、BDNF水平存在显著差异(F=22.752,F=31.506,F=38.294,P0.01)。血清NSE、GFAP水平与MMSE评分正相关(r=0.641,r=0.604,P0.05),BDNF与MMSE评分负相关(r=0.582,P0.05)。结论脑出血患者血清NSE、GFAP、BDNF水平与脑出血患者卒中后认知功能障碍密切相关,可用于判断脑出血患者认知功能障碍的严重程度。